FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Gladwell, W Middleton, L Cook, D Ciencewicki, J Kleeberger, SR AF Gladwell, W. Middleton, L. Cook, D. Ciencewicki, J. Kleeberger, S. R. TI Susceptibility And Response To Respiratory Syncytial Virus Infection Enhanced By Exposure To Hyperoxic Conditions SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Gladwell, W.; Cook, D.; Ciencewicki, J.; Kleeberger, S. R.] NIEHS, Res Triangle Pk, NC 27709 USA. [Middleton, L.] Stanford Univ Sch, Stanford, CA USA. EM gladwell@niehs.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A2728 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838202006 ER PT J AU Habgood, A Tatler, AL John, AE Laurent, GJ Wahl, SM Johnson, SR Jenkins, RG AF Habgood, A. Tatler, A. L. John, A. E. Laurent, G. J. Wahl, S. M. Johnson, S. R. Jenkins, R. G. TI Investigating The Role Of Secretory Leukocyte Protease Inhibitor On The Development Of Pulmonary Fibrosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Habgood, A.; Tatler, A. L.; John, A. E.; Johnson, S. R.; Jenkins, R. G.] Univ Nottingham, Nottingham, England. [Laurent, G. J.] UCL, London, England. [Wahl, S. M.] NIH, Bethesda, MD 20892 USA. EM anthony.habgood@nottingham.ac.uk NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A1955 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838201115 ER PT J AU Habibi, M Smith, BM Parikh, M Chahal, H Shimbo, D Prince, MR Michos, ED Gomes, A Watson, KE Hoffman, EA Bluemke, DA Lima, JA Barr, RG AF Habibi, M. Smith, B. M. Parikh, M. Chahal, H. Shimbo, D. Prince, M. R. Michos, E. D. Gomes, A. Watson, K. E. Hoffman, E. A. Bluemke, D. A. Lima, J. A. Barr, R. G. TI Left Atrial Strain And Volume On Magnetic Resonance Imaging (mri) In Patients With COPD And Emphysema: The Multi-Ethnic Study Of Atherosclerosis (MESA) COPD Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Habibi, M.; Chahal, H.; Michos, E. D.; Lima, J. A.] Johns Hopkins Univ, Baltimore, MD USA. [Smith, B. M.; Parikh, M.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Shimbo, D.] Columbia Univ, New York, NY USA. [Prince, M. R.; Barr, R. G.] Columbia Univ, Presbyterian Hosp, New York, NY USA. [Gomes, A.; Watson, K. E.] Ronald Reagan UCLA Med Ctr, Los Angeles, CA USA. [Hoffman, E. A.] Univ Iowa, Iowa City, IA USA. [Bluemke, D. A.] NIH, Bethesda, MD 20892 USA. EM mhabibi3@jhmi.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A4357 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203711 ER PT J AU Haney, C Leung, JM Szymanski, E Olivier, KN Holland, SM AF Haney, C. Leung, J. M. Szymanski, E. Olivier, K. N. Holland, S. M. CA NIAID NIH TI Familial Bronchiectasis: A Case For Autosomal Dominant Mounier-Kuhn Syndrome? SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 108th International Congress of the American-Thoracic-Society CY MAY 16-21, 2014 CL San Diego, CA SP Amer Thorac Soc C1 [Haney, C.; Leung, J. M.] NIH, Bethesda, MD 20892 USA. [Szymanski, E.; Holland, S. M.] NIAID, NIH, Bethesda, MD 20892 USA. [Olivier, K. N.] NIAID, Bethesda, MD 20892 USA. EM haneyc@niaid.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A1751 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838200739 ER PT J AU Hussain, S Sangtian, S Rice, A George, M Snyder, RJ Garantziotis, S AF Hussain, S. Sangtian, S. Rice, A. George, M. Snyder, R. J. Garantziotis, S. TI Modulation Of Pre-Existing Inflammation In Peripheral Blood Monocytes From Healthy And Diabetic Subjects After Nanomaterial Exposures SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Hussain, S.; Sangtian, S.; Rice, A.; George, M.; Snyder, R. J.; Garantziotis, S.] NIEHS, Res Triangle Pk, NC 27709 USA. EM salik.hussain@nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3807 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203179 ER PT J AU Hussain, S Sangtian, S Snyder, RJ Marshburn, J Rice, A Bonner, JC Garantziotis, S AF Hussain, S. Sangtian, S. Snyder, R. J. Marshburn, J. Rice, A. Bonner, J. C. Garantziotis, S. TI Human Bronchial Epithelia Exposure To Multi-Walled Carbon Nanotubes Induces Inflammasome-Dependent Pyroptosis And A Profibrotic Response SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Hussain, S.; Sangtian, S.; Snyder, R. J.; Marshburn, J.; Rice, A.; Garantziotis, S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Bonner, J. C.] North Carolina State Univ, Raleigh, NC USA. EM salik.hussain@nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 3 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3806 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203178 ER PT J AU Jaswal, DS Leung, JM Sun, J Cui, X Li, Y Kern, S Welsh, J Natanson, C Eichacker, PQ AF Jaswal, D. S. Leung, J. M. Sun, J. Cui, X. Li, Y. Kern, S. Welsh, J. Natanson, C. Eichacker, P. Q. TI Tidal Volume Practices In Acute Lung Injury And Acute Respiratory Distress Syndrome Since 2000: A Systematic Literature Review SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Jaswal, D. S.; Leung, J. M.; Sun, J.; Cui, X.; Li, Y.; Kern, S.; Welsh, J.; Natanson, C.; Eichacker, P. Q.] NIH, Bethesda, MD 20892 USA. EM dharmvir.jaswal@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3067 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838202344 ER PT J AU Jaswal, DS Cui, X Suffredini, AF Eichacker, PQ AF Jaswal, D. S. Cui, X. Suffredini, A. F. Eichacker, P. Q. TI A Systematic Review Of Literature Provided To The National Quality Forum (nqf) To Validate The "severe Sepsis And Septic Shock: Management Bundle Performance Measure (pm)" SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Jaswal, D. S.; Cui, X.; Suffredini, A. F.; Eichacker, P. Q.] NIH, Bethesda, MD 20892 USA. EM dharmvir.jaswal@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A2197 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838201356 ER PT J AU Javaheri, S Sharma, R Weng, J Wang, R Rosen, BD Bluemke, DA Lima, JA Redline, S AF Javaheri, S. Sharma, R. Weng, J. Wang, R. Rosen, B. D. Bluemke, D. A. Lima, J. A. Redline, S. TI Association Of Left Ventricular Structure And Function With Obstructive Sleep Apnea (osa) SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Javaheri, S.; Weng, J.; Wang, R.; Redline, S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Javaheri, S.; Sharma, R.; Rosen, B. D.; Lima, J. A.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Bluemke, D. A.] NIH, Bethesda, MD 20892 USA. EM sjavaheri@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A2404 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838201563 ER PT J AU Jones, AM Yao, J Taveira-DaSilva, AM Moss, J AF Jones, A. M. Yao, J. Taveira-DaSilva, A. M. Moss, J. TI Effect Of Sirolimus In Patients With Lymphangioleiomyomatosis On The Progression Of Lung Disease By High-Resolution Computed Tomography Scans SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Jones, A. M.; Yao, J.; Taveira-DaSilva, A. M.; Moss, J.] NIH, Bethesda, MD 20892 USA. EM jonesam@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A2122 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838201281 ER PT J AU Kadri, S Hohmann, S Danner, RL AF Kadri, S. Hohmann, S. Danner, R. L. TI Multi-Drug Resistant Gram Negative Bacterial Infections: A Comparison Of Mortality Estimation Strategies (colistrack Vs. Cdc) SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Kadri, S.; Danner, R. L.] NIH, Bethesda, MD 20892 USA. [Hohmann, S.] Univ Hlth Syst Consortium, Chicago, IL USA. EM sameer.kadri@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3781 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203153 ER PT J AU Kadri, S Remy, KE Strich, J Gea-Banacloche, J Leitman, S AF Kadri, S. Remy, K. E. Strich, J. Gea-Banacloche, J. Leitman, S. TI G-Csf Stimulated Donor Granulocyte Infusions Increase Resolution Of Invasive Fusarium Infection In Immunocompromised Hosts SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Kadri, S.; Remy, K. E.; Gea-Banacloche, J.; Leitman, S.] NIH, Bethesda, MD 20892 USA. [Strich, J.] Georgetown Sch Med, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A2711 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838201869 ER PT J AU Karnekar, R Malur, A Butt, A Jacob, M Rehman, Z Bowling, M Shaw, R Fessler, MB Barna, BP Thomassen, M AF Karnekar, R. Malur, A. Butt, A. Jacob, M. Rehman, Z. Bowling, M. Shaw, R. Fessler, M. B. Barna, B. P. Thomassen, M. TI Reduced Abca1 Expression In Alveolar Macrophages From Obese Individuals: Possible Ivolvement Of Mir33a SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Karnekar, R.; Malur, A.; Butt, A.; Jacob, M.; Rehman, Z.; Bowling, M.; Shaw, R.; Barna, B. P.; Thomassen, M.] East Carolina Univ, Greenville, NC USA. [Fessler, M. B.] Natl Inst Environm Hlth, Res Triangle Pk, NC USA. EM thomassenm@ecu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3679 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203051 ER PT J AU Lee, M Jeong, I Choi, H Song, T Chen, R Joh, J Han, S Kim, Y Cho, R Via, LE Barry, CE AF Lee, M. Jeong, I. Choi, H. Song, T. Chen, R. Joh, J. Han, S. Kim, Y. Cho, R. Via, L. E. Barry, C. E. TI The Efficacy Of Linezolid For The Treatment Of Chronic Extensively Drug-Resistant Tuberculosis In Korea SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Lee, M.; Choi, H.; Song, T.; Han, S.; Kim, Y.; Cho, R.] Int TB Res Ctr, Seoul, South Korea. [Lee, M.; Jeong, I.; Joh, J.] Natl Med Ctr, Seoul, South Korea. [Chen, R.; Via, L. E.; Barry, C. E.] NIAID, NIH, Bethesda, MD 20892 USA. EM drsunny21c@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A2561 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838201719 ER PT J AU Li, Y Cui, X Malide, DA Yu, Z Fitz, Y Eichacker, PQ AF Li, Y. Cui, X. Malide, D. A. Yu, Z. Fitz, Y. Eichacker, P. Q. TI Nitric Oxide Contributes To The Arterial Relaxant Effects Of B. Anthracis Edema Toxin In The Rat Aortic Ring Model SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 108th International Congress of the American-Thoracic-Society CY MAY 16-21, 2014 CL San Diego, CA SP Amer Thorac Soc C1 [Li, Y.; Cui, X.; Fitz, Y.; Eichacker, P. Q.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Malide, D. A.; Yu, Z.] NHLBI, NIH, Bethesda, MD 20892 USA. EM yli@mail.cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A1655 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838200643 ER PT J AU Madenspacher, JH Gowdy, KM Azzam, KM Fessler, MB AF Madenspacher, J. H. Gowdy, K. M. Azzam, K. M. Fessler, M. B. TI A Role For Cholesterol 25-Hydroxylase In Resolution Of Inflammation Following Pulmonary Innate Immune Challenge SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Madenspacher, J. H.; Gowdy, K. M.; Azzam, K. M.; Fessler, M. B.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A4007 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203361 ER PT J AU McCaw, ZR Klimczak, L Burkholder, A Wiltshire, T Fargo, D Kleeberger, SR Verhein, KC AF McCaw, Z. R. Klimczak, L. Burkholder, A. Wiltshire, T. Fargo, D. Kleeberger, S. R. Verhein, K. C. TI Gene Expression Profiling Predicts Response To Respiratory Syncytial Virus (rsv) In Inbred Strains Of Mice SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [McCaw, Z. R.; Klimczak, L.; Burkholder, A.; Fargo, D.; Kleeberger, S. R.; Verhein, K. C.] NIEHS, Res Triangle Pk, NC 27709 USA. [Wiltshire, T.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. EM zrmacc@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3820 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203192 ER PT J AU Mushaben, E Dai, C Keeran, K Nugent, G Yu, ZX Levine, SJ AF Mushaben, E. Dai, C. Keeran, K. Nugent, G. Yu, Z. -X. Levine, S. J. TI The Macrophage Scavenger Receptor Cd163 Suppresses Airway Hyperreactivity In A Murine Model Of Experimental Cockroach-Induced Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Mushaben, E.; Dai, C.; Keeran, K.; Nugent, G.; Yu, Z. -X.; Levine, S. J.] NIH, Bethesda, MD 20892 USA. EM Elizabeth.Mushaben@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A4194 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203548 ER PT J AU Nannes, CE Remy, KE AF Nannes, C. E. Remy, K. E. TI Romiplostim-Associated Acute Coronary Thrombosis With Auto-Revascularization SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Nannes, C. E.] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. [Remy, K. E.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A6199 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838205819 ER PT J AU Narute, PS Machado, RF Cai, R Sun, J Logun, C Shelhamer, JH Suffredini, AF AF Narute, P. S. Machado, R. F. Cai, R. Sun, J. Logun, C. Shelhamer, J. H. Suffredini, A. F. TI Effects Of Inhaled Nitric Oxide Or Carbon Monoxide On Micrornas In Bronchoalveolar Lavage Of Healthy Humans After Segmental Challenge With Saline Or Endotoxin SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Narute, P. S.; Cai, R.; Sun, J.; Logun, C.; Shelhamer, J. H.; Suffredini, A. F.] NIH, Bethesda, MD 20892 USA. [Machado, R. F.] Univ Illinois, Chicago, IL USA. EM asuffredini@cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A5768 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838205388 ER PT J AU Narute, PS Seam, N Tropea, M Logun, C Cai, R Sun, J Shelhamer, JH Meduri, GU Suffredini, AF AF Narute, P. S. Seam, N. Tropea, M. Logun, C. Cai, R. Sun, J. Shelhamer, J. H. Meduri, G. U. Suffredini, A. F. TI Microrna Expression In Peripheral Blood Mononuclear Cells From Patients With Acute Respiratory Distress Syndrome Treated With Corticosteroids SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Narute, P. S.; Tropea, M.; Logun, C.; Cai, R.; Sun, J.; Shelhamer, J. H.; Suffredini, A. F.] NIH, Bethesda, MD 20892 USA. [Seam, N.] VA Med Ctr Washington DC, Washington, DC USA. [Meduri, G. U.] VA Med Ctr, Memphis, TN USA. EM asuffredini@cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A5017 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838204509 ER PT J AU Narute, PS Logun, C Cai, R Sun, J Shelhamer, JH Suffredini, AF AF Narute, P. S. Logun, C. Cai, R. Sun, J. Shelhamer, J. H. Suffredini, A. F. TI The Secretion Of Mirna From Normal Human Bronchial Epithelial Cells: Effects Of Endotoxin, Nitric Oxide Or Carbon Monoxide SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Narute, P. S.; Logun, C.; Cai, R.; Sun, J.; Suffredini, A. F.] NIH, Bethesda, MD 20892 USA. [Shelhamer, J. H.] NIH, Ctr Clin, Bethesda, MD 20892 USA. EM asuffredini@cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A4220 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203574 ER PT J AU Nichols, JL McCaw, ZR Verhein, KC Gladwell, W Bushel, P Kleeberger, S AF Nichols, J. L. McCaw, Z. R. Verhein, K. C. Gladwell, W. Bushel, P. Kleeberger, S. TI Genomic Analysis Of Postnatal Lung Development And Characterization Of Susceptibility To Hyperoxic Lung Injury SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Nichols, J. L.] US EPA, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27711 USA. [McCaw, Z. R.; Verhein, K. C.; Gladwell, W.; Bushel, P.; Kleeberger, S.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A6631 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838206429 ER PT J AU Nwankwor, O Garber, NA Rosenthal, GL Remy, KE AF Nwankwor, O. Garber, N. A. Rosenthal, G. L. Remy, K. E. TI Dexmedetomidine Infusion In Young Critically Ill Children Has Significant Negative Chronotropic Effects In Absence Of Defined Bradycardia SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Nwankwor, O.; Garber, N. A.; Rosenthal, G. L.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Remy, K. E.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3247 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838202523 ER PT J AU Obeidat, M Hao, K Bosse, Y Laviolette, M Nickle, DC Postma, DS Timens, W Gharib, SA Tobin, MD Hall, IP London, SJ Sin, DD Pare, PD AF Obeidat, M. Hao, K. Bosse, Y. Laviolette, M. Nickle, D. C. Postma, D. S. Timens, W. Gharib, S. A. Tobin, M. D. Hall, I. P. London, S. J. Sin, D. D. Pare, P. D. CA CHARGE SpiroMeta Consortia TI Integrative Genomics Approach To Unravel The Molecular Mechanisms Underlying Variations In Lung Function Measures SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Obeidat, M.; Sin, D. D.; Pare, P. D.] Univ British Columbia, St Pauls Hosp, Ctr Heart Lung Innovat, Vancouver, BC, Canada. [Hao, K.] Mt Sinai Sch Med, New York, NY USA. [Bosse, Y.; Laviolette, M.] Univ Laval, Quebec City, PQ, Canada. [Nickle, D. C.] Merck Res Labs, Boston, MA USA. [Postma, D. S.; Timens, W.] Univ Groningen, Groningen, Netherlands. [Gharib, S. A.] Univ Washington, Seattle, WA 98195 USA. [Tobin, M. D.] Univ Leicester, Leicester, Leics, England. [Hall, I. P.] Univ Nottingham, Nottingham, England. [London, S. J.] NIEHS, Res Triangle Pk, NC 27709 USA. EM maen.obeidat@hli.ubc.ca NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A6363 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838206162 ER PT J AU Olivier, KN Gupta, R Daley, CL Winthrop, KL Ruoss, S Addrizzo-Harris, DJ Flume, P Dorgan, D Salathe, MA Brown-Elliott, BA Wallace, RJ Griffith, DE AF Olivier, K. N. Gupta, R. Daley, C. L. Winthrop, K. L. Ruoss, S. Addrizzo-Harris, D. J. Flume, P. Dorgan, D. Salathe, M. A. Brown-Elliott, B. A. Wallace, R. J. Griffith, D. E. CA Arikace NTM Study Grp TI A Randomized, Double-Blind, Placebo-Controlled Study Of Liposomal Amikacin For Inhalation (arikace (R)) In Patients With Recalcitrant Nontuberculous Mycobacterial Lung Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Olivier, K. N.] NIAID, Bethesda, MD 20892 USA. [Gupta, R.] Insmed Inc, Monmouth Jct, NJ USA. [Daley, C. L.] Natl Jewish Hlth, Denver, CO USA. [Winthrop, K. L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Ruoss, S.] Stanford Univ, Stanford, CA 94305 USA. [Addrizzo-Harris, D. J.] NYU, Sch Med, New York, NY USA. [Flume, P.] Med Coll South Carolina, Charleston, SC USA. [Dorgan, D.] Univ Penn, Philadelphia, PA 19104 USA. [Salathe, M. A.] Univ Miami, Miami, FL USA. [Brown-Elliott, B. A.; Wallace, R. J.; Griffith, D. E.] Univ Texas Hlth Ctr Tyler, Tyler, TX USA. EM olivierk@niaid.nih.gov NR 0 TC 6 Z9 7 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A4126 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203480 ER PT J AU Pino-Yanes, M Thakur, N Gignoux, CR Galanter, JM Roth, LA Eng, C Nishimura, KK Oh, SS Huntsman, S Nguyen, EA Hu, D Drake, KA Conti, DV Moreno-Estrada, A Sandoval, K Winkler, CA Borrell, LN Lurmann, F Islam, T Davis, A Farber, HJ Meade, K Avila, PC Serebrisky, D Bibbins-Domingo, K Lenoir, MA Ford, JG Brigino-Buenaventura, E Rodriguez-Cintron, W Thyne, S Sen, S Rodriguez-Santana, JR Bustamante, C Williams, L Gilliland, FD Gauderman, WJ Kumar, R Torgerson, DG Burchard, EG AF Pino-Yanes, M. Thakur, N. Gignoux, C. R. Galanter, J. M. Roth, L. A. Eng, C. Nishimura, K. K. Oh, S. S. Huntsman, S. Nguyen, E. A. Hu, D. Drake, K. A. Conti, D. V. Moreno-Estrada, A. Sandoval, K. Winkler, C. A. Borrell, L. N. Lurmann, F. Islam, T. Davis, A. Farber, H. J. Meade, K. Avila, P. C. Serebrisky, D. Bibbins-Domingo, K. Lenoir, M. A. Ford, J. G. Brigino-Buenaventura, E. Rodriguez-Cintron, W. Thyne, S. Sen, S. Rodriguez-Santana, J. R. Bustamante, C. Williams, L. Gilliland, F. D. Gauderman, W. J. Kumar, R. Torgerson, D. G. Burchard, E. G. TI Genetic Ancestry Influences Asthma Susceptibility And Lung Function Among LatINOS SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Pino-Yanes, M.; Thakur, N.; Gignoux, C. R.; Galanter, J. M.; Roth, L. A.; Eng, C.; Nishimura, K. K.; Oh, S. S.; Huntsman, S.; Nguyen, E. A.; Hu, D.; Drake, K. A.; Bibbins-Domingo, K.; Sen, S.; Torgerson, D. G.; Burchard, E. G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Conti, D. V.; Islam, T.; Gilliland, F. D.; Gauderman, W. J.] Univ Southern Calif, Los Angeles, CA USA. [Moreno-Estrada, A.; Sandoval, K.; Bustamante, C.] Stanford Univ, Palo Alto, CA 94304 USA. [Winkler, C. A.] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Borrell, L. N.] CUNY, Bronx, NJ USA. [Lurmann, F.] Sonoma Technol Inc, Petaluma, CA USA. [Davis, A.; Meade, K.] Childrens Hosp & Res Ctr, Oakland, CA USA. [Farber, H. J.] Baylor Coll Med, Houston, TX 77030 USA. [Avila, P. C.] Northwestern Univ, Chicago, IL 60611 USA. [Serebrisky, D.] Jacobi Med Ctr, Bronx, NY USA. [Lenoir, M. A.] Bay Area Pediat, Oakland, CA USA. [Ford, J. G.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Brigino-Buenaventura, E.] Kaiser Permanente, Vallejo Med Ctr, Vallejo, CA USA. [Rodriguez-Cintron, W.] Vet Caribbean Hlth Care Syst, San Juan, PR USA. [Thyne, S.] San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Rodriguez-Santana, J. R.] Ctr Neumol Pediat, San Juan, PR USA. [Williams, L.] Henry Ford Hlth Syst, Ctr Hlth Policy & Hlth Serv Res, Detroit, MI USA. [Kumar, R.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Kumar, R.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. EM mdelpino@ull.es NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3834 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203206 ER PT J AU Qiu, P Cui, X Li, Y Fitz, Y Ferreyra, G Wang, S Wang, H Moayeri, M Leppla, S Suffredini, AF Danner, R Eichacker, PQ AF Qiu, P. Cui, X. Li, Y. Fitz, Y. Ferreyra, G. Wang, S. Wang, H. Moayeri, M. Leppla, S. Suffredini, A. F. Danner, R. Eichacker, P. Q. TI Treatment With 3-MorpholINOSydnoime (sin-1), An No And O2-Donor Agent, Improves Survival In Bacillus Anthracis Lethal Toxin-Challenged Rats SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 108th International Congress of the American-Thoracic-Society CY MAY 16-21, 2014 CL San Diego, CA SP Amer Thorac Soc C1 [Qiu, P.; Cui, X.; Li, Y.; Fitz, Y.; Ferreyra, G.; Wang, S.; Wang, H.; Suffredini, A. F.; Danner, R.; Eichacker, P. Q.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Moayeri, M.; Leppla, S.] NIAID, NIH, Bethesda, MD 20892 USA. EM qiup@cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A1652 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838200640 ER PT J AU Remy, KE Baird, JS AF Remy, K. E. Baird, J. S. TI An 18 Year Old Presenting With Acute, Severe Hypercalcemia Causing Direct Myocardial Injury SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Remy, K. E.] NIH, Bethesda, MD 20892 USA. [Baird, J. S.] Columbia Univ, Sch Med, New York, NY USA. EM kenneth.remy@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A6133 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838205753 ER PT J AU Remy, KE Cui, X Solomon, SB Sun, J Li, Y Eichacker, PQ AF Remy, K. E. Cui, X. Solomon, S. B. Sun, J. Li, Y. Eichacker, P. Q. TI Raxibacumab Treatment Improves Survival In A Fluid And Vasopressor Supported Canine Model Of B. Anthracis Lethal And Edema Toxin Associated Shock SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Remy, K. E.; Cui, X.; Solomon, S. B.; Sun, J.; Li, Y.; Eichacker, P. Q.] NIH, Bethesda, MD 20892 USA. EM kenneth.remy@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3113 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838202390 ER PT J AU Shaffer, RK Haney, C Freeman, AM Prevots, DR Holland, SM Olivier, KN AF Shaffer, R. K. Haney, C. Freeman, A. M. Prevots, D. R. Holland, S. M. Olivier, K. N. TI Prevalence And Clinical Significance Of Nocardia And Cryptococcus Species In Pulmonary Nontuberculous Mycobacteria (p-Ntm) Patients SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Shaffer, R. K.; Haney, C.; Freeman, A. M.; Prevots, D. R.; Holland, S. M.; Olivier, K. N.] NIAID, Bethesda, MD 20892 USA. EM robyn.shaffer@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A4116 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203470 ER PT J AU Snyder, RJ Hussain, S Sangtian, S Rice, A Marshburn, J George, M Garantziotis, S AF Snyder, R. J. Hussain, S. Sangtian, S. Rice, A. Marshburn, J. George, M. Garantziotis, S. TI Prevention Of Terminal Differentiation In Primary Human Bronchial Epithelial Cells Exposed To Multi-Walled Carbon Nanotubes SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Snyder, R. J.; Hussain, S.; Sangtian, S.; Rice, A.; Marshburn, J.; George, M.; Garantziotis, S.] NIEHS, Durham, NC USA. EM snyder3@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3805 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203177 ER PT J AU Stober, V Majors, A Wisniewski, HG Aronica, MA Garantziotis, S AF Stober, V. Majors, A. Wisniewski, H. -G. Aronica, M. A. Garantziotis, S. TI Tsg-6 Promotes Hyperresponsiveness Of Naive Tracheal Rings SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Stober, V.; Garantziotis, S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Majors, A.; Aronica, M. A.] Cleveland Clin, Dept Pathobiol, Cleveland, OH 44106 USA. [Majors, A.; Aronica, M. A.] Cleveland Clin, Resp Inst, Cleveland, OH 44106 USA. [Wisniewski, H. -G.] NYU, Langone Med Ctr, New York, NY USA. RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A5601 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838205221 ER PT J AU Taveira-DaSilva, AM Jones, AM Julien-Williams, P Haughey, M Stylianou, M Glasgow, CG Moss, J AF Taveira-DaSilva, A. M. Jones, A. M. Julien-Williams, P. Haughey, M. Stylianou, M. Glasgow, C. G. Moss, J. TI Fasting Decreases The Size Of Abdomino-Pelvic Lymphangioleiomyomas SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Taveira-DaSilva, A. M.; Jones, A. M.; Julien-Williams, P.; Haughey, M.; Glasgow, C. G.; Moss, J.] NIH, Bethesda, MD 20892 USA. [Stylianou, M.] NHLBI, NIH, Bethesda, MD 20892 USA. EM dasilvaa@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A2124 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838201283 ER PT J AU Taveira-DaSilva, AM Jones, AM Julien-Williams, P Stylianou, M Moss, J AF Taveira-DaSilva, A. M. Jones, A. M. Julien-Williams, P. Stylianou, M. Moss, J. TI Retrospective Review Of Combined Sirolimus And Simvastatin Therapy In Lymphangioleiomyomatosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Taveira-DaSilva, A. M.; Jones, A. M.; Julien-Williams, P.; Moss, J.] NHLBI, NIH, Bethesda, MD 20892 USA. [Stylianou, M.] NIH, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A2123 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838201282 ER PT J AU Trempus, C Garantziotis, S AF Trempus, C. Garantziotis, S. TI Extracellular Matrix Interactions With Primary Cilia In Human Airway Smooth Muscle Cells SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Trempus, C.; Garantziotis, S.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A2671 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838201829 ER PT J AU Verhein, KC Nichols, JL Panduri, V Gladwell, W Marzec, J McCaw, Z Reeves, N Malphurs, J Solomon, G Wiltshire, T Burkholder, A Fargo, D Bell, D Van Houten, B Kleeberger, SR AF Verhein, K. C. Nichols, J. L. Panduri, V. Gladwell, W. Marzec, J. McCaw, Z. Reeves, N. Malphurs, J. Solomon, G. Wiltshire, T. Burkholder, A. Fargo, D. Bell, D. Van Houten, B. Kleeberger, S. R. TI Genetic Determinants Of Oxidant-Induced Nuclear And Mitochondrial Dna Lesions In A Neonatal Inbred Mouse Model Of Acute Lung Injury SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Verhein, K. C.; Panduri, V.; Gladwell, W.; Marzec, J.; McCaw, Z.; Reeves, N.; Malphurs, J.; Solomon, G.; Burkholder, A.; Fargo, D.; Bell, D.; Kleeberger, S. R.] NIEHS, Res Triangle Pk, NC 27709 USA. [Nichols, J. L.] US EPA, Res Triangle Pk, NC 27711 USA. [Wiltshire, T.] Univ N Carolina, Chapel Hill, NC USA. [Van Houten, B.] Univ Pittsburgh, Pittsburgh, PA USA. EM verheinkc@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3816 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203188 ER PT J AU Wang, TW Lan, Q Rothman, N Wei, H Steiling, K Liu, G Alekseyev, Y Hosgood, H Downward, G Reiss, B Wei, F Xu, J Lenburg, M Vermeulen, R Spira, A AF Wang, T. W. Lan, Q. Rothman, N. Wei, H. Steiling, K. Liu, G. Alekseyev, Y. Hosgood, H., III Downward, G. Reiss, B. Wei, F. Xu, J. Lenburg, M. Vermeulen, R. Spira, A. TI Buccal Epithelial Gene-Expression Reflects The Physiological Response To Smoky Vs. Smokeless Coal Exposure SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Wang, T. W.; Steiling, K.; Liu, G.; Alekseyev, Y.; Lenburg, M.; Spira, A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Lan, Q.; Rothman, N.; Wei, H.] NCI, Rockville, MD USA. [Hosgood, H., III] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Downward, G.; Vermeulen, R.] Univ Utrecht, Utrecht, Netherlands. [Reiss, B.] Univ Washington, Seattle, WA 98195 USA. [Wei, F.] China Natl Environm Monitoring Ctr, Beijing, Peoples R China. [Xu, J.] Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. EM wateresa@bu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3822 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838203194 ER PT J AU Yang, IV Pedersen, B Liu, A O'Connor, GT Teach, SJ Kattan, M Misiak, RT Gruchalla, R Steinbach, SF Szefler, SJ Gill, MA Calatroni, A David, G Hennessy, C Davidson, EJ Gergen, P Togias, A Busse, WW Schwartz, DA AF Yang, I. V. Pedersen, B. Liu, A. O'Connor, G. T. Teach, S. J. Kattan, M. Misiak, R. T. Gruchalla, R. Steinbach, S. F. Szefler, S. J. Gill, M. A. Calatroni, A. David, G. Hennessy, C. Davidson, E. J. Gergen, P. Togias, A. Busse, W. W. Schwartz, D. A. CA Inner City Asthma Consortium ICAC TI Nasal Epithelial Dna Methylation And Gene Expression Profiles Of Allergic Asthma In The Inner City SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Yang, I. V.; Pedersen, B.; Hennessy, C.; Davidson, E. J.; Schwartz, D. A.] Univ Colorado, Aurora, CO USA. [Liu, A.; Szefler, S. J.] Natl Jewish Hlth, Denver, CO USA. [O'Connor, G. T.; Steinbach, S. F.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Teach, S. J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Kattan, M.] Columbia Univ, Med Ctr, New York, NY USA. [Misiak, R. T.] Henry Ford Hosp, Detroit, MI 48202 USA. [Gruchalla, R.; Gill, M. A.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Calatroni, A.; David, G.] Rho Fed Syst Inc, Chapel Hill, NC USA. [Gergen, P.; Togias, A.] NIAID, Bethesda, MD 20892 USA. [Busse, W. W.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. EM ivana.yang@ucdenver.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A3375 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838202651 ER PT J AU Yao, X Gao, M Meyer, K Keeran, K Nugent, G Jeffries, K Qu, X Yu, ZX Yang, Y Raghavachari, N Levine, SJ AF Yao, X. Gao, M. Meyer, K. Keeran, K. Nugent, G. Jeffries, K. Qu, X. Yu, Z. -X. Yang, Y. Raghavachari, N. Levine, S. J. TI Disabled-1 Attenuates House Dust Mite-Induced Airway Inflammation By Suppressing The Recruitment Of Intraepithelial Mast Cells SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Yao, X.; Gao, M.; Meyer, K.; Keeran, K.; Nugent, G.; Jeffries, K.; Qu, X.; Yu, Z. -X.; Yang, Y.; Raghavachari, N.; Levine, S. J.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A5355 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838204839 ER PT J AU Young, MT Sandler, DP Deroo, LA Vedal, S Kaufman, JD London, S AF Young, M. T. Sandler, D. P. Deroo, L. A. Vedal, S. Kaufman, J. D. London, S. TI Traffic-Related Air Pollution Exposure And Adult Incident Asthma In A Cohort Of Us Women SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Young, M. T.; Vedal, S.; Kaufman, J. D.] Univ Washington, Seattle, WA 98195 USA. [Sandler, D. P.; Deroo, L. A.; London, S.] NIEHS, Res Triangle Pk, NC 27709 USA. EM myoung3@uw.edu NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A2298 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838201457 ER PT J AU Zhou, Y Herzog, E He, CH Peng, X Lee, CM Gulati, M Gochuico, BR Gahl, WA Lee, CG Elias, JA AF Zhou, Y. Herzog, E. He, C-H Peng, X. Lee, C-M Gulati, M. Gochuico, B. R. Gahl, W. A. Lee, C. G. Elias, J. A. TI Elevated Chitinase-3-Like-1 And Impaired Trafficking Of Il-13r alpha 2 Contribute To Pulmonary Injury And Fibroproliferative Repair In Hermansky-Pudlak Syndrome SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Zhou, Y.; Herzog, E.; He, C-H; Peng, X.; Lee, C-M; Gulati, M.; Lee, C. G.] Yale Univ, Sch Med, New Haven, CT USA. [Gochuico, B. R.; Gahl, W. A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Elias, J. A.] Brown Univ, Providence, RI 02912 USA. EM y.zhou@yale.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2014 VL 189 MA A1245 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V45TF UT WOS:000209838200235 ER PT J AU Goldman, D Rosser, AA AF Goldman, David Rosser, Alexandra A. TI MAOA-Environment Interactions: Results May Vary SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID MONOAMINE OXIDASE-A; BEHAVIOR; CHILDREN; GENE C1 [Goldman, David; Rosser, Alexandra A.] NIAAA, Rockville, MD 20852 USA. RP Goldman, D (reprint author), NIAAA, 5625 Fishers Lane, Rockville, MD 20852 USA. EM david.goldman@nih.hhs.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 9 TC 5 Z9 5 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 1 PY 2014 VL 75 IS 1 BP 2 EP 3 DI 10.1016/j.biopsych.2013.09.015 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 269TW UT WOS:000328265800001 PM 24314060 ER PT J AU Sutin, AR Cutler, RG Camandola, S Uda, M Feldman, NH Cucca, F Zonderman, AB Mattson, MP Ferrucci, L Schlessinger, D Terracciano, A AF Sutin, Angelina R. Cutler, Roy G. Camandola, Simonetta Uda, Manuela Feldman, Neil H. Cucca, Francesco Zonderman, Alan B. Mattson, Mark P. Ferrucci, Luigi Schlessinger, David Terracciano, Antonio TI Impulsivity is Associated with Uric Acid: Evidence from Humans and Mice SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Excitement seeking; impulse control; impulsivity; mouse model; personality traits; uric acid ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; LOW REARING ACTIVITY; LESCH-NYHAN-DISEASE; PERSONALITY-TRAITS; 5-FACTOR MODEL; BODY-WEIGHT; RATS; HYPERURICEMIA; POPULATION; LEVEL AB Background: The ability to control impulses varies greatly, and difficulty with impulse control can have severe consequences; in the extreme, it is the defining feature of many psychiatric disorders. Evidence from disparate lines of research suggests that uric acid is elevated in psychiatric disorders characterized by high impulsivity, such as attention-deficit/hyperactivity disorder and bipolar disorder. The present research tests the hypothesis that impulsivity is associated with higher uric acid in humans and mice. Methods: Using two longitudinal, nonclinical community samples (total n = 6883), we tested whether there is an association between uric acid and normal variation in trait impulsivity measured with the Revised NEO Personality Inventory. We also examined the effect of uric acid on behavior by comparing wild-type mice, which naturally have low levels of uric acid, with mice genetically modified to accumulate high levels of uric acid. Results: In both human samples, the emotional aspects of trait impulsivity, specifically impulsiveness and excitement seeking, were associated with higher levels of uric acid concurrently and when uric acid was measured 3 to 5 years later. Consistent with the human data, the genetically modified mice displayed significantly more exploratory and novelty-seeking behavior than the wild-type mice. Conclusions: Higher uric acid was associated with impulsivity in both humans and mice. The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity and may suggest potential targets for therapeutic intervention. C1 [Sutin, Angelina R.] Florida State Univ, Coll Med, Dept Med Humanities & Social Sci, Tallahassee, FL 32306 USA. [Terracciano, Antonio] Florida State Univ, Coll Med, Dept Geriatr, Tallahassee, FL 32306 USA. [Sutin, Angelina R.; Zonderman, Alan B.; Terracciano, Antonio] NIA, Lab Behav Neurosci, NIH, Bethesda, MD 20892 USA. [Cutler, Roy G.; Camandola, Simonetta; Feldman, Neil H.; Mattson, Mark P.] NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. [Schlessinger, David] NIA, Genet Lab, NIH, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Uda, Manuela; Cucca, Francesco] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Sutin, AR (reprint author), Florida State Univ, Coll Med, 1115 W Call St, Tallahassee, FL 32306 USA. EM angelina.sutin@med.fsu.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This research was supported, in part, by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 52 TC 15 Z9 15 U1 0 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 1 PY 2014 VL 75 IS 1 BP 31 EP 37 DI 10.1016/j.biopsych.2013.02.024 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 269TW UT WOS:000328265800007 PM 23582268 ER PT J AU Bondi, CO Taha, AY Tock, JL Totah, NKB Cheon, Y Torres, GE Rapoport, SI Moghaddam, B AF Bondi, Corina O. Taha, Ameer Y. Tock, Jody L. Totah, Nelson K. B. Cheon, Yewon Torres, Gonzalo E. Rapoport, Stanley I. Moghaddam, Bita TI Adolescent Behavior and Dopamine Availability Are Uniquely Sensitive to Dietary Omega-3 Fatty Acid Deficiency SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Addiction; anxiety; nutrition; cognition; fatty acids; schizophrenia ID POLYUNSATURATED FATTY-ACIDS; BRAIN DOCOSAHEXAENOIC ACID; MEDIAL PREFRONTAL CORTEX; RAT-BRAIN; DOCOSAPENTAENOIC ACID; PSYCHIATRIC-DISORDERS; PSYCHOTIC DISORDERS; RECEPTOR BLOCKADE; FRONTAL-CORTEX; SCHIZOPHRENIA AB Background: Understanding the nature of environmental factors that contribute to behavioral health is critical for successful prevention strategies in individuals at risk for psychiatric disorders. These factors are typically experiential in nature, such as stress and urbanicity, but nutrition-in particular dietary deficiency of omega-3 polyunsaturated fatty acids (n-3 PUFAs)-has increasingly been implicated in the symptomatic onset of schizophrenia and mood disorders, which typically occurs during adolescence to early adulthood. Thus, adolescence might be the critical age range for the negative impact of diet as an environmental insult. Methods: A rat model involving consecutive generations of n-3 PUFA deficiency was developed on the basis of the assumption that dietary trends toward decreased consumption of these fats began 4-5 decades ago when the parents of current adolescents were born. Behavioral performance in a wide range of tasks as well as markers of dopamine-related neurotransmission was compared in adolescents and adults fed n-3 PUFA adequate and deficient diets. Results: In adolescents, dietary n-3 PUFA deficiency across consecutive generations produced a modality-selective and task-dependent impairment in cognitive and motivated behavior distinct from the deficits observed in adults. Although this dietary deficiency affected expression of dopamine-related proteins in both age groups in adolescents but not adults, there was an increase in tyrosine hydroxylase expression that was selective to the dorsal striatum. Conclusions: These data support a nutritional contribution to optimal cognitive and affective functioning in adolescents. Furthermore, they suggest that n-3 PUFA deficiency disrupts adolescent behaviors through enhanced dorsal striatal dopamine availability. C1 [Bondi, Corina O.; Tock, Jody L.; Totah, Nelson K. B.; Moghaddam, Bita] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA 15260 USA. [Torres, Gonzalo E.] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15260 USA. [Taha, Ameer Y.; Cheon, Yewon; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Moghaddam, B (reprint author), Univ Pittsburgh, Dept Neurosci, A210 Langley Hall, Pittsburgh, PA 15260 USA. EM bita@pitt.edu FU United States National Institutes of Health [R21 (MH097219)]; National Institute on Aging Intramural Research Program FX This research was supported by Grant R21 (MH097219) from the United States National Institutes of Health, and the National Institute on Aging Intramural Research Program. NR 66 TC 22 Z9 23 U1 3 U2 26 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 1 PY 2014 VL 75 IS 1 BP 38 EP 46 DI 10.1016/j.biopsych.2013.06.007 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 269TW UT WOS:000328265800008 PM 23890734 ER PT S AU Miller, DS AF Miller, David S. BE Fricker, G Ott, M Mahringer, A TI ABC Transporters at the Blood-Brain Barrier SO BLOOD BRAIN BARRIER (BBB) SE Topics in Medicinal Chemistry Series LA English DT Article; Book Chapter DE BCRP; Blood-brain barrier; Brain capillary endothelium; Disease; Drug delivery; MRP; P-glycoprotein; Regulation ID CANCER RESISTANCE PROTEIN; P-GLYCOPROTEIN EXPRESSION; PREGNANE-X-RECEPTOR; BINDING CASSETTE TRANSPORTERS; CONSTITUTIVE ANDROSTANE RECEPTOR; XENOBIOTIC EFFLUX TRANSPORTERS; CENTRAL-NERVOUS-SYSTEM; MEDIATED UP-REGULATION; NECROSIS-FACTOR-ALPHA; SPINAL CORD BARRIER AB In the blood-brain barrier several ABC transporters are expressed at the luminal, blood-facing, plasma membrane of the brain capillary endothelial cells. There they function as ATP-driven efflux pumps for xenobiotics and endogenous metabolites, thus providing an important element of the barrier. When these transporters limit neurotoxicant entry into the CNS, they are neuroprotective; when they limit therapeutic drug entry, they become major obstacles to drug delivery to treat CNS diseases. Here I review function and regulation of ABC transporters at the blood-brain barrier, with an emphasis on recently disclosed mechanisms that alter transporter expression and transport activity. C1 [Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Miller, DS (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 79 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 1862-2461 BN 978-3-662-43787-2; 978-3-662-43786-5 J9 TOP MED CHEM SER JI Top. Med. Chem. PY 2014 VL 10 BP 49 EP 69 DI 10.1007/7355_2013_31 D2 10.1007/978-3-662-43787-2 PG 21 WC Chemistry, Medicinal; Neurosciences; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Neurosciences & Neurology GA BE9ZC UT WOS:000378380100004 ER PT S AU Kovac, P AF Kovac, Pavol BE VanDerMarel, G Codee, J TI In Lieu of an Introduction SO CARBOHYDRATE CHEMISTRY: PROVEN SYNTHETIC METHODS, VOL 2 SE Carbohydrate Chemistry-Proven Synthetic Methods LA English DT Editorial Material; Book Chapter ID URONIC-ACID DERIVATIVES; STEREOSELECTIVE-SYNTHESIS; CHEMICAL-SYNTHESIS C1 [Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. NR 17 TC 0 Z9 0 U1 1 U2 1 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA SN 2372-9163 BN 978-1-4398-7595-7; 978-1-4398-7594-0 J9 CARBOHYD CHEM PY 2014 VL 2 BP XI EP XXV PG 15 WC Biochemical Research Methods; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA BE0XL UT WOS:000367295900001 ER PT S AU Xu, P Castelli, R Kovac, P AF Xu, Peng Castelli, Riccardo Kovac, Pavol BE VanDerMarel, G Codee, J TI Synthesis and Characterization of Tetra-O-propargyl Pentaerythritol SO CARBOHYDRATE CHEMISTRY: PROVEN SYNTHETIC METHODS, VOL 2 SE Carbohydrate Chemistry-Proven Synthetic Methods LA English DT Article; Book Chapter C1 [Xu, Peng; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. [Castelli, Riccardo] Leiden Univ, Leiden Inst Chem, NL-2300 RA Leiden, Netherlands. RP Kovac, P (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov NR 10 TC 2 Z9 2 U1 1 U2 1 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA SN 2372-9163 BN 978-1-4398-7595-7; 978-1-4398-7594-0 J9 CARBOHYD CHEM PY 2014 VL 2 BP 213 EP 216 PG 4 WC Biochemical Research Methods; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA BE0XL UT WOS:000367295900025 ER PT S AU Soliman, SE Chinoy, Z Kovac, P AF Soliman, Sameh E. Chinoy, Zoeisha Kovac, Pavol BE VanDerMarel, G Codee, J TI Improved Synthesis of Ethyl (2,3,4,6-Tetra-beta-D-acetyl-beta-D-galactopyranosyI)-(1 -> 3)-4,6-O-benzylidene-2-deoxy-1-thio-2-trichloroacetamido-D-beta-glucopyr anoside SO CARBOHYDRATE CHEMISTRY: PROVEN SYNTHETIC METHODS, VOL 2 SE Carbohydrate Chemistry-Proven Synthetic Methods LA English DT Article; Book Chapter C1 [Soliman, Sameh E.; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. [Chinoy, Zoeisha] Univ Georgia, Athens, GA 30602 USA. RP Kovac, P (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov NR 6 TC 0 Z9 0 U1 1 U2 1 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA SN 2372-9163 BN 978-1-4398-7595-7; 978-1-4398-7594-0 J9 CARBOHYD CHEM PY 2014 VL 2 BP 217 EP 221 PG 5 WC Biochemical Research Methods; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA BE0XL UT WOS:000367295900026 ER PT J AU Benavente, OR Pearce, LA McClure, LA Conwit, R Hart, RG AF Benavente, O. R. Pearce, L. A. McClure, L. A. Conwit, R. Hart, R. G. TI Effect of Blood Pressure Lowering on Cognition in Patients with Lacunar Stroke. The Secondary Prevention of Small Subcortical Strokes (SPS3) trial. SO CEREBROVASCULAR DISEASES LA English DT Meeting Abstract C1 [Benavente, O. R.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [McClure, L. A.] Univ Alabama Birmingham, Birmingham, AL USA. [Conwit, R.] NINDS, NIH, Bethesda, MD 20892 USA. [Hart, R. G.] McMaster Univ, Hamilton, ON, Canada. NR 0 TC 0 Z9 0 U1 1 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1015-9770 EI 1421-9786 J9 CEREBROVASC DIS JI Cerebrovasc. Dis. PY 2014 VL 37 SU 1 BP 33 EP 33 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA V43ZE UT WOS:000209718500042 ER PT J AU Parides, MK Overbey, JR Stapf, C Moskowitz, AJ Moy, C Salman, RA Vicaut, EC Mohr, JP AF Parides, M. K. Overbey, J. R. Stapf, C. Moskowitz, A. J. Moy, C. Salman, R. Al-Shahi Vicaut, E. C. Mohr, J. P. TI Projecting longer term results in the ARUBA trial SO CEREBROVASCULAR DISEASES LA English DT Meeting Abstract C1 [Parides, M. K.; Overbey, J. R.; Moskowitz, A. J.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Stapf, C.; Vicaut, E. C.] Hop Lariboisiere, F-75475 Paris, France. [Moy, C.] NINDS, Bethesda, MD 20892 USA. [Salman, R. Al-Shahi] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Mohr, J. P.] Columbia Univ, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1015-9770 EI 1421-9786 J9 CEREBROVASC DIS JI Cerebrovasc. Dis. PY 2014 VL 37 SU 1 BP 190 EP 191 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA V43ZE UT WOS:000209718501105 ER PT J AU Lynch, J Benson, R Hsia, A Nadareishvilli, Z Merino, J Latour, L Luby, M AF Lynch, J. Benson, R. Hsia, A. Nadareishvilli, Z. Merino, J. Latour, L. Luby, M. TI Stroke in Multiple Vascular Territories SO CEREBROVASCULAR DISEASES LA English DT Meeting Abstract C1 [Lynch, J.; Latour, L.; Luby, M.] NINDS, NIH, Bethesda, MD 20892 USA. [Benson, R.; Hsia, A.] Washington Hosp Ctr, NIH Stroke Program, Washington, DC 20010 USA. [Nadareishvilli, Z.] Suburban Hosp, NIH Stroke Program, Bethesda, MD USA. [Merino, J.] Johns Hopkins Community Phys, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1015-9770 EI 1421-9786 J9 CEREBROVASC DIS JI Cerebrovasc. Dis. PY 2014 VL 37 SU 1 MA B1917 BP 501 EP 501 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA V43ZE UT WOS:000209718504017 ER PT J AU Boja, ES Kinsinger, CR Rodriguez, H Srinivas, P AF Boja, Emily S. Kinsinger, Christopher R. Rodriguez, Henry Srinivas, Pothur CA Omics Integration Workshop TI Integration of omics sciences to advance biology and medicine SO CLINICAL PROTEOMICS LA English DT Article DE Omics integration; Omics science; Clinical application; Risk prediction; Proteomics; Metabolomics; Genomics AB In the past two decades, our ability to study cellular and molecular systems has been transformed through the development of omics sciences. While unlimited potential lies within massive omics datasets, the success of omics sciences to further our understanding of human disease and/or translating these findings to clinical utility remains elusive due to a number of factors. A significant limiting factor is the integration of different omics datasets (i.e., integromics) for extraction of biological and clinical insights. To this end, the National Cancer Institute (NCI) and the National Heart, Lung and Blood Institute (NHLBI) organized a joint workshop in June 2012 with the focus on integration issues related to multi-omics technologies that needed to be resolved in order to realize the full utility of integrating omics datasets by providing a glimpse into the disease as an integrated "system". The overarching goals were to (1) identify challenges and roadblocks in omics integration, and (2) facilitate the full maturation of 'integromics' in biology and medicine. Participants reached a consensus on the most significant barriers for integrating omics sciences and provided recommendations on viable approaches to overcome each of these barriers within the areas of technology, bioinformatics and clinical medicine. C1 [Boja, Emily S.; Kinsinger, Christopher R.; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, NIH, Bethesda, MD 20892 USA. [Srinivas, Pothur] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Boja, ES (reprint author), NCI, Off Canc Clin Prote Res, NIH, Bethesda, MD 20892 USA. EM bojae@mail.nih.gov; kinsingc@mail.nih.gov NR 45 TC 3 Z9 3 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1542-6416 EI 1559-0275 J9 CLIN PROTEOM JI Clin. Proteom. PY 2014 VL 11 AR 45 DI 10.1186/1559-0275-11-45 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V42YR UT WOS:000209649600040 ER PT J AU Boja, ES Rodriguez, H AF Boja, Emily S. Rodriguez, Henry TI Proteogenomic convergence for understanding cancer pathways and networks SO CLINICAL PROTEOMICS LA English DT Review DE Protein identification and quantitation; Post-translational modification; Targeted proteomics; Proteogenomics; Protein networks; Signaling pathways; Mathematical and computational modeling; Omics integration; Systems biology AB During the past several decades, the understanding of cancer at the molecular level has been primarily focused on mechanisms on how signaling molecules transform homeostatically balanced cells into malignant ones within an individual pathway. However, it is becoming more apparent that pathways are dynamic and crosstalk at different control points of the signaling cascades, making the traditional linear signaling models inadequate to interpret complex biological systems. Recent technological advances in high throughput, deep sequencing for the human genomes and proteomic technologies to comprehensively characterize the human proteomes in conjunction with multiplexed targeted proteomic assays to measure panels of proteins involved in biologically relevant pathways have made significant progress in understanding cancer at the molecular level. It is undeniable that proteomic profiling of differentially expressed proteins under many perturbation conditions, or between normal and "diseased" states is important to capture a first glance at the overall proteomic landscape, which has been a main focus of proteomics research during the past 15-20 years. However, the research community is gradually shifting its heavy focus from that initial discovery step to protein target verification using multiplexed quantitative proteomic assays, capable of measuring changes in proteins and their interacting partners, isoforms, and post-translational modifications (PTMs) in response to stimuli in the context of signaling pathways and protein networks. With a critical link to genotypes (i.e., high throughput genomics and transcriptomics data), new and complementary information can be gleaned from multi-dimensional omics data to (1) assess the effect of genomic and transcriptomic aberrations on such complex molecular machinery in the context of cell signaling architectures associated with pathological diseases such as cancer (i.e., from genotype to proteotype to phenotype); and (2) target pathway-and network-driven changes and map the fluctuations of these functional units (proteins) responsible for cellular activities in response to perturbation in a spatiotemporal fashion to better understand cancer biology as a whole system. C1 [Boja, Emily S.; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, NIH, 31 Ctr Dr,MSC 2580, Bethesda, MD 20892 USA. RP Boja, ES (reprint author), NCI, Off Canc Clin Prote Res, NIH, 31 Ctr Dr,MSC 2580, Bethesda, MD 20892 USA. EM bojae@mail.nih.gov NR 146 TC 12 Z9 12 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1542-6416 EI 1559-0275 J9 CLIN PROTEOM JI Clin. Proteom. PY 2014 VL 11 AR 22 DI 10.1186/1559-0275-11-22 PG 17 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V42YR UT WOS:000209649600015 PM 24994965 ER PT J AU Norheim, OF Baltussen, R Johri, M Chisholm, D Nord, E Brock, DW Carlsson, P Cookson, R Daniels, N Danis, M Fleurbaey, M Johansson, KA Kapiriri, L Littlejohns, P Mbeeli, T Rao, KD Edejer, TTT Wikler, D AF Norheim, Ole F. Baltussen, Rob Johri, Mira Chisholm, Dan Nord, Erik Brock, Dan W. Carlsson, Per Cookson, Richard Daniels, Norman Danis, Marion Fleurbaey, Marc Johansson, Kjell A. Kapiriri, Lydia Littlejohns, Peter Mbeeli, Thomas Rao, Krishna D. Edejer, Tessa Tan-Torres Wikler, Dan TI Guidance on priority setting in health care (GPS-Health): the inclusion of equity criteria not captured by cost-effectiveness analysis SO COST EFFECTIVENESS AND RESOURCE ALLOCATION LA English DT Article DE Priority setting; Resource allocation; Cost-effectiveness; Equity; Population health AB This Guidance for Priority Setting in Health Care (GPS-Health), initiated by the World Health Organization, offers a comprehensive map of equity criteria that are relevant to health care priority setting and should be considered in addition to cost-effectiveness analysis. The guidance, in the form of a checklist, is especially targeted at decision makers who set priorities at national and sub-national levels, and those who interpret findings from cost-effectiveness analysis. It is also targeted at researchers conducting cost-effectiveness analysis to improve reporting of their results in the light of these other criteria. The guidance was develop through a series of expert consultation meetings and involved three steps: i) methods and normative concepts were identified through a systematic review; ii) the review findings were critically assessed in the expert consultation meetings which resulted in a draft checklist of normative criteria; iii) the checklist was validated though an extensive hearing process with input from a range of relevant stakeholders. The GPS-Health incorporates criteria related to the disease an intervention targets (severity of disease, capacity to benefit, and past health loss); characteristics of social groups an intervention targets (socioeconomic status, area of living, gender; race, ethnicity, religion and sexual orientation); and non-health consequences of an intervention (financial protection, economic productivity, and care for others). C1 [Norheim, Ole F.; Johansson, Kjell A.] Univ Bergen, Dept Global Publ Hlth & Primary Care, N-5020 Bergen, Norway. [Baltussen, Rob] Radboud Univ Nijmegen, Med Ctr, Nijmegen Int Ctr Hlth Syst Res & Educ NICHE, Nijmegen, Netherlands. [Johri, Mira] CRCHUM, Quebec City, PQ, Canada. [Chisholm, Dan] WHO, Dept Hlth Syst Financing, Geneva, Switzerland. [Nord, Erik] Norwegian Inst Publ Hlth, Oslo, Norway. [Brock, Dan W.] Harvard Univ, Harvard Med Sch, Cambridge, MA USA. [Carlsson, Per] Linkoping Univ, Natl Ctr Prior Setting Hlth Care, Linkoping, Sweden. [Cookson, Richard] Univ York, Hlth Econ, York, N Yorkshire, England. [Daniels, Norman] Harvard Univ, Harvard Sch Publ Hlth, Cambridge, MA USA. [Danis, Marion] NIH Clin Ctr, Sect Ethics & Hlth Policy, Bethesda, MD USA. [Fleurbaey, Marc] Princeton Univ, Woodrow Wilson Sch Publ & Int Affairs, Princeton, NJ USA. [Kapiriri, Lydia] McMaster Univ, Dept Hlth, Hamilton, MT USA. [Littlejohns, Peter] Kings Coll London, Previous affiliat Natl Inst Hlth & Care Excellenc, Div Hlth & Social Care Res, Dept Primary Care & Publ Hlth Sci, London, England. [Rao, Krishna D.] Kings Coll London, Previous affiliat Natl Inst Hlth & Care Excellenc, Div Hlth & Social Care Res, Dept Primary Care & Publ Hlth Sci, London, England. [Carlsson, Per; Johansson, Kjell A.] Publ Hlth Fdn India, New Delhi, India. RP Norheim, OF (reprint author), Univ Bergen, Dept Global Publ Hlth & Primary Care, N-5020 Bergen, Norway. EM ole.norheim@igs.uib.no RI Baltussen, R.M.P.M./L-4181-2015; OI Johri, Mira/0000-0001-5642-787X; Norheim, Ole F./0000-0002-5748-5956 FU Young Investigator Grant for Ole F. Norheim, Norwegian Research Council [611720]; Brocher Foundation; Canadian Institutes for Health Research (CIHR) FX The first meeting to develop the guidance document in Geneva September 2010 was funded by a Young Investigator Grant for Ole F. Norheim, Norwegian Research Council (grant no 611720). The Brocher Foundation provided support for the second meeting of experts in June 2011. MJ acknowledges a New Investigator Award from the Canadian Institutes for Health Research (CIHR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 16 Z9 16 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-7547 J9 COST EFFECT RESOUR A JI Cost Effect. Resour Alloc. PY 2014 VL 12 AR 18 DI 10.1186/1478-7547-12-18 PG 8 WC Health Policy & Services SC Health Care Sciences & Services GA V45UD UT WOS:000209840600018 PM 25246855 ER PT J AU Trabert, B Chodick, G Shalev, V Sella, T Longnecker, MP McGlynn, KA AF Trabert, Britton Chodick, Gabriel Shalev, Varda Sella, Tal Longnecker, Matthew P. McGlynn, Katherine A. TI Gestational Diabetes and the Risk of Cryptorchidism and Hypospadias SO EPIDEMIOLOGY LA English DT Letter ID CONGENITAL-MALFORMATIONS; INFANTS C1 [Trabert, Britton; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Chodick, Gabriel; Shalev, Varda; Sella, Tal] Maccabi Healthcare Serv, Div Med, Tel Aviv, Israel. [Chodick, Gabriel; Shalev, Varda; Sella, Tal] Tel Aviv Univ, Sackler Fac, IL-69978 Tel Aviv, Israel. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Trabert, B (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM britton.trabert@nih.gov RI Trabert, Britton/F-8051-2015; OI Longnecker, Matthew/0000-0001-6073-5322 FU Intramural NIH HHS [Z01 CP010126-13] NR 8 TC 3 Z9 3 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD JAN PY 2014 VL 25 IS 1 BP 152 EP 153 DI 10.1097/EDE.0000000000000014 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 268XW UT WOS:000328205200025 PM 24296929 ER PT J AU Ghosh, SK Bond, MR Love, DC Ashwell, GG Krause, MW Hanover, JA AF Ghosh, Salil K. Bond, Michelle R. Love, Dona C. Ashwell, G. Gilbert Krause, Michael W. Hanover, John A. TI Disruption of O-GIcNAc cycling in C. elegans perturbs nucleotide sugar pools and complex glycans SO FRONTIERS IN ENDOCRINOLOGY LA English DT Article DE O-GIcNAcylation; nucleotide sugars; hexosamines; C. elegans/nematode; glycogen; trehalose AB The carbohydrate modification of serine and threonine residues with O-linked beta-N-acetylglucosamine (O-GIcNAc) is ubiquitous and governs cellular processes ranging from cell signaling to apoptosis. The O-GIcNAc modification along with other carbohydrate modifications, including N-linked and O-linked glycans, glycolipids, and sugar polymers, all require the use of the nucleotide sugar UDP-GIcNAc, the end product of the hexosamine biosynthetic pathway (HBP). In this paper, we describe the biochemical consequences resulting from perturbation of the O-GIcNAc pathway in C. elegans lacking O-GIcNAc transferase and O-GIcNAcase activities. In ogt-1 null animals, steady-state levels of UDP-GIcNAc/UDP-GaINAc and UDP-glucose were substantially elevated. Transcripts of genes encoding for key members in the HBP (gfat-2, gna-2, C36A4.4) and trehalose metabolism (tre-1, tre-2, tps-2) were elevated in ogt-1 null animals. While there is no evidence to suggest changes in the profile of N-linked glycans in the ogt-1 and oga-1 mutants, glycans insensitive to PNGase digestion (including O-linked glycans, glycolipids, and glycopolymers) were altered in these strains. Our data support that changes in O-GIcNAcylation alters nucleotide sugar production, overall glycan composition, and transcription of genes encoding glycan processing enzymes. These data along with our previous findings that disruption in O-GIcNAc cycling alters macronutrient storage underscores the noteworthy influence this posttranslational modification plays in nutrient sensing. C1 [Ghosh, Salil K.; Bond, Michelle R.; Love, Dona C.; Ashwell, G. Gilbert; Hanover, John A.] NIDDK, Lab Cell & Mol Biol, NIH, Bldg 8 Room B127,9000 Rockville Pike, Bethesda, MD 20892 USA. [Krause, Michael W.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hanover, JA (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, Bldg 8 Room B127,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jah@helix.nih.gov NR 44 TC 4 Z9 4 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PY 2014 VL 5 AR 197 DI 10.3389/fendo.2014.00197 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V44LF UT WOS:000209749800195 PM 25505447 ER PT J AU Janssens, J Etienne, H Idriss, S Azmi, A Martin, B Maudsley, S AF Janssens, Jonathan Etienne, Harmonie Idriss, Sherif Azmi, Abdelkrim Martin, Bronwen Maudsley, Stuart TI Systems-level G protein-coupled receptor therapy across a neurodegenerative continuum by the GLP-1 receptor system SO FRONTIERS IN ENDOCRINOLOGY LA English DT Review DE transcriptomics and proteomics; pharmacotherapeutics; pathophysiology; heptahelical G protein-coupled receptor AB With our increasing appreciation of the true complexity of diseases and pathophysiologies, it is clear that this knowledge needs to inform the future development of pharmacotherapeutics. For many disorders, the disease mechanism itself is a complex process spanning multiple signaling networks, tissues, and organ systems. Identifying the precise nature and locations of the pathophysiology is crucial for the creation of systemically effective drugs. Diseases once considered constrained to a limited range of organ systems, e.g., central neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington' disease (HD), the role of multiple central and peripheral organ systems in the etiology of such diseases is now widely accepted. With this knowledge, it is increasingly clear that these seemingly distinct neurodegenerative disorders (AD, PD, and HD) possess multiple pathophysiological similarities thereby demonstrating an inter-related continuum of disease-related molecular alterations. With this systems-level appreciation of neurodegenerative diseases, it is now imperative to consider that pharmacotherapeutics should be developed specifically to address the systemic imbalances that create the disorders. Identification of potential systems-level signaling axes may facilitate the generation of therapeutic agents with synergistic remedial activity across multiple tissues, organ systems, and even diseases. Here, we discuss the potentially therapeutic systems-level interaction of the glucagon-like peptide 1 (GLP-1) ligand receptor axis with multiple aspects of the AD, PD, and HD neurodegenerative continuum. C1 [Janssens, Jonathan; Etienne, Harmonie; Idriss, Sherif; Azmi, Abdelkrim; Maudsley, Stuart] Univ Antwerp VIB, Translat Neurobiol Grp, Dept Mol Genet, Univ Pl 1,Bldg V, B-2020 Antwerp, Belgium. [Martin, Bronwen] NIA, Metab Unit, NIH, Bethesda, MD 20892 USA. RP Maudsley, S (reprint author), Univ Antwerp VIB, Translat Neurobiol Grp, Dept Mol Genet, Univ Pl 1,Bldg V, B-2020 Antwerp, Belgium. EM stuart.maudsley@molgen.vib-ua.be NR 208 TC 6 Z9 6 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PY 2014 VL 5 AR 142 DI 10.3389/fendo.2014.00142 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V44LF UT WOS:000209749800142 PM 25225492 ER PT J AU Kimura, S AF Kimura, Shioko TI Thyroid regeneration: how stem cells play a role? SO FRONTIERS IN ENDOCRINOLOGY LA English DT Review DE adult-resident thyroid stem/progenitor cells; partial thyroidectomy; solid cell nest; ultimobranchial body cyst; side population; sphere/spheroid culture; OCT4 expression AB Many tissues if not all are thought to contain stem cells that are responsible for regeneration and repair of the tissue after injury. Dysregulation of tissue regeneration may result in various pathological conditions, among which cancer is the most extensively studied. Notably, the so-called cancer stem cells or tumor-initiating cells, have been studied in order to understand the mechanisms of carcinogenesis and/or metastasis. However, the nature of cancer stem cells, let alone normal stem/progenitor cells, particularly those of the thyroid remains elusive. There remains a gap in knowledge between adult thyroid stem/progenitor cells and cancer stem cells of the thyroid, and if and/or how they are related to each other. Understanding of the mechanism for thyroid regeneration and mode of participation of normal adult thyroid stem/progenitor cells in this process will hopefully yield a more complete understanding of the nature of thyroid cancer stem cells, and/or help understand the pathogenesis of other thyroid diseases. This review summarizes the current understanding of adult thyroid stem/progenitor cells, with particular emphasis on how they contribute to thyroid regeneration. C1 [Kimura, Shioko] NCI, Lab Metab, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM kimuras@mail.nih.gov FU National Cancer Institute Intramural Research Program [1ZIABC005522] FX This work was supported by the National Cancer Institute Intramural Research Program (Grant 1ZIABC005522). NR 97 TC 1 Z9 1 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PY 2014 VL 5 AR 55 DI 10.3389/fendo.2014.00055 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V44LF UT WOS:000209749800057 PM 24782833 ER PT J AU Wang, R van Keeken, NMA Siddiqui, S Dijksman, LM Maudsley, S Derval, D van Dam, PS Martin, B AF Wang, Rui van Keeken, Nika M. A. Siddiqui, Sana Dijksman, Lea M. Maudsley, Stuart Derval, Diana van Dam, P. Sytze Martin, Bronwen TI Higher TNF-alpha IGF-1, and leptin levels are found in tasters than non-tasters SO FRONTIERS IN ENDOCRINOLOGY LA English DT Article DE taste; TNF-alpha; leptin; IGF-1; BMI AB Taste perception is controlled by taste cells that are present in the tongue that produce and secrete various metabolic hormones. Recent studies have demonstrated that taste receptors in tongue, gut, and pancreas are associated with local hormone secretion. The aim of this study was to determine whether there is a link between taste sensitivity and levels of circulating metabolic hormones in humans and whether taste sensitivity is potentially related to peripheral metabolic regulation. Thirty-one subjects were recruited and separated into tasters and non-tasters based on their phenol thiocarbamide (PTC) bitter taste test results. Fasting plasma and saliva were collected and levels of hormones and cytokines were assayed. We observed significant differences in both hormone levels and hormone body mass index (BMI) correlation between tasters and non-tasters. Tasters had higher plasma levels of leptin (p = 0.05), tumor necrosis factor-alpha (INF-alpha) (p = 0.04), and insulin-like growth factor 1 (IGF-1) (p = 0.03). There was also a trend toward increased IGF-1 levels in the saliva of tasters (p = 0.06). We found a positive correlation between plasma levels of glucose and BMI (R = 0.4999, p = 0.04) exclusively in non-tasters. In contrast, plasma C-peptide levels were found to be positively correlated to BMI (R = 0.5563, p = 0.03) in tasters. Saliva INF-alpha levels were negatively correlated with BMI in tasters (R = 0.5908, p = 0.03). Our findings demonstrate that there are differences in circulating levels of leptin, INF-alpha, and IGF-1 between tasters and non -tasters. These findings indicate that in addition to the regulation of food consumption, taste perception also appears to be tightly linked to circulating metabolic hormone levels. People with different taste sensitivity may respond differently to the nutrient stimulation. Further work investigating the link between taste perception and peripheral metabolic control could potentially lead to the development of novel therapies for obesity or Type 2 diabetes. C1 [Wang, Rui; Martin, Bronwen] NIA, Metab Unit, NIH, Baltimore, MD 21224 USA. [van Keeken, Nika M. A.; van Dam, P. Sytze] Onze Lieve Vrouw Hosp, Dept Internal Med, Amsterdam, Netherlands. [Siddiqui, Sana; Maudsley, Stuart] NIA, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA. [Dijksman, Lea M.] Onze Lieve Vrouw Hosp, Teaching Hosp, Amsterdam, Netherlands. [Maudsley, Stuart] Univ Antwerp VIB, Dept Mol Genet, Antwerp, Belgium. [Derval, Diana] Better Immune Syst Fdn, Amsterdam, Netherlands. RP Martin, B (reprint author), NIA, Metab Unit, 251 Bayview Blvd,Suite 100 Room 08C009, Baltimore, MD 21224 USA. EM martinbro@mail.nih.gov FU Better Immune System Foundation; Onze Lieve Vrouwe Gasthuis; HDSA COE grant; Intramural Research Program of the National Institute on Aging, National Institutes of Health; NINDS [16375]; [AG000915-01]; [AG000917-01] FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, the Better Immune System Foundation, and Onze Lieve Vrouwe Gasthuis. We would like to thank the volunteers that took part in this study for their time and dedication. We would like to thank Better Immune System volunteers who helped recruit the subjects. We also thank the NIH fellows' editorial board for their help with manuscript editing. Supporting grants: AG000915-01, AG000917-01, NINDS 16375, HDSA COE grant. NR 46 TC 3 Z9 3 U1 1 U2 8 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PY 2014 VL 5 AR 125 DI 10.3389/fendo.2014.00125 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V44LF UT WOS:000209749800125 PM 25120532 ER PT J AU Bielekova, B Vodovotz, Y An, G Hallenbeck, J AF Bielekova, Bibiana Vodovotz, Yoram An, Gary Hallenbeck, John TI How implementation of systems biology into clinical trials accelerates understanding of diseases SO FRONTIERS IN NEUROLOGY LA English DT Review DE systems biology; clinical trials; clinical trials methodology; multiple sclerosis; polygenic diseases AB Systems biology comprises a series of concepts and approaches that have been used successfully both to delineate novel biological mechanisms and to drive translational advances. The goal of systems biology is to re-integrate putatively critical elements extracted from multi-modality datasets in order to understand how interactions among multiple components form functional networks at the organism/patient-level, and how dysfunction of these networks underlies a particular disease. Due to the genetic and environmental diversity of human subjects, identification of critical elements related to a particular disease process from cross-sectional studies requires prohibitively large cohorts. Alternatively, implementation of systems biology principles to interventional clinical trials represents a unique opportunity to gain predictive understanding of complex diseases in comparatively small cohorts of patients. This paper reviews systems biology principles applicable to translational research, focusing on lessons from systems approaches to inflammation applied to multiple sclerosis. We suggest that employing systems biology methods in the design and execution of biomarker-supported, proof-of-principle clinical trials provides a singular opportunity to merge therapeutic development with a basic understanding of disease processes. The ultimate goal is to develop predictive computational models of the disease, which will revolutionize diagnostic process and provide mechanistic understanding necessary for personalized therapeutic approaches. Added, biologically meaningful information can be derived from diagnostic tests, if they are interpreted in functional relationships, rather than as independent measurements. Such systems biology based diagnostics will transform disease taxonomies from phenotypical to molecular and will allow physicians to select optimal therapeutic regimens for individual patients. C1 [Bielekova, Bibiana] NINDS, Neuroimmunol Dis Unit, NIH, Bethesda, MD 20892 USA. [Bielekova, Bibiana] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Vodovotz, Yoram] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Vodovotz, Yoram; An, Gary] McGowan Inst Regenerat Med, Ctr Inflammat & Regenerat Modeling, Pittsburgh, PA USA. [An, Gary] Northwestern Univ, Dept Surg, Chicago, IL 60611 USA. [Hallenbeck, John] NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Bielekova, B (reprint author), NINDS, NIH, NIB, Bld10-R,5C103,10 Ctr Dr,MSC1400, Bethesda, MD 20892 USA. EM bibi.bielekova@nih.gov OI An, Gary/0000-0003-4549-9004 FU US National Institute of Neurological Disorders and Stroke (NINDS)/US National Institutes of Health (NIH); National Science Foundation (NSF) [0830-370-V601]; National Institute of Disability and Rehabilitation Research (NIDRR) [H133E070024]; National Institutes of Health (NIH) [P50GM053789] FX The study was supported by the intramural research program of the US National Institute of Neurological Disorders and Stroke (NINDS)/US National Institutes of Health (NIH) and by National Science Foundation (NSF) 0830-370-V601, National Institute of Disability and Rehabilitation Research (NIDRR) H133E070024 and National Institutes of Health (NIH) P50GM053789. The authors are grateful to Ronald Germain, Henry McFarland, Dorian McGovern, Walter Koroshetz and Irene Cortese (all NIH) for their critical review of the manuscript and helpful suggestions. The authors also acknowledge that the imposed word limit requirements precluded inclusion of other mechanistically supported Phase I/II trials in MS that provided equally informative knowledge about MS disease process. NR 60 TC 8 Z9 8 U1 0 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PY 2014 VL 5 AR 102 DI 10.3389/fneur.2014.00102 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V42QW UT WOS:000209629300099 PM 25018747 ER PT J AU Heinzelmann, M Reddy, SY French, LM Wang, D Lee, H Barr, T Baxter, T Mysliwiec, V Gill, J AF Heinzelmann, Morgan Reddy, Swarnalatha Y. French, Louis M. Wang, Dan Lee, Hyunhwa Barr, Taura Baxter, Tristin Mysliwiec, Vincent Gill, Jessica TI Military personnel with chronic symptoms following blast traumatic brain injury have differential expression of neuronal recovery and epidermal growth factor receptor genes SO FRONTIERS IN NEUROLOGY LA English DT Article DE traumatic brain injury; military; post-concussive disorder; gene-expression AB Objective: Approximately one-quarter of military personnel who deployed to combat stations sustained one or more blast-related, closed-head injuries. Blast injuries result from the detonation of an explosive device. The mechanisms associated with blast exposure that give rise to traumatic brain injury (TBI), and place military personnel at high risk for chronic symptoms of post-concussive disorder (PCD), post-traumatic stress disorder (PTSD), and depression are not elucidated. Methods:To investigate the mechanisms of persistent blast-related symptoms, we examined expression profiles of transcripts across the genome to determine the role of gene activity in chronic symptoms following blast-TBI. Active duty military personnel with (1) a medical record of a blast-TBI that occurred during deployment (n= 19) were compared to control participants without TBI (n = 17). Controls were matched to cases on demographic factors including age, gender, and race, and also in diagnoses of sleep disturbance, and symptoms of PTSD and depression. Due to the high number of PCD symptoms in the TBI+ group, we did not match on this variable. Using expression profiles of transcripts in microarray platform in peripheral samples of whole blood, significantly differentially expressed gene lists were generated. Statistical threshold is based on criteria of 1.5 magnitude fold-change (up or down) and p-values with multiple test correction (false discovery rate <0.05). Results:There were 34 transcripts in 29 genes that were differentially regulated in blast-TBI participants compared to controls. Up-regulated genes included epithelial cell transforming sequence and zinc finger proteins, which are necessary for astrocyte differentiation following injury. Tensin-1, which has been implicated in neuronal recovery in pre-clinical TBI models, was down-regulated in blast-TBI participants. Protein ubiquitination genes, such as epidermal growth factor receptor, were also down-regulated and identified as the central regulators in the gene network determined by interaction pathway analysis. Conclusion: In this study, we identified a gene-expression pathway of delayed neuronal recovery in military personnel a blast-TBI and chronic symptoms. Future work is needed to determine if therapeutic agents that regulate these pathways may provide novel treatments for chronic blast-TBI-related symptoms. C1 [Heinzelmann, Morgan; Reddy, Swarnalatha Y.; Wang, Dan; Lee, Hyunhwa; Gill, Jessica] NINR, NIH, Bethesda, MD 20892 USA. [French, Louis M.] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [French, Louis M.] Walter Reed Natl Mil Med Ctr, Def & Vet Brain Injury Ctr, Bethesda, MD USA. [Barr, Taura] W Virginia Univ, Hlth Sci Ctr, Morgantown, WV 26506 USA. [Baxter, Tristin; Mysliwiec, Vincent] Madigan Army Med Ctr, Sleep Med Clin, Tacoma, WA 98431 USA. RP Gill, J (reprint author), NINR, 1 Cloister Court,Room 256, Bethesda, MD 20814 USA. EM gillj@mail.nih.gov RI Reddy, Swarna/G-5349-2013 FU Center for Neuroscience and Regenerative Medicine [60855] FX This study was funded, in part, by the Center for Neuroscience and Regenerative Medicine (Grant 60855). NR 54 TC 4 Z9 5 U1 2 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PY 2014 VL 5 AR 198 DI 10.3389/fneur.2014.00198 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V42QW UT WOS:000209629300186 PM 25346719 ER PT J AU Leigh, R Urrutia, VC Llinas, RH Gottesman, RF Krakauer, JW Hillis, AE AF Leigh, Richard Urrutia, Victor C. Llinas, Rafael H. Gottesman, Rebecca F. Krakauer, John W. Hillis, Argye E. TI A comparison of two methods for MRI classification of at-risk tissue and core infarction SO FRONTIERS IN NEUROLOGY LA English DT Article DE MR RESCUE; DEFUSE 2; MRI; penumbra; DWI; PWI; at-risk tissue; core infarction AB Objective: To compare how at-risk tissue and core infarction were defined in two major trials that tested the use of MRI in selecting acute stroke patients for endovascular recanalization therapy. Methods: MRIs from 12 patients evaluated for possible endovascular therapy were processed using the methods published from two major trials, MR RESCUE and DEFUSE 2. Specifically, volumes of at-risk tissue and core infarction were generated from each patient's MRI. MRIs were then classified as whether or not they met criteria for salvageable tissue: "penumbral pattern" for MR RESCUE and/or "target profile" for DEFUSE 2 as defined by each trial. Results: Volumes of at-risk tissue measured by the two definitions were correlated (p = 0.017) while the volumes of core infarct were not (p = 0.059). The volume of at-risk tissue was consistently larger when defined by the penumbral pattern than the target profile while the volume of core infarct was consistently larger when defined by the target profile than the penumbral pattern. When these volumes were used to classify the MRI scans, 9 out of 12 patients (75%) were classified as having a penumbral pattern, while only 4 out of 12 patients (33%) were classified as having a target profile. Of the 9 patients classified as penumbral pattern, 5 (55%) were classified differently by the target profile. Interpretation: Our analysis found that the MR RESCUE trial defined salvageable tissue in a way that made it more likely for patients be labeled as favorable for treatment. For the cohort of patients examined in this study, had they been enrolled in both trials, most of the patients identified as having salvageable tissue by the MR RESCUE trial would not have been considered to have salvageable tissue in the DEFUSE 2 trial. Caution should be taken in concluding that MRI selection for endovascular therapy is not effective as imaging selection criteria were substantially different between the two trials. C1 [Leigh, Richard; Urrutia, Victor C.; Llinas, Rafael H.; Gottesman, Rebecca F.; Krakauer, John W.; Hillis, Argye E.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Leigh, R (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, NIH, 10 Ctr Dr,Bldg 10,Room B1D-733,MSC 1063, Bethesda, MD 20892 USA. EM richard.leigh@nih.gov OI Urrutia, Victor/0000-0002-4995-6949 FU NINDS NIH HHS [R01 NS047691] NR 12 TC 2 Z9 2 U1 0 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PY 2014 VL 5 AR 155 DI 10.3389/fneur.2014.00155 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V42QW UT WOS:000209629300148 PM 25232348 ER PT J AU Christopher, AB Ochoa, S Krushansky, E Francis, R Tian, X Zahid, M Munoz, R Lo, CW AF Christopher, Adam B. Ochoa, Sebastian Krushansky, Evonne Francis, Richard Tian, Xin Zahid, Maliha Munoz, Ricardo Lo, Cecilia W. TI The effects temperature and anesthetic agents on ciliary function in murine respiratory epithelia SO FRONTIERS IN PEDIATRICS LA English DT Article DE ciliary beat frequency; dexmedetomidine; fentanyl; isoflurane; hypothermia AB Background: Mucus transport mediated by motile cilia in the airway is an important defense mechanism for prevention of respiratory infections. As cilia motility can be depressed by hypothermia or exposure to anesthetics, in this study, we investigated the individual and combined effects of dexmedetomidine (dex), fentanyl (fen), and/or isoflurane (iso) at physiologic and low temperatures on cilia motility in mouse tracheal airway epithelia. These anesthetic combinations and low temperature conditions are often used in the setting of cardiopulmonary bypass surgery, surgical repair of congenital heart disease, and cardiac intensive care. Methods: C57BL/6J mouse tracheal epithelia were excised and cilia dynamics were captured by videomicroscopy following incubation at 15, 22-24, and 37 degrees C with different combinations of therapeutic concentrations of dex (10 nM), fen (10 nM), and iso (0.01 %). Airway ciliary motion was assessed and compared across conditions by measuring ciliary beat frequency and ciliary flow velocity. Statistical analysis was carried out using unpaired t-tests, analysis of variance, and multivariate linear regression. Results:There was a linear correlation between cilia motility and temperature. Fen exerted cilia stimulatory effects, while dex and iso each had ciliodepressive effects. When added together, fen + iso, dex + iso, and dex+ fen + iso were all cilia inhibitory. In contrast fenl + dex did not significantly alter ciliary function. Conclusion: We show that ciliary motility is stimulated by fen, but depressed by dex or iso. However, when used in combination, ciliary motility showed changes indicative of complex drug drug and drug temperature interactions not predicted by simple summation of their individual effects. Similar studies are needed to examine the human airway epithelia and its response to anesthetics. C1 [Christopher, Adam B.; Francis, Richard; Zahid, Maliha; Lo, Cecilia W.] Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA USA. [Ochoa, Sebastian; Krushansky, Evonne; Tian, Xin; Munoz, Ricardo; Lo, Cecilia W.] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15261 USA. [Tian, Xin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Lo, CW (reprint author), Univ Pittsburgh, Dept Dev Biol, Rangos Res Ctr 8120, 530 45th St, Pittsburgh, PA 15201 USA. EM cel36@pitt.edu RI Francis, Richard/P-2524-2015 NR 28 TC 6 Z9 6 U1 0 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2296-2360 J9 FRONT PEDIATR JI Front. Pediatr. PY 2014 VL 2 AR 111 DI 10.3389/fped.2014.00111 PG 9 WC Pediatrics SC Pediatrics GA V46PX UT WOS:000209897200110 PM 25360434 ER PT S AU Rees, MG Gloyn, AL AF Rees, Matthew G. Gloyn, Anna L. BE Gloyn, AL McCarthy, MI TI Translating Genetic Association Signals for Diabetes and Metabolic Traits into Molecular Mechanisms for Disease SO GENETICS IN DIABETES: TYPE 2 DIABETES AND RELATED TRAITS SE Frontiers in Diabetes LA English DT Article; Book Chapter ID GENOME-WIDE ASSOCIATION; GLUCOKINASE REGULATORY PROTEIN; HUMAN PANCREATIC-ISLETS; INSULIN-SECRETION; SUSCEPTIBILITY LOCI; PROVIDES INSIGHTS; P446L VARIANT; TRANSFER-RNA; CELL LINE; TYPE-2 AB More than 80 genetic loci affecting type 2 diabetes (T2D) risk have been published to date. However, the causative variant(s) and biology underlying the associations at the vast majority of these loci remain elusive, in part due to an incomplete understanding of the genes and pathways involved in T2D development and progression. This highlights two interrelated challenges: the need for functional elucidation of the effects of individual variants, and the need to broadly and comprehensively investigate the function of implicated genes to understand how their modulation contributes to disease risk. This chapter discusses the approaches beginning to bear fruit in addressing both of these challenges, including the characterization of nonsynonymous common variants or collections of rare variants (e.g. GCKR, MTNR1B), the assignment of novel gene function relevant to disease processes (e.g. CDKAL1), the value of integrating genetic association results with datasets for expression or epigenetic factors (e.g. TCF7L2, KLF14), and emerging systems genetics approaches focusing on pathways, protein-protein interactions, and gene-gene interactions. These instructive studies suggest a template for future functional investigations into the variants and genes underlying T2D risk. (C) 2014 S. Karger AG, Basel C1 [Rees, Matthew G.; Gloyn, Anna L.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Gloyn, Anna L.] Churchill Hosp, Oxford Univ Hosp Trust, NIHR Oxford Biomed Res Ctr, Oxford, England. [Rees, Matthew G.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Gloyn, AL (reprint author), Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LE, England. EM anna.gloyn@drl.ox.ac.uk NR 50 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 0251-5342 BN 978-3-318-02700-6; 978-3-318-02699-3 J9 FRONT DIABETES JI Front.Diabetes PY 2014 VL 23 BP 133 EP 145 DI 10.1159/000362473 D2 10.1159/isbn.978-3-318-02700-6 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA BG2UO UT WOS:000387711300012 ER PT B AU Bindewald, E Shapiro, BA AF Bindewald, Eckart Shapiro, Bruce A. BE Poptsova, MS TI Comparative Methods for RNA Structure Prediction SO GENOME ANALYSIS: CURRENT PROCEDURES AND APPLICATIONS LA English DT Article; Book Chapter ID SECONDARY STRUCTURE PREDICTION; SELECTIVE 2'-HYDROXYL ACYLATION; CONTEXT-FREE GRAMMARS; DYNAMIC-PROGRAMMING ALGORITHM; COMPARATIVE SEQUENCE-ANALYSIS; SINGLE NUCLEOTIDE RESOLUTION; BASE-PAIRING PROBABILITIES; FREE-ENERGY MINIMIZATION; PRIMER EXTENSION SHAPE; INCLUDING PSEUDOKNOTS AB The appreciation of the pervasiveness of RNA biology continues to increase. The vastness of available sequence information calls for computational tools that aid in a variety of prediction problems, such as RNA structure prediction, RNA-RNA interaction prediction and genomic scans for conserved RNA structural elements. Comparative methods for RNA structure prediction employ a set of homologous RNA sequences; this additional information can then be used to not only estimate energy contributions, but also information in the form of compensatory base changes. Different software tools make use of this information in a fascinating variety of ways. This paper surveys current comparative approaches for RNA structure predictions and discusses a variety of future trends. C1 [Bindewald, Eckart] SAIC Frederick Inc, Basic Sci Program, Ctr Canc Res, Nanobiol Program,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Shapiro, Bruce A.] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21701 USA. RP Bindewald, E (reprint author), SAIC Frederick Inc, Basic Sci Program, Ctr Canc Res, Nanobiol Program,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM eckart@mail.nih.gov; shapirbr@mail.nih.gov NR 131 TC 0 Z9 0 U1 0 U2 0 PU CAISTER ACADEMIC PRESS PI WYMONDHAM PA 32 HEWITTS LANE, WYMONDHAM NR 18 0JA, ENGLAND BN 978-1-908230-68-3; 978-1-908230-29-4 PY 2014 BP 287 EP 305 PG 19 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA BF7MU UT WOS:000384249900015 ER PT J AU Miettinen, M AF Miettinen, Markku TI Immunohistochemistry of soft tissue tumours - review with emphasis on 10 markers SO HISTOPATHOLOGY LA English DT Review DE CD31; CD34; desmin; DOG1; EMA; ERG; immunohistochemistry; IT; keratins; S100 protein; sarcoma; SMA ID GASTROINTESTINAL STROMAL TUMORS; CELL ANTIGEN CD34; POSITIVE EPITHELIOID ANGIOSARCOMA; MALIGNANT FIBROUS HISTIOCYTOMA; GRADE FIBROMYXOID SARCOMA; DIFFERENTIAL-DIAGNOSIS; ENDOTHELIAL-CELLS; VASCULAR TUMORS; H-CALDESMON; C-KIT AB Immunohistochemistry is an integral component in the proper analysis of soft tissue tumours, and a simple panel of six markers is useful in practical triage: CD34, desmin, epithelial membrane antigen (EMA), keratin cocktail AE1/AE3, S100 protein and alpha smooth muscle actin (SMA). These markers frequently assist in the differential diagnosis of fibroblastic, myoid, nerve sheath and perineurial cell tumours, synovial and epithelioid sarcoma and others. However, they all are multispecific, so that one has to be cognizant of their distribution in normal and neoplastic tissues. Four additional useful markers for specific tumour types are discussed here: CD31 and ERG for vascular endothelial tumours, and KIT and DOG1/Ano-1 for gastrointestinal stromal tumours (GISTs). However, hardly any marker is totally monospecific for any one type of tumour. Furthermore, variably lineage-specific markers do not usually distinguish between benign and malignant proliferations, so that this distinction has to be made on histological grounds. Immunohistochemical evaluation is most useful, efficient and cost-effective when used in the context of careful histological evaluation by an experienced pathologist, aware of all diagnostic entities and their histological spectra. Additional diagnostic steps that must be considered in difficult cases include clinicoradiological correlation and additional sampling of remaining wet tissue, if possible. C1 NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Miettinen, M (reprint author), NCI, Pathol Lab, 9000 Rockville Pike,Bldg 10,Room 2B50, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov FU NCI FX This work was supported as a part of NCI's intramural research programme. The author reports no conflicts of interest regarding the contents of this paper. NR 86 TC 16 Z9 17 U1 2 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 EI 1365-2559 J9 HISTOPATHOLOGY JI Histopathology PD JAN PY 2014 VL 64 IS 1 BP 101 EP 118 DI 10.1111/his.12298 PG 18 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 269CU UT WOS:000328219100009 PM 24111893 ER PT J AU Berl, MM Mayo, J Parks, EN Rosenberger, LR VanMeter, J Ratner, NB Vaidya, CJ Gaillard, WD AF Berl, Madison M. Mayo, Jessica Parks, Erin N. Rosenberger, Lisa R. VanMeter, John Ratner, Nan Bernstein Vaidya, Chandan J. Gaillard, William Davis TI Regional Differences in the Developmental Trajectory of Lateralization of the Language Network SO HUMAN BRAIN MAPPING LA English DT Article DE language; fMRI; pediatric; lateralization ID HUMAN CEREBRAL-CORTEX; FUNCTIONAL MRI; NORMAL-CHILDREN; YOUNG-CHILDREN; METHODOLOGICAL ISSUES; PARTIAL EPILEPSY; NEURAL-NETWORKS; BRAIN-LESIONS; FMRI LANGUAGE; DOMINANCE AB The timing and developmental factors underlying the establishment of language dominance are poorly understood. We investigated the degree of lateralization of traditional frontotemporal and modulatory prefrontal-cerebellar regions of the distributed language network in children (n = 57) ages 4 to 12a critical period for language consolidation. We examined the relationship between the strength of language lateralization and neuropsychological measures and task performance. The fundamental language network is established by four with ongoing maturation of language functions as evidenced by strengthening of lateralization in the traditional frontotemporal language regions; temporal regions were strongly and consistently lateralized by age seven, while frontal regions had greater variability and were less strongly lateralized through age 10. In contrast, the modulatory prefrontal-cerebellar regions were the least strongly lateralized and degree of lateralization was not associated with age. Stronger core language skills were significantly correlated with greater right lateralization in the cerebellum. Hum Brain Mapp 35:270-284, 2014. (c) 2012 Wiley Periodicals, Inc. C1 [Berl, Madison M.; Mayo, Jessica; Parks, Erin N.; Rosenberger, Lisa R.; Vaidya, Chandan J.; Gaillard, William Davis] Childrens Natl Med Ctr, Dept Neurosci, Washington, DC 20010 USA. [VanMeter, John] Georgetown Univ, Ctr Funct & Mol Imaging, Washington, DC USA. [Ratner, Nan Bernstein] Univ Maryland, Dept Hearing & Speech Sci, College Pk, MD 20742 USA. [Vaidya, Chandan J.] Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. [Gaillard, William Davis] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Gaillard, William Davis] Georgetown Univ, Sch Med, Dept Neurol, Washington, DC USA. RP Berl, MM (reprint author), Childrens Natl Med Ctr, Div Pediat Neuropsychol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM mberl@childrensnational.org FU National Institutes of Health (NIH) [NINDS R01 NS44280, NCRR M01RR020359]; Epilepsy Foundation; Children's Research Institute; NINDS Clinical Epilepsy Section Division of Intramural Research, Intellectual and Developmental Research Center [HD040677-07] FX Contract grant sponsor: National Institutes of Health (NIH); Contract grant number: NINDS R01 NS44280 (to W. D. G.) NCRR M01RR020359; Contract grant sponsors: Epilepsy Foundation (Partnership for Pediatric Research to M. M. B.); Children's Research Institute (Avery Award to M. M. B.); NINDS Clinical Epilepsy Section Division of Intramural Research, Intellectual and Developmental Research Center; Contract grant number: HD040677-07. NR 86 TC 18 Z9 18 U1 2 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JAN PY 2014 VL 35 IS 1 BP 270 EP 284 DI 10.1002/hbm.22179 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 264EN UT WOS:000327859900022 PM 23033058 ER PT J AU Lanuza, MA Santafe, MM Garcia, N Besalduch, N Tomas, M Obis, T Priego, M Nelson, PG Tomas, J AF Lanuza, Maria A. Santafe, Manel M. Garcia, Neus Besalduch, Nuria Tomas, Marta Obis, Teresa Priego, Mercedes Nelson, Phillip G. Tomas, Josep TI Protein kinase C isoforms at the neuromuscular junction: localization and specific roles in neurotransmission and development SO JOURNAL OF ANATOMY LA English DT Review DE electrical stimulation; immunofluorescence; isoforms; neuromuscular junction; neurotransmission; protein kinase C; synapse elimination ID MOTOR-NERVE TERMINALS; HUMAN SKELETAL-MUSCLE; PRESYNAPTIC MUSCARINIC RECEPTORS; NICOTINIC ACETYLCHOLINE-RECEPTOR; MODULATE TRANSMITTER RELEASE; RAT PHRENIC-NERVE; SYNAPSE ELIMINATION; PHORBOL ESTER; ADULT-RAT; IN-VITRO AB The protein kinase C family (PKC) regulates a variety of neural functions including neurotransmitter release. The selective activation of a wide range of PKC isoforms in different cells and domains is likely to contribute to the functional diversity of PKC phosphorylating activity. In this review, we describe the isoform localization, phosphorylation function, regulation and signalling of the PKC family at the neuromuscular junction. Data show the involvement of the PKC family in several important functions at the neuromuscular junction and in particular in the maturation of the synapse and the modulation of neurotransmission in the adult. C1 [Lanuza, Maria A.; Santafe, Manel M.; Garcia, Neus; Besalduch, Nuria; Tomas, Marta; Obis, Teresa; Priego, Mercedes; Tomas, Josep] Univ Rovira & Virgili, UHN, Fac Med & Ciencies Salut, Reus 43201, Spain. [Nelson, Phillip G.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Lanuza, MA (reprint author), Univ Rovira & Virgili, UHN, Fac Med & Ciencies Salut, Carrer St Llorenc 21, Reus 43201, Spain. EM mariaangel.lanuza@urv.cat OI Santafe, Manel/0000-0002-5462-5108; OBIS IBANEZ, TERESA/0000-0003-1569-1070 FU MEC [SAF2011-23711]; Catalan Government (Generalitat) [2009SGR0 1248] FX This work was supported by a grant from MEC (SAF2011-23711) and a grant from the Catalan Government (Generalitat) (2009SGR0 1248). NR 94 TC 3 Z9 3 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-8782 EI 1469-7580 J9 J ANAT JI J. Anat. PD JAN PY 2014 VL 224 IS 1 SI SI BP 61 EP 73 DI 10.1111/joa.12106 PG 13 WC Anatomy & Morphology SC Anatomy & Morphology GA 268PC UT WOS:000328182000008 PM 24102585 ER PT J AU Stampalija, T Chaiworapongsa, T Romero, R Tarca, AL Bhatti, G Chiang, PJ Than, NG Ferrazzi, E Hassan, SS Yeo, L AF Stampalija, Tamara Chaiworapongsa, Tinnakorn Romero, Roberto Tarca, Adi L. Bhatti, Gaurav Chiang, Po Jen Than, Nandor Gabor Ferrazzi, Enrico Hassan, Sonia S. Yeo, Lami TI Soluble ST2, a modulator of the inflammatory response, in preterm and term labor SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Acute histologic chorioamnionitis; amniotic fluid; IL-33; intra-amniotic infection/inflammation; mRNA expression ID TUMOR-NECROSIS-FACTOR; AMNIOTIC-FLUID INTERLEUKIN-6; TOLL-LIKE-RECEPTORS; MONOCYTE CHEMOTACTIC PROTEIN-1; POLYMERASE-CHAIN-REACTION; CHRONIC LUNG-DISEASE; HUMAN FETAL MEMBRANES; WHITE-MATTER LESIONS; BLOOD-CELL COUNT; EXPERIMENTAL INTRAUTERINE INFECTION AB Objective: Intra-amniotic infection/inflammation (IAI) is causally linked with spontaneous preterm labor and delivery. The ST2L receptor and its soluble form (sST2) are capable of binding to interleukin (IL)-33, a member of the IL-1 superfamily. Members of this cytokine family have been implicated in the onset of spontaneous preterm labor in the context of infection. Soluble ST2 has anti-inflammatory properties, and plasma concentrations are elevated in systemic inflammation, such as sepsis, acute pyelonephritis in pregnancy and the fetal inflammatory response syndrome. The aims of this study were to examine: (1) whether amniotic fluid concentrations of sST2 change with IAI, preterm, and term parturition; and (2) if mRNA expression of ST2 in the chorioamniotic membranes changes with acute histologic chorioamnionitis in women who deliver preterm. Method: A cross-sectional study was conducted to determine amniotic fluid concentrations of sST2 in: (1) women with preterm labor (PTL) who delivered at term (n = 49); (2) women with PTL who delivered preterm without IAI (n = 21); (3) women with PTL who delivered preterm with IAI (n = 31); (4) term pregnancies not in labor (n = 13); and (5) term pregnancies in labor (n = 43). The amniotic fluid concentration of sST2 was determined by ELISA. The mRNA expression of ST2 in the chorioamniotic membranes of women who delivered preterm with (n = 24), and without acute histologic chorioamnionitis (n = 19) was determined by qRT-PCR. Results: (1) Patients with PTL who delivered preterm with IAI had a lower median amniotic fluid concentration of sST2 compared to those with PTL who delivered preterm without IAI [median 410 ng/mL, inter-quartile range (IQR) 152-699 ng/mL versus median 825 ng/mL, IQR 493-1216 ng/mL; p = 0.0003] and those with PTL who delivered at term [median 410 ng/mL, IQR 152-699 ng/mL versus median 673 ng/mL, IQR 468-1045 ng/mL; p = 0.0003]; (2) no significant differences in the median amniotic fluid concentration of sST2 were observed between patients with PTL who delivered at term and those who delivered preterm without IAI (p = 0.4), and between women at term in labor and those at term not in labor (p = 0.9); (3) the mean mRNA expression of ST2 was 4-fold lower in women who delivered preterm with acute histologic chorioamnionitis than in those without this lesion (p = 0.008). Conclusions: The median sST2 amniotic fluid concentration and mRNA expression of ST2 by chorioamniotic membranes is lower in PTL associated with IAI and acute histologic chorioamnionitis than in PTL without these conditions. Changes in the median amniotic fluid sST2 concentration are not observed in preterm and term parturition without IAI. Thus, amniotic fluid sST2 in the presence of IAI behaves differently when compared to sST2 in the plasma of individuals affected by fetal inflammatory response syndrome, acute pyelonephritis in pregnancy, and adult sepsis. Decreased concentrations of sST2 in IAI are likely to promote a pro-inflammatory response, which is important for parturition in the context of infection. C1 [Stampalija, Tamara; Chaiworapongsa, Tinnakorn; Romero, Roberto; Tarca, Adi L.; Bhatti, Gaurav; Chiang, Po Jen; Than, Nandor Gabor; Hassan, Sonia S.; Yeo, Lami] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Stampalija, Tamara; Chaiworapongsa, Tinnakorn; Romero, Roberto; Tarca, Adi L.; Bhatti, Gaurav; Chiang, Po Jen; Than, Nandor Gabor; Hassan, Sonia S.; Yeo, Lami] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Stampalija, Tamara; Chaiworapongsa, Tinnakorn; Than, Nandor Gabor; Hassan, Sonia S.; Yeo, Lami] Wayne State Univ, Dept Obstet Gynecol, Detroit, MI 48201 USA. [Stampalija, Tamara; Ferrazzi, Enrico] Univ Milan, Childrens Hosp V Buzzi, Dept Obstet Gynecol, Milan, Italy. [Tarca, Adi L.] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM tchaiwor@med.wayne.edu; romeror@maih.nih.gov RI Stampalija, Tamara/K-4900-2014 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); Federal funds from NICHD, NIH [HSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HSN275201300006C. NR 217 TC 5 Z9 5 U1 1 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD JAN PY 2014 VL 27 IS 2 BP 111 EP 121 DI 10.3109/14767058.2013.806894 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 269RL UT WOS:000328259500001 PM 23688338 ER PT J AU Chaiworapongsa, T Romero, R Korzeniewski, SJ Cortez, JM Pappas, A Tarca, AL Chaemsaithong, P Dong, Z Yeo, L Hassan, SS AF Chaiworapongsa, Tinnakorn Romero, Roberto Korzeniewski, Steven J. Cortez, Josef M. Pappas, Athina Tarca, Adi L. Chaemsaithong, Piya Dong, Zhong Yeo, Lami Hassan, Sonia S. TI Plasma concentrations of angiogenic/anti-angiogenic factors have prognostic value in women presenting with suspected preeclampsia to the obstetrical triage area: a prospective study SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Maternal outcome; neonatal outcome; placental growth factor; pregnancy; soluble endoglin; soluble vascular endothelial growth factor receptor-1 ID ELEVATED LIVER-ENZYMES; PREGNANCY-INDUCED HYPERTENSION; GROWTH-FACTOR RECEPTOR-1; LOW PLATELET COUNT; POSTERIOR LEUKOENCEPHALOPATHY SYNDROME; LATE-ONSET PREECLAMPSIA; FOR-GESTATIONAL-AGE; SERUM URIC-ACID; SOLUBLE ENDOGLIN; MATERNAL COMPLICATIONS AB Objective: To prospectively determine the prognostic value of maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng) and soluble vascular endothelial growth factor receptors-1 and -2 (sVEGFR-1 and -2) in identifying patients with suspected preeclampsia (PE), who require preterm delivery (PTD) or develop adverse outcomes. Study design: This prospective cohort study included 85 consecutive patients who presented to the obstetrical triage area at 20-36 weeks with a diagnosis of "rule out PE." Patients were classified as: 1) those who remained stable until term (n = 37); and 2) those who developed severe PE and required PTD (n = 48). Plasma concentrations of PlGF, sEng and sVEGFR-1 and -2 were determined by ELISA. Results: Patients with PlGF/sVEGFR-1 <= 0.05 multiples of the median (MoM) or PlGF/sEng <= 0.07 MoM were more likely to deliver preterm due to PE [adjusted odd ratio (aOR) 7.4 and 8.8], and to develop maternal (aOR 3.7 and 2.4) or neonatal complications (aOR 10.0 and 10.1). Among patients who presented <34 weeks of gestation, PlGF/sVEGFR-1 <= 0.035 MoM or PlGF/sEng <= 0.05 MoM had a sensitivity of 89% (16/18), specificity of 96% (24/25) and likelihood ratio for a positive test of 22 to identify patients who delivered within 2 weeks. The addition of the PlGF/sVEGFR-1 ratio to standard clinical tests improved the sensitivity at a fixed false-positive rate of 3% (p = 0.004) for the identification of patients who were delivered due to PE within 2 weeks. Among patients who had a plasma concentration of PlGF/sVEGFR-1 ratio <= 0.035 MoM, 0.036-0.34 MoM and >= 0.35 MoM, the rates of PTD <34 weeks were 94%, 27% and 7%, respectively. Conclusions: The determination of angiogenic/anti-angiogenic factors has prognostic value in patients presenting to the obstetrical triage area with suspected PE for the identification of those requiring preterm delivery and at risk for adverse maternal/neonatal outcomes. C1 [Chaiworapongsa, Tinnakorn; Romero, Roberto; Korzeniewski, Steven J.; Tarca, Adi L.; Chaemsaithong, Piya; Dong, Zhong; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Korzeniewski, Steven J.; Chaemsaithong, Piya; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet Gynecol, Detroit, MI 48201 USA. [Cortez, Josef M.; Pappas, Athina] Wayne State Univ, Dept Pediat, Detroit, MI 48201 USA. [Tarca, Adi L.] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. RP Chaiworapongsa, T (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM tchaiwor@med.wayne.edu; romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); Federal funds from NICHD, NIH [HHSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HHSN275201300006C. NR 123 TC 22 Z9 22 U1 1 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD JAN PY 2014 VL 27 IS 2 BP 132 EP 144 DI 10.3109/14767058.2013.806905 PG 13 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 269RL UT WOS:000328259500004 PM 23687930 ER PT S AU Perera, L Beard, WA Pedersen, LG Wilson, SH AF Perera, Lalith Beard, William A. Pedersen, Lee G. Wilson, Samuel H. BE Christov, CZ TI Applications of Quantum Mechanical/Molecular Mechanical Methods to the Chemical Insertion Step of DNA and RNA Polymerization SO METAL-CONTAINING ENZYMES SE Advances in Protein Chemistry and Structural Biology LA English DT Review; Book Chapter ID BIOMOLECULAR SIMULATION PROGRAM; NUCLEOTIDYL TRANSFER-REACTION; ERROR-FREE BYPASS; POLYMERASE-BETA; ACTIVE-SITE; CATALYTIC MECHANISM; CONFORMATIONAL-CHANGES; MOLECULAR-DYNAMICS; ENZYME CATALYSIS; QM/MM METHODS AB We review theoretical attempts to model the chemical insertion reactions of nucleoside triphosphates catalyzed by the nucleic acid polymerases using combined quantum mechanical/molecular mechanical methodology. Due to an existing excellent database of high-resolution X-ray crystal structures, the DNA polymerase beta system serves as a useful template for discussion and comparison. The convergence of structures of high-quality complexes and continued developments of theoretical techniques suggest a bright future for understanding the global features of nucleic acid polymerization. C1 [Perera, Lalith; Beard, William A.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Pedersen, Lee G.] Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC USA. RP Perera, L (reprint author), NIEHS, Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM pereral2@niehs.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [HL-06350]; NIEHS NIH HHS [Z01-ES043010, Z01-ES050158, Z01-ES050161] NR 77 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 1876-1623 BN 978-0-12-800012-0 J9 ADV PROTEIN CHEM STR JI Adv. Protein Chem. Struct. Biol. PY 2014 VL 97 BP 83 EP 113 DI 10.1016/bs.apcsb.2014.10.001 PG 31 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BF5HT UT WOS:000382006500005 PM 25458356 ER PT S AU Zhou, B Lin, MY Sun, T Knight, AL Sheng, ZH AF Zhou, Bing Lin, Mei-Yao Sun, Tao Knight, Adam L. Sheng, Zu-Hang BE Murphy, AN Chan, DC TI Characterization of Mitochondrial Transport in Neurons SO MITOCHONDRIAL FUNCTION SE Methods in Enzymology LA English DT Review; Book Chapter ID AMYOTROPHIC-LATERAL-SCLEROSIS; AXONAL-TRANSPORT; CORTICAL-NEURONS; IN-VIVO; SYNAPSES; TRAFFICKING; ENDOCYTOSIS; MORPHOLOGY; MECHANISM; MOTILITY AB Mitochondria are cellular power plants that supply ATP to power various biological activities essential for neuronal growth, survival, and function. Due to extremely varied morphological features, neurons face exceptional challenges to maintain energy homeostasis. Neurons require specialized mechanisms distributing mitochondria to distal synapses where energy is in high demand. Axons and synapses undergo activity-dependent remodeling, thereby altering mitochondrial distribution. The uniform microtubule polarity has made axons particularly useful for exploring mechanisms regulating mitochondrial transport. Mitochondria alter their motility under stress conditions or when their integrity is impaired. Therefore, research into the mechanisms regulating mitochondrial motility in healthy and diseased neurons is an important emerging frontier in neurobiology. In this chapter, we discuss the current protocols in the characterization of axonal mitochondrial transport in primary neuron cultures isolated from embryonic rats and adult mice. We also briefly discuss new procedures developed in our lab in analyzing mitochondrial motility patterns at presynaptic terminals and evaluate their impact on synaptic vesicle release. C1 [Zhou, Bing; Lin, Mei-Yao; Sun, Tao; Knight, Adam L.; Sheng, Zu-Hang] NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU Intramural NIH HHS NR 36 TC 0 Z9 0 U1 4 U2 5 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 BN 978-0-12-801415-8 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2014 VL 547 BP 75 EP 96 DI 10.1016/B978-0-12-801415-8.00005-9 PG 22 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Cell Biology; Neurosciences SC Biochemistry & Molecular Biology; Cell Biology; Neurosciences & Neurology GA BF4XK UT WOS:000381757800006 PM 25416353 ER PT S AU Holmes-Hampton, GP Tong, WH Rouault, TA AF Holmes-Hampton, Gregory P. Tong, Wing-Hang Rouault, Tracey A. BE Murphy, AN Chan, DC TI Biochemical and Biophysical Methods for Studying Mitochondrial Iron Metabolism SO MITOCHONDRIAL FUNCTION SE Methods in Enzymology LA English DT Review; Book Chapter ID RAY-FLUORESCENCE MICROSCOPY; PERFUSION-TURNBULL METHODS; ELECTRON-PARAMAGNETIC-RES; CLUSTER SCAFFOLD PROTEIN; FIELD EPR SPECTROSCOPY; HUMAN JURKAT CELLS; FRIEDREICHS-ATAXIA; FERROUS IRON; PAROXYSMAL MYOGLOBINURIA; SUCCINATE-DEHYDROGENASE AB Iron is a heavily utilized element in organisms and numerous mechanisms accordingly regulate the trafficking, metabolism, and storage of iron. Despite the high regulation of iron homeostasis, several diseases and mutations can lead to the misregulation and often accumulation of iron in the cytosol or mitochondria of tissues. To understand the genesis of iron overload, it is necessary to employ various techniques to quantify iron in organisms and mitochondria. This chapter discusses techniques for determining the total iron content of tissue samples, ranging from colorimetric determination of iron concentrations, atomic absorption spectroscopy, inductively coupled plasma-optical emission spectroscopy, and inductively coupled plasma-mass spectrometry. In addition, we discuss in situ techniques for analyzing iron including electron microscopic non-heme iron histochemistry, electron energy loss spectroscopy, synchrotron X-ray fluorescence imaging, and confocal Raman microscopy. Finally, we discuss biophysical methods for studying iron in isolated mitochondria, including ultraviolet-visible, electron paramagnetic resonance, X-ray absorbance, and Mossbauer spectroscopies. This chapter should aid researchers to select and interpret mitochondrial iron quantifications. C1 [Holmes-Hampton, Gregory P.; Tong, Wing-Hang; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov FU Intramural NIH HHS NR 146 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 BN 978-0-12-801415-8 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2014 VL 547 BP 275 EP 307 DI 10.1016/B978-0-12-801415-8.00015-1 PG 33 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Cell Biology; Neurosciences SC Biochemistry & Molecular Biology; Cell Biology; Neurosciences & Neurology GA BF4XK UT WOS:000381757800016 PM 25416363 ER PT J AU Geguchadze, R Wang, ZM Zourelias, L Perez-Riveros, P Edwards, PC Machen, L Passineau, MJ AF Geguchadze, Ramaz Wang, Zhimin Zourelias, Lee Perez-Riveros, Paola Edwards, Paul C. Machen, Laurie Passineau, Michael J. TI Proteomic profiling of salivary gland after nonviral gene transfer mediated by conventional plasmids and minicircles SO MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT LA English DT Article AB In this study, we compared gene transfer efficiency and host response to ultrasound-assisted, nonviral gene transfer with a conventional plasmid and a minicircle vector in the submandibular salivary glands of mice. Initially, we looked at gene transfer efficiency with equimolar amounts of the plasmid and minicircle vectors, corroborating an earlier report showing that minicircle is more efficient in the context of a physical method of gene transfer. We then sought to characterize the physiological response of the salivary gland to exogenous gene transfer using global proteomic profiling. Somewhat surprisingly, we found that sonoporation alone, without a gene transfer vector present, had virtually no effect on the salivary gland proteome. However, when a plasmid vector was used, we observed profound perturbations of the salivary gland proteome that compared in magnitude to that seen in a previous report after high doses of adeno-associated virus. Finally, we found that gene transfer with a minicircle induces only minor proteomic alterations that were similar to sonoporation alone. Using mass spectrometry, we assigned protein IDs to 218 gel spots that differed between plasmid and minicircle. Bioinformatic analysis of these proteins demonstrated convergence on 68 known protein interaction pathways, most notably those associated with innate immunity, cellular stress, and morphogenesis. C1 [Geguchadze, Ramaz; Wang, Zhimin; Zourelias, Lee; Machen, Laurie; Passineau, Michael J.] Allegheny Hlth Network, Gene Therapy Program, Pittsburgh, PA 15212 USA. [Perez-Riveros, Paola] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. [Edwards, Paul C.] Indiana Univ, Sch Dent, Dept Oral Pathol Med & Radiol, Indianapolis, IN USA. RP Passineau, MJ (reprint author), Allegheny Hlth Network, Gene Therapy Program, Pittsburgh, PA 15212 USA. EM mpassine@wpahs.org OI Edwards, Paul/0000-0001-7884-8480 FU National Institutes of Health grants [5R03DE020118, 1R01DE022973] FX This work was supported by National Institutes of Health grants 5R03DE020118 and 1R01DE022973 (to M.J.P.). The authors wish to thank Alexander Zambon and Nathan Salomonis for their assistance with the GO-Elite pathway analysis software. NR 31 TC 4 Z9 4 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2329-0501 J9 MOL THER-METH CLIN D JI Mol.Ther.-Methods Clin. Dev. PY 2014 VL 1 AR UNSP 14007 DI 10.1038/mtm.2014.7 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA V46YD UT WOS:000209918600019 PM 25414909 ER PT J AU Wu, CF Hong, SG Winkler, T Spencer, DM Jares, A Ichwan, B Nicolae, A Guo, V Larochelle, A Dunbar, CE AF Wu, Chuanfeng Hong, So Gun Winkler, Thomas Spencer, David M. Jares, Alexander Ichwan, Brian Nicolae, Alina Guo, Vicky Larochelle, Andre Dunbar, Cynthia E. TI Development of an inducible caspase-9 safety switch for pluripotent stem cell-based therapies SO MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT LA English DT Article AB Induced pluripotent stem cell (iPSC) therapies offer a promising path for patient-specific regenerative medicine. However, tumor formation from residual undifferentiated iPSC or transformation of iPSC or their derivatives is a risk. Inclusion of a suicide gene is one approach to risk mitigation. We introduced a dimerizable-"inducible caspase-9" (iCasp9) suicide gene into mouse iPSC (miPSC) and rhesus iPSC (RhiPSC) via a lentivirus, driving expression from either a cytomegalovirus (CMV), elongation factor-1 alpha (EF1 alpha) or pluripotency-specific EOS-C(3+) promoter. Exposure of the iPSC to the synthetic chemical dimerizer, AP1903, in vitro induced effective apoptosis in EF1 alpha-iCasp9-expressing (EF1 alpha)-iPSC, with less effective killing of EOS-C(3+)-iPSC and CMV-iPSC, proportional to transgene expression in these cells. AP1903 treatment of EF1 alpha-iCasp9 miPSC in vitro delayed or prevented teratomas. AP1903 administration following subcutaneous or intravenous delivery of EF1 alpha-iPSC resulted in delayed teratoma progression but did not ablate tumors. EF1 alpha-iCasp9 expression was downregulated during in vitro and in vivo differentiation due to DNA methylation at CpG islands within the promoter, and methylation, and thus decreased expression, could be reversed by 5-azacytidine treatment. The level and stability of suicide gene expression will be important for the development of suicide gene strategies in iPSC regenerative medicine. C1 [Wu, Chuanfeng; Hong, So Gun; Winkler, Thomas; Jares, Alexander; Ichwan, Brian; Guo, Vicky; Larochelle, Andre; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Spencer, David M.] Bellicum Pharmaceut Inc, Houston, TX USA. [Nicolae, Alina] NCI, Lab Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov RI Wu, Chuanfeng/A-1109-2016; OI Jares, Alexander/0000-0001-8387-2362 FU National Heart, Lung, and Blood Institute (NHLBI); National Center for Regenerative Medicine (NCRM) FX This work was supported by intramural funding from the National Heart, Lung, and Blood Institute (NHLBI) and the National Center for Regenerative Medicine (NCRM). We thank Jichun Chen and Marie Desierto from the Hematology Branch, and ZuXi Yu from the NHLBI pathology core facility for their assistance with teratoma assays, and Vivian Diaz from NIH Mouse Imaging Facility (MIF) for GFP live cell imaging. We thank Gianpietro Dotti for providing the pCDH-iCasp9-2A-h. CD19 lentiviral vector. D.M.S. is employed by Bellicum Pharmaceuticals. The other authors declare no conflict of interest. NR 48 TC 12 Z9 12 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2329-0501 J9 MOL THER-METH CLIN D JI Mol.Ther.-Methods Clin. Dev. PY 2014 VL 1 AR UNSP 14053 DI 10.1038/mtm.2014.53 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA V46YD UT WOS:000209918600065 PM 26052521 ER PT S AU Pryde, DC Groft, SC AF Pryde, David C. Groft, Stephen C. BE Pryde, DC Palmer, MJ TI Definitions, History and Regulatory Framework for Rare Diseases and Orphan Drugs SO ORPHAN DRUGS AND RARE DISEASES SE RSC Drug Discovery Series LA English DT Article; Book Chapter ID INNOVATION; GENE C1 [Pryde, David C.] Pfizer Neusentis, Worldwide Med Chem, Portway Bldg,Granta Pk, Cambridge CB21 6GS, England. [Groft, Stephen C.] NIH, Natl Ctr Adv Translat Sci, Off Rare Dis Res, Bethesda, MD 20892 USA. RP Pryde, DC (reprint author), Pfizer Neusentis, Worldwide Med Chem, Portway Bldg,Granta Pk, Cambridge CB21 6GS, England. EM David.Pryde@pfizer.com NR 31 TC 0 Z9 0 U1 0 U2 0 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, CAMBRIDGE CB4 4WF, CAMBS, ENGLAND SN 2041-3203 BN 978-1-78262-420-2; 978-1-84973-806-4 J9 RSC DRUG DISCOV JI RSC Drug Discov. PY 2014 VL 38 BP 3 EP 31 D2 10.1039/9781782624202 PG 29 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BG0WH UT WOS:000386536600003 ER PT B AU Merril, CR AF Merril, Carl R. BE Borysowski, J Miedzybrodzki, R Gorski, A TI Phage Therapy Current Research and Applications Foreword SO PHAGE THERAPY: CURRENT RESEARCH AND APPLICATIONS LA English DT Editorial Material; Book Chapter ID BACTERIOPHAGE C1 [Merril, Carl R.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Merril, CR (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 2 U2 2 PU CAISTER ACADEMIC PRESS PI WYMONDHAM PA 32 HEWITTS LANE, WYMONDHAM NR 18 0JA, ENGLAND BN 978-1-908230-74-4; 978-1-908230-40-9 PY 2014 BP XI EP XII PG 2 WC Biotechnology & Applied Microbiology; Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA BF7MX UT WOS:000384251600001 ER PT S AU Zhang, JW Ferre-D'Amare, AR AF Zhang, Jinwei Ferre-D'Amare, Adrian R. BE BurkeAguero, DH TI A Flexible, Scalable Method for Preparation of Homogeneous Aminoacylated tRNAs SO RIBOSWITCH DISCOVERY, STRUCTURE AND FUNCTION SE Methods in Enzymology LA English DT Review; Book Chapter ID MISACYLATED TRANSFER-RNAS; EF-TU; CRYSTAL-STRUCTURE; PROTECTING GROUP; AMINO-ACID; RIBOZYME; MUTANTS; COMPLEX; DOMAIN; GTP AB Transfer RNAs (tRNAs) are cellular courier molecules that decipher the genetic code in messenger RNAs and enable the transfer of appropriate esterified amino acids to the growing peptide chain. The preparation of biophysical quantities of homogeneous aminoacylated tRNAs has remained a significant technical challenge. This is primarily due to the difficulty in removing contaminating nonaminoacylated tRNAs that are have very similar properties overall, as well as the hydrolytic instability of the aminoacyl linkage. We describe a flexible, scalable method to prepare homogeneous aminoacylated tRNAs that is also broadly compatible with mutant, misacylated, or otherwise aberrant tRNAs and other RNAs. This method combines ribozyme-mediated aminoacylation with reversible N-pentenoylation of the esterified amino acid, which not only protects against spontaneous deacylation but also provides a hydrophobic purification handle. This protocol makes it straightforward to produce biophysical quantities of natural and unnatural aminoacylated tRNAs and has proven essential for mechanistic investigations of the T-box riboswitches. C1 [Zhang, Jinwei; Ferre-D'Amare, Adrian R.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU Intramural NIH HHS [Z99 HL999999, ZIA HL006102-04, ZIA HL006150-03, ZIA HL006188-01] NR 24 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 BN 978-0-12-801122-5 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2014 VL 549 BP 105 EP 113 DI 10.1016/B978-0-12-801122-5.00005-2 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BF4XX UT WOS:000381763600006 PM 25432746 ER PT S AU Warner, KD Ferre-D'Amare, AR AF Warner, Katherine Deigan Ferre-D'Amare, Adrian R. BE BurkeAguero, DH TI Crystallographic Analysis of TPP Riboswitch Binding by Small-Molecule Ligands Discovered Through Fragment-Based Drug Discovery Approaches SO RIBOSWITCH DISCOVERY, STRUCTURE AND FUNCTION SE Methods in Enzymology LA English DT Review; Book Chapter ID STRUCTURAL BASIS; GLMS RIBOZYME; RNA; TOOL; CRYOCRYSTALLOGRAPHY AB Riboswitches are structured mRNA elements that regulate gene expression in response to metabolite or second-messenger binding and are promising targets for drug discovery. Fragment-based drug discovery methods have identified weakly binding small molecule "fragments" that bind a thiamine pyrophosphate (TPP) riboswitch. However, these fragments require substantial chemical elaboration into more potent, drug-like molecules. Structure determination of the fragments bound to the riboswitch is the necessary next step. In this chapter, we describe the methods for co-crystallization and structure determination of fragment-bound TPP riboswitch structures. We focus on considerations for screening crystallization conditions across multiple crystal forms and provide guidance for building the fragment into the refined crystallographic model. These methods are broadly applicable for crystallographic analyses of any small molecules that bind structured RNAs. C1 [Warner, Katherine Deigan; Ferre-D'Amare, Adrian R.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Warner, Katherine Deigan] Univ Cambridge, Dept Chem, Cambridge, England. RP Ferre-D'Amare, AR (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU Intramural NIH HHS [Z99 HL999999, ZIA HL006102-04, ZIA HL006150-03, ZIA HL006188-01] NR 33 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 BN 978-0-12-801122-5 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2014 VL 549 BP 221 EP 233 DI 10.1016/B978-0-12-801122-5.00010-6 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BF4XX UT WOS:000381763600011 PM 25432751 ER PT J AU Gong, BS Wang, C Su, ZQ Hong, HX Thierry-Mieg, J Thierry-Mieg, D Shi, LM Auerbach, SS Tong, WD Xu, J AF Gong, Binsheng Wang, Charles Su, Zhenqiang Hong, Huixiao Thierry-Mieg, Jean Thierry-Mieg, Danielle Shi, Leming Auerbach, Scott S. Tong, Weida Xu, Joshua TI Transcriptomic profiling of rat liver samples in a comprehensive study design by RNA-Seq SO SCIENTIFIC DATA LA English DT Article AB RNA-Seq provides the capability to characterize the entire transcriptome in multiple levels including gene expression, allele specific expression, alternative splicing, fusion gene detection, and etc. The US FDA-led SEQC (i.e., MAQC-III) project conducted a comprehensive study focused on the transcriptome profiling of rat liver samples treated with 27 chemicals to evaluate the utility of RNA-Seq in safety assessment and toxicity mechanism elucidation. The chemicals represented multiple chemogenomic modes of action (MOA) and exhibited varying degrees of transcriptional response. The paired-end 100 bp sequencing data were generated using Illumina HiScanSQ and/or HiSeq 2000. In addition to the core study, six animals (i.e., three aflatoxin B1 treated rats and three vehicle control rats) were sequenced three times, with two separate library preparations on two sequencing machines. This large toxicogenomics dataset can serve as a resource to characterize various aspects of transcriptomic changes (e.g., alternative splicing) that are byproduct of chemical perturbation. C1 [Gong, Binsheng; Su, Zhenqiang; Hong, Huixiao; Shi, Leming; Tong, Weida; Xu, Joshua] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Wang, Charles] Loma Linda Univ, Sch Med, Ctr Genom, Loma Linda, CA 92350 USA. [Wang, Charles] Loma Linda Univ, Sch Med, Div Microbiol & Mol Genet, Loma Linda, CA 92350 USA. [Thierry-Mieg, Jean; Thierry-Mieg, Danielle] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20814 USA. [Shi, Leming] Fudan Univ, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. [Shi, Leming] Fudan Univ, MOE Key Lab Contemporary Anthropol, Sch Life Sci, Shanghai 201203, Peoples R China. [Shi, Leming] Fudan Univ, MOE Key Lab Contemporary Anthropol, Sch Pharm, Shanghai 201203, Peoples R China. [Auerbach, Scott S.] NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. RP Auerbach, SS (reprint author), NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM auerbachs@niehs.nih.gov; weida.tong@fda.hhs.gov; zhihua.xu@fda.hhs.gov RI THIERRY-MIEG, Jean/F-1975-2017 OI THIERRY-MIEG, Jean/0000-0002-0396-6789 FU Intramural Research Program of the NIH, National Library of Medicine FX This dataset was generated for the SEQC toxicogenomics study and the related research manuscript8. The authors would like to thank Philippe Rocca-Serra for his guidance and assistance in sample metadata collection and coding with ISA-TAB. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. The views presented in this article do not necessarily reflect current or future opinion or policy of the US Food and Drug Administration. Any mention of commercial products is for clarification and not intended as an endorsement. NR 24 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PY 2014 VL 1 AR 140021 DI 10.1038/sdata.2014.21 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V45VG UT WOS:000209843500014 ER PT J AU Harpaz, R Odgers, D Gaskin, G DuMouchel, W Winnenburg, R Bodenreider, O Ripple, A Szarfman, A Sorbello, A Horvitz, E White, RW Shah, NH AF Harpaz, Rave Odgers, David Gaskin, Greg DuMouchel, William Winnenburg, Rainer Bodenreider, Olivier Ripple, Anna Szarfman, Ana Sorbello, Alfred Horvitz, Eric White, Ryen W. Shah, Nigam H. TI A time-indexed reference standard of adverse drug reactions SO SCIENTIFIC DATA LA English DT Article AB Undetected adverse drug reactions (ADRs) pose a major burden on the health system. Data mining methodologies designed to identify signals of novel ADRs are of deep importance for drug safety surveillance. The development and evaluation of these methodologies requires proper reference benchmarks. While progress has recently been made in developing such benchmarks, our understanding of the performance characteristics of the data mining methodologies is limited because existing benchmarks do not support prospective performance evaluations. We address this shortcoming by providing a reference standard to support prospective performance evaluations. The reference standard was systematically curated from drug labeling revisions, such as new warnings, which were issued and communicated by the US Food and Drug Administration in 2013. The reference standard includes 62 positive test cases and 75 negative controls, and covers 44 drugs and 38 events. We provide usage guidance and empirical support for the reference standard by applying it to analyze two data sources commonly mined for drug safety surveillance. C1 [Harpaz, Rave; Odgers, David; Gaskin, Greg; Shah, Nigam H.] Stanford Univ, Ctr Biomed Informat Res, Stanford, CA 94305 USA. [DuMouchel, William] Oracle Hlth Sci, Bedford, MA 01730 USA. [Winnenburg, Rainer; Bodenreider, Olivier; Ripple, Anna] NIH, Natl Lib Med, Bethesda, MD 20894 USA. [Szarfman, Ana; Sorbello, Alfred] US FDA, Silver Spring, MD 20993 USA. [Horvitz, Eric; White, Ryen W.] Microsoft Res, Redmond, WA 98052 USA. RP Harpaz, R (reprint author), Stanford Univ, Ctr Biomed Informat Res, Stanford, CA 94305 USA. EM rharpaz@stanford.edu FU NIH [U54-HG004028]; NIGMS [GM101430- 01A1]; Med Scholars fellowship from the Stanford School of Medicine; Intramural Research Program of the NIH, National Library of Medicine; Microsoft Research FX R.H. and N.H.S. acknowledge support by NIH grant U54-HG004028 for the National Center for Biomedical Ontology and by NIGMS grant GM101430- 01A1. D.O. acknowledges support by NIGMS grant GM101430- 01A1. G.G. is supported by a Med Scholars fellowship from the Stanford School of Medicine. This work was supported in part by the Intramural Research Program of the NIH, National Library of Medicine, and Microsoft Research. NR 29 TC 6 Z9 6 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PY 2014 VL 1 AR 140043 DI 10.1038/sdata.2014.43 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V45VG UT WOS:000209843500039 ER PT J AU Messina, JP Brady, OJ Pigott, DM Brownstein, JS Hoen, AG Hay, SI AF Messina, Jane P. Brady, Oliver J. Pigott, David M. Brownstein, John S. Hoen, Anne G. Hay, Simon I. TI A global compendium of human dengue virus occurrence SO SCIENTIFIC DATA LA English DT Article AB A global geographic database of human dengue virus occurrence was produced to generate a global risk map and associated burden estimates(1). Herein we present the database, which comprises occurrence data linked to point or polygon locations, derived from peer-reviewed literature and case reports as well as informal online sources. Entries date from 1960 to 2012. We describe all data collection processes in full, as well as geo-positioning, database management and quality-control procedures. This is the most comprehensive database of confirmed human dengue infection to-date, consisting of 8,309 geo-positioned occurrences in total. C1 [Messina, Jane P.; Brady, Oliver J.; Pigott, David M.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, South Pk Rd, Oxford OX1 3PS, England. [Brownstein, John S.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Brownstein, John S.] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA 02115 USA. [Hoen, Anne G.] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Hanover, NH 03755 USA. [Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Messina, JP (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, South Pk Rd, Oxford OX1 3PS, England. EM jane.messina@zoo.ox.ac.uk OI Brady, Oliver/0000-0002-3235-2129; Hay, Simon/0000-0002-0611-7272 FU Wellcome Trust [095066]; BBSRC Industrial CASE studentship; International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS) [21803]; Sir Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX S.I.H. is funded by a Senior Research Fellowship from the Wellcome Trust (095066). O.J.B. is funded by a BBSRC Industrial CASE studentship. J.P.M. is funded by the International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS, 21803, http://www.idams.eu). D.M.P. is funded by a Sir Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford. S.I.H. also acknowledges funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 6 TC 16 Z9 17 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PY 2014 VL 1 AR 140004 DI 10.1038/sdata.2014.4 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V45VG UT WOS:000209843500035 ER PT J AU Mylne, A Brady, OJ Huang, Z Pigott, DM Golding, N Kraemer, MUG Hay, SI AF Mylne, Adrian Brady, Oliver J. Huang, Zhi Pigott, David M. Golding, Nick Kraemer, Moritz U. G. Hay, Simon I. TI A comprehensive database of the geographic spread of past human Ebola outbreaks SO SCIENTIFIC DATA LA English DT Article AB Ebola is a zoonotic filovirus that has the potential to cause outbreaks of variable magnitude in human populations. This database collates our existing knowledge of all known human outbreaks of Ebola for the first time by extracting details of their suspected zoonotic origin and subsequent human-to-human spread from a range of published and non-published sources. In total, 22 unique Ebola outbreaks were identified, composed of 117 unique geographic transmission clusters. Details of the index case and geographic spread of secondary and imported cases were recorded as well as summaries of patient numbers and case fatality rates. A brief text summary describing suspected routes and means of spread for each outbreak was also included. While we cannot yet include the ongoing Guinea and DRC outbreaks until they are over, these data and compiled maps can be used to gain an improved understanding of the initial spread of past Ebola outbreaks and help evaluate surveillance and control guidelines for limiting the spread of future epidemics. C1 [Mylne, Adrian; Brady, Oliver J.; Huang, Zhi; Pigott, David M.; Golding, Nick; Kraemer, Moritz U. G.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Hay, SI (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. EM simon.hay@zoo.ox.ac.uk OI Golding, Nick/0000-0001-8916-5570; Brady, Oliver/0000-0002-3235-2129; Hay, Simon/0000-0002-0611-7272 FU BBSRC; Wellcome Trust [095066]; Bill & Melinda Gates Foundation [OPP1093011, OPP1106023, OPP1053338]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Sir Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford; German Academic Exchange Service (DAAD) FX O.J.B. is funded by a BBSRC studentship. S.I.H. is funded by a Senior Research Fellowship from the Wellcome Trust (#095066) which also supports A.M. and a grant from the Bill & Melinda Gates Foundation (#OPP1093011). S.I.H. would also like to acknowledge funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. Z.H. is funded by the Bill & Melinda Gates Foundation (#OPP1106023). D.M.P. is funded by a Sir Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford. N.G. is funded by a grant from the Bill & Melinda Gates Foundation (#OPP1053338). M.U.G.K. is funded by the German Academic Exchange Service (DAAD) through a graduate scholarship. Funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 13 Z9 13 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PY 2014 VL 1 AR 140042 DI 10.1038/sdata.2014.42 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V45VG UT WOS:000209843500038 ER PT J AU Pigott, DM Golding, N Messina, JP Battle, KE Duda, KA Balard, Y Bastien, P Pratlong, F Brownstein, JS Freifeld, CC Mekaru, SR Madoff', LC George, DB Myers, MF Hay, SI AF Pigott, David M. Golding, Nick Messina, Jane P. Battle, Katherine E. Duda, Kirsten A. Balard, Yves Bastien, Patrick Pratlong, Francine Brownstein, John S. Freifeld, Clark C. Mekaru, Sumiko R. Madoff', Lawrence C. George, Dylan B. Myers, Monica F. Hay, Simon I. TI Global database of leishmaniasis occurrence locations, 1960-2012 SO SCIENTIFIC DATA LA English DT Article AB The leishmaniases are neglected tropical diseases of significant public health importance. However, information on their global occurrence is disparate and sparse. This database represents an attempt to collate reported leishmaniasis occurrences from 1960 to 2012. Methodology for the collection of data from the literature, abstraction of case locations and data processing procedures are described here. In addition, strain archives and online data resources were accessed. A total of 12,563 spatially and temporally unique occurrences of both cutaneous and visceral leishmaniasis comprise the database, ranging in geographic scale from villages to states. These data can be used for a variety of mapping and spatial analyses covering multiple resolutions. C1 [Pigott, David M.; Golding, Nick; Messina, Jane P.; Battle, Katherine E.; Duda, Kirsten A.; Myers, Monica F.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Tinbergen Bldg,South Pk Rd, Oxford OX1 3PS, England. [Balard, Yves; Bastien, Patrick; Pratlong, Francine] Univ Montpellier I, UFR Med, F-34295 Montpellier, France. [Balard, Yves; Bastien, Patrick; Pratlong, Francine] CNRS 5290 IRD 224, UMR MiVEGEC, Lab Parasitol Mycol, F-34295 Montpellier, France. [Bastien, Patrick; Pratlong, Francine] CHRU Montpellier, Dept Parasitol Mycol, Ctr Natl Reference Leishmanioses, F-34295 Montpellier, France. [Brownstein, John S.; Freifeld, Clark C.; Mekaru, Sumiko R.] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA USA. [Brownstein, John S.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Madoff', Lawrence C.] Int Soc Infect Dis, ProMED Mail, Worcester, MA 01655 USA. [Madoff', Lawrence C.] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [George, Dylan B.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Pigott, DM (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Tinbergen Bldg,South Pk Rd, Oxford OX1 3PS, England. EM david.pigott@zoo.ox.ac.uk OI Hay, Simon/0000-0002-0611-7272; Golding, Nick/0000-0001-8916-5570; Battle, Katherine/0000-0003-2401-2615 FU Sir Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford; Wellcome trust [095066]; Bill & Melinda gates Foundation [OPP1053338]; International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS, European Commission 7th Framework Programme) [21803]; French Institut de Veille Sanitaire (InVS); NIH National Library of Medicine [R01LM010812] FX D.M.P. is funded by a Sir Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford. S.I.H. is funded by a Senior Research Fellowship from the Wellcome trust (095066) which also supports K.A.D. and K.E.B., N.G. is funded by a grant from the Bill & Melinda gates Foundation (#OPP1053338). J.P.M. is funded by, and S.I.H. acknowledges the support of, the International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS, European Commission 7th Framework Programme (#21803) http://www.idams.eu). Y.B., F.P. and P.B. acknowledge financial support by the French Institut de Veille Sanitaire (InVS). J.S.B., S.R.M. and C.F. acknowledge the funding from NIH National Library of Medicine (R01LM010812). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. S.I.H. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 20 TC 8 Z9 8 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PY 2014 VL 1 AR 140036 DI 10.1038/sdata.2014.36 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V45VG UT WOS:000209843500031 ER PT J AU Xu, J Su, ZQ Hong, HX Thierry-Mieg, J Thierry-Mieg, D Kreil, DP Mason, CE Tong, WD Shi, LM AF Xu, Joshua Su, Zhenqiang Hong, Huixiao Thierry-Mieg, Jean Thierry-Mieg, Danielle Kreil, David P. Mason, Christopher E. Tong, Weida Shi, Leming TI Cross-platform ultradeep transcriptomic profiling of human reference RNA samples by RNA-Seq SO SCIENTIFIC DATA LA English DT Article AB Whole-transcriptome sequencing ('RNA-Seq') has been drastically changing the scale and scope of genomic research. In order to fully understand the power and limitations of this technology, the US Food and Drug Administration (FDA) launched the third phase of the MicroArray Quality Control (MAQC-III) project, also known as the SEquencing Quality Control (SEQC) project. Using two well-established human reference RNA samples from the first phase of the MAQC project, three sequencing platforms were tested across more than ten sites with built-in truths including spike-in of external RNA controls (ERCC), titration data and qPCR verification. The SEQC project generated over 30 billion sequence reads representing the largest RNA-Seq data ever generated by a single project on individual RNA samples. This extraordinarily ultradeep transcriptomic data set and the known truths built into the study design provide many opportunities for further research and development to advance the improvement and application of RNA-Seq. C1 [Xu, Joshua; Su, Zhenqiang; Hong, Huixiao; Tong, Weida; Shi, Leming] US FDA, Div Bioinformat cs & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Thierry-Mieg, Jean; Thierry-Mieg, Danielle] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20814 USA. [Kreil, David P.] Boku Univ Vienna, Chair Bioinformat Res Grp, Vienna, Austria. [Kreil, David P.] Univ Warwick, Coventry CV4 7AL, W Midlands, England. [Mason, Christopher E.] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA. [Mason, Christopher E.] Weill Cornell Med Coll, Inst Computat Biomed, New York, NY 10021 USA. [Shi, Leming] Fudan Univ, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. [Shi, Leming] Fudan Univ, MOE Key Lab Contemporary Anthropol, Sch Life Sci, Shanghai 201203, Peoples R China. [Shi, Leming] Fudan Univ, MOE Key Lab Contemporary Anthropol, Sch Pharm, Shanghai 201203, Peoples R China. RP Tong, WD (reprint author), US FDA, Div Bioinformat cs & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM leming.shi@gmail.com RI THIERRY-MIEG, Jean/F-1975-2017 OI THIERRY-MIEG, Jean/0000-0002-0396-6789 FU Intramural Research Program of the NIH, National Library of Medicine FX The authors would like to acknowledge all the participants of the SEQC project, particularly the sequencing sites for generating the high-quality data set. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. The views presented in this article do not necessarily reflect current or future opinion or policy of the US Food and Drug Administration. Any mention of commercial products is for clarification and not intended as an endorsement. NR 22 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PY 2014 VL 1 AR 140020 DI 10.1038/sdata.2014.20 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V45VG UT WOS:000209843500013 ER PT B AU Lever, C Kaplan, R Burgess, N AF Lever, Colin Kaplan, Raphael Burgess, Neil BE Derdikman, D Knierim, JJ TI The Function of Oscillations in the Hippocampal Formation SO SPACE, TIME AND MEMORY IN THE HIPPOCAMPAL FORMATION LA English DT Article; Book Chapter ID IRREGULAR ACTIVITY STATE; LONG-TERM POTENTIATION; MEDIAL TEMPORAL-LOBE; HIGH-FREQUENCY OSCILLATIONS; GAMMA-BAND SYNCHRONIZATION; HUMAN SPATIAL NAVIGATION; HUMAN THETA-OSCILLATIONS; WORKING-MEMORY TASK; FREELY MOVING RATS; CAT VISUAL-CORTEX AB Some of the strongest experimental and computational links between oscillations and cognition concern the oscillations in the hippocampal formation supporting spatial and mnemonic processing. We review experimental and theoretical work concerning well-established hippocampal oscillations such as theta, gamma, and high-frequency ripples and how they relate to spatial, mnemonic, and anxiety-related representation and behaviour. We specifically consider the following computational roles for oscillations: organising processing into discrete chunks, as seen in encoding versus retrieval scheduling; ordinal and metric coding by oscillatory phase; temporal integration by oscillatory phase; and interregional communication. The literature on oscillations has typically been concerned with changes in band-specific power. Here, focusing on the theta oscillation, we summarise how key variables are linked not only to power but also to frequency and to coherence. We conclude that the hippocampal formation provides an invaluable model system for understanding the functional roles of neuronal oscillations and the interaction between oscillations. C1 [Lever, Colin] Univ Durham, Dept Psychol, Durham DH1 3LE, England. [Kaplan, Raphael] NIMH, Lab Brain & Cognit, Bethseda, MD USA. [Kaplan, Raphael; Burgess, Neil] UCL Inst Cognit Neurosci, London WC1N 3AR, England. [Burgess, Neil] UCL Inst Neurol, London WC1N 3BG, England. RP Lever, C (reprint author), Univ Durham, Dept Psychol, Durham DH1 3LE, England. EM colin.lever@durham.ac.uk; n.burgess@ucl.ac.uk NR 247 TC 7 Z9 7 U1 1 U2 1 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, A-1201 VIENNA, AUSTRIA BN 978-3-7091-1292-2; 978-3-7091-1291-5 PY 2014 BP 303 EP 350 DI 10.1007/978-3-7091-1292-2_12 D2 10.1007/978-3-7091-1292-2 PG 48 WC Neurosciences SC Neurosciences & Neurology GA BE6BF UT WOS:000373804400013 ER PT B AU Kuhn, JH Clawson, AN Radoshitzky, SR Wahl-Jensen, V Bavari, S Jahrling, PB AF Kuhn, Jens H. Clawson, Anna N. Radoshitzky, Sheli R. Wahl-Jensen, Victoria Bavari, Sina Jahrling, Peter B. BE Singh, SK Ruzek, D TI Viral Hemorrhagic Fevers History and Definitions SO VIRAL HEMORRHAGIC FEVERS LA English DT Article; Book Chapter ID LASSA FEVER; SWINE-FEVER; VIRUS C1 [Kuhn, Jens H.; Clawson, Anna N.; Wahl-Jensen, Victoria; Jahrling, Peter B.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 20852 USA. [Radoshitzky, Sheli R.; Bavari, Sina] US Army, Med Res Inst Infect Dis, Frederick, MD USA. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 20852 USA. NR 34 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-8431-7; 978-1-4398-8429-4 PY 2014 BP 3 EP 13 PG 11 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BF0KX UT WOS:000379007900003 ER PT B AU Huzella, LM Cann, JA Lackemeyer, M Wahl-Jensen, V Jahrling, PB Kuhn, JH Perry, DL AF Huzella, Louis M. Cann, Jennifer A. Lackemeyer, Matthew Wahl-Jensen, Victoria Jahrling, Peter B. Kuhn, Jens H. Perry, Donna L. BE Singh, SK Ruzek, D TI General Disease Pathology in Filoviral and Arenaviral Infections SO VIRAL HEMORRHAGIC FEVERS LA English DT Article; Book Chapter ID EBOLA HEMORRHAGIC-FEVER; MARBURG-VIRUS-DISEASE; I INTERFERON INDUCTION; CYNOMOLGUS MACAQUES; LASSA FEVER; ELECTRON-MICROSCOPY; ENDOTHELIAL-CELLS; RHESUS-MONKEY; PATHOGENESIS; ZAIRE C1 [Huzella, Louis M.; Cann, Jennifer A.; Lackemeyer, Matthew; Wahl-Jensen, Victoria; Jahrling, Peter B.; Kuhn, Jens H.; Perry, Donna L.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. RP Huzella, LM (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. NR 78 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-8431-7; 978-1-4398-8429-4 PY 2014 BP 15 EP 29 PG 15 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BF0KX UT WOS:000379007900004 ER PT B AU Shurtleff, AC Warren, TK Morrow, D Radoshitzky, SR Kuhn, JH Bavari, S AF Shurtleff, Amy C. Warren, Travis K. Morrow, Derek Radoshitzky, Sheli R. Kuhn, Jens H. Bavari, Sina BE Singh, SK Ruzek, D TI Animal Models of Viral Hemorrhagic Fevers SO VIRAL HEMORRHAGIC FEVERS LA English DT Article; Book Chapter ID EBOLA-VIRUS-INFECTION; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; KNOCKOUT MOUSE MODEL; GUINEA-PIGS; MARBURG VIRUS; LASSA-VIRUS; JUNIN VIRUS; CYNOMOLGUS MACAQUES; RHESUS MACAQUES; PERIPHERAL-BLOOD C1 [Shurtleff, Amy C.] US Army, Integrated Toxicol Div, Med Res Inst Infect Dis, Ft Detrick, MD USA. [Warren, Travis K.; Morrow, Derek; Radoshitzky, Sheli R.] US Army, Med Res Inst Infect Dis, Frederick, MD USA. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Bavari, Sina] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Shurtleff, AC (reprint author), US Army, Integrated Toxicol Div, Med Res Inst Infect Dis, Ft Detrick, MD USA. NR 132 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-8431-7; 978-1-4398-8429-4 PY 2014 BP 81 EP 98 PG 18 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BF0KX UT WOS:000379007900008 ER PT B AU Wahl-Jensen, V Radoshitzky, SR de Kok-Mercado, F Taylor, SL Bavari, S Jahrling, PB Kuhn, JH AF Wahl-Jensen, Victoria Radoshitzky, Sheli R. de Kok-Mercado, Fabian Taylor, Shannon L. Bavari, Sina Jahrling, Peter B. Kuhn, Jens H. BE Singh, SK Ruzek, D TI Role of Rodents and Bats in Human Viral Hemorrhagic Fevers SO VIRAL HEMORRHAGIC FEVERS LA English DT Article; Book Chapter ID HANTAVIRUS-PULMONARY-SYNDROME; GUANARITO VIRUS ARENAVIRIDAE; MASTOMYS-NATALENSIS; JUNIN VIRUS; EBOLA-VIRUS; RENAL SYNDROME; LASSA-VIRUS; WEST-AFRICA; MACHUPO VIRUS; CALOMYS-MUSCULINUS C1 [Wahl-Jensen, Victoria; de Kok-Mercado, Fabian; Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. [Radoshitzky, Sheli R.] US Army, Med Res Inst Infect Dis, Frederick, MD USA. [Taylor, Shannon L.] US Army, Div Virol, Med Res Inst Infect Dis, Ft Detrick, MD USA. [Bavari, Sina] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Wahl-Jensen, V (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. NR 156 TC 3 Z9 3 U1 2 U2 2 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-8431-7; 978-1-4398-8429-4 PY 2014 BP 99 EP 127 PG 29 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BF0KX UT WOS:000379007900009 ER PT B AU Risi, GF Arminio, T AF Risi, George F. Arminio, Thomas BE Singh, SK Ruzek, D TI Biosafety Issues and Clinical Management of Hemorrhagic Fever Virus Infections SO VIRAL HEMORRHAGIC FEVERS LA English DT Article; Book Chapter ID ANTICOAGULANT PROTEIN C2; FACTOR VIIA/TISSUE FACTOR; DENGUE SHOCK SYNDROME; RIFT-VALLEY FEVER; EBOLA-VIRUS; SEVERE SEPSIS; LASSA FEVER; POSTEXPOSURE PROTECTION; NEMATODE ANTICOAGULANT; NONHUMAN-PRIMATES C1 [Risi, George F.] NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. [Risi, George F.] Infect Dis Specialists PC, Missoula, MT USA. [Arminio, Thomas] NIH, Integrated Res Facil, Div Occupat Hlth & Safety, Rocky Mt Labs, Hamilton, MT USA. RP Risi, GF (reprint author), NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. NR 128 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-8431-7; 978-1-4398-8429-4 PY 2014 BP 129 EP 147 PG 19 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BF0KX UT WOS:000379007900010 ER PT B AU Radoshitzky, SR de Kok-Mercado, F Jahrling, PB Bavari, S Kuhn, JH AF Radoshitzky, Sheli R. de Kok-Mercado, Fabian Jahrling, Peter B. Bavari, Sina Kuhn, Jens H. BE Singh, SK Ruzek, D TI Bolivian Hemorrhagic Fever SO VIRAL HEMORRHAGIC FEVERS LA English DT Article; Book Chapter ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; NEW-WORLD ARENAVIRUSES; FINGER-Z-PROTEIN; VIRAL-RNA SYNTHESIS; I INTERFERON INDUCTION; STABLE SIGNAL PEPTIDE; PH-INDUCED ACTIVATION; GLYCOPROTEIN GP-C; JUNIN VIRUS; LASSA-VIRUS C1 [Radoshitzky, Sheli R.] US Army, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [de Kok-Mercado, Fabian; Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Bavari, Sina] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Radoshitzky, SR (reprint author), US Army, Med Res Inst Infect Dis, Frederick, MD 21702 USA. NR 162 TC 1 Z9 1 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-8431-7; 978-1-4398-8429-4 PY 2014 BP 339 EP 358 PG 20 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BF0KX UT WOS:000379007900021 ER PT B AU Radoshitzky, SR de Kok-Mercado, F Jahrling, PB Bavari, S Kuhn, JH AF Radoshitzky, Sheli R. de Kok-Mercado, Fabian Jahrling, Peter B. Bavari, Sina Kuhn, Jens H. BE Singh, SK Ruzek, D TI "Venezuelan" Hemorrhagic Fever SO VIRAL HEMORRHAGIC FEVERS LA English DT Article; Book Chapter ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; FINGER-Z-PROTEIN; NEW-WORLD ARENAVIRUSES; VIRAL-RNA SYNTHESIS; ENVELOPE GLYCOPROTEIN COMPLEX; STABLE SIGNAL PEPTIDE; PH-INDUCED ACTIVATION; LASSA-VIRUS; JUNIN VIRUS; GUANARITO VIRUS C1 [Radoshitzky, Sheli R.] US Army, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [de Kok-Mercado, Fabian; Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Bavari, Sina] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Radoshitzky, SR (reprint author), US Army, Med Res Inst Infect Dis, Frederick, MD 21702 USA. NR 148 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-8431-7; 978-1-4398-8429-4 PY 2014 BP 359 EP 377 PG 19 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BF0KX UT WOS:000379007900022 ER PT B AU Bradfute, SB Bavari, S Jahrling, PB Kuhn, JH AF Bradfute, Steven B. Bavari, Sina Jahrling, Peter B. Kuhn, Jens H. BE Singh, SK Ruzek, D TI Marburg Virus Disease SO VIRAL HEMORRHAGIC FEVERS LA English DT Article; Book Chapter ID PROTECTS NONHUMAN-PRIMATES; VERVET MONKEY DISEASE; ATTENUATED RECOMBINANT VACCINE; LAKE-VICTORIA-MARBURGVIRUS; HEMORRHAGIC-FEVER; EBOLA-VIRUS; FILOVIRUS INFECTION; MATRIX PROTEIN; GUINEA-PIGS; POSTEXPOSURE PROTECTION C1 [Bradfute, Steven B.] Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Bavari, Sina] US Army Med Res Inst Infect Dis, Ft Detrick, MD USA. [Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. RP Bradfute, SB (reprint author), Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. NR 115 TC 0 Z9 0 U1 1 U2 1 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-8431-7; 978-1-4398-8429-4 PY 2014 BP 457 EP 479 PG 23 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BF0KX UT WOS:000379007900027 ER PT J AU Yoshinaga, K PrabhuDas, M Davies, C White, K Caron, K Golos, T Fazleabas, A Paria, B Mor, G Paul, S Ye, XQ Dey, SK Spencer, T Roberts, RM AF Yoshinaga, Koji PrabhuDas, Mercy Davies, Christopher White, Kenneth Caron, Kathleen Golos, Thaddeus Fazleabas, Asgerally Paria, Bibhash Mor, Gil Paul, Soumen Ye, Xiaoqin Dey, Sudhansu K. Spencer, Thomas Roberts, Robert Michael TI Interdisciplinary Collaborative Team for Blastocyst Implantation Research: inception and perspectives SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Letter C1 [Yoshinaga, Koji] NICHD, Fertil & Infertil Branch, NIH, DHHS, Bethesda, MD 20892 USA. [PrabhuDas, Mercy] NIAID, Basic Immunol Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Davies, Christopher; White, Kenneth] Utah State Univ, Coll Agr, Dept Anim Dairy & Vet Sci, Logan, UT 84322 USA. [Caron, Kathleen] Univ N Carolina, Dept Cell & Mol Physiol, Chapel Hill, NC USA. [Golos, Thaddeus] Univ Wisconsin, Dept Comparat Biosci, Madison, WI 53706 USA. [Golos, Thaddeus] Univ Wisconsin, Dept Obstet & Gynecol, Madison, WI 53706 USA. [Fazleabas, Asgerally] Michigan State Univ, Coll Human Med, Dept Obstet Gynecol & Reprod Biol, Grand Rapids, MI USA. [Paria, Bibhash] Vanderbilt Univ, Sch Med, Dept Pediat Neonatol, Nashville, TN 37212 USA. [Mor, Gil] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Paul, Soumen] Univ Kansas, Med Ctr, Inst Reprod Biol & Med, Kansas City, KS 66103 USA. [Ye, Xiaoqin] Univ Georgia, Dept Physiol & Pharmacol, Athens, GA 30602 USA. [Dey, Sudhansu K.] Cincinnati Childrens Hosp Med Ctr, Dept Reprod Sci, Cincinnati, OH 45229 USA. [Spencer, Thomas] Washington State Univ, Dept Anim Sci, Pullman, WA 99164 USA. [Roberts, Robert Michael] Univ Missouri, Life Sci Ctr, Columbia, MO USA. RP Yoshinaga, K (reprint author), NICHD, Fertil & Infertil Branch, NIH, DHHS, Bldg 6100,Room 8B01, Bethesda, MD 20892 USA. EM ky6a@nih.gov OI Spencer, Thomas/0000-0003-2815-766X FU NICHD NIH HHS [R01 HD067759, R01 HD042280, R01 HD062546, R01 HD065939]; NIH HHS [P51 OD011106] NR 3 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 EI 1600-0897 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD JAN PY 2014 VL 71 IS 1 BP 1 EP 11 DI 10.1111/aji.12173 PG 11 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 267DO UT WOS:000328077100001 PM 24286196 ER PT J AU Castillo-Castrejon, M Meraz-Cruz, N Gomez-Lopez, N Flores-Pliego, A Beltran-Montoya, J Viveros-Alcaraz, M Vadillo-Ortega, F AF Castillo-Castrejon, Marisol Meraz-Cruz, Noemi Gomez-Lopez, Nardhy Flores-Pliego, Arturo Beltran-Montoya, Jorge Viveros-Alcaraz, Martin Vadillo-Ortega, Felipe TI Choriodecidual Cells From Term Human Pregnancies Show Distinctive Functional Properties Related to the Induction of Labor SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE Amniochorion; choriodecidua; fetal membranes; inflammation; labor ID PRETERM PARTURITION; FETAL MEMBRANES; LEUKOCYTES; MATRIX-METALLOPROTEINASE-9; MYOMETRIUM; CERVIX; INTERLEUKIN-8; AMNIOCHORION; EXPRESSION; CYTOKINES AB ProblemHuman parturition is associated with an intrauterine pro-inflammatory environment in the choriodecidua. Evidence that some mediators of this signaling cascade also elicit responses leading to labor prompted us to characterize the cellular sources of these mediators in the human choriodecidua. Method of studyLeukocyte-enriched preparations from human choriodecidua (ChL) and intervillous placental blood leukocytes (PL) were maintained in culture. Secretions of inflammatory cytokines, chemokines, and MMP-9 were documented. Leukocyte phenotype of ChL and PL was determined by flow cytometry using specific fluorochrome-conjugated antibodies. Results and ConclusionsChL showed a distinct pro-inflammatory secretion pattern of cytokines and chemokines when compared with PL, including higher amounts of TNF- and IL-6, and decreased secretions of IL-4 and IL-1ra. ChL also secreted more MIP-1 and MCP-1 and MMP-9 than PL. No significant differences were found in leukocytes subsets between compartments. Based on our findings, we propose that ChL isolated from fetal membranes at term are functionally different from PL and may collaborate to modulate the microenvironment linked to induction and progression of human labor. C1 [Castillo-Castrejon, Marisol; Meraz-Cruz, Noemi; Vadillo-Ortega, Felipe] Inst Nacl Med Genom, UNAM, Fac Med, Unidad Vinculac, Mexico City 14610, DF, Mexico. [Castillo-Castrejon, Marisol] Univ Nacl Autonoma Mexico, Programa Posgrad Ciencias Biol, Mexico City 04510, DF, Mexico. [Gomez-Lopez, Nardhy] Wayne State Univ, NICHD, Dept Obstet & Gynecol, Sch Med,Perinatol Res Branch,NIH, Detroit, MI USA. [Gomez-Lopez, Nardhy] Wayne State Univ, NICHD, Dept Immunol & Microbiol, Sch Med,Perinatol Res Branch,NIH, Detroit, MI USA. [Flores-Pliego, Arturo; Beltran-Montoya, Jorge] Inst Nacl Perinatol Isidro Espinosa de los Reyes, Mexico City, DF, Mexico. [Viveros-Alcaraz, Martin] Secretaria Salud DF, Hosp Materno Infantil Inguaran, Mexico City, DF, Mexico. RP Vadillo-Ortega, F (reprint author), Inst Nacl Med Genom, UNAM, Fac Med, Unidad Vinculac, Perifer Sur 4809, Mexico City 14610, DF, Mexico. EM felipe.vadillo@gmail.com RI Gomez-Lopez, Nardhy/R-7664-2016; OI Gomez-Lopez, Nardhy/0000-0002-3406-5262; Flores Pliego, Arturo/0000-0001-7876-6098 FU U.S. National Institute for Environmental Health Sciences [R01 ES016932]; National Institutes of Health; National Council of Science and Technology (CONACyT); U.N.A.M. [PAPIIT IA200612-2]; Consejo Nacional de Ciencia y Tecnologia (CONACyT) [203418]; Wayne State University Research Initiative in Maternal, Perinatal, and Child health (Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health) FX Support for this work was provided partially by Grant No: R01 ES016932 from the U.S. National Institute for Environmental Health Sciences and the National Institutes of Health. M.C.C. received a scholarship and financial support provided by the National Council of Science and Technology (CONACyT) and U.N.A.M. (PAPIIT IA200612-2). This paper constitutes a partial fulfillment of the Graduate Program in Biological Sciences of the National Autonomous University of Mexico (UNAM). Marisol Castillo-Castrejon acknowledges the scholarship provided by the Consejo Nacional de Ciencia y Tecnologia (CONACyT No. 203418). N.G-L is funded by Wayne State University Research Initiative in Maternal, Perinatal, and Child health (Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health). The authors thank Marie O'Neill for reviewing the manuscript prior to the submission. NR 38 TC 10 Z9 10 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 EI 1600-0897 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD JAN PY 2014 VL 71 IS 1 BP 86 EP 93 DI 10.1111/aji.12179 PG 8 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 267DO UT WOS:000328077100009 PM 24286217 ER PT J AU Schuck, P Gillis, RB Besong, TMD Almutairi, F Adams, GG Rowe, AJ Harding, SE AF Schuck, Peter Gillis, Richard B. Besong, Tabot M. D. Almutairi, Fahad Adams, Gary G. Rowe, Arthur J. Harding, Stephen E. TI SEDFIT-MSTAR: molecular weight and molecular weight distribution analysis of polymers by sedimentation equilibrium in the ultracentrifuge SO ANALYST LA English DT Article ID INTEGRAL-EQUATIONS; MUCUS GLYCOPROTEINS; INTERFERENCE OPTICS; SYSTEMS; MACROMOLECULES; COEFFICIENTS; PROGRAM; MODEL AB Sedimentation equilibrium (analytical ultracentrifugation) is one of the most inherently suitable methods for the determination of average molecular weights and molecular weight distributions of polymers, because of its absolute basis (no conformation assumptions) and inherent fractionation ability (without the need for columns or membranes and associated assumptions over inertness). With modern instrumentation it is also possible to run up to 21 samples simultaneously in a single run. Its application has been severely hampered because of difficulties in terms of baseline determination (incorporating estimation of the concentration at the air/solution meniscus) and complexity of the analysis procedures. We describe a new method for baseline determination based on a smart-smoothing principle and built into the highly popular platform SEDFIT for the analysis of the sedimentation behavior of natural and synthetic polymer materials. The SEDFIT-MSTAR procedure - which takes only a few minutes to perform - is tested with four synthetic data sets (including a significantly non-ideal system), a naturally occurring protein (human IgG1) and two naturally occurring carbohydrate polymers (pullulan and l-carrageenan) in terms of (i) weight average molecular weight for the whole distribution of species in the sample (ii) the variation in "point" average molecular weight with local concentration in the ultracentrifuge cell and (iii) molecular weight distribution. C1 [Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Gillis, Richard B.; Besong, Tabot M. D.; Almutairi, Fahad; Adams, Gary G.; Rowe, Arthur J.; Harding, Stephen E.] Univ Nottingham, Natl Ctr Macromol Hydrodynam, Sch Biosci, Loughborough LE12 5RD, England. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bldg 13,Rm 3N17,13 South Dr, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov; steve.harding@nottingham.ac.uk OI Schuck, Peter/0000-0002-8859-6966; Harding, Stephen E./0000-0002-7798-9692 FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health; Royal Society; Biotechnology and Biological Sciences Research Council FX This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (PS), the Royal Society (SEH) and the Biotechnology and Biological Sciences Research Council (SEH, GGA and RG). NR 38 TC 19 Z9 20 U1 0 U2 22 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0003-2654 EI 1364-5528 J9 ANALYST JI Analyst PY 2014 VL 139 IS 1 BP 79 EP 92 DI 10.1039/c3an01507f PG 14 WC Chemistry, Analytical SC Chemistry GA 259TE UT WOS:000327548400011 PM 24244936 ER PT J AU Qi, YC Li, XL Ma, XR Xu, LY Zhang, XF Jiang, XH Hong, J Cui, B Ning, G Wang, S AF Qi, Yicheng Li, Xiaoli Ma, Xinran Xu, Lingyan Zhang, Xiaofang Jiang, Xiaohua Hong, Jie Cui, Bin Ning, Guang Wang, Shu TI The role of osteopontin in the induction of the CD40 ligand in Graves' disease SO CLINICAL ENDOCRINOLOGY LA English DT Article ID AUTOIMMUNE THYROID-DISEASE; CELL-ACTIVATION; T-CELLS; EXPRESSION; RECEPTOR; TNF; PATHOGENESIS; GENERATION; CYTOKINE AB ObjectiveGraves' disease (GD) is a common autoimmune disease involved autoantibody production. Although we previously reported that osteopontin (OPN), a proinflammatory protein, affected development of GD through NF-B activation, little is known about the role of OPN in regulating immunoglobulin production in GD. CD40 Ligand (CD40L) is expressed on the surface of activated CD4+T cells and costimulates CD40 on B cells, stimulating production of immunoglobulins, a process which has been reported to play a vital role in immunological signalling transduction in several autoimmune diseases. This study sought to characterize the relationship between CD40L and GD development, as well as investigating the role of OPN in modulating immunoglobulin production in GD via CD40L. MethodsForty incident patients with GD, twenty-one patients with GD in remission and twenty-seven healthy controls were recruited. Both membrane-bound and soluble forms of CD40L were measured, and their correlations with clinical parameters were studied. In addition, correlation between OPN and CD40L level was also examined. Furthermore, we studied the regulatory effect of OPN on CD40L in CD4+T cells. ResultsWe demonstrated that the CD40L levels were enhanced in patients with GD and recovered in patients with GD in remission. CD40L levels correlated with clinical GD diagnostic parameters and OPN concentration. Moreover, human recombinant OPN and plasma samples from patients with GD increased CD40L expression, which could be significantly suppressed by OPN monoclonal antibody. In addition, CD40L antibody blocked the immunoglobulin production augmented by OPN in cultured peripheral blood mononuclear cells (PBMCs), isolated from patients with GD and healthy subjects. ConclusionThese results indicate that CD40L is induced by OPN and serves as the downstream effector of OPN for immunoglobulin production in GD development. C1 [Qi, Yicheng; Li, Xiaoli; Zhang, Xiaofang; Jiang, Xiaohua; Hong, Jie; Cui, Bin; Ning, Guang; Wang, Shu] Shanghai Jiao Tong Univ, Sch Med, Shanghai Clin Ctr Endocrine & Metab Dis, Dept Endocrinol & Metab,Ruijin Hosp, Shanghai 200025, Peoples R China. [Qi, Yicheng; Li, Xiaoli; Ma, Xinran; Xu, Lingyan; Cui, Bin; Ning, Guang; Wang, Shu] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Lab Endocrinol & Metab, Shanghai, Peoples R China. [Qi, Yicheng; Li, Xiaoli; Ma, Xinran; Xu, Lingyan; Cui, Bin; Ning, Guang; Wang, Shu] Shanghai Jiao Tong Univ, Sch Med, Shanghai 200025, Peoples R China. [Ma, Xinran; Xu, Lingyan] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Ning, G (reprint author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Clin Ctr Endocrine & Metab Dis, Rui Jin Hosp, 197 Rui Jin 2nd Rd, Shanghai 200025, Peoples R China. EM guangning@medmail.com.cn; shuwang9999@163.com FU National Natural Science Foundation of China [81270872]; Shanghai Municipal Natural Science Foundation [11495803400]; Sector Funds of Ministry of Health [201002002, 201202008]; National Key New Drug Creation and Manufacturing Program of Ministry of Science and Technology [2012ZX09303006-001] FX This study was supported by the grants from the National Natural Science Foundation of China (No. 81270872), Shanghai Municipal Natural Science Foundation (No. 11495803400), the Sector Funds of Ministry of Health (No. 201002002, No. 201202008) and The National Key New Drug Creation and Manufacturing Program of Ministry of Science and Technology (No. 2012ZX09303006-001). NR 35 TC 2 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD JAN PY 2014 VL 80 IS 1 BP 128 EP 134 DI 10.1111/cen.12229 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 263IJ UT WOS:000327801300018 PM 23617736 ER PT S AU O'Connell, KF Golden, A AF O'Connell, Kevin F. Golden, Andy BE Paddock, SW TI Confocal Imaging of the Microtubule Cytoskeleton in C. elegans Embryos and Germ Cells SO CONFOCAL MICROSCOPY: METHODS AND PROTOCOLS, 2ND EDITION SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Microtubules; Centrosomes; C. elegans; Immunofluorescence; GFP ID CAENORHABDITIS-ELEGANS; IMMUNOFLUORESCENCE MICROSCOPY; PROTEINS; NEMATODE; SPINDLE; SPERM AB The microtubule cytoskeleton plays important roles in a number of cellular processes including cell division, establishing and maintaining cell architecture and polarity, and intracellular trafficking. The identification and characterization of factors required for the proper functioning of the microtubule cytoskeleton have been aided by approaches that combine sensitive and rapid methods for high-resolution optical imaging, such as confocal microscopy, with the powerful genetics available in model organisms. Here we present methods for confocal imaging of live and fixed tissues of the nematode C. elegans, a model organism that has been employed with great success to study the microtubule cytoskeleton and its roles in cell division and cell polarity. C1 [O'Connell, Kevin F.; Golden, Andy] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP O'Connell, KF (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NR 16 TC 1 Z9 1 U1 0 U2 18 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-58829-351-0; 978-1-60761-847-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1075 BP 257 EP 272 DI 10.1007/978-1-60761-847-8_13 D2 10.1007/978-1-60761-847-8 PG 16 WC Microscopy; Radiology, Nuclear Medicine & Medical Imaging SC Microscopy; Radiology, Nuclear Medicine & Medical Imaging GA BIE12 UT WOS:000327800100014 PM 24052357 ER PT B AU Schlom, J Palena, C Gulley, JL Greiner, JW Tsang, KY Madan, RA Hodge, JW AF Schlom, Jeffrey Palena, Claudia Gulley, James L. Greiner, John W. Tsang, Kwong-Yok Madan, Ravi A. Hodge, James W. BE Lattime, EC Gerson, SL TI The Use of T Cell Costimulation to Enhance the Immunogenicity of Tumors SO GENE THERAPY OF CANCER: TRANSLATIONAL APPROACHES FROM PRECLINICAL STUDIES TO CLINICAL IMPLEMENTATION, 3RD EDITION LA English DT Article; Book Chapter DE Cancer; vaccines; poxviruses; TRICOM; immunotherapy; intratumoral vaccination; immunostimulatory molecules; costimulatory molecules ID RECOMBINANT VACCINIA VIRUS; DIVERSIFIED SUBCUTANEOUS/INTRATUMORAL VACCINATION; INDEPENDENT PROSTATE-CANCER; COLONY-STIMULATING FACTOR; LYMPHOCYTIC-LEUKEMIA CLL; ANTITUMOR IMMUNITY; PHASE-I; COMBINATION THERAPY; INTRATUMORAL VACCINATION; POXVIRUS VECTORS AB The use of recombinant poxviral vectors containing transgenes for tumor-associated antigens, along with transgenes directed against one or more costimulatory molecules or other immunostimulatory entities, as "conventional" vaccines for cancer therapy is now well documented in numerous preclinical studies and completed and ongoing clinical studies. This chapter reviews the status of the use of recombinant poxviral vectors containing multiple costimulatory molecules to enhance the immunogenicity of tumor cells. This can be accomplished by the ex vivo infection of tumor cells with recombinant poxviral vectors containing immunostimulatory molecules and the subsequent use of these tumor cells as vaccines or by the direct intratumoral injection of recombinant poxviral vectors containing immunostimulatory molecules. Preclinical studies have reported the successful use of these modalities to enhance both antigen-specific T cell responses and antitumor effects. To date, however, few clinical trials have actually been carried out to further evaluate these potentially efficacious modalities in the management of a range of cancers. C1 [Schlom, Jeffrey; Palena, Claudia; Gulley, James L.; Greiner, John W.; Tsang, Kwong-Yok; Madan, Ravi A.; Hodge, James W.] NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 NR 50 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-394632-4; 978-0-12-394295-1 PY 2014 BP 315 EP 334 DI 10.1016/B978-0-12-394295-1.00022-6 PG 20 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA BIE16 UT WOS:000327801200025 ER PT J AU Sneller, MC Lane, HC AF Sneller, M. C. Lane, H. C. TI HIV/IL-2 and EBV-associated lymphoproliferative diseases: cause and effect or coincidence? SO HIV MEDICINE LA English DT Editorial Material ID REGULATORY T-CELLS; HODGKIN-LYMPHOMA; HIV-INFECTION; INTERLEUKIN-2; THERAPY; AIDS C1 [Sneller, M. C.; Lane, H. C.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Sneller, MC (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 12 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-2662 EI 1468-1293 J9 HIV MED JI HIV Med. PD JAN PY 2014 VL 15 IS 1 BP 1 EP 2 DI 10.1111/hiv.12092 PG 2 WC Infectious Diseases SC Infectious Diseases GA 262LC UT WOS:000327735700001 PM 24299219 ER PT J AU Madan, I Than, NG Romero, R Chaemsaithong, P Miranda, J Tarca, AL Bhatti, G Draghici, S Yeo, L Mazor, M Hassan, SS Chaiworapongsa, T AF Madan, Ichchha Than, Nandor Gabor Romero, Roberto Chaemsaithong, Piya Miranda, Jezid Tarca, Adi L. Bhatti, Gaurav Draghici, Sorin Yeo, Lami Mazor, Moshe Hassan, Sonia S. Chaiworapongsa, Tinnakorn TI The peripheral whole-blood transcriptome of acute pyelonephritis in human pregnancy SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Adaptive immunity; high-dimensional biology; infection during pregnancy; innate immunity; mRNA; PAX gene; urinary tract infection ID RESPIRATORY-DISTRESS-SYNDROME; URINARY-TRACT-INFECTIONS; REGULATORY T-CELLS; UROPATHOGENIC ESCHERICHIA-COLI; GENERALIZED SHWARTZMAN REACTION; HOST-PATHOGEN INTERACTIONS; GENE-EXPRESSION PROFILES; MATERNAL-FETAL INTERFACE; MICROARRAY ANALYSIS; IMMUNE TOLERANCE AB Objective: Human pregnancy is characterized by activation of the innate immune response and suppression of adaptive immunity. The former is thought to provide protection against infection for the mother, and the latter, tolerance against paternal antigens expressed in fetal cells. Acute pyelonephritis is associated with an increased risk of acute respiratory distress syndrome and sepsis in pregnant (vs. nonpregnant) women. The objective of this study was to describe the gene expression profile (transcriptome) of maternal whole blood in acute pyelonephritis. Method: A case-control study was conducted to include pregnant women with acute pyelonephritis (n=15) and women with a normal pregnancy (n=34). Affymetrix HG-U133 Plus 2.0 arrays (Affymetrix, Santa Clara, CA, USA) were used for gene expression profiling. A linear model was used to test the association between the presence of pyelonephritis and gene expression levels while controlling for white blood cell count and gestational age. A fold change of 1.5 was considered significant at a false discovery rate of 0.1. A subset of differentially expressed genes (n=56) was tested with real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) (cases, n=19; controls, n=59). Gene ontology and pathway analyses were applied. Results: A total of 983 genes were differentially expressed in acute pyelonephritis: 457 were upregulated and 526 were downregulated. Significant enrichment of 300 biological processes and 63 molecular functions was found in pyelonephritis. Significantly impacted pathways in pyelonephritis included (a) cytokine-cytokine receptor interaction, (b) T-cell receptor signaling, (c) Jak-STAT signaling, and (d) complement and coagulation cascades. Of 56 genes tested by qRT-PCR, 48 (85.7%) had confirmation of differential expression. Conclusion: This is the first study of the transcriptomic signature of whole blood in pregnant women with acute pyelonephritis. Acute infection during pregnancy is associated with the increased expression of genes involved in innate immunity and the decreased expression of genes involved in lymphocyte function. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Madan, Ichchha; Than, Nandor Gabor; Romero, Roberto; Chaemsaithong, Piya; Miranda, Jezid; Tarca, Adi L.; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. [Madan, Ichchha; Than, Nandor Gabor; Romero, Roberto; Chaemsaithong, Piya; Miranda, Jezid; Tarca, Adi L.; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Madan, Ichchha; Than, Nandor Gabor; Chaemsaithong, Piya; Miranda, Jezid; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Tarca, Adi L.; Bhatti, Gaurav; Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. [Mazor, Moshe] Ben Gurion Univ Negev, Dept Obstet & Gynecol, Soroka Univ Med Ctr, Sch Med, IL-84105 Beer Sheva, Israel. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov OI Draghici, Sorin/0000-0002-0786-8377 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD/NIH [HHSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH), and, in part, with federal funds from NICHD/NIH under contract no. HHSN275201300006C. NR 148 TC 4 Z9 4 U1 1 U2 7 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD JAN PY 2014 VL 42 IS 1 BP 31 EP 53 DI 10.1515/jpm-2013-0085 PG 23 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 262VE UT WOS:000327765200005 PM 24293448 ER PT J AU Kent, EE Mitchell, SA Oakley-Girvan, I Arora, NK AF Kent, Erin E. Mitchell, Sandra A. Oakley-Girvan, Ingrid Arora, Neeraj K. TI The importance of symptom surveillance during follow-up care of leukemia, bladder, and colorectal cancer survivors SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Cancer survivorship; Symptom burden; Symptom management; Late effects; Health-related quality of life ID QUALITY-OF-LIFE; PATIENT-REPORTED OUTCOMES; LONG-TERM; MANAGEMENT; DIAGNOSIS; DISTRESS; SURGERY; BURDEN; SYSTEM; NEEDS AB We examined cancer survivors' experience of bothersome symptoms, association of symptom bother with health-related quality of life (HRQOL), survivors' perception of symptom care, and their symptom-related information needs. Using self-report survey measures, survivors of leukemia, bladder, or colorectal cancer who were 2-5 years post-diagnosis and received follow-up care in the past year (N = 623) provided information about the presence of bothersome symptoms, symptom-related information needs, adequacy of symptom-related care, and their physical and mental HRQOL. Multivariable statistical analyses were conducted to identify correlates of symptom bother, inadequate care, and symptom information needs and to examine the association between symptom bother and HRQOL. Twenty-eight percent of the 606 respondents experienced symptom bother in the past year (46 % of leukemia, 24 % of bladder, and 26 % of colorectal cancer survivors). Younger survivors, those of Hispanic ethnicity, with low income, those with recurrent cancer, and chemotherapy recipients were more likely to report symptom bother (all p < 0.05). Symptom bother was associated with lower physical and mental HRQOL (p < 0.001). While 92 % of survivors with symptoms discussed them with their follow-up care physician, 52 % of these reported receiving inadequate symptom care. Survivors reporting inadequate symptom care were 2.5 times as likely to identify symptom information needs compared to those who received adequate care (p < 0.05). One in four cancer survivors report symptoms 2-5 years post-diagnosis, and only half of these survivors receive adequate care to address those symptoms. Research that refines and tests symptom care interventions for this population is warranted. C1 [Kent, Erin E.; Mitchell, Sandra A.; Arora, Neeraj K.] Natl Canc Inst, Div Canc Control & Populat Sci, Outcomes Res Branch, Appl Res Program, Rockville, MD 20850 USA. [Oakley-Girvan, Ingrid] Canc Prevent Inst Calif, Fremont, CA 94538 USA. RP Kent, EE (reprint author), Natl Canc Inst, Div Canc Control & Populat Sci, Outcomes Res Branch, Appl Res Program, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM erin.kent@nih.gov FU National Cancer Institute [N01-PC-35136] FX Support for data collection was provided by the National Cancer Institute (Contract No. N01-PC-35136) as a contract to the Cancer Prevention Institute of California (formerly known as the Northern California Cancer Center). NR 46 TC 5 Z9 5 U1 3 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD JAN PY 2014 VL 22 IS 1 BP 163 EP 172 DI 10.1007/s00520-013-1961-x PG 10 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 264QL UT WOS:000327895000021 PM 24018909 ER PT J AU de Jong, LW Forsberg, LE Vidal, JS Sigurdsson, S Zijdenbos, AP Garcia, M Eiriksdottir, G Gudnason, V van Buchem, MA Launer, LJ AF de Jong, Laura W. Forsberg, Lars E. Vidal, Jean-Sebastien Sigurdsson, Sigurdur Zijdenbos, Alex P. Garcia, Melissa Eiriksdottir, Gudny Gudnason, Vilmundur van Buchem, Mark A. Launer, Lenore J. TI Different susceptibility of medial temporal lobe and basal ganglia atrophy rates to vascular risk factors SO NEUROBIOLOGY OF AGING LA English DT Article DE Medial temporal lobe; Hippocampus; Basal ganglia; Thalamus; Atrophy; Aging; Vascular risk factor ID SMALL-VESSEL DISEASE; APOLIPOPROTEIN-E GENOTYPE; VIRCHOW-ROBIN SPACES; WHITE-MATTER LESIONS; BLOOD-PRESSURE; ALZHEIMERS-DISEASE; HIPPOCAMPAL ATROPHY; AGES-REYKJAVIK; MIDLIFE; POPULATION AB Atrophy of the medial temporal lobe (MTL) and basal ganglia (BG) are characteristic of various neurodegenerative diseases in older people. In search of potentially modifiable factors that lead to atrophy in these structures, we studied the association of vascular risk factors with atrophy of the MTL and BG in 368 nondemented men and women (born, 1907-1935) who participated in the Age, Gene/Environment, Susceptibility-Reykjavik Study. A fully automated segmentation pipeline estimated volumes of the MTL and BG from whole-brain magnetic resonance imaging performed at baseline and 2.4 years later. Linear regression models showed higher systolic and diastolic blood pressures and the presence of Apo E epsilon 4 were independently associated with increased atrophy of the MTL but no association of vascular risk factors with atrophy of the BG. The different susceptibility of MTL and BG atrophy to the vascular risk factors suggests perfusion of the BG is relatively preserved when vascular risk factors are present. (C) 2014 Elsevier Inc. All rights reserved. C1 [de Jong, Laura W.; van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Forsberg, Lars E.] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Vidal, Jean-Sebastien] Hop Broca, AP HP, Serv Gerontol 2, Paris, France. [Vidal, Jean-Sebastien] Univ Paris 05, Sorbonne Paris 5, EA 4468, Paris, France. [Sigurdsson, Sigurdur; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Zijdenbos, Alex P.] Biospective Inc, Montreal, PQ, Canada. [Garcia, Melissa; Launer, Lenore J.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. RP Launer, LJ (reprint author), Lab Epidemiol Demog & Biometry, Gateway Bldg,3C309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov RI Gudnason, Vilmundur/K-6885-2015; Vidal, Jean-Sebastien/D-1941-2016 OI Gudnason, Vilmundur/0000-0001-5696-0084; Vidal, Jean-Sebastien/0000-0001-6770-0720 FU National Institutes of Health [N01-AG-1-2100]; National Institute on Aging Intramural Research Program,; Althingi (Icelandic Parliament); Netherlands Organisation for Health Research and Development (AGIKO) [92003536]; Dutch Genomics Initiative [NCHA 050-060-810]; Hjartavernd (Icelandic Heart Association) FX The authors thank the participants of the AGES-Reykjavik Study and the Icelandic Heart Association clinic staff for their invaluable contribution. This work was supported by the National Institutes of Health (N01-AG-1-2100), National Institute on Aging Intramural Research Program, the Hjartavernd (Icelandic Heart Association), and the Althingi (Icelandic Parliament). Dr de Jong is supported by the Netherlands Organisation for Health Research and Development (AGIKO grant number 92003536). Prof van Buchem is supported by an unrestricted grant from the Dutch Genomics Initiative (NCHA 050-060-810). NR 41 TC 5 Z9 5 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN PY 2014 VL 35 IS 1 BP 72 EP 78 DI 10.1016/j.neurobiolaging.2013.07.009 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 251AI UT WOS:000326898400008 PM 23992618 ER PT J AU Wang, Y Mattson, MP AF Wang, Yue Mattson, Mark P. TI L-type Ca2+ currents at CA1 synapses, but not CA3 or dentate granule neuron synapses, are increased in 3xTgAD mice in an age-dependent manner SO NEUROBIOLOGY OF AGING LA English DT Article DE 3xTgAD mice; Aging; L-type Ca2+ currents; CA1 ID ALZHEIMERS-DISEASE MICE; CALCIUM-CHANNEL BLOCKER; AMYLOID-BETA; MOUSE MODEL; HIPPOCAMPAL-NEURONS; SYNAPTIC PLASTICITY; PYRAMIDAL NEURONS; CELL-DEATH; IN-VIVO; NEUROFIBRILLARY TANGLES AB Abnormal neuronal excitability and impaired synaptic plasticity might occur before the degeneration and death of neurons in Alzheimer's disease (AD). To elucidate potential biophysical alterations underlying aberrant neuronal network activity in AD, we performed whole-cell patch clamp analyses of L-type (nifedipine-sensitive) Ca2+ currents (L-VGCC), 4-eaminopyridine-sensitive K+ currents, and AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid) and NMDA (N-methyl-D-aspartate) currents in CA1, CA3, and dentate granule neurons in hippocampal slices from young, middle-age, and old 3xTgAD mice and age-matched wild type mice. 3xTgAD mice develop progressive widespread accumulation of amyloid beta-peptide, and selective hyperphosphorylated tau pathology in hippocampal CA1 neurons, which are associated with cognitive deficits, but independent of overt neuronal degeneration. An age-related elevation of L-type Ca2+ channel current density occurred in CA1 neurons in 3xTgAD mice, but not in wild type mice, with the magnitude being significantly greater in older 3xTgAD mice. The NMDA current was also significantly elevated in CA1 neurons of old 3xTgAD mice compared with in old wild type mice. There were no differences in the amplitude of K+ or AMPA currents in CA1 neurons of 3xTgAD mice compared with wild type mice at any age. There were no significant differences in Ca2+, K+, AMPA, or NMDA currents in CA3 and dentate neurons from 3xTgAD mice compared with wild type mice at any age. Our results reveal an age-related increase of L-VGCC density in CA1 neurons, but not in CA3 or dentate granule neurons, of 3xTgAD mice. These findings suggest a potential contribution of altered L-VGCC to the selective vulnerability of CA1 neurons to tau pathology in the 3xTgAD mice and to their degeneration in AD patients. Published by Elsevier Inc. C1 [Wang, Yue; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Wang, Y (reprint author), NIA, Intramural Res Program, Dept Neurosci, Baltimore, MD 21224 USA. EM wangyu@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health. The authors thank the Comparative Medicine Section of the National Institute on Aging for technical support. NR 69 TC 12 Z9 13 U1 1 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN PY 2014 VL 35 IS 1 BP 88 EP 95 DI 10.1016/j.neurobiolaging.2013.07.007 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 251AI UT WOS:000326898400010 PM 23932880 ER PT B AU Walsh, ER Bolland, S AF Walsh, Elizabeth R. Bolland, Silvia BA Ackerman, ME Nimmerjahn, F BF Ackerman, ME Nimmerjahn, F TI B Cells Development, Differentiation, and Regulation by Fc gamma Receptor IIB in the Humoral Immune Response SO ANTIBODY FC: LINKING ADAPTIVE AND INNATE IMMUNITY LA English DT Article; Book Chapter ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; FOLLICULAR DENDRITIC CELLS; COATED PIT LOCALIZATION; RIIB-DEFICIENT MICE; MOUSE BONE-MARROW; GERMINAL-CENTER; T-CELLS; PLASMA-CELLS; LYMPH-NODES; SUBCAPSULAR SINUS C1 [Walsh, Elizabeth R.; Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Bolland, S (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. NR 100 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-394818-2; 978-0-12-394802-1 PY 2014 BP 115 EP 129 PG 15 WC Immunology SC Immunology GA BHU43 UT WOS:000326685100006 ER PT B AU Sun, P AF Sun, Peter BA Ackerman, ME Nimmerjahn, F BF Ackerman, ME Nimmerjahn, F TI Structural Recognition of Immunoglobulins by Fc gamma Receptors SO ANTIBODY FC: LINKING ADAPTIVE AND INNATE IMMUNITY LA English DT Article; Book Chapter ID C-REACTIVE PROTEIN; AMYLOID-P COMPONENT; SMALL NUCLEAR RIBONUCLEOPROTEIN; AFFINITY IGE RECEPTOR; EPSILON-RI-ALPHA; CRYSTAL-STRUCTURE; BINDING-SITE; 3-DIMENSIONAL STRUCTURE; RHEUMATOID-ARTHRITIS; EFFECTOR FUNCTIONS C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Sun, P (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. NR 89 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-394818-2; 978-0-12-394802-1 PY 2014 BP 131 EP 144 PG 14 WC Immunology SC Immunology GA BHU43 UT WOS:000326685100007 ER PT B AU Clatworthy, MR AF Clatworthy, Menna R. BA Ackerman, ME Nimmerjahn, F BF Ackerman, ME Nimmerjahn, F TI Fc gamma Receptor Polymorphisms and Susceptibility to Infection SO ANTIBODY FC: LINKING ADAPTIVE AND INNATE IMMUNITY LA English DT Article; Book Chapter ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; IIA CD32 POLYMORPHISM; C-REACTIVE PROTEIN; STREPTOCOCCUS-PNEUMONIAE INFECTION; PLASMODIUM-FALCIPARUM MALARIA; DENGUE VIRUS-INFECTION; ANTIBODY-DEPENDENT ENHANCEMENT; NECROSIS-FACTOR-ALPHA; MENINGOCOCCAL DISEASE; HUMAN MONOCYTES C1 [Clatworthy, Menna R.] Univ Cambridge, Sch Clin Med, Cambridge Inst Med Res, Cambridge, England. [Clatworthy, Menna R.] Univ Cambridge, Sch Clin Med, Dept Med, Cambridge, England. [Clatworthy, Menna R.] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Clatworthy, MR (reprint author), Univ Cambridge, Sch Clin Med, Cambridge Inst Med Res, Cambridge, England. NR 135 TC 2 Z9 2 U1 0 U2 5 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-394818-2; 978-0-12-394802-1 PY 2014 BP 217 EP 237 PG 21 WC Immunology SC Immunology GA BHU43 UT WOS:000326685100012 ER PT J AU Shah, NN Wayne, AS Wilson, WH AF Shah, Nirali N. Wayne, Alan S. Wilson, Wyndham H. BE Marcus, R Sweetenham, JW Williams, ME TI Burkitt and lymphoblastic lymphoma: clinical therapy and outcome SO LYMPHOMA: PATHOLOGY, DIAGNOSIS, AND TREATMENT, 2ND EDITION LA English DT Article; Book Chapter ID FRANKFURT-MUNSTER GROUP; CHILDRENS CANCER GROUP; HIGH-DOSE METHOTREXATE; CRANIAL RADIOTHERAPY; ONCOLOGY-GROUP; BFM 90; LEUKEMIA; CHILDHOOD; PROTOCOL; TRIAL C1 [Shah, Nirali N.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wayne, Alan S.] Univ So Calif, Childrens Hosp Los Angeles, Keck Sch Med, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA USA. [Wilson, Wyndham H.] NCI, Lymphoma Therapeut Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Shah, NN (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 34 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-107-01059-8 PY 2014 BP 172 EP 190 PG 19 WC Oncology; Hematology SC Oncology; Hematology GA BIA08 UT WOS:000327127000013 ER PT J AU Gorlick, R Kolb, EA Keir, ST Maris, JM Reynolds, CP Kang, MH Carol, H Lock, R Billups, CA Kurmasheva, RT Houghton, PJ Smith, MA AF Gorlick, Richard Kolb, E. Anders Keir, Stephen T. Maris, John M. Reynolds, C. Patrick Kang, Min H. Carol, Hernan Lock, Richard Billups, Catherine A. Kurmasheva, Raushan T. Houghton, Peter J. Smith, Malcolm A. TI Initial Testing (Stage 1) of the Polo-Like Kinase Inhibitor Volasertib (BI 6727), by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; Plk inhibitor; preclinical testing ID ANTITUMOR-ACTIVITY; TUMOR-GROWTH; IN-VITRO; OSTEOSARCOMA; SCREEN; CELLS; TARGET; CANCER; POLO-LIKE-KINASE-1; EXPRESSION AB BackgroundVolasertib (BI 6727) is a potent inhibitor of Polo-like kinase 1 (Plk1), that is overexpressed in several childhood cancers and cell lines. Because of its novel mechanism of action, volasertib was evaluated through the PPTP. ProceduresVolasertib was tested against the PPTP in vitro cell line panel at concentrations from 0.1nM to 1.0M and against the PPTP in vivo xenograft panels administered IV at a dose of 30mg/kg (solid tumors) or 15mg/kg (ALL models) using a q7dx3 schedule. ResultsIn vitro volasertib demonstrated cytotoxic activity, with a median relative IC50 value of 14.1nM, (range 6.0-135nM). Volasertib induced significant differences in EFS in 19 of 32 (59%) of the evaluable solid tumor xenografts and in 2 of 4 (50%) of the evaluable ALL xenografts. Volasertib induced tumor growth inhibition meeting criteria for intermediate EFS T/C (>2) activity in 11 of 30 (37%) evaluable solid tumor xenografts, including neuroblastoma (4 of 6) and glioblastoma (2 of 3) panels, and 2 of 4 ALL models. Objective responses (CR's) were observed for 4 of 32 solid tumor (two neuroblastoma, one glioblastoma, and one rhabdomyosarcoma) and one of four ALL xenografts. ConclusionsVolasertib shows potent in vitro activity against the PPTP cell lines with no histotype selectivity. In vivo, volasertib induced regressions in several xenograft models. However, pharmacokinetic data suggest that mice tolerate higher systemic exposure to volasertib than humans, suggesting that the current results may over-estimate potential clinical efficacy against the childhood cancers studied. Pediatr Blood Cancer 2014;61:158-164. (c) 2013 Wiley Periodicals, Inc. C1 [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Carol, Hernan; Lock, Richard] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Billups, Catherine A.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Gorlick, R (reprint author), Montefiore Med Ctr, Dept Pediat, 3415 Bainbridge Ave, Bronx, NY 10467 USA. EM rgorlick@montefiore.org RI Houghton, Peter/E-3265-2011; Lock, Richard/G-4253-2013; OI Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX National Cancer Institute; Grant numbers: NO1-CM-42216; CA21765; CA108786 NR 25 TC 24 Z9 24 U1 3 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JAN PY 2014 VL 61 IS 1 BP 158 EP 164 DI 10.1002/pbc.24616 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 249GG UT WOS:000326765100026 PM 23956067 ER PT B AU Resnik, DB AF Resnik, David B. BE Curd, M Psillos, S TI ETHICS OF SCIENCE SO ROUTLEDGE COMPANION TO PHILOSOPHY OF SCIENCE. 2ND EDITION SE Routledge Philosophy Companion LA English DT Article; Book Chapter C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 7 TC 0 Z9 0 U1 1 U2 4 PU ROUTLEDGE PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND BN 978-1-135-01109-3; 978-0-415-51874-1 J9 ROUTL PHILOS COMPAN PY 2014 BP 181 EP 190 PG 10 WC History & Philosophy Of Science SC History & Philosophy of Science GA BIB84 UT WOS:000327316600018 ER PT J AU Colbert, RA Tran, TM Layh-Schmitt, G AF Colbert, Robert A. Tran, Tri M. Layh-Schmitt, Gerlinde TI HLA-B27 misfolding and ankylosing spondylitis SO MOLECULAR IMMUNOLOGY LA English DT Review DE MHC class I; Protein misfolding; Endoplasmic reticulum stress; Unfolded protein response; Autophagy; Ankylosing spondylitis; Spondyloarthritis ID UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; TUMOR-NECROSIS-FACTOR; IFN-BETA INDUCTION; I HEAVY-CHAINS; TRANSGENIC RATS; INFLAMMATORY DISEASE; TRANSCRIPTION FACTOR; HLA-B27-TRANSGENIC RATS; CELL-SURVIVAL AB Understanding how HLA-B27 contributes to the pathogenesis of spondyloarthritis continues to be an important goal. Current efforts are aimed largely on three areas of investigation; peptide presentation to CD8T cells, abnormal forms of the HLA-B27 heavy chain and their recognition by leukocyte immunoglobulin-like receptors on immune effector cells, and HLA-B27 heavy chain misfolding and intrinsic biological effects on affected cells. In this chapter we review our current understanding of the causes and consequences of HLA-B27 misfolding, which can be defined biochemically as a propensity to oligomerize and form complexes in the endoplasmic reticulum (ER) with the chaperone BiP (HSPA5/GRP78). HLA-B27 misfolding is linked to an unusual combination of polymorphisms that identify this allele, and cause the heavy chain to fold and load peptides inefficiently. Misfolding can result in ER-associated degradation (ERAD) of heavy chains, which is mediated in part by the E3 ubiquitin ligase HRD1 (SYVN1), and the ubiquitin conjugating enzyme UBE2JL. Upregulation of HLA-B27 and accumulation of misfolded heavy chains can activate ER stress signaling pathways that orchestrate the unfolded protein response. In transgenic rats where HLA-B27 is overexpressed, UPR activation is prominent. However, it is specific for heavy chain misfolding, since overexpression of HLA-B7, an allele that does not misfold, fails to generate ER stress. UPR activation has been linked to cytokine dysregulation, promoting IL-23, IFN beta, and IL-1 alpha production, and may activate the IL-23/IL-17 axis in these rats. IL-l alpha and IFN beta are pro- and anti-osteoclastogenic cytokines, respectively, that modulate osteoclast development in HLA-B27-expressing transgenic rat monocytes. Translational studies of patient derived cells expressing HLA-B27 at physiologic levels have provided evidence that ER stress and UPR activation can occur in peripheral blood, but this has not been reported to date in isolated macrophages. Inflamed gastrointestinal tissue reveals evidence for HLA-B27 misfolding, ERAD, and autophagy, without acute UPR activation. A more complete picture of conditions that impact HLA-B27 folding and misfolding, the full spectrum and time course of consequences of ER stress, and critical cell types involved is needed to understand the role of HLA-B27 misfolding in spondyloarthritis pathogenesis. Published by Elsevier Ltd. C1 [Colbert, Robert A.; Tran, Tri M.; Layh-Schmitt, Gerlinde] NIAMSD, Pediat Translat Res Branch, NIH, Bethesda, MD 20892 USA. RP Colbert, RA (reprint author), NIAMS, NIH, Bldg 10 CRC,Room 1-5142,10 Ctr Dr,MSC 1102, Bethesda, MD 20892 USA. EM colbertr@mail.nih.gov FU Intramural NIH HHS [ZIA AR041184-04] NR 78 TC 45 Z9 50 U1 2 U2 44 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JAN PY 2014 VL 57 IS 1 SI SI BP 44 EP 51 DI 10.1016/j.molimm.2013.07.013 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 248AG UT WOS:000326665500007 PM 23993278 ER PT S AU Cicala, C Arthos, J AF Cicala, Claudia Arthos, James BE Vicenzi, E Poli, G TI Virion Attachment and Entry: HIV gp120 Env Biotinylation, gp120 Env, or Integrin Ligand-Binding Assay SO HUMAN RETROVIRUSES: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE HIV-1 gp120; Integrin; gp120 biotinylation; Binding assay; Retinoic acid; MAdCAM ID RETINOIC ACID; CELLS; ALPHA(4)BETA(7) AB The HIV-1 entry receptors are CD4 and a chemokine receptor (CCR5 or CXCR4). In addition it has recently been demonstrated that HIV-1 gp120 binds to and signals through integrin alpha(4)beta(7), the gut-homing receptor (Arthos et al., Nat Immunol 9(3):301-309, 2008). Integrin alpha(4)beta(7) is not an entry receptor for HIV-1, although it can facilitate virion attachment to target cells (Arthos et al., Nat Immunol 9(3):301-309, 2008; Cicala et al., Proc Natl Acad Sci U S A 106:20877-20882, 2009). Recombinant HIV-1 gp120s bind to integrin alpha(4)beta(7) in a manner similar to its natural ligands (MAdCAM-1, V-CAM-1, fibronectin) (Andrew et al., J Immunol 153:3847-3861, 1994). gp120-alpha(4)beta(7) interactions are detected in a manner similar to assays developed for the natural ligands of alpha(4)beta(7). In this chapter we describe a method for the analysis of integrin-gp120 binding via a cell-based binding assay. In vitro ligand-integrin affinity can be modified by the presence of divalent cations (Mn2+, Mg2+, Ca2+) (Leitinger et al., Leitinger Biochim Biophys Acta 1498:91-98, 2000). Here we describe a protocol to detect biotinylated recombinant HIV-1 gp120 binding to integrin alpha(4)beta(7) in both primary cells and cell lines expressing the gut-homing receptor. C1 [Cicala, Claudia; Arthos, James] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Cicala, C (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 13 TC 2 Z9 2 U1 0 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-670-2; 978-1-62703-669-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1087 BP 3 EP 12 DI 10.1007/978-1-62703-670-2_1 D2 10.1007/978-1-62703-670-2 PG 10 WC Immunology; Virology SC Immunology; Virology GA BHR82 UT WOS:000326509000003 PM 24158809 ER PT S AU Andrew, A Strebel, K AF Andrew, Amy Strebel, Klaus BE Vicenzi, E Poli, G TI HIV-1 Accessory Proteins: Vpu and Vif SO HUMAN RETROVIRUSES: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Vif; Vpu; Accessory protein; Restriction factor; Virus-host interactions ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4 AB HIV-1 Vif and Vpu are accessory factors involved in late stages of viral replication. Vif regulates viral infectivity by preventing virion incorporation of APOBEC3G and other members of the family of cytidine deaminases, while Vpu causes degradation of CD4 and promotes virus release by functionally inactivating the host factor BST-2. This chapter described techniques used for the characterization of Vif and Vpu and their functional interaction with host factors. Many of the techniques are, however, applicable to the functional analysis of other viral proteins. C1 [Andrew, Amy; Strebel, Klaus] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Andrew, A (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA AI000669-21] NR 5 TC 1 Z9 1 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-670-2; 978-1-62703-669-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1087 BP 135 EP 158 DI 10.1007/978-1-62703-670-2_12 D2 10.1007/978-1-62703-670-2 PG 24 WC Immunology; Virology SC Immunology; Virology GA BHR82 UT WOS:000326509000014 PM 24158820 ER PT S AU Arakelyan, A Fitzgerald, W Grivel, JC Vanpouille, C Margolis, L AF Arakelyan, Anush Fitzgerald, Wendy Grivel, Jean-Charles Vanpouille, Christophe Margolis, Leonid BE Vicenzi, E Poli, G TI Histocultures(Tissue Explants) in Human Retrovirology SO HUMAN RETROVIRUSES: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Human tissue; HIV; Histoculture; Explants; Pathogenesis; Flow cytometry ID HUMAN LYMPHOID-TISSUE; IMMUNODEFICIENCY-VIRUS TYPE-1; EX-VIVO; MEASLES-VIRUS; HIV TYPE-1; INFECTION; CULTURE; PATHOGENESIS; REPLICATION; PHENOTYPE AB Viral pathogenesis is studied predominantly in cultures of primary isolated cells or cell lines. Many retroviruses efficiently replicate only in activated cells. Therefore, in order to become efficient viral producers cells should be artificially activated, a procedure which significantly changes cell physiology. However, for many viral diseases, like HIV-1 and other retroviruses' diseases, critical pathogenic events occur in tissues. Therefore, cell isolation from their native microenvironment prevents single-cell cultures from faithfully reflecting important aspects of cell-cell and cell-pathogen interactions that occur in the context of complex tissue cytoarchitecture. Tissue explants (histocultures) that retain tissue cytoarchitecture and many aspects of cell-cell interactions more faithfully represent in vivo tissue features. Human histocultures constitute an adequate model for studying viral pathogenesis under controlled laboratory conditions. Protocols for various human histocultures as applied to study retroviral pathogenesis, in particular of HIV-1, have been refined by our laboratory and are described in the present publication. Histocultures of human tonsils and lymph nodes, as well as of recto-sigmoid and cervicovaginal tissues can be used to study viral transmission, pathogenesis and as a preclinical platform for antivirals evaluation. C1 [Arakelyan, Anush; Fitzgerald, Wendy; Grivel, Jean-Charles; Vanpouille, Christophe; Margolis, Leonid] NICHHD, Sect Intercellular Interact, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Arakelyan, A (reprint author), NICHHD, Sect Intercellular Interact, Program Phys Biol, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA HD001416-21, ZIA HD001416-20] NR 30 TC 2 Z9 2 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-670-2; 978-1-62703-669-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1087 BP 233 EP 248 DI 10.1007/978-1-62703-670-2_19 D2 10.1007/978-1-62703-670-2 PG 16 WC Immunology; Virology SC Immunology; Virology GA BHR82 UT WOS:000326509000021 PM 24158827 ER PT S AU Wiegand, A Maldarelli, F AF Wiegand, Ann Maldarelli, Frank BE Vicenzi, E Poli, G TI Single-Copy Quantification of HIV-1 in Clinical Samples SO HUMAN RETROVIRUSES: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE HIV; RNA; PCR; Single-copy assay ID ACTIVE ANTIRETROVIRAL THERAPY; LOW-LEVEL VIREMIA; VIRUS TYPE-1 RNA; RALTEGRAVIR INTENSIFICATION; PROGNOSTIC VALUE; PLASMA SAMPLES; MONITOR V1.5; PCR ASSAY; T-CELLS; REPLICATION AB HIV replication in humans proceeds with substantial viral RNA levels in plasma. Antiretroviral therapy results in suppression but not eradication of HIV infection. Continuous therapy is essential for durable clinical responses. Discontinuing antiretroviral therapy results in prompt rebound in viremia. The source of HIV during suppressive therapy and mechanisms of persistence remain uncertain. Sensitive assays for HIV have been useful in quantifying viremia in response to antiretroviral therapy and in experimental studies of drug intensification, drug simplification, and potential anatomic sanctuary site investigations. As clinical eradication strategies move forward, robust, sensitive quantitative assays for HIV at low levels represent essential laboratory support modalities. Here we describe in detail an assay for HIV-1 RNA with single-copy sensitivity. C1 [Wiegand, Ann; Maldarelli, Frank] NCI, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, NIH, Frederick, MD 21701 USA. RP Wiegand, A (reprint author), NCI, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, NIH, Frederick, MD 21701 USA. NR 33 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-670-2; 978-1-62703-669-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1087 BP 251 EP 260 DI 10.1007/978-1-62703-670-2_20 D2 10.1007/978-1-62703-670-2 PG 10 WC Immunology; Virology SC Immunology; Virology GA BHR82 UT WOS:000326509000022 PM 24158828 ER PT S AU Klase, ZA Houzet, L Jeang, KT AF Klase, Zachary A. Houzet, Laurent Jeang, Kuan-Teh BE Vicenzi, E Poli, G TI Quantification of miRNA by Poly(A)-RT-qPCR Arrays and Verification of Target Sites in HIV-1 Using a One-LTR Infectious Molecular Clone SO HUMAN RETROVIRUSES: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE miRNA; qPCR array; RNA isolation; Small RNA labeling; One-LTR molecular clone ID VIRUS-REPLICATION; MICRORNAS; RNAI; IDENTIFICATION; SUPPRESSOR; ELEMENT; PROTEIN; PATHWAY; DICER AB Quantitative PCR (qPCR) provides a robust method for quantifying DNA species. By combining modern qPCR techniques with the isolation of small RNA, the polyadenylation of the RNA, and the use of reverse transcriptase to create miRNA derived cDNA, it is now possible to use qPCR to quantify miRNA. This method is scalable and provides a useful addition to the retrovirologists' toolbox. Here, we also describe the use of one-LTR infectious molecular clones to verify miRNA target sites within the retroviral LTR. C1 [Klase, Zachary A.; Houzet, Laurent] NIAID, NIH, Bethesda, MD 20892 USA. [Jeang, Kuan-Teh] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Klase, ZA (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 22 TC 1 Z9 1 U1 1 U2 9 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-670-2; 978-1-62703-669-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1087 BP 285 EP 296 DI 10.1007/978-1-62703-670-2_23 D2 10.1007/978-1-62703-670-2 PG 12 WC Immunology; Virology SC Immunology; Virology GA BHR82 UT WOS:000326509000025 PM 24158831 ER PT J AU Li, YY Parker, LE AF Li, YuanYuan Parker, Lynne E. TI Nearest neighbor imputation using spatial-temporal correlations in wireless sensor networks SO INFORMATION FUSION LA English DT Article DE Wireless sensor networks; kd-Tree; Missing data imputation; Nearest neighbor imputation ID CLASSIFICATION AB Missing data is common in Wireless Sensor Networks (WSNs), especially with multi-hop communications. There are many reasons for this phenomenon, such as unstable wireless communications, synchronization issues, and unreliable sensors. Unfortunately, missing data creates a number of problems for WSNs. First, since most sensor nodes in the network are battery-powered, it is too expensive to have the nodes retransmit missing data across the network. Data re-transmission may also cause time delays when detecting abnormal changes in an environment. Furthermore, localized reasoning techniques on sensor nodes (such as machine learning algorithms to classify states of the environment) are generally not robust enough to handle missing data. Since sensor data collected by a WSN is generally correlated in time and space, we illustrate how replacing missing sensor values with spatially and temporally correlated sensor values can significantly improve the network's performance. However, our studies show that it is important to determine which nodes are spatially and temporally correlated with each other. Simple techniques based on Euclidean distance are not sufficient for complex environmental deployments. Thus, we have developed a novel Nearest Neighbor (NN) imputation method that estimates missing data in WSNs by learning spatial and temporal correlations between sensor nodes. To improve the search time, we utilize a kd-tree data structure, which is a non-parametric, data-driven binary search tree. Instead of using traditional mean and variance of each dimension for kd-tree construction, and Euclidean distance for kd-tree search, we use weighted variances and weighted Euclidean distances based on measured percentages of missing data. We have evaluated this approach through experiments on sensor data from a volcano dataset collected by a network of Crossbow motes, as well as experiments using sensor data from a highway traffic monitoring application. Our experimental results show that our proposed K-NN imputation method has a competitive accuracy with state-of-the-art Expectation-Maximization (EM) techniques, while using much simpler computational techniques, thus making it suitable for use in resource-constrained WSNs. (C) 2012 Elsevier B.V. All rights reserved. C1 [Li, YuanYuan] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Parker, Lynne E.] Univ Tennessee, Dept Elect Engn & Comp Sci, Distributed Intelligence Lab, Knoxville, TN 37996 USA. RP Li, YY (reprint author), NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM yuanyuan.li@nih.gov NR 24 TC 15 Z9 15 U1 2 U2 36 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1566-2535 EI 1872-6305 J9 INFORM FUSION JI Inf. Fusion PD JAN PY 2014 VL 15 SI SI BP 64 EP 79 DI 10.1016/j.inffus.2012.08.007 PG 16 WC Computer Science, Artificial Intelligence; Computer Science, Theory & Methods SC Computer Science GA 244UE UT WOS:000326414900008 ER PT J AU Sadjadi, A Derakhshan, MH Yazdanbod, A Boreiri, M Parsaeian, M Babaei, M Alimohammadian, M Samadi, F Etemadi, A Pourfarzi, F Ahmadi, E Delavari, A Islami, F Farzadfar, F Sotoudeh, M Nikmanesh, A Alizadeh, BZ de Bock, GH Malekzadeh, R AF Sadjadi, Alireza Derakhshan, Mohammad H. Yazdanbod, Abbas Boreiri, Majid Parsaeian, Mahbubeh Babaei, Masoud Alimohammadian, Masoomeh Samadi, Fatemeh Etemadi, Arash Pourfarzi, Farhad Ahmadi, Emad Delavari, Alireza Islami, Farhad Farzadfar, Farshad Sotoudeh, Masoud Nikmanesh, Arash Alizadeh, Behrooz Z. de Bock, Geertruida H. Malekzadeh, Reza TI Neglected role of hookah and opium in gastric carcinogenesis: A cohort study on risk factors and attributable fractions SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE gastric cancer; precancerous lesions; Helicobacter pylori; smoking; hookah; opium ID HELICOBACTER-PYLORI INFECTION; CANCER INCIDENCE; INTESTINAL METAPLASIA; WATERPIPE SMOKE; SALT INTAKE; POPULATION; IRAN; METAANALYSIS; REGISTRY; CONSUMPTION AB A recent study showed an association between hookah/opium use and gastric cancer but no study has investigated the relationship with gastric precancerous lesions. We examined the association between hookah/opium and gastric precancerous lesions and subsequent gastric cancer. In a population-based cohort study, 928 randomly selected, healthy, Helicobacter pylori-infected subjects in Ardabil Province, Iran, were followed for 10 years. The association between baseline precancerous lesions and lifestyle risk factors (including hookah/opium) was analyzed using logistic regression and presented as odds ratios (ORs) and 95% confidence intervals (CIs). We also calculated hazard ratios (HRs) and 95% CIs for the associations of lifestyle risk factors and endoscopic and histological parameters with incident gastric cancers using Cox regression models. Additionally, the proportion of cancers attributable to modifiable risk factors was calculated. During 9,096 person-years of follow-up, 36 new cases of gastric cancer were observed (incidence rate: 3.96/1,000 persons-years). Opium consumption was strongly associated with baseline antral (OR: 3.2; 95% CI: 1.2-9.1) and body intestinal metaplasia (OR: 7.3; 95% CI: 2.5-21.5). Opium (HR: 3.2; 95% CI: 1.4-7.7), hookah (HR: 3.4; 95% CI: 1.7-7.1) and cigarette use (HR: 3.2; 95% CI: 1.4-7.5), as well as high salt intake, family history of gastric cancer, gastric ulcer and histological atrophic gastritis and intestinal metaplasia of body were associated with higher risk of gastric cancer. The fraction of cancers attributable jointly to high salt, low fruit intake, smoking (including hookah) and opium was 93% (95% CI: 83-98). Hookah and opium use are risk factors for gastric cancer as well as for precancerous lesions. Hookah, opium, cigarette and high salt intake are important modifiable risk factors in this high-incidence gastric cancer area. What's new? Gastric cancer strikes Iranian men more often than any other cancer, and previous studies report a connection between gastric cancer and hookah, a traditional smoking device in the region. This study probed the factors associated with precancerous lesions and gastric cancer, including hookah and opium use. They found that both hookah and opium use increased the likelihood of developing cancer, as did high salt intake and cigarette smoking. C1 [Sadjadi, Alireza; Derakhshan, Mohammad H.; Boreiri, Majid; Etemadi, Arash; Ahmadi, Emad; Delavari, Alireza; Islami, Farhad; Sotoudeh, Masoud; Nikmanesh, Arash; Alizadeh, Behrooz Z.; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Ctr, Tehran 1411713135, Iran. [Sadjadi, Alireza; Alizadeh, Behrooz Z.; de Bock, Geertruida H.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Derakhshan, Mohammad H.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Yazdanbod, Abbas; Babaei, Masoud; Samadi, Fatemeh; Pourfarzi, Farhad] Ardabil Univ Med Sci, Gastrointestinal Canc Res Ctr, Ardebil, Iran. [Parsaeian, Mahbubeh; Farzadfar, Farshad] Univ Tehran Med Sci, Endocrinol & Metab Res Inst, Noncommunicable Dis Res Ctr, Tehran 1411713135, Iran. [Alimohammadian, Masoomeh] Univ Tehran Med Sci, Sch Publ Hlth, Tehran 1411713135, Iran. [Etemadi, Arash] NCI, Div Canc Epidemiol & Genet, Bethesda, MA USA. [Islami, Farhad] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran 1411713135, Iran. EM g.h.de.bock@umcg.nl; malek@tums.ac.ir RI Etemadi, Arash/C-1386-2016; Derakhshan, Mohammad/K-8694-2016; de Bock, Geertruida/F-6529-2014; OI Etemadi, Arash/0000-0002-3458-1072; de Bock, Geertruida/0000-0003-3104-4471; Ziad Alizadeh, Behrooz/0000-0002-1415-8007; Malekzadeh, Reza/0000-0003-1043-3814 FU Digestive Disease Research Center of Tehran, University of Medical Sciences; Iran's National Elites Foundation; National Cancer Institute at the National Institutes of Health, USA FX Grant sponsor: Digestive Disease Research Center of Tehran, University of Medical Sciences; Grant sponsor: Iran's National Elites Foundation; Grant sponsor: National Cancer Institute at the National Institutes of Health, USA NR 40 TC 17 Z9 17 U1 0 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JAN 1 PY 2014 VL 134 IS 1 BP 181 EP 188 DI 10.1002/ijc.28344 PG 8 WC Oncology SC Oncology GA 238WI UT WOS:000325982000019 PM 23797606 ER PT J AU Fleming, JL Dworkin, AM Allain, DC Fernandez, S Wei, L Peters, SB Iwenofu, OH Ridd, K Bastian, BC Toland, AE AF Fleming, Jessica L. Dworkin, Amy M. Allain, Dawn C. Fernandez, Soledad Wei, Lai Peters, Sara B. Iwenofu, O. Hans Ridd, Katie Bastian, Boris C. Toland, Amanda Ewart TI Allele-specific imbalance mapping identifies HDAC9 as a candidate gene for cutaneous squamous cell carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE HDAC9; cutaneous squamous cell carcinoma; allelic-specific imbalance; Skts5 ID REGULATORY T-CELLS; SUSCEPTIBILITY GENE; SKIN; MICE; EXPRESSION; SURVIVAL; LOCI AB More than 3.5 million nonmelanoma skin cancers were treated in 2006; of these 700,000 were cutaneous squamous cell carcinomas (cSCCs). Despite clear environmental causes for cSCC, studies also suggest genetic risk factors. A cSCC susceptibility locus, Skts5, was identified on mouse chromosome 12 by linkage analysis. The orthologous locus to Skts5 in humans maps to 7p21 and 7q31. These loci show copy number increases in approximate to 10% of cSCC tumors. Here, we show that an additional 15-22% of tumors exhibit copy-neutral loss of heterozygosity. Furthermore, our previous data identified microsatellite markers on 7p21 and 7q31 that demonstrate preferential allelic imbalance (PAI) in cSCC tumors. On the basis of these results, we hypothesized that the human orthologous locus to Skts5 would house a gene important in human cSCC development and that tumors would demonstrate allele-specific somatic alterations. To test this hypothesis, we performed quantitative genotyping of 108 single nucleotide polymorphisms (SNPs) mapping to candidate genes at human SKTS5 in paired normal and tumor DNAs. Nine SNPs in HDAC9 (rs801540, rs1178108, rs1178112, rs1726610, rs10243618, rs11764116, rs1178355, rs10269422 and rs12540872) showed PAI in tumors. These data suggest that HDAC9 variants may be selected for during cSCC tumorigenesis. What's new? While inherited risk factors have been suggested to play a role in cutaneous squamous cell carcinomas (cSCC) in addition to environmental causes, so far few well-validated genetic risk variants exist. Human 7p21 however shows evidence of preferential allelic imbalance (PAI) and copy neutral loss of heterozygosity in cSCCs. 7p21 is orthologous to a mouse skin cancer susceptibility locus, Skts5. Here, candidate genes at Skts5 identified from the mouse were assessed for evidence of PAI in human cSCCs. Multiple variants in HDAC9 were identified that show evidence of allele-specific gains in cSCC, suggesting that HDAC9 may be important in cSCC development. C1 [Fleming, Jessica L.; Toland, Amanda Ewart] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Fleming, Jessica L.; Allain, Dawn C.; Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Dworkin, Amy M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Allain, Dawn C.] Arthur G James Canc Hosp, Clin Canc Genet Program, Columbus, OH USA. [Allain, Dawn C.] Arthur G James Canc Hosp, Human Canc Genet Program, Columbus, OH USA. [Allain, Dawn C.] Ohio State Univ, Wexner Med Ctr, Richard J Solove Res Inst, Columbus, OH 43210 USA. [Allain, Dawn C.; Toland, Amanda Ewart] Ohio State Univ, Dept Internal Med, Div Human Genet, Med Ctr, Columbus, OH 43210 USA. [Fernandez, Soledad; Wei, Lai] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Peters, Sara B.; Iwenofu, O. Hans] Ohio State Univ, Dept Pathol & Lab Med, Columbus, OH 43210 USA. [Ridd, Katie; Bastian, Boris C.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Ridd, Katie; Bastian, Boris C.] Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Bastian, Boris C.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. RP Toland, AE (reprint author), 998 Biomed Res Tower,460 W 12th Ave, Columbus, OH 43210 USA. EM amanda.toland@osumc.edu RI Allain, Dawn/E-2634-2011; Iwenofu, Obiajulu/E-3293-2011; OI Toland, Amanda/0000-0002-0271-1792 FU American Cancer Society [RSG-07-083 MGO]; National Cancer Institute [CA134461]; National Institutes of Arthritis and Musculoskeletal and Skin, Ohio State University Comprehensive Cancer Center FX Grant sponsor: American Cancer Society; Grant number: RSG-07-083 MGO; Grant sponsor: National Cancer Institute; Grant number: CA134461; Grant sponsors: National Institutes of Arthritis and Musculoskeletal and Skin, Ohio State University Comprehensive Cancer Center NR 23 TC 4 Z9 4 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JAN 1 PY 2014 VL 134 IS 1 BP 244 EP 248 DI 10.1002/ijc.28339 PG 5 WC Oncology SC Oncology GA 238WI UT WOS:000325982000026 PM 23784969 ER PT B AU Makareeva, E Leikin, S AF Makareeva, Elena Leikin, Sergey BE Shapiro, JR TI Collagen Structure, Folding and Function SO OSTEOGENESIS IMPERFECTA: A TRANSLATIONAL APPROACH TO BRITTLE BONE DISEASE LA English DT Article; Book Chapter ID EHLERS-DANLOS-SYNDROME; RECESSIVE OSTEOGENESIS IMPERFECTA; EPITHELIUM-DERIVED FACTOR; SYNDROME TYPE-VII; CARBOXYL-TERMINAL PROPEPTIDE; CONNECTIVE-TISSUE DISORDERS; HYPEROSTOSIS CAFFEY-DISEASE; TRIPLE-HELIX FORMATION; RETICULUM EXIT SITES; CIS-TRANS-ISOMERASE C1 [Makareeva, Elena; Leikin, Sergey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Makareeva, E (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 NR 172 TC 6 Z9 6 U1 0 U2 10 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-397789-2; 978-0-12-397165-4 PY 2014 BP 71 EP 84 DI 10.1016/B978-0-12-397165-4.00007-1 PG 14 WC Orthopedics SC Orthopedics GA BHP54 UT WOS:000326245700009 ER PT B AU Kram, V Young, MF AF Kram, Vardit Young, Marian F. BE Shapiro, JR TI Bone Matrix Proteoglycans in Skeletal Function SO OSTEOGENESIS IMPERFECTA: A TRANSLATIONAL APPROACH TO BRITTLE BONE DISEASE LA English DT Article; Book Chapter ID HEPARAN-SULFATE PROTEOGLYCANS; LEUCINE-RICH PROTEOGLYCANS; COLLAGEN TYPE-I; GROWTH-FACTOR-BETA; LARGE AGGREGATING PROTEOGLYCAN; FIBROMODULIN-DEFICIENT MICE; REPEAT PROTEIN FAMILY; AGGRECAN GENE AGC1; OSTEOGENESIS IMPERFECTA; EXTRACELLULAR-MATRIX C1 [Kram, Vardit; Young, Marian F.] Natl Inst Dent & Craniofacial Res, Mol Biol Bones & Teeth Sect, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Kram, V (reprint author), Natl Inst Dent & Craniofacial Res, Mol Biol Bones & Teeth Sect, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. NR 142 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-397789-2; 978-0-12-397165-4 PY 2014 BP 85 EP 95 DI 10.1016/B978-0-12-397165-4.00008-3 PG 11 WC Orthopedics SC Orthopedics GA BHP54 UT WOS:000326245700010 ER PT J AU Choi, HJ Shung, KK AF Choi, Hojong Shung, K. Kirk TI Novel power MOSFET-based expander for high frequency ultrasound systems SO ULTRASONICS LA English DT Article DE Protection devices; Expander; Power MOSFET; High frequency ultrasound system; Ultrasonic transducers AB The function of an expander is to obstruct the noise signal transmitted by the pulser so that it does not pass into the transducer or receive electronics, where it can produce undesirable ring-down in an ultrasound imaging application. The most common type is a diode-based expander, which is essentially a simple diode-pair, is widely used in pulse-echo measurements and imaging applications because of its simple architecture. However, diode-based expanders may degrade the performance of ultrasonic transducers and electronic components on the receiving and transmitting sides of the ultrasound systems, respectively. Since they are non-linear devices, they cause excessive signal attenuation and noise at higher frequencies and voltages. In this paper, a new type of expander that utilizes power MOSFET components, which we call a power MOSFET-based expander, is introduced and evaluated for use in high frequency ultrasound imaging systems. The performance of a power MOSFET-based expander was evaluated relative to a diode-based expander by comparing the noise figure (NF), insertion loss (IL), total harmonic distortion (THD), response time (RT), electrical impedance (EI) and dynamic power consumption (DPC). The results showed that the power MOSFET-based expander provided better NF (0.76 dB), IL (-0.3 dB) and THD (-62.9 dB), and faster RT (82 ns) than did the diode-based expander (NF (2.6 dB), IL (-1.4 dB), THD (-56.0 dB) and RT (119 ns)) at 70 MHz. The -6 dB bandwidth and the peak-to-peak voltage of the echo signal received by the transducer using the power MOSFET-based expander improved by 17.4% and 240% compared to the diode-based expander, respectively. The new power MOSFET-based expander was shown to yield lower NF, IL and THD, faster RT and lower ring down than the diode-based expander at the expense of higher dynamic power consumption. (C) 2013 Elsevier B. V. All rights reserved. C1 [Choi, Hojong] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA USA. Univ So Calif, Dept Biomed Engn, Los Angeles, CA USA. RP Choi, HJ (reprint author), Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA USA. EM hojongch@usc.edu FU National Institute of Health [P41-EB002182] FX This research was supported by National Institute of Health Grant #P41-EB002182. The authors thank Mr. Thomas Cummins and Dr. Jay Mung for their English correction and editing contribution. NR 37 TC 4 Z9 4 U1 1 U2 31 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0041-624X J9 ULTRASONICS JI Ultrasonics PD JAN PY 2014 VL 54 IS 1 BP 121 EP 130 DI 10.1016/j.ultras.2013.04.018 PG 10 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 215XJ UT WOS:000324244100015 PM 23835308 ER PT J AU Kuka, M Ashwell, JD AF Kuka, Mirela Ashwell, Jonathan D. TI A method for high purity sorting of rare cell subsets applied to T-DC SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Flow cytometry; Sorting; T-DC; Purification ID DENDRITIC CELLS; FLOW-CYTOMETRY; IDENTIFICATION; EXPRESSION; VARIANTS; ZBTB46 AB T-DC are a recently described subset of polyclonal alpha beta T-cells with dendritic cell properties. Because of their low number in peripheral immune compartments, isolation and characterization of T-DC with existing purification methods are technically challenging. Here we describe a customized gating strategy and a flow cytometry-based cell sorting protocol for isolation of T-DC. The protocol was developed because, despite very conservative gating for dead-cell and doublet exclusion, cells obtained with normal sorting procedures were enriched for T-DC but not pure. Re-sorting the output of the first round of sorting results in highly pure T-DC. Cells obtained with this method are viable and can be used for in vitro characterization. Moreover, this double-round sorting strategy can be universally applied to the isolation of other rare cell subsets. (C) 2013 Elsevier B.V. All rights reserved. C1 [Kuka, Mirela; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kuka, M (reprint author), Ist Sci San Raffaele, Div Immunol Transplantat & Infect Dis, Via Olgettina 58, I-20132 Milan, Italy. EM kuka.mirela@hsr.it; jda@pop.nci.nih.gov OI KUKA, MIRELA/0000-0001-9418-1559 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. We thank Ivana Munitic, Barbara J. Taylor, and Karen M. Wolcott for helpful suggestions. NR 12 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD DEC 31 PY 2013 VL 400 SI SI BP 111 EP 116 DI 10.1016/j.jim.2013.10.002 PG 6 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 287JS UT WOS:000329538700014 PM 24120843 ER PT J AU Gu, S Cheung, HH Lee, TL Lu, G Poon, WS Chan, WY AF Gu, Shen Cheung, Hoi Hung Lee, Tin Lap Lu, Gang Poon, Wai Sang Chan, Wai Yee TI Molecular Mechanisms of Regulation and Action of microRNA-199a in Testicular Germ Cell Tumor and Glioblastomas SO PLOS ONE LA English DT Article ID HEPATOCELLULAR-CARCINOMA; CANCER CELLS; EXPRESSION; GENES; METHYLATION; RNAS; IDENTIFICATION; PROLIFERATION; MIR-199A; REVEALS AB MicroRNA-199a (miRNA-199a) has been shown to have comprehensive functions and behave differently in different systems and diseases. It is encoded by two loci in the human genome, miR-199a-1 in chromosome 19 and miR-199a-2 in chromosome 1. Both loci give rise to the same miRNAs (miR-199a-5p and miR-199a-3p). The cause of the diverse action of the miRNA in different systems is not clear. However, it is likely due to different regulation of the two genomic loci and variable targets of the miRNA in different cells and tissues. Here we studied promoter methylation of miR-199a in testicular germ cell tumors (TGCTs) and glioblastomas (gliomas) and discovered that hypermethylation in TGCTs of both miR-199a-1 and -2 resulted in its reduced expression, while hypomethylation of miR-199a-2 but not -1 in gliomas may be related to its elevated expression. We also identified a common regulator, REST, which preferentially bound to the methylated promoters of both miR-199a-1 and miR-199a-2. The action of miR-199a is dependent on its downstream targets. We identified MAFB as a putative target of miRNA-199a-5p in TGCTs and confirmed that the tumor suppression activity of the microRNA is mediated by its target MAFB. By studying the mechanisms that control the expressions of miR-199a and its various downstream targets, we hope to use miR-199a as a model to understand the complexity of miRNA biology. C1 [Gu, Shen; Lee, Tin Lap; Lu, Gang; Chan, Wai Yee] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Cheung, Hoi Hung] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Clin & Dev Genom, NIH, Bethesda, MD USA. [Lu, Gang; Poon, Wai Sang] Chinese Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China. RP Chan, WY (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. EM chanwy@cuhk.edu.hk RI Poon, Wai Sang/F-1558-2011; Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Chinese University of Hong Kong; Vigconic International project fund; RGC GRF [475910] FX This study is partially supported by the start-up fund provided to WYC by the Chinese University of Hong Kong, the Vigconic International project fund, and RGC GRF No: 475910. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 9 Z9 9 U1 0 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 DEC 31 PY 2013 VL 8 IS 12 AR e83980 DI 10.1371/journal.pone.0083980 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 284NF UT WOS:000329325200154 PM 24391856 ER PT J AU de Maturana, EL Ye, YQ Calle, ML Rothman, N Urrea, V Kogevinas, M Petrus, S Chanock, SJ Tardon, A Garcia-Closas, M Gonzalez-Neira, A Vellalta, G Carrato, A Navarro, A Lorente-Galdos, B Silverman, DT Real, FX Wu, XF Malats, N AF Lopez de Maturana, Evangelina Ye, Yuanqing Luz Calle, M. Rothman, Nathaniel Urrea, Victor Kogevinas, Manolis Petrus, Sandra Chanock, Stephen J. Tardon, Adonina Garcia-Closas, Montserrat Gonzalez-Neira, Anna Vellalta, Gemma Carrato, Alfredo Navarro, Arcadi Lorente-Galdos, Belen Silverman, Debra T. Real, Francisco X. Wu, Xifeng Malats, Nuria TI Application of Multi-SNP Approaches Bayesian LASSO and AUC-RF to Detect Main Effects of Inflammatory-Gene Variants Associated with Bladder Cancer Risk SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; B SIGNALING PATHWAY; SUSCEPTIBILITY LOCI; COLORECTAL-CANCER; REGRESSION; POLYMORPHISM; SELECTION; MARKERS; PREDISPOSITION; IDENTIFICATION AB The relationship between inflammation and cancer is well established in several tumor types, including bladder cancer. We performed an association study between 886 inflammatory-gene variants and bladder cancer risk in 1,047 cases and 988 controls from the Spanish Bladder Cancer (SBC)/EPICURO Study. A preliminary exploration with the widely used univariate logistic regression approach did not identify any significant SNP after correcting for multiple testing. We further applied two more comprehensive methods to capture the complexity of bladder cancer genetic susceptibility: Bayesian Threshold LASSO (BTL), a regularized regression method, and AUC-Random Forest, a machine-learning algorithm. Both approaches explore the joint effect of markers. BTL analysis identified a signature of 37 SNPs in 34 genes showing an association with bladder cancer. AUC-RF detected an optimal predictive subset of 56 SNPs. 13 SNPs were identified by both methods in the total population. Using resources from the Texas Bladder Cancer study we were able to replicate 30% of the SNPs assessed. The associations between inflammatory SNPs and bladder cancer were reexamined among non-smokers to eliminate the effect of tobacco, one of the strongest and most prevalent environmental risk factor for this tumor. A 9 SNP-signature was detected by BTL. Here we report, for the first time, a set of SNP in inflammatory genes jointly associated with bladder cancer risk. These results highlight the importance of the complex structure of genetic susceptibility associated with cancer risk. C1 [Lopez de Maturana, Evangelina; Petrus, Sandra; Gonzalez-Neira, Anna; Real, Francisco X.; Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. [Ye, Yuanqing; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Luz Calle, M.; Urrea, Victor; Petrus, Sandra] Univ Vic, Dept Syst Biol, Vic, Spain. [Rothman, Nathaniel; Chanock, Stephen J.; Garcia-Closas, Montserrat; Silverman, Debra T.] NCI, Div Canc Epidemiol & Genet, US Dept HHS, Bethesda, MD 20892 USA. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Kogevinas, Manolis; Vellalta, Gemma] Inst Municipal Invest Med Hosp del Mar, Barcelona, Spain. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Carrato, Alfredo] Hosp Univ Elche, Elche, Spain. [Carrato, Alfredo] Hosp Univ Ramon y Cajal, Madrid, Spain. [Navarro, Arcadi; Lorente-Galdos, Belen; Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Navarro, Arcadi; Lorente-Galdos, Belen] Inst Biol Evolutiva UPF CSIC, Barcelona, Spain. [Navarro, Arcadi] Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Spain. [Navarro, Arcadi; Lorente-Galdos, Belen] Inst Nacl Bioinformat, Barcelona, Spain. RP Malats, N (reprint author), Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. EM nmalats@cnio.es RI Navarro, Arcadi/F-1592-2011; Gonzalez-Neira, Anna/C-5791-2015; Calle, M.Luz/D-2704-2015; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Real Arribas, Francisco/H-5275-2015; Kogevinas, Manolis/C-3918-2017; OI Lorente-Galdos, Belen/0000-0001-5390-2452; Navarro, Arcadi/0000-0003-2162-8246; Urrea Gales, Victor/0000-0002-2577-856X; Calle, M.Luz/0000-0001-9334-415X; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Real Arribas, Francisco/0000-0001-9501-498X; Lopez de Maturana, Evangelina/0000-0001-9425-3911 FU Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III [G03/174, 00/0745, PI051436, PI061614, PI09-02102]; Ministry of Science and Innovation, Spain [MTM2008-06747-C02-02]; AGAUR-Generalitat de Catalunya [2009SGR-581]; Fundaciola Maratode TV3; Red Tematica de Investigacion Cooperativa en Cancer (RTICC); Asociacion Espanola Contra el Cancer (AECC); Spanish National Institute for Bioinformatics; Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA; MD Anderson [U01 CA 127615, R01 CA 74880, P50 CA 91846]; Betty B. Marcus Chair fund in Cancer Prevention; UT Research Trust; [EU-FP7-201663]; [RO1-CA089715]; [CA34627]; [R01 CA 131335] FX The work was partially supported by the Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III (G03/174, 00/0745, PI051436, PI061614, PI09-02102, G03/174 and Sara Borrell fellowship to ELM) and Ministry of Science and Innovation (MTM2008-06747-C02-02 and FPU fellowship award to VU), Spain; AGAUR-Generalitat de Catalunya (Grant 2009SGR-581); Fundaciola Maratode TV3; Red Tematica de Investigacion Cooperativa en Cancer (RTICC); Asociacion Espanola Contra el Cancer (AECC); EU-FP7-201663; and RO1-CA089715 and CA34627; the Spanish National Institute for Bioinformatics (www.inab.org); and by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA. MD Anderson support for this project included U01 CA 127615 (XW); R01 CA 74880 (XW); P50 CA 91846 (XW, CPD); Betty B. Marcus Chair fund in Cancer Prevention (XW); UT Research Trust fund (XW) and R01 CA 131335 (JG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 7 Z9 7 U1 2 U2 18 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 DEC 31 PY 2013 VL 8 IS 12 AR e83745 DI 10.1371/journal.pone.0083745 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 284NF UT WOS:000329325200116 PM 24391818 ER PT J AU Polston, JE Pritchett, CE Tomasko, JM Rogers, AM Leggio, L Thanos, PK Volkow, ND Hajnal, A AF Polston, James E. Pritchett, Carolyn E. Tomasko, Jonathan M. Rogers, Ann M. Leggio, Lorenzo Thanos, Panayotis K. Volkow, Nora D. Hajnal, Andras TI Roux-en-Y Gastric Bypass Increases Intravenous Ethanol Self-Administration in Dietary Obese Rats SO PLOS ONE LA English DT Article ID STIMULATES LOCOMOTOR-ACTIVITY; BARIATRIC SURGERY; NUCLEUS-ACCUMBENS; ALCOHOL METABOLISM; ENERGY-EXPENDITURE; GHRELIN LEVELS; FOOD REWARD; SWEET TASTE; DOPAMINE; CONSUMPTION AB Roux-en-Y gastric bypass surgery (RYGB) is an effective treatment for severe obesity. Clinical studies however have reported susceptibility to increased alcohol use after RYGB, and preclinical studies have shown increased alcohol intake in obese rats after RYGB. This could reflect a direct enhancement of alcohol's rewarding effects in the brain or an indirect effect due to increased alcohol absorption after RGYB. To rule out the contribution that changes in alcohol absorption have on its rewarding effects, here we assessed the effects of RYGB on intravenously (IV) administered ethanol (1%). For this purpose, high fat (60% kcal from fat) diet-induced obese male Sprague Dawley rats were tested similar to 2 months after RYGB or sham surgery (SHAM) using both fixed and progressive ratio schedules of reinforcement to evaluate if RGYB modified the reinforcing effects of IV ethanol. Compared to SHAM, RYGB rats made significantly more active spout responses to earn IV ethanol during the fixed ratio schedule, and achieved higher breakpoints during the progressive ratio schedule. Although additional studies are needed, our results provide preliminary evidence that RYGB increases the rewarding effects of alcohol independent of its effects on alcohol absorption. C1 [Polston, James E.; Pritchett, Carolyn E.; Hajnal, Andras] Penn State Univ, Dept Neural & Behav Sci, Coll Med, Hershey, PA 17033 USA. [Tomasko, Jonathan M.; Rogers, Ann M.; Hajnal, Andras] Penn State Univ, Dept Surg, Coll Med, Hershey, PA USA. [Leggio, Lorenzo] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Leggio, Lorenzo] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Leggio, Lorenzo] Brown Univ, Dept Behav & Social Sci, Providence, RI 02912 USA. [Thanos, Panayotis K.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Volkow, Nora D.] NIAAA Intramural Program, Lab Neuroimaging, NIH, Bethesda, MD USA. RP Hajnal, A (reprint author), Penn State Univ, Dept Neural & Behav Sci, Coll Med, Hershey, PA 17033 USA. EM ahajnal@psu.edu RI Leggio, Lorenzo/M-2972-2016; OI Hajnal, Andras/0000-0001-7297-7134 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK080899] FX This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK080899 (to AH). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 11 Z9 11 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 DEC 31 PY 2013 VL 8 IS 12 AR e83741 DI 10.1371/journal.pone.0083741 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 284NF UT WOS:000329325200114 PM 24391816 ER PT J AU Qi, LN Li, LQ Chen, YY Chen, ZH Bai, T Xiang, BD Qin, X Xiao, KY Peng, MH Liu, ZM Liu, TW Qin, X Li, S Han, ZG Mo, ZN Santella, RM Winkler, CA O'Brien, SJ Peng, T AF Qi, Lu-Nan Li, Le-Qun Chen, Yuan-Yuan Chen, Zhao-Hong Bai, Tao Xiang, Bang-De Qin, Xiao Xiao, Kai-Yin Peng, Min-Hao Liu, Zhi-Ming Liu, Tang-Wei Qin, Xue Li, Shan Han, Ze-Guang Mo, Zeng-Nan Santella, Regina M. Winkler, Cheryl A. O'Brien, Stephen J. Peng, Tao TI Genome-Wide and Differential Proteomic Analysis of Hepatitis B Virus and Aflatoxin B1 Related Hepatocellular Carcinoma in Guangxi, China SO PLOS ONE LA English DT Article ID HEAT-SHOCK PROTEINS; LIVER-CANCER; RISK-FACTORS; LUNG-CANCER; DNA DOMAIN; CELL-DEATH; AKR1B10; EXPRESSION; OVEREXPRESSION; HYBRIDIZATION AB Both hepatitis B virus (HBV) and aflatoxin B1 (AFB1) exposure can cause liver damage as well as increase the probability of hepatocellular carcinoma (HCC). To investigate the underlying genetic changes that may influence development of HCC associated with HBV infection and AFB1 exposure, HCC patients were subdivided into 4 groups depending upon HBV and AFB1 exposure status: (HBV(+)/AFB1(+), HBV(+)/AFB1(-), HBV(-)/AFB1(+), HBV(-)/AFB1(-)). Genetic abnormalities and protein expression profiles were analyzed by array-based comparative genomic hybridization and isobaric tagging for quantitation. A total of 573 chromosomal aberrations (CNAs) including 184 increased and 389 decreased were detected in our study population. Twenty-five recurrently altered regions (RARs; chromosomal alterations observed in >= 10 patients) in chromosomes were identified. Loss of 4q13.3-q35.2, 13q12.1-q21.2 and gain of 7q11.2-q35 were observed with a higher frequency in the HBV(+)/AFB1(+), HBV(+)/AFB1(-) and HBV(-)/AFB1(+) groups compared to the HBV(-)/AFB(-) group. Loss of 8p12-p23.2 was associated with high TNM stage tumors (P = 0.038) and was an unfavorable prognostic factor for tumor-free survival (P =0.045). A total of 133 differentially expressed proteins were identified in iTRAQ proteomics analysis, 69 (51.8%) of which mapped within identified RARs. The most common biological processes affected by HBV and AFB1 status in HCC tumorigenesis were detoxification and drug metabolism pathways, antigen processing and anti-apoptosis pathways. Expression of AKR1B10 was increased significantly in the HBV(+)/AFB1(+) and HBV(-)/AFB1(+) groups. A significant correlation between the expression of AKR1B10 mRNA and protein levels as well as AKR1B10 copy number was observered, which suggest that AKR1B10 may play a role in AFB1-related hepatocarcinogenesis. In summary, a number of genetic and gene expression alterations were found to be associated with HBV and AFB1- related HCC. The possible synergistic effects of HBV and AFB1 in hepatocarcinogenesis warrant further investigations. C1 [Qi, Lu-Nan; Li, Le-Qun; Chen, Zhao-Hong; Bai, Tao; Xiang, Bang-De] Guangxi Med Univ, Tumor Hosp, Dept Hepatobiliary Surg, Nanning, Guangxi Provinc, Peoples R China. [Chen, Yuan-Yuan] Guangxi Med Univ, Affiliated Hosp 1, Dept Ultrasound, Nanning, Guangxi Provinc, Peoples R China. [Qin, Xiao; Xiao, Kai-Yin; Peng, Min-Hao; Liu, Zhi-Ming; Liu, Tang-Wei; Peng, Tao] Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Nanning, Guangxi Provinc, Peoples R China. [Qin, Xue; Li, Shan] Guangxi Med Univ, Affiliated Hosp 1, Dept Clin Lab, Nanning, Guangxi Provinc, Peoples R China. [Han, Ze-Guang] China Natl Human Genome Ctr Shanghai, Shanghai, Peoples R China. [Mo, Zeng-Nan] Guangxi Med Univ, Affiliated Hosp 1, Dept Urol & Nephrol Surg, Nanning, Guangxi Provinc, Peoples R China. [Santella, Regina M.] Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, New York, NY USA. [Winkler, Cheryl A.; O'Brien, Stephen J.; Peng, Tao] NCI, Lab Genom Divers, NIH, Frederick, MD 21701 USA. RP Peng, T (reprint author), Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Nanning, Guangxi Provinc, Peoples R China. EM pengtaocn@hotmail.com OI O'Brien, Stephen J./0000-0001-7353-8301 FU National Nature Science Foundation of China [NSFC 81072321, 30960021, 30460143, 30560133]; Program for New Century Excellent Talents in University (NCET, Chinese Ministry of Educationministry of educationministry of education); Guangxi Nature Sciences [GKJ 0236030, 0632007-1E, 0640101, GKG 0592007-1A]; Guangxi Health Ministry Medicine [Z2010108]; USA National Institutes of Health [ES05116, ES09089] FX This work was supported in part by the National Nature Science Foundation of China (NSFC 81072321, 30960021, 30460143, and 30560133), Program for New Century Excellent Talents in University (NCET, 2009 Chinese Ministry of Educationministry of educationministry of education), Guangxi Nature Sciences Grant (GKJ 0236030,0632007-1E, 0640101, GKG 0592007-1A), Guangxi Health Ministry Medicine Grant (Z2010108), and the USA National Institutes of Health Grants (ES05116 and ES09089). The authors thank Ms. Li Guan and Yu-Chun Zhou (Laboratory of Genomic Diversity, National Cancer Institute at Frederick, USA) and Mr. Li Jia Quan (Laboratory Center, GMU, China) for their laboratory assistance. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 8 Z9 8 U1 2 U2 16 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 DEC 31 PY 2013 VL 8 IS 12 AR e83465 DI 10.1371/journal.pone.0083465 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 284NF UT WOS:000329325200068 PM 24391771 ER PT J AU Renner, LD Eswaramoorthy, P Ramamurthi, KS Weibel, DB AF Renner, Lars D. Eswaramoorthy, Prahathees Ramamurthi, Kumaran S. Weibel, Douglas B. TI Studying Biomolecule Localization by Engineering Bacterial Cell Wall Curvature SO PLOS ONE LA English DT Article ID LIQUID-CRYSTALLINE DROPLETS; ESCHERICHIA-COLI; BACILLUS-SUBTILIS; PROTEIN LOCALIZATION; MEMBRANE CURVATURE; ACTIN MREB; SHAPE; CARDIOLIPIN; PEPTIDOGLYCAN; CYTOSKELETON AB In this article we describe two techniques for exploring the relationship between bacterial cell shape and the intracellular organization of proteins. First, we created microchannels in a layer of agarose to reshape live bacterial cells and predictably control their mean cell wall curvature, and quantified the influence of curvature on the localization and distribution of proteins in vivo. Second, we used agarose microchambers to reshape bacteria whose cell wall had been chemically and enzymatically removed. By combining microstructures with different geometries and fluorescence microscopy, we determined the relationship between bacterial shape and the localization for two different membrane-associated proteins: i) the cell-shape related protein MreB of Escherichia coli, which is positioned along the long axis of the rod-shaped cell; and ii) the negative curvature-sensing cell division protein DivIVA of Bacillus subtilis, which is positioned primarily at cell division sites. Our studies of intracellular organization in live cells of E. coli and B. subtilis demonstrate that MreB is largely excluded from areas of high negative curvature, whereas DivIVA localizes preferentially to regions of high negative curvature. These studies highlight a unique approach for studying the relationship between cell shape and intracellular organization in intact, live bacteria. C1 [Renner, Lars D.; Weibel, Douglas B.] Univ Wisconsin, Dept Biochem, Madison, WI 53705 USA. [Renner, Lars D.] Tech Univ Dresden, D-01062 Dresden, Germany. [Renner, Lars D.] Max Bergmann Ctr Biomat, Dresden, Germany. [Eswaramoorthy, Prahathees; Ramamurthi, Kumaran S.] NCI, NIH, Bethesda, MD 20892 USA. [Weibel, Douglas B.] Univ Wisconsin, Dept Biomed Engn, Madison, WI USA. RP Weibel, DB (reprint author), Univ Wisconsin, Dept Biochem, 420 Henry Mall, Madison, WI 53705 USA. EM weibel@biochem.wisc.edu RI Renner, Lars/D-6291-2012; Ramamurthi, Kumaran/P-3516-2015 OI Renner, Lars/0000-0003-0178-1788; FU National Science Foundation [DMR-1121288]; National Institutes of Health [1DP2OD008735-01]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; University of Wisconsin Materials Research Science and Engineering Center [DMR-1121288]; DFG; Alfred P. Sloan Foundation FX This research was funded by the National Science Foundation (DMR-1121288; L. D. R., D. B. W., http://www.nsf.gov/mps/dmr/highlights.jsp), the National Institutes of Health (1DP2OD008735-01; L. D. R., D. B. W., http://www.nih.gov/), and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (K. S. R. and P. E., http://www.nih.gov/). The authors gratefully acknowledge use of facilities and instrumentation supported by the University of Wisconsin Materials Research Science and Engineering Center (DMR-1121288, http://mrsec.wisc.edu/), and acknowledge support from a DFG Postdoctoral Fellowship (to L. D. R., http://www.dfg.de/) and an Alfred P. Sloan Foundation Fellowship (to D. B. W., http://www.sloan.org/sloan-research-fellowships/). 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 8 U1 0 U2 34 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 DEC 31 PY 2013 VL 8 IS 12 AR e84143 DI 10.1371/journal.pone.0084143 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 284MV UT WOS:000329323900048 PM 24391905 ER PT J AU Wang, Y Goh, JO Resnick, SM Davatzikos, C AF Wang, Ying Goh, Joshua O. Resnick, Susan M. Davatzikos, Christos TI Imaging-Based Biomarkers of Cognitive Performance in Older Adults Constructed via High- Dimensional Pattern Regression Applied to MRI and PET SO PLOS ONE LA English DT Article ID FMRI TIME-SERIES; ALZHEIMERS-DISEASE; MEMORY; BRAIN; AGE; CLASSIFICATION; IMPAIRMENT; DIAGNOSIS; MACHINE; SEGMENTATION AB In this study, we used high-dimensional pattern regression methods based on structural (gray and white matter; GM and WM) and functional (positron emission tomography of regional cerebral blood flow; PET) brain data to identify cross-sectional imaging biomarkers of cognitive performance in cognitively normal older adults from the Baltimore Longitudinal Study of Aging (BLSA). We focused on specific components of executive and memory domains known to decline with aging, including manipulation, semantic retrieval, long-term memory (LTM), and short-term memory (STM). For each imaging modality, brain regions associated with each cognitive domain were generated by adaptive regional clustering. A relevance vector machine was adopted to model the nonlinear continuous relationship between brain regions and cognitive performance, with cross-validation to select the most informative brain regions (using recursive feature elimination) as imaging biomarkers and optimize model parameters. Predicted cognitive scores using our regression algorithm based on the resulting brain regions correlated well with actual performance. Also, regression models obtained using combined GM, WM, and PET imaging modalities outperformed models based on single modalities. Imaging biomarkers related to memory performance included the orbito-frontal and medial temporal cortical regions with LTM showing stronger correlation with the temporal lobe than STM. Brain regions predicting executive performance included orbito-frontal, and occipito-temporal areas. The PET modality had higher contribution to most cognitive domains except manipulation, which had higher WM contribution from the superior longitudinal fasciculus and the genu of the corpus callosum. These findings based on machine-learning methods demonstrate the importance of combining structural and functional imaging data in understanding complex cognitive mechanisms and also their potential usage as biomarkers that predict cognitive status. C1 [Wang, Ying; Davatzikos, Christos] Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. [Goh, Joshua O.; Resnick, Susan M.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Goh, Joshua O.] Natl Taiwan Univ, Coll Med, Grad Inst Brain & Mind Sci, Taipei 10764, Taiwan. RP Wang, Y (reprint author), Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. EM ying.wang@uphs.upenn.edu RI GOH, JOSHUA/C-8063-2016 OI GOH, JOSHUA/0000-0001-7808-5452 FU National Institutes of Health (NIH) [R01AG14971]; Intramural Research Program, National Institute on Aging, NIH; [N01-AG-3-124] FX This work was supported by the National Institutes of Health (NIH) grant R01AG14971, by N01-AG-3-124, and by the Intramural Research Program, National Institute on Aging, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 2 Z9 2 U1 2 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 DEC 31 PY 2013 VL 8 IS 12 AR UNSP e85460 DI 10.1371/journal.pone.0085460 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 284MV UT WOS:000329323900154 PM 24392010 ER PT J AU Bosch, FX Broker, TR Forman, D Moscicki, AB Gillison, ML Doorbar, J Stern, PL Stanley, M Arbyn, M Poljak, M Cuzick, J Castle, PE Schiller, JT Markowitz, LE Fisher, WA Canfell, K Denny, LA Franco, EL Steben, M Kane, MA Schiffman, M Meijer, CJLM Sankaranarayanan, R Castellsague, X Kim, JJ Brotons, M Alemany, L Albero, G Diaz, M de Sanjose, S AF Xavier Bosch, F. Broker, Thomas R. Forman, David Moscicki, Anna-Barbara Gillison, Maura L. Doorbar, John Stern, Peter L. Stanley, Margaret Arbyn, Marc Poljak, Mario Cuzick, Jack Castle, Philip E. Schiller, John T. Markowitz, Lauri E. Fisher, William A. Canfell, Karen Denny, Lynette A. Franco, Eduardo L. Steben, Marc Kane, Mark A. Schiffman, Mark Meijer, Chris J. L. M. Sankaranarayanan, Rengaswamy Castellsague, Xavier Kim, Jane J. Brotons, Maria Alemany, Laia Albero, Ginesa Diaz, Mireia de Sanjose, Silvia CA ICO Monograph 'Comprehensive Conto TI Comprehensive Control of Human Papillomavirus Infections and Related Diseases SO VACCINE LA English DT Review DE HPV; Cervical cancer; Anal cancer; Penile cancer; Vaginal cancer ID CERVICAL-CANCER; PREVENTION; COUNTRIES; VACCINES; WORLD AB Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread optimally universal implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph 'Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Xavier Bosch, F.; Castellsague, Xavier; Brotons, Maria; Alemany, Laia; Albero, Ginesa; Diaz, Mireia; de Sanjose, Silvia] IDIBELL, Catalan Inst Oncol, Canc Epidemiol Res Program, Lhospitalet De Llobregat, Barcelona, Spain. [Broker, Thomas R.] Univ Alabama Birmingham, Birmingham, AL USA. [Forman, David] Int Agcy Res Canc, Sect Canc Informat, F-69372 Lyon, France. [Moscicki, Anna-Barbara] Univ Calif San Francisco, Dept Pediat, Div Adolescent Med, San Francisco, CA USA. [Gillison, Maura L.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Doorbar, John] Natl Inst Med Res, Div Virol, London NW7 1AA, England. [Stern, Peter L.] Univ Manchester, Paterson Inst Canc Res, Manchester, Lancs, England. [Stanley, Margaret] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Arbyn, Marc] Sci Inst Publ Hlth, Canc Epidemiol Unit, Brussels, Belgium. [Arbyn, Marc] Univ Antwerp, Lab Cell Biol & Histol, B-2020 Antwerp, Belgium. [Poljak, Mario] Univ Ljubljana, Fac Med, Inst Microbiol & Immunol, Ljubljana, Slovenia. [Cuzick, Jack] Queen Mary Univ London, Wolfson Inst Prevent Med, London, England. [Castle, Philip E.] Global Canc Initiat, Chestertown, MD USA. [Schiller, John T.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Markowitz, Lauri E.] Ctr Dis Control & Prevent, Natl Ctr HIV Viral Hepatitis STD & TB Prevent, Atlanta, GA USA. [Fisher, William A.] Univ Western Ontario, Dept Psychol, Social Sci Ctr 7428, London, ON, Canada. [Fisher, William A.] Univ Western Ontario, Dept Obstet & Gynaecol, Social Sci Ctr 7428, London, ON, Canada. [Canfell, Karen] Univ NSW, Prince Wales Clin Sch, Lowy Canc Res Ctr, Newcastle, NSW, Australia. [Canfell, Karen] NSW Canc Council, Canc Epidemiol Res Unit, Sydney, NSW, Australia. [Denny, Lynette A.] Univ Cape Town, Groote Schuur Hosp, Dept Obstet & Gynaecol, ZA-7925 Cape Town, South Africa. [Denny, Lynette A.] Univ Cape Town, Groote Schuur Hosp, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Franco, Eduardo L.] McGill Univ, Div Canc Epidemiol, Montreal, PQ, Canada. [Steben, Marc] Inst Natl Sante Publ Quebec, Montreal, PQ, Canada. [Kane, Mark A.] Consultant Immunizat Policy, Mercer Isl, WA USA. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Meijer, Chris J. L. M.] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Sankaranarayanan, Rengaswamy] Int Agcy Res Canc, Screening Grp, F-69372 Lyon, France. [Castellsague, Xavier; Alemany, Laia; Albero, Ginesa; de Sanjose, Silvia] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain. [Kim, Jane J.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. RP Bosch, FX (reprint author), IDIBELL, Catalan Inst Oncol, Canc Epidemiol Res Program, Lhospitalet De Llobregat, Barcelona, Spain. EM admincerp@iconcologia.net RI Albero, Ginesa/G-7248-2015; de Sanjose Llongueras, Silvia/H-6339-2014; Bruni, Laia/N-5816-2014; BOSCH JOSE, FRANCESC XAVIER/J-6339-2012; Castellsague Pique, Xavier/N-5795-2014; DIAZ SANCHIS, MIREIA/H-6335-2014; OI Bruni, Laia/0000-0003-3943-0326; Albero, Ginesa/0000-0002-9400-1914; Kjaer, Susanne/0000-0002-8347-1398; BOSCH JOSE, FRANCESC XAVIER/0000-0002-7172-3412; Castellsague Pique, Xavier/0000-0002-0802-3595; Franco, Eduardo/0000-0002-4409-8084 FU European Commission [HEALTH-F3-2010-242061, HEALTH-F2-2011-282562, 242061]; Instituto de Salud Carlos III (Spanish Government) [FIS PI08/1535, FIS PI10/02995, FIS PI11/02090, FIS PI11/02096, FIS PI11/02104, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095, RD12/0036/0056, CIBERESP]; Agencia de Gestio d'Ajuts Universitaris i de Recerca Generalitat de Catalunya (Catalonian Government) [AGAUR 2005SGR00695, AGAUR 2009SGR126]; USPHS/NIH/National Cancer Institute [CA36200, CA83679]; US Public Health Service (National Cancer Institute, National Institutes of Health, Department of Health and Human Services) [R37 CA51323]; National Institute of AIDS and Infectious Disease [RC1 AI86051]; UK Medical Research Council [MC_U117584278]; Belgian Foundation Against Cancer (Brussels, Belgium); International Agency for Research on Cancer (Lyon, France); Cancer Research UK [A10404]; National Health and Medical Research Council, Australia [CDF APP1007994, 1007518]; Bill and Melinda Gates Foundation, USA [35537]; U.S. National Cancer Institute [U54 CA164336, R01 CA160744-01A1]; Bill and Melinda Gates Foundation [30505]; Cancer Council NSW, Australia FX The work was partially supported by public grants from the European Commission (7th Framework Programme grants HEALTH-F3-2010-242061, PREHDICT and HEALTH-F2-2011-282562, HPV AHEAD), from the Instituto de Salud Carlos III (Spanish Government) (grants FIS PI08/1535, FIS PI10/02995, FIS PI11/02090, FIS PI11/02096, FIS PI11/02104, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095, RD12/0036/0056 and CIBERESP) and from the Agencia de Gestio d'Ajuts Universitaris i de Recerca Generalitat de Catalunya (Catalonian Government) (grants AGAUR 2005SGR00695 and AGAUR 2009SGR126), who had no role in data collection, analysis or interpretation of results. Thomas R. Broker receives research support from the USPHS/NIH/National Cancer Institute (grants "Human Papillomavirus Gene Expression" CA36200 and "Mechanisms of Human Papillomavirus DNA Replication" CA83679). Anna-Barbara Moscicki's work is supported by US Public Health Service grant R37 CA51323 (National Cancer Institute, National Institutes of Health, Department of Health and Human Services) and National Institute of AIDS and Infectious Disease RC1 AI86051. John Doorbar is funded by the UK Medical Research Council through program grant MC_U117584278 (Molecular Biology of Human Papillomavirus Infection). Marc Arbyn received financial support from: (1) the 7th Framework Programme of DG Research of the European Commission through the PREHDICT project (grant No. 242061, coordinated by the Vrije Universiteit Amsterdam, the Netherlands) and through the HPV AHEAD Network (FP7-HEALTH-2011-282562); (2) the Belgian Foundation Against Cancer (Brussels, Belgium); and (3) the International Agency for Research on Cancer (Lyon, France). Jack Cuzick was supported in part by Cancer Research UK programme grant A10404. Karen Canfell is supported by grants from the National Health and Medical Research Council, Australia (CDF APP1007994 and Project Grant #1007518), by non-commercial government and academic consulting agreements in Australia, New Zealand and the UK, and by Cancer Council NSW, Australia. Lynette A. Denny was partially supported by Bill and Melinda Gates Foundation, USA (35537). The work of Chris J.L.M. Meijer received support via the 7th Framework Programme of DG Research of the European commission through the PREHDICT project (grant 242061, coordinated via the Vrije Universiteit Amsterdam). Jane J. Kim is supported in part by grants from the U.S. National Cancer Institute (U54 CA164336, R01 CA160744-01A1) and the Bill and Melinda Gates Foundation (30505) for modeling of HPV and cervical cancer in developing countries. NR 20 TC 15 Z9 20 U1 9 U2 43 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 31 PY 2013 VL 31 SU 7 BP H1 EP H31 DI 10.1016/j.vaccine.2013.10.003 PG 31 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 288HM UT WOS:000329602600003 PM 24332295 ER PT J AU Desrosiers, M DeWerd, L Deye, J Lindsay, P Murphy, MK Mitch, M Macchiarini, F Stojadinovic, S Stone, H AF Desrosiers, Marc DeWerd, Larry Deye, James Lindsay, Patricia Murphy, Mark K. Mitch, Michael Macchiarini, Francesca Stojadinovic, Strahinja Stone, Helen TI The Importance of Dosimetry Standardization in Radiobiology SO JOURNAL OF RESEARCH OF THE NATIONAL INSTITUTE OF STANDARDS AND TECHNOLOGY LA English DT Article DE dosimetry; dosimetry protocols; dosimetry standards; radiobiology; radiobiology protocols; radiobiology standards ID RADIOTHERAPY; PROTOCOL; PHOTON; ENERGY AB Radiation dose is central to much of radiobiological research. Precision and accuracy of dose measurements and reporting of the measurement details should be sufficient to allow the work to be interpreted and repeated and to allow valid comparisons to be made, both in the same laboratory and by other laboratories. Despite this, a careful reading of published manuscripts suggests that measurement and reporting of radiation dosimetry and setup for radiobiology research is frequently inadequate, thus undermining the reliability and reproducibility of the findings. To address these problems and propose a course of action, the National Cancer Institute (NCI), the National Institute of Allergy and Infectious Diseases (NIAID), and the National Institute of Standards and Technology (NIST) brought together representatives of the radiobiology and radiation physics communities in a workshop in September, 2011. The workshop participants arrived at a number of specific recommendations as enumerated in this paper and they expressed the desirability of creating dosimetry standard operating procedures (SOPs) for cell culture and for small and large animal experiments. It was also felt that these SOPs would be most useful if they are made widely available through mechanism(s) such as the web, where they can provide guidance to both radiobiologists and radiation physicists, be cited in publications, and be updated as the field and needs evolve. Other broad areas covered were the need for continuing education through tutorials at national conferences, and for journals to establish standards for reporting dosimetry. This workshop did not address issues of dosimetry for studies involving radiation focused at the sub-cellular level, internally-administered radionuclides, biodosimetry based on biological markers of radiation exposure, or dose reconstruction for epidemiological studies. C1 [Desrosiers, Marc; Mitch, Michael] NIST, Gaithersburg, MD 20899 USA. [DeWerd, Larry] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Deye, James; Stone, Helen] NCI, NIH, Bethesda, MD 20892 USA. [Lindsay, Patricia] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Murphy, Mark K.] Battelle Pacific Northwest Natl Lab, Richland, WA USA. [Macchiarini, Francesca] Natl Inst Allergy & Infect Dis, NIH, Bethesda, MD USA. [Stojadinovic, Strahinja] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Desrosiers, M (reprint author), NIST, Gaithersburg, MD 20899 USA. EM marc.desrosiers@nist.gov; ladewerd@facstaff.wisc.edu; deyej@mail.nih.gov; Patricia.Lindsay@rmp.uhn.on.ca; michael.mitch@nist.gov; michael.mitch@nist.gov; fmacchiarini@niaid.nih.gov; Strahinja.Stojadinovic@UTSouthwestern.edu; stoneh@mail.nih.gov NR 16 TC 7 Z9 7 U1 1 U2 7 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 1044-677X J9 J RES NATL INST STAN JI J. Res. Natl. Inst. Stand. Technol. PD DEC 30 PY 2013 VL 118 DI 10.6028/jres.118.021 PG 16 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA 289TC UT WOS:000329704000001 PM 26401441 ER PT J AU Bosch, FX Broker, TR Forman, D Moscicki, AB Gillison, ML Doorbar, J Stern, PL Stanley, M Arbyn, M Poljak, M Cuzick, J Castle, PE Schiller, JT Markowitz, LE Fisher, WA Canfell, K Denny, LA Franco, EL Steben, M Kane, MA Schiffman, M Meijer, CJLM Sankaranarayanan, R Castellsague, X Kim, JJ Brotons, M Alemany, L Albero, G Diaz, M de Sanjose, S AF Xavier Bosch, F. Broker, Thomas R. Forman, David Moscicki, Anna-Barbara Gillison, Maura L. Doorbar, John Stern, Peter L. Stanley, Margaret Arbyn, Marc Poljak, Mario Cuzick, Jack Castle, Philip E. Schiller, John T. Markowitz, Lauri E. Fisher, William A. Canfell, Karen Denny, Lynette A. Franco, Eduardo L. Steben, Marc Kane, Mark A. Schiffman, Mark Meijer, Chris J. L. M. Sankaranarayanan, Rengaswamy Castellsague, Xavier Kim, Jane J. Brotons, Maria Alemany, Laia Albero, Ginesa Diaz, Mireia de Sanjose, Silvia CA ICO Monograph 'Comprehensive Contr TI Comprehensive Control of Human Papillomavirus Infections and Related Diseases SO VACCINE LA English DT Review DE HPV; Cervical cancer; Anal cancer; Penile cancer; Vaginal cancer; Vulvar cancer; Oropharyngeal cancer; Screening; HPV vaccination; HPV testing; Prevention ID CERVICAL-CANCER; PREVENTION; COUNTRIES; VACCINES; WORLD AB Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread-optimally universal-implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph 'Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Xavier Bosch, F.; Castellsague, Xavier; Kim, Jane J.; Brotons, Maria; Alemany, Laia; Albero, Ginesa; Diaz, Mireia; de Sanjose, Silvia] IDIBELL, Catalan Inst Oncol ICO, Canc Epidemiol Res Program, Lhospitalet De Llobregat, Barcelona, Spain. [Broker, Thomas R.] Univ Alabama Birmingham, Birmingham, AL USA. [Forman, David] Int Agcy Res Canc, Sect Canc Informat, F-69372 Lyon, France. [Moscicki, Anna-Barbara] Univ Calif San Francisco, Dept Pediat, Div Adolescent Med, San Francisco, CA USA. [Gillison, Maura L.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH USA. [Doorbar, John] Natl Inst Med Res, Div Virol, London NW7 1AA, England. [Stern, Peter L.] Univ Manchester, Paterson Inst Canc Res, Manchester, Lancs, England. [Stanley, Margaret] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Arbyn, Marc] Sci Inst Publ Hlth, Canc Epidemiol Unit, Brussels, Belgium. [Arbyn, Marc] Univ Antwerp, Lab Cell Biol & Histol, B-2020 Antwerp, Belgium. [Poljak, Mario] Univ Ljubljana, Fac Med, Inst Microbiol & Immunol, Ljubljana, Slovenia. [Cuzick, Jack] Queen Mary Univ London, Wolfson Inst Prevent Med, London, England. [Castle, Philip E.] Global Canc Initiat, Chestertown, MD USA. [Schiller, John T.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Markowitz, Lauri E.] Ctr Dis Control & Prevent, Natl Ctr HIV Viral Hepatitis STD & TB Prevent, Atlanta, GA USA. [Fisher, William A.] Univ Western Ontario, Dept Psychol, Social Sci Ctr, London, ON, Canada. [Fisher, William A.] Univ Western Ontario, Dept Obstet & Gynaecol, Social Sci Ctr, London, ON, Canada. [Canfell, Karen] Univ NSW, Prince Wales Clin Sch, Lowy Canc Res Ctr, Sydney, NSW, Australia. [Canfell, Karen] NSW Canc Council, Canc Epidemiol Res Unit, Sydney, NSW, Australia. [Denny, Lynette A.] Univ Cape Town, Groote Schuur Hosp, Dept Obstet & Gynaecol, ZA-7925 Cape Town, South Africa. [Denny, Lynette A.] Univ Cape Town, Groote Schuur Hosp, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Franco, Eduardo L.] McGill Univ, Div Canc Epidemiol, Montreal, PQ, Canada. [Steben, Marc] Inst Natl Sante Publ Quebec, Montreal, PQ, Canada. [Kane, Mark A.] Consultant Immunizat Policy, Mercer Isl, WA USA. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Meijer, Chris J. L. M.] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Sankaranarayanan, Rengaswamy] Int Agcy Res Canc, Screening Grp, F-69372 Lyon, France. [Castellsague, Xavier; Alemany, Laia; Albero, Ginesa; de Sanjose, Silvia] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain. [Kim, Jane J.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. RP Bosch, FX (reprint author), IDIBELL, Catalan Inst Oncol ICO, Canc Epidemiol Res Program, Lhospitalet De Llobregat, Barcelona, Spain. EM admincerp@iconcologia.net RI de Sanjose Llongueras, Silvia/H-6339-2014; Bruni, Laia/N-5816-2014; BOSCH JOSE, FRANCESC XAVIER/J-6339-2012; Castellsague Pique, Xavier/N-5795-2014; DIAZ SANCHIS, MIREIA/H-6335-2014; Albero, Ginesa/G-7248-2015; OI BOSCH JOSE, FRANCESC XAVIER/0000-0002-7172-3412; Castellsague Pique, Xavier/0000-0002-0802-3595; Albero, Ginesa/0000-0002-9400-1914; Kjaer, Susanne/0000-0002-8347-1398; Bruni, Laia/0000-0003-3943-0326; Franco, Eduardo/0000-0002-4409-8084 FU European Commission [HEALTH-F3-2010-242061, HEALTH-F2-2011-282562]; Instituto de Salud Carlos III (Spanish Government) [FIS PI08/1535, FIS PI10/02995, FIS PI11/02090, FIS PI11/02096, FIS PI11/02104, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095, RD12/0036/0056, CIBERESP]; Agencia de Gestio d'Ajuts Universitaris i de Recerca - Generalitat de Catalunya (Catalonian Government) [AGAUR 2005SGR00695, AGAUR 2009SGR126]; USPHS/NIH/National Cancer Institute [CA36200, CA83679]; US Public Health Service grant (National Cancer Institute, National Institutes of Health, Department of Health and Human Services) [R37 CA51323]; National Institute of AIDS and Infectious Disease [RC1 AI86051]; UK Medical Research Council [MC_U117584278]; European Commission through the PREHDICT project [242061]; European Commission through HPV AHEAD Network [FP7-HEALTH-2011-282562]; Belgian Foundation Against Cancer (Brussels, Belgium); International Agency for Research on Cancer (Lyon, France); Cancer Research UK [A10404]; National Health and Medical Research Council, Australia [CDF APP1007994, 1007518]; Cancer Council NSW, Australia; Bill and Melinda Gates Foundation, USA [35537]; U.S. National Cancer Institute [U54 CA164336, R01 CA160744-01A1]; Bill and Melinda Gates Foundation [30505] FX The work was partially supported by public grants from the European Commission (7th Framework Programme grants HEALTH-F3-2010-242061, PREHDICT and HEALTH-F2-2011-282562, HPV AHEAD), from the Instituto de Salud Carlos III (Spanish Government) (grants FIS PI08/1535, FIS PI10/02995, FIS PI11/02090, FIS PI11/02096, FIS PI11/02104, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095, RD12/0036/0056 and CIBERESP) and from the Agencia de Gestio d'Ajuts Universitaris i de Recerca - Generalitat de Catalunya (Catalonian Government) (grants AGAUR 2005SGR00695 and AGAUR 2009SGR126), who had no role in data collection, analysis or interpretation of results. Thomas R. Broker receives research support from the USPHS/NIH/National Cancer Institute (grants "Human Papillomavirus Gene Expression" CA36200 and "Mechanisms of Human Papillomavirus DNA Replication" CA83679). Anna-Barbara Moscicki's work is supported by US Public Health Service grant R37 CA51323 (National Cancer Institute, National Institutes of Health, Department of Health and Human Services) and National Institute of AIDS and Infectious Disease RC1 AI86051. John Doorbar is funded by the UK Medical Research Council through program grant MC_U117584278 (Molecular Biology of Human Papillomavirus Infection). Marc Arbyn received financial support from: (1) the 7th Framework Programme of DG Research of the European Commission through the PREHDICT project (grant No. 242061, coordinated by the Vrije Universiteit Amsterdam, the Netherlands) and through the HPV AHEAD Network (FP7-HEALTH-2011-282562); (2) the Belgian Foundation Against Cancer (Brussels, Belgium); and (3) the International Agency for Research on Cancer (Lyon, France). Jack Cuzick was supported in part by Cancer Research UK programme grant A10404. Karen Canfell is supported by grants from the National Health and Medical Research Council, Australia (CDF APP1007994 and Project Grant #1007518), by non-commercial government and academic consulting agreements in Australia, New Zealand and the UK, and by Cancer Council NSW, Australia. Lynette A. Denny was partially supported by Bill and Melinda Gates Foundation, USA (35537). The work of Chris J.L.M. Meijer received support via the 7th Framework Programme of DG Research of the European commission through the PREHDICT project (grant 242061, coordinated via the Vrije Universiteit Amsterdam). Jane J. Kim is supported in part by grants from the U.S. National Cancer Institute (U54 CA164336, R01 CA160744-01A1) and the Bill and Melinda Gates Foundation (30505) for modeling of HPV and cervical cancer in developing countries. NR 20 TC 0 Z9 1 U1 1 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 30 PY 2013 VL 31 SU 6 BP G1 EP G31 DI 10.1016/j.vaccine.2013.10.002 PG 31 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 289LR UT WOS:000329684500003 PM 24331817 ER PT J AU Peer, CJ Brown, JL Martin, TJ Roth, J Spencer, SD Brassil, P McNeill, KA Kreisl, TN Fine, HA Figg, WD AF Peer, Cody J. Brown, Jeffrey L. Martin, Timothy J. Roth, Jeffrey Spencer, Shawn D. Brassil, Patrick McNeill, Katharine A. Kreisl, Teri N. Fine, Howard A. Figg, William D. TI A novel uHPLC-MS/MS method for the quantitation of AZD7451 (AZ12607092) in human plasma SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Tropomyosin-related kinase; Ultra-high performance liquid; chromatography; Tandem mass spectrometry ID RECEPTORS AB Tropomyosin-related kinases (Trk) are tyrosine kinase receptors implicated in tumor proliferation, invasion, and survival signaling across a number of tumors, making them potentially attractive targets for the treatment of cancer. AZD7451 is a potent and selective inhibitor of Trk kinases currently undergoing a Phase I dose escalation in glioblastoma multiforme at the National Cancer Institute. A key part of early clinical testing for AZD7451 involves demonstrating that pharmacokinetic half-life and clinical exposures of AZD7451 are sufficient to inhibit Trk receptors in preclinical models. To address this need, an ultra sensitive analytical method was developed to measure the AZD7451 profile in human plasma. A liquid-liquid extraction recovered >80% of AZD7451 before quantitative analysis by ultra HPLC-MS/MS. A Varian Polaris (R) C18-A column and a mass transition of m/z 383.5 -> 340.5 (m/z 389.6 -> 342.0 for the internal standard [H-2(6)]-AZD7451) was used, and a dynamic calibration range of 0.5-1000 ng/mL was established, which provided a sensitive (<8.5% deviation), and precise (<6%) quantitative assay for AZD7451. AZD7451 demonstrated stability in human plasma at room temperature for 24 h (<7% change) and after extraction at 4 degrees C for 24 h (<8% change), and was stable through 4 freeze/thaw cycles (<8% change). This method was used to measure AZD7451 plasma levels in clinical samples to confirm the sensitivity at several time points following AZD7451 treatment in subjects with glioblastoma. Published by Elsevier B.V. C1 [Peer, Cody J.; Martin, Timothy J.; Roth, Jeffrey; Figg, William D.] NCI, Clin Pharmacol Program, Off Clin Director, Bethesda, MD 20892 USA. [Brown, Jeffrey L.; Brassil, Patrick] AstraZeneca, Waltham, MA USA. [Spencer, Shawn D.] Fairleigh Dickinson Univ, Sch Pharm, Div Pharmaceut Sci, Florham Pk, NJ USA. [McNeill, Katharine A.; Kreisl, Teri N.; Fine, Howard A.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [McNeill, Katharine A.; Fine, Howard A.] NYU, Brain Tumor Ctr, Langone Med Ctr, New York, NY USA. [McNeill, Katharine A.; Fine, Howard A.] NYU, Inst Canc, Langone Med Ctr, New York, NY USA. RP Figg, WD (reprint author), Clin Pharmacol Program, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU Intramural Research Program of the NIH; National Cancer Institute and in part by a CRADA between the National Cancer Institute and AstraZeneca [02429] FX This study was funded in part the Intramural Research Program of the NIH, National Cancer Institute and in part by a CRADA between the National Cancer Institute and AstraZeneca (#02429). This is a US Government work. There are no restrictions on its use. The views expressed within this paper do not necessarily reflect those of the US Government. We thank the nursing staff of the National Cancer Institute and the fellows of the Medical Oncology Branch at the National Cancer Institute for their care of our patients; Cynthia Graves for data management assistance; and Cancer Therapy and Evaluation Program for sponsoring the trial. Most importantly, we appreciate the patients with cancer who enroll in investigational trials to advance the knowledge of this disease. NR 10 TC 1 Z9 1 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 EI 1873-376X J9 J CHROMATOGR B JI J. Chromatogr. B PD DEC 30 PY 2013 VL 942 BP 107 EP 112 DI 10.1016/j.jchromb.2013.10.023 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 270FH UT WOS:000328303800015 PM 24239935 ER PT J AU Bosch, FX Broker, TR Forman, D Moscicki, AB Gillison, ML Doorbar, J Stern, PL Stanley, M Arbyn, M Poljak, M Cuzick, J Castle, PE Schiller, JT Markowitz, LE Fisher, WA Canfell, K Denny, LA Franco, EL Steben, M Kane, MA Schiffman, M Meijer, CJLM Sankaranarayanan, R Castellsague, X Kim, JJ Brotons, M Alemanya, L Albero, G Diaz, M de Sanjose, S AF Bosch, F. Xavier Broker, Thomas R. Forman, David Moscicki, Anna-Barbara Gillison, Maura L. Doorbar, John Stern, Peter L. Stanley, Margaret Arbyn, Marc Poljak, Mario Cuzick, Jack Castle, Philip E. Schiller, John T. Markowitz, Lauri E. Fisher, William A. Canfell, Karen Denny, Lynette A. Franco, Eduardo L. Steben, Marc Kane, Mark A. Schiffman, Mark Meijer, Chris J. L. M. Sankaranarayanan, Rengaswamy Castellsague, Xavier Kim, Jane J. Brotons, Maria Alemanya, Laia Albero, Ginesa Diaz, Mireia de Sanjose, Silvia CA ICO Monograph Comprehensive Contro TI Comprehensive Control of Human Papillomavirus Infections and Related Diseases SO VACCINE LA English DT Review DE HPV; Cervical cancer; Anal cancer; Penile cancer; Vaginal cancer; Vulvar cancer; Oropharyngeal cancer; Screening; HPV vaccination; HPV testing; Prevention ID CERVICAL-CANCER; PREVENTION; COUNTRIES; VACCINES; WORLD AB Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread-optimally universal-implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph 'Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Bosch, F. Xavier; Castellsague, Xavier; Brotons, Maria; Alemanya, Laia; Albero, Ginesa; Diaz, Mireia; de Sanjose, Silvia] IDIBELL, Inst Catala Oncol Catalan Inst Oncol ICO, Canc Epidemiol Res Program, Lhospitalet De Llobregat, Barcelona, Spain. [Broker, Thomas R.] Univ Alabama Birmingham, Birmingham, AL USA. [Forman, David] Int Agcy Res Canc, Sect Canc Informat, F-69372 Lyon, France. [Moscicki, Anna-Barbara] Univ Calif San Francisco, Dept Pediat, Div Adolescent Med, San Francisco, CA USA. [Gillison, Maura L.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Doorbar, John] Natl Inst Med Res, Div Virol, London NW7 1AA, England. [Stern, Peter L.] Univ Manchester, Paterson Inst Canc Res, Manchester, Lancs, England. [Stanley, Margaret] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Arbyn, Marc] Sci Inst Publ Hlth, Canc Epidemiol Unit, Brussels, Belgium. [Arbyn, Marc] Univ Antwerp, Lab Cell Biol & Histol, B-2020 Antwerp, Belgium. [Poljak, Mario] Univ Ljubljana, Fac Med, Inst Microbiol & Immunol, Ljubljana, Slovenia. [Cuzick, Jack] Queen Mary Univ London, Wolfson Inst Prevent Med, London, England. [Castle, Philip E.] Global Canc Initiat, Chestertown, MD USA. [Schiller, John T.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Markowitz, Lauri E.] Ctr Dis Control & Prevent, Natl Ctr HIV Viral Hepatitis STD & TB Prevent, Atlanta, GA USA. [Fisher, William A.] Univ Western Ontario, Dept Psychol, Social Sci Ctr, London, ON, Canada. [Fisher, William A.] Univ Western Ontario, Dept Obstet & Gynaecol, Social Sci Ctr, London, ON, Canada. [Canfell, Karen] Univ NSW, Prince Wales Clin Sch, Lowy Canc Res Ctr, Sydney, NSW, Australia. [Canfell, Karen] NSW Canc Council, Canc Epidemiol Res Unit, Sydney, NSW, Australia. [Denny, Lynette A.] Univ Cape Town, Dept Obstet & Gynaecol, Groote Schuur Hosp, Cape Town, South Africa. [Denny, Lynette A.] Univ Cape Town, Inst Infect Dis & Mol Med, Groote Schuur Hosp, Cape Town, South Africa. [Franco, Eduardo L.] McGill Univ, Div Canc Epidemiol, Montreal, PQ, Canada. [Steben, Marc] Inst Natl Sante Publ Quebec, Montreal, PQ, Canada. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Meijer, Chris J. L. M.] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Sankaranarayanan, Rengaswamy] Int Agcy Res Canc, Screening Grp, F-69372 Lyon, France. [Castellsague, Xavier; Alemanya, Laia; Albero, Ginesa; de Sanjose, Silvia] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain. [Kim, Jane J.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. RP Bosch, FX (reprint author), IDIBELL, Inst Catala Oncol Catalan Inst Oncol ICO, Canc Epidemiol Res Program, Lhospitalet De Llobregat, Barcelona, Spain. EM admincerp@iconcologia.net RI Castellsague Pique, Xavier/N-5795-2014; de Sanjose Llongueras, Silvia/H-6339-2014; DIAZ SANCHIS, MIREIA/H-6335-2014; Albero, Ginesa/G-7248-2015; BOSCH JOSE, FRANCESC XAVIER/J-6339-2012 OI Castellsague Pique, Xavier/0000-0002-0802-3595; Albero, Ginesa/0000-0002-9400-1914; Franco, Eduardo/0000-0002-4409-8084; BOSCH JOSE, FRANCESC XAVIER/0000-0002-7172-3412 FU European Commission [HEALTH-F3-2010-242061, HEALTH-F2-2011-282562]; Instituto de Salud Carlos III (Spanish Government) [FIS PI08/1535, FIS PI10/02995, FIS PI11/02090, FIS PI11/02096, FIS PI11/02104, RCESP C03/09, RTICESP C03110, RTIC RD06/0020/0095, RD12/0036/0056, CIBERESP]; Agenda de Gestio d'Ajuts Universitaris i de Recerca - Generalitat de Catalunya (Catalonian Government) [AGAUR 2005SGR00695, AGAUR 2009SGR126]; USPHS/NIH/National Cancer Institute [CA36200, CA83679]; US Public Health Service (National Cancer Institute, National Institutes of Health, Department of Health and Human Services) [R37 CA51323]; National Institute of AIDS and Infectious Disease [RC1 AI86051]; UK Medical Research Council [MC_U117584278]; European Commission through PREHDICT [242061]; European Commission through HPV AHEAD Network [FP7-HEALTH-2011-282562]; Belgian Foundation Against Cancer (Brussels, Belgium); International Agency for Research on Cancer (Lyon, France); Cancer Research UK [A10404]; National Health and Medical Research Council, Australia [CDF APP1007994, 1007518]; non-commercial government and academic consulting agreements in Australia, New Zealand; non-commercial government and academic consulting agreements in Australia, New Zealand, UK; Cancer Council NSW, Australia; Bill and Melinda Gates Foundation, USA [35537]; U.S. National Cancer Institute [U54 CA164336, R01 CA160744-01A1]; Bill and Melinda Gates Foundation [30505] FX The work was partially supported by public grants from the European Commission (7th Framework Programme grants HEALTH-F3-2010-242061, PREHDICT and HEALTH-F2-2011-282562, HPV AHEAD), from the Instituto de Salud Carlos III (Spanish Government) (grants FIS PI08/1535, FIS PI10/02995, FIS PI11/02090, FIS PI11/02096, FIS PI11/02104, RCESP C03/09, RTICESP C03110, RTIC RD06/0020/0095, RD12/0036/0056 and CIBERESP) and from the Agenda de Gestio d'Ajuts Universitaris i de Recerca - Generalitat de Catalunya (Catalonian Government) (grants AGAUR 2005SGR00695 and AGAUR 2009SGR126), who had no role in data collection, analysis or interpretation of results. Thomas R. Broker receives research support from the USPHS/NIH/National Cancer Institute (grants "Human Papillomavirus Gene Expression" CA36200 and "Mechanisms of Human Papillomavirus DNA Replication" CA83679). Anna-Barbara Moscicki's work is supported by US Public Health Service grant R37 CA51323 (National Cancer Institute, National Institutes of Health, Department of Health and Human Services) and National Institute of AIDS and Infectious Disease RC1 AI86051. John Doorbar is funded by the UK Medical Research Council through program grant MC_U117584278 (Molecular Biology of Human Papillomavirus Infection). Marc Arbyn received financial support from: (1) the 7th Framework Programme of DG Research of the European Commission through the PREHDICT project (grant No. 242061, coordinated by the Vrije Universiteit Amsterdam, the Netherlands) and through the HPV AHEAD Network (FP7-HEALTH-2011-282562); (2) the Belgian Foundation Against Cancer (Brussels, Belgium); and (3) the International Agency for Research on Cancer (Lyon, France). Jack Cuzick was supported in part by Cancer Research UK programme grant A10404. Karen Canfell is supported by grants from the National Health and Medical Research Council, Australia (CDF APP1007994 and Project Grant #1007518), by non-commercial government and academic consulting agreements in Australia, New Zealand and the UK, and by Cancer Council NSW, Australia. Lynette A. Denny was partially supported by Bill and Melinda Gates Foundation, USA (35537). The work of Chris J.L.M. Meijer received support via the 7th Framework Programme of DG Research of the European commission through the PREHDICT project (grant 242061, coordinated via the Vrije Universiteit Amsterdam). Jane J. Kim is supported in part by grants from the U.S. National Cancer Institute (U54 CA164336, R01 CA160744-01A1) and the Bill and Melinda Gates Foundation (30505) for modeling of HPV and cervical cancer in developing countries. NR 20 TC 0 Z9 0 U1 2 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 29 PY 2013 VL 31 SU 5 BP F1 EP F31 DI 10.1016/j.vaccine.2013.10.001 PG 31 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 289LQ UT WOS:000329684400003 PM 24331745 ER PT J AU De Vuyst, H Alemany, L Lacey, C Chibwesha, CJ Sahasrabuddhe, V Banura, C Denny, L Parham, GP AF De Vuyst, Hugo Alemany, Laia Lacey, Charles Chibwesha, Carla J. Sahasrabuddhe, Vikrant Banura, Cecily Denny, Lynette Parham, Groesbeck P. TI The Burden of Human Papillomavirus Infections and Related Diseases in Sub-Saharan Africa SO VACCINE LA English DT Review DE HPV epidemiology; Cervical cancer; Anogenital cancers; Genital warts; Sub-Saharan Africa ID HUMAN-IMMUNODEFICIENCY-VIRUS; SQUAMOUS INTRAEPITHELIAL LESIONS; INVASIVE CERVICAL-CARCINOMA; RISK HUMAN-PAPILLOMAVIRUS; HIV-SEROPOSITIVE MEN; SOUTH-AFRICA; HPV INFECTION; ANTIRETROVIRAL THERAPY; CODON-72 POLYMORPHISM; MALE CIRCUMCISION AB Despite the scarcity of high quality cancer registries and lack of reliable mortality data, it is clear that human papillomavirus (HPV)-associated diseases, particularly cervical cancer, are major causes of morbidity and mortality in sub-Saharan Africa (SSA). Cervical cancer incidence rates in SSA are the highest in the world and the disease is the most common cause of cancer death among women in the region. The high incidence of cervical cancer is a consequence of the inability of most countries to either initiate or sustain cervical cancer prevention services. In addition, it appears that the prevalence of HPV in women with normal cytology is higher than in more developed areas of the world, at an average of 24%. There is, however, significant regional variation in SSA, with the highest incidence of HPV infection and cervical cancer found in Eastern and Western Africa. It is expected that, due to aging and growth of the population, but also to lack of access to appropriate prevention services and the concomitant human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic, cervical cancer incidence and mortality rates in SSA will rise over the next 20 years. HPV16 and 18 are the most common genotypes in cervical cancer in SSA, although other carcinogenic HPV types, such as HPV45 and 35, are also relatively more frequent compared with other world regions. Data on other HPV-related anogenital cancers including those of the vulva, vagina, anus, and penis, are limited. Genital warts are common and associated with HPV types 6 and 11. HIV infection increases incidence and prevalence of all HPV-associated diseases. Sociocultural determinants of HPV-related disease, as well as the impact of forces that result in social destabilization, demand further study. Strategies to reduce the excessive burden of HPV-related diseases in SSA include age-appropriate prophylactic HPV vaccination, cervical cancer prevention services for women of the reproductive ages, and control of HIV/AIDS. This article forms part of a regional report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Sub-Saharan Africa Region"Vaccine Volume 31, Supplement 5, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012. (C) 2013 Published by Elsevier Ltd. C1 [De Vuyst, Hugo] Int Agcy Res Canc WHO IARC, Infect & Canc Epidemiol Grp, Lyon, France. [Alemany, Laia] Inst Catala Oncol Catalan Inst Oncol ICO, Canc Epidemiol Res Program, Unit Infect & Canc UNIC, Lhospitalet De Llobregat, Barcelona, Spain. [Alemany, Laia] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain. [Lacey, Charles] Univ York, Hull York Med Sch, Ctr Immunol & Infect, York YO10 5DD, N Yorkshire, England. [Chibwesha, Carla J.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Chibwesha, Carla J.] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Sahasrabuddhe, Vikrant] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Banura, Cecily] Makerere Univ, Coll Hlth Sci, Dept Child Hlth & Dev Ctr, Kampala, Uganda. [Denny, Lynette] Univ Cape Town, Dept Obstet & Gynaecol, Groote Schuur Hosp, Cape Town, South Africa. [Denny, Lynette] Univ Cape Town, Inst Infect Dis & Mol Med, Groote Schuur Hosp, Cape Town, South Africa. [Parham, Groesbeck P.] Univ N Carolina, Dept Obstet & Gynecol, UNC Global Womens Hlth, Chapel Hill, NC USA. RP Parham, GP (reprint author), Univ N Carolina, Dept Obstet & Gynecol, UNC Global Womens Hlth, Chapel Hill, NC USA. EM groesbeckparham@cidrz.org FU Bill & Melinda Gates Foundation (BMGF), USA [35537]; Instituto de Salud Carlos III (Spanish Government) [RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095, RD12/0036/0056, CIBERESP]; Agencia de Gestio d'Ajuts Universitaris i de Recerca - Generalitat de Catalunya (Catalonian Government) [AGAUR 2005SGR00695, AGAUR 2009SGR126] FX This work was supported by the Bill & Melinda Gates Foundation (BMGF), USA (grant number 35537). Laia Alemany's work was partially supported by public grants from the Instituto de Salud Carlos III (Spanish Government) (grants RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095, RD12/0036/0056 and CIBERESP) and from the Agencia de Gestio d'Ajuts Universitaris i de Recerca - Generalitat de Catalunya (Catalonian Government) (grants AGAUR 2005SGR00695 and AGAUR 2009SGR126). NR 97 TC 27 Z9 27 U1 4 U2 22 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 29 PY 2013 VL 31 SU 5 BP F32 EP F46 DI 10.1016/j.vaccine.2012.07.092 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 289LQ UT WOS:000329684400004 PM 24331746 ER PT J AU Prentice, RL Zhao, SS Johnson, M Aragaki, A Hsia, J Jackson, RD Rossouw, JE Manson, JE Hanash, SM AF Prentice, Ross L. Zhao, Shanshan Johnson, Melissa Aragaki, Aaron Hsia, Judith Jackson, Rebecca D. Rossouw, Jacques E. Manson, JoAnn E. Hanash, Samir M. TI Proteomic risk markers for coronary heart disease and stroke: validation and mediation of randomized trial hormone therapy effects on these diseases SO GENOME MEDICINE LA English DT Article ID GROWTH-FACTOR-I; CONJUGATED EQUINE ESTROGENS; C-REACTIVE PROTEIN; ISCHEMIC-STROKE; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; PLUS PROGESTIN; BETA-2-MICROGLOBULIN; PREDICTION; BETA(2)-MICROGLOBULIN AB Background: We previously reported mass spectrometry-based proteomic discovery research to identify novel plasma proteins related to the risk of coronary heart disease (CHD) and stroke, and to identify proteins with concentrations affected by the use of postmenopausal hormone therapy. Here we report CHD and stroke risk validation studies for highly ranked proteins, and consider the extent to which protein concentration changes relate to disease risk or provide an explanation for hormone therapy effects on these outcomes. Methods: Five proteins potentially associated with CHD (beta-2 microglobulin (B2M), alpha-1-acid glycoprotein 1 (ORM1), thrombospondin-1(THBS1), complement factor D pre-protein (CFD), and insulin-like growth factor binding protein 1 (IGFBP1)) and five potentially associated with stroke (B2M, IGFBP2, IGFBP4, IGFBP6, and hemopexin (HPX)) had high discovery phase significance level ranking and an available ELISA assay, and were included in case-control validation studies within the Women's Health Initiative (WHI) hormone therapy trials. Protein concentrations, at baseline and 1 year following randomization, were assessed for 358 CHD cases and 362 stroke cases, along with corresponding disease-free controls. Disease association, and mediation of estrogen-alone and estrogen plus progestin effects on CHD and stroke risk, were assessed using logistic regression. Results: B2M, THBS1, and CFD were confirmed (P < 0.05) as novel CHD risk markers, and B2M, IGFBP2, and IGFBP4 were confirmed as novel stroke disease risk markers, while the assay for HPX proved to be unreliable. The change from baseline to 1 year in B2M was associated (P < 0.05) with subsequent stroke risk, and trended similarly with subsequent CHD risk. Change from baseline to 1 year in IGFBP1 was also associated with CHD risk, and this change provided evidence of hormone therapy effect mediation. Conclusions: Plasma B2M is confirmed to be an informative risk marker for both CHD and stroke. The B2M increase experienced by women during the first year of hormone therapy trial participation conveys cardiovascular disease risk. The increase in IGFBP1 similarly conveys CHD risk, and the magnitude of the IGFBP1 increase following hormone therapy may be a mediator of hormone therapy effects. Plasma THBS1 and CFD are confirmed as CHD risk markers, and plasma IGFBP4 and IGFBP2 are confirmed as stroke risk markers. C1 [Prentice, Ross L.; Zhao, Shanshan; Johnson, Melissa; Aragaki, Aaron] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Hsia, Judith] AstraZeneca LP, Res & Dev, Wilmington, DE 19803 USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol, Columbus, OH 43210 USA. [Rossouw, Jacques E.] NHLBI, WHI Project Off, NIH, Bethesda, MD 20892 USA. [Manson, JoAnn E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Hanash, Samir M.] Univ Texas MD Anderson Canc Ctr, Red & Charline McCombs Inst Early Detect & Treatm, Dept Clin Canc Prevent, Houston, TX 77030 USA. RP Prentice, RL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,POB 19024, Seattle, WA 98109 USA. EM rprentic@whi.org FU National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [R21HL105927]; National Heart, Lung and Blood Institute [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; National Cancer Institute [P01CA53996] FX This work was supported by National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services grant R21HL105927 (Prentice). The Women's Health Initiative Program (all investigators) is also supported by the National Heart, Lung and Blood Institute under contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Dr. Prentice's work was also partially supported by grant P01CA53996 from the National Cancer Institute. NR 41 TC 7 Z9 7 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD DEC 27 PY 2013 VL 5 AR 112 DI 10.1186/gm517 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 295JA UT WOS:000330111200001 PM 24373343 ER PT J AU Harel, A Kravitz, D Baker, CI AF Harel, Assaf Kravitz, Dwight Baker, Chris I. TI Beyond perceptual expertise: revisiting the neural substrates of expert object recognition SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Review DE expertise; object recognition; visual perception; fMRI; review; visual cortex ID FUSIFORM FACE AREA; HUMAN EXTRASTRIATE CORTEX; PRIMARY VISUAL-CORTEX; CHESS EXPERTS; HUMAN BRAIN; TEXTURE-DISCRIMINATION; ACTION ANTICIPATION; DOMAIN SPECIFICITY; BASKETBALL PLAYERS; TASK CONSTRAINTS AB Real-world expertise provides a valuable opportunity to understand how experience shapes human behavior and neural function. In the visual domain, the study of expert object recognition, such as in car enthusiasts or bird watchers, has produced a large, growing, and often-controversial literature. Here, we synthesize this literature, focusing primarily on results from functional brain imaging, and propose an interactive framework that incorporates the impact of high-level factors, such as attention and conceptual knowledge, in supporting expertise. This framework contrasts with the perceptual view of object expertise that has concentrated largely on stimulus driven processing in visual cortex. One prominent version of this perceptual account has almost exclusively focused on the relation of expertise to face processing and, in terms of the neural substrates, has centered on face-selective cortical regions such as the Fusiform Face Area (FFA). We discuss the limitations of this face-centric approach as well as the more general perceptual view, and highlight that expert related activity is CO found throughout visual cortex, not just FFA, with a strong relationship between neural response and behavioral expertise even in the earliest stages of visual processing, (ii) found outside visual cortex in areas such as parietal and prefrontal cortices, and (iii) modulated by the attentional engagement of the observer suggesting that it is neither automatic nor driven solely by stimulus properties. These findings strongly support a framework in which object expertise emerges from extensive interactions within and between the visual system and other cognitive systems, resulting in widespread, distributed patterns of expertise-related activity across the entire cortex. C1 [Harel, Assaf; Kravitz, Dwight; Baker, Chris I.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Harel, A (reprint author), NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM assaf.harel@nih.gov OI Baker, Chris/0000-0001-6861-8964; Harel, Assaf/0000-0002-4899-6156 FU Intramural Research Program of the US National Institutes of Health (NIH), National Institute of Mental Health (NIMH) FX The authors thank Hans Op de Beeck, Marlene Behrmann, and Alex Martin for helpful discussions. This research was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Institute of Mental Health (NIMH). NR 144 TC 18 Z9 18 U1 8 U2 55 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD DEC 27 PY 2013 VL 7 AR 885 DI 10.3389/fnhum.2013.00885 PG 12 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 283LF UT WOS:000329246900001 PM 24409134 ER PT J AU Boone-Heinonen, J Diez-Roux, AV Goff, DC Loria, CM Kiefe, CI Popkin, BM Gordon-Larsen, P AF Boone-Heinonen, Janne Diez-Roux, Ana V. Goff, David C. Loria, Catherine M. Kiefe, Catarina I. Popkin, Barry M. Gordon-Larsen, Penny TI The Neighborhood Energy Balance Equation: Does Neighborhood Food Retail Environment plus Physical Activity Environment = Obesity? The CARDIA Study SO PLOS ONE LA English DT Article ID BODY-MASS INDEX; RESIDENTIAL SELF-SELECTION; ARTERY RISK DEVELOPMENT; BUILT ENVIRONMENT; LONGITUDINAL-ASSOCIATIONS; HEALTHY FOODS; WEIGHT STATUS; DIET QUALITY; URBAN SPRAWL; YOUNG-ADULTS AB Background: Recent obesity prevention initiatives focus on healthy neighborhood design, but most research examines neighborhood food retail and physical activity (PA) environments in isolation. We estimated joint, interactive, and cumulative impacts of neighborhood food retail and PA environment characteristics on body mass index (BMI) throughout early adulthood. Methods and Findings: We used cohort data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study [n=4,092; Year 7 (24-42 years, 1992-1993) followed over 5 exams through Year 25 (2010-2011); 12,921 person-exam observations], with linked time-varying geographic information system-derived neighborhood environment measures. Using regression with fixed effects for individuals, we modeled time-lagged BMI as a function of food and PA resource density (counts per population) and neighborhood development intensity (a composite density score). We controlled for neighborhood poverty, individual-level sociodemographics, and BMI in the prior exam; and included significant interactions between neighborhood measures and by sex. Using model coefficients, we simulated BMI reductions in response to single and combined neighborhood improvements. Simulated increase in supermarket density (from 25th to 75th percentile) predicted inter-exam reduction in BMI of 0.09 kg/m(2) [estimate (95% CI): -0.09 (-0.16, -0.02)]. Increasing commercial PA facility density predicted BMI reductions up to 0.22 kg/m(2) in men, with variation across other neighborhood features [estimate (95% CI) range: -0.14 (-0.29, 0.01) to -0.22 (-0.37, -0.08)]. Simultaneous increases in supermarket and commercial PA facility density predicted inter-exam BMI reductions up to 0.31 kg/m(2) in men [estimate (95% CI) range: -0.23 (-0.39, -0.06) to -0.31 (-0.47, -0.15)] but not women. Reduced fast food restaurant and convenience store density and increased public PA facility density and neighborhood development intensity did not predict reductions in BMI. Conclusions: Findings suggest that improvements in neighborhood food retail or PA environments may accumulate to reduce BMI, but some neighborhood changes may be less beneficial to women. C1 [Boone-Heinonen, Janne] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Diez-Roux, Ana V.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Goff, David C.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Loria, Catherine M.] NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Kiefe, Catarina I.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Popkin, Barry M.; Gordon-Larsen, Penny] Univ N Carolina, Carolina Populat Ctr, Dept Nutr, Chapel Hill, NC 27599 USA. RP Gordon-Larsen, P (reprint author), Univ N Carolina, Carolina Populat Ctr, Dept Nutr, Chapel Hill, NC 27599 USA. EM gordon_larsen@unc.edu FU National Heart, Lung, and Blood Institute (NHLBI); University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; NHLBI [AG0005]; National Institutes of Health [R01 HL104580, R01- HL114091]; UNC-CH Clinic Nutrition Research Center [NIH DK56350]; Carolina Population Center [R24HD050924]; University of Alabama at Birmingham Coordinating Center [N01-HC-95095]; University of Alabama at Birmingham Field Center [N01-HC-48047]; University of Minnesota Field Center [N01-HC-48048]; Northwestern University Field Center [N01-HC-48049]; Kaiser Foundation Research Institute from the National Heart, Lung and Blood Institute [N01-HC-48050]; Interdisciplinary Obesity Training postdoctoral fellowship [T32MH075854-04] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C & HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). This manuscript has been reviewed by CARDIA for scientific content. Funding for this study comes from the National Institutes of Health: (R01 HL104580, R01- HL114091). Additional funding has come from the UNC-CH Clinic Nutrition Research Center (NIH DK56350) and the Carolina Population Center (R24HD050924); from contracts with the University of Alabama at Birmingham Coordinating Center, N01-HC-95095; University of Alabama at Birmingham Field Center, N01-HC-48047; University of Minnesota Field Center, N01-HC-48048; Northwestern University Field Center, N01-HC-48049; and Kaiser Foundation Research Institute, N01-HC-48050 from the National Heart, Lung and Blood Institute. Analysis was supported by the Interdisciplinary Obesity Training postdoctoral fellowship (T32MH075854-04). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 17 Z9 17 U1 6 U2 31 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 DEC 27 PY 2013 VL 8 IS 12 AR e85141 DI 10.1371/journal.pone.0085141 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281RE UT WOS:000329117900126 PM 24386458 ER PT J AU Deng, C He, XM Hsueh, AJW AF Deng, Cheng He, Ximiao Hsueh, Aaron J. W. TI A Single-Nucleotide Polymorphism of Human Neuropeptide S Gene Originated from Europe Shows Decreased Bioactivity SO PLOS ONE LA English DT Article ID INHIBITS FOOD-INTAKE; HUMAN GENOME; RAT-BRAIN; IN-VITRO; PHARMACOLOGICAL CHARACTERIZATION; RECEPTOR ACTIVATION; EXPRESSING NEURONS; COCAINE-SEEKING; MICE; POPULATION AB Using accumulating SNP (Single-Nucleotide Polymorphism) data, we performed a genome-wide search for polypeptide hormone ligands showing changes in the mature regions to elucidate genotype/phenotype diversity among various human populations. Neuropeptide S (NPS), a brain peptide hormone highly conserved in vertebrates, has diverse physiological effects on anxiety, fear, hyperactivity, food intake, and sleeping time through its cognate receptor-NPSR. Here, we report a SNP rs4751440 (L-6-NPS) causing non-synonymous substitution on the 6th position (V to L) of the NPS mature peptide region. L-6-NPS has a higher allele frequency in Europeans than other populations and probably originated from European ancestors similar to 25,000 yrs ago based on haplotype analysis and Approximate Bayesian Computation. Functional analyses indicate that L-6-NPS exhibits a significant lower bioactivity than the wild type NPS, with similar to 20-fold higher EC50 values in the stimulation of NPSR. Additional evolutionary and mutagenesis studies further demonstrate the importance of the valine residue in the 6th position for NPS functions. Given the known physiological roles of NPS receptor in inflammatory bowel diseases, asthma pathogenesis, macrophage immune responses, and brain functions, our study provides the basis to elucidate NPS evolution and signaling diversity among human populations. C1 [Deng, Cheng; Hsueh, Aaron J. W.] Stanford Univ, Sch Med, Dept Ob Gyn, Program Reprod & Stem Cell Biol, Stanford, CA 94305 USA. [He, Ximiao] NCI, NIH, Bethesda, MD 20892 USA. RP Deng, C (reprint author), Stanford Univ, Sch Med, Dept Ob Gyn, Program Reprod & Stem Cell Biol, Stanford, CA 94305 USA. EM cdeng@stanford.edu; aaron.hsueh@stanford.edu NR 72 TC 0 Z9 0 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 27 PY 2013 VL 8 IS 12 AR e83009 DI 10.1371/journal.pone.0083009 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281RE UT WOS:000329117900017 PM 24386135 ER PT J AU Harmon, QE Laughlin, SK Baird, DD AF Harmon, Quaker E. Laughlin, Shannon K. Baird, Donna D. TI Keloids and Ultrasound Detected Fibroids in Young African American Women SO PLOS ONE LA English DT Article ID UTERINE LEIOMYOMAS; PATHOGENESIS; PREVALENCE; EXPRESSION; SCARS; RISK AB Objective: Keloids and fibroids share a number of biologic and demographic similarities however there are no published reports of the association between them. The objective of this study was to investigate the association between self-reported keloids and ultrasound detected fibroids in a population of young African American women. Study Design: The Study of Environment, Life-style & Fibroids (SELF), is a volunteer cohort of over 1600 African American women aged 23-34 years recruited in Detroit, Michigan. Enrollment occurred between December 2010 and December 2012. Data are available for the first 1196 participants. Participants self-reported a history of raised (hypertrophic) scars or scars extending beyond the limits of the original injury (keloid) and had an enrollment pelvic ultrasound examination to detect prevalent fibroids. Log linear regression was used to model the association between abnormal scars and prevalent fibroids controlling for possible covariates. Among women with fibroids, associations between particular fibroid characteristics (tumor location, size or number) and scarring were assessed using chi-square and Mann Whitney U-tests. Results: Both abnormal scarring (keloids, 9.0%; hypertrophic scars, 28.3%) and fibroids (23.3%) were common in this cohort. There was no indication [ adjusted Risk Ratio (95% Confidence Interval): 0.7 (0.5-1.1)] of an association between self-reported keloids and prevalent fibroids. Nor was there any association with hypertrophic scars. Specific characteristics of the prevalent fibroids were not associated with abnormal scarring. Conclusion: Despite similarly dysregulated extracellular matrices in keloids and fibroids, these conditions did not tend to co-occur in this young African American population. C1 [Harmon, Quaker E.; Baird, Donna D.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Laughlin, Shannon K.] Mayo Clin, Dept Obstet & Gynecol, Rochester, MN USA. RP Harmon, QE (reprint author), NIEHS, Epidemiol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM quaker.harmon@nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Harmon, Quaker/0000-0002-5866-848X FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences; American Recovery and Reinvestment Act funds designated for National Institute of Health research FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Funding also came from the American Recovery and Reinvestment Act funds designated for National Institute of Health research. SELF website: detroitself.org. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 4 Z9 4 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 DEC 27 PY 2013 VL 8 IS 12 AR e84737 DI 10.1371/journal.pone.0084737 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281RE UT WOS:000329117900108 PM 24386410 ER PT J AU Kainerstorfer, JM Polizzotto, MN Uldrick, TS Rahman, R Hassan, M Najafizadeh, L Ardeshirpour, Y Wyvill, KM Aleman, K Smith, PD Yarchoan, R Gandjbakhche, AH AF Kainerstorfer, Jana M. Polizzotto, Mark N. Uldrick, Thomas S. Rahman, Rafa Hassan, Moinuddin Najafizadeh, Laleh Ardeshirpour, Yasaman Wyvill, Kathleen M. Aleman, Karen Smith, Paul D. Yarchoan, Robert Gandjbakhche, Amir H. TI Evaluation of Non-Invasive Multispectral Imaging as a Tool for Measuring the Effect of Systemic Therapy in Kaposi Sarcoma SO PLOS ONE LA English DT Article ID INDEPENDENT-COMPONENT ANALYSIS; GROWTH-FACTOR; AIDS; RECOGNITION; HERPESVIRUS; MODEL; PCA; HIV AB Diffuse multi-spectral imaging has been evaluated as a potential non-invasive marker of tumor response. Multi-spectral images of Kaposi sarcoma skin lesions were taken over the course of treatment, and blood volume and oxygenation concentration maps were obtained through principal component analysis (PCA) of the data. These images were compared with clinical and pathological responses determined by conventional means. We demonstrate that cutaneous lesions have increased blood volume concentration and that changes in this parameter are a reliable indicator of treatment efficacy, differentiating responders and non-responders. Blood volume decreased by at least 20% in all lesions that responded by clinical criteria and increased in the two lesions that did not respond clinically. Responses as assessed by multi-spectral imaging also generally correlated with overall patient clinical response assessment, were often detectable earlier in the course of therapy, and are less subject to observer variability than conventional clinical assessment. Tissue oxygenation was more variable, with lesions often showing decreased oxygenation in the center surrounded by a zone of increased oxygenation. This technique could potentially be a clinically useful supplement to existing response assessment in KS, providing an early, quantitative, and non-invasive marker of treatment effect. C1 [Kainerstorfer, Jana M.; Rahman, Rafa; Hassan, Moinuddin; Najafizadeh, Laleh; Ardeshirpour, Yasaman; Gandjbakhche, Amir H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Analyt & Funct Biophoton, NIH, Bethesda, MD USA. [Polizzotto, Mark N.; Uldrick, Thomas S.; Wyvill, Kathleen M.; Aleman, Karen; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Smith, Paul D.] Natl Inst Biomed Imaging & Bioengn, Biomed Instrumentat & Multiscale Imaging Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. RP Gandjbakhche, AH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Analyt & Funct Biophoton, NIH, Bethesda, MD USA. EM amir@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Biomedical Imaging and Bioengineering; National Cancer Institute; NCI, National Institutes of Health [HHSN26120080001E] FX The research was funded by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Biomedical Imaging and Bioengineering, and the National Cancer Institute. Additional funding provided by the NCI, National Institutes of Health under Contract No. HHSN26120080001E. Bevacizumab was provided to the NCI through a Cooperative Research and Development Agreements with Genentech. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 3 Z9 3 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 27 PY 2013 VL 8 IS 12 AR e83887 DI 10.1371/journal.pone.0083887 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281RE UT WOS:000329117900066 PM 24386302 ER PT J AU Konikoff, J Brookmeyer, R Longosz, AF Cousins, MM Celum, C Buchbinder, SP Seage, GR Kirk, GD Moore, RD Mehta, SH Margolick, JB Brown, J Mayer, KH Koblin, BA Justman, JE Hodder, SL Quinn, TC Eshleman, SH Laeyendecker, O AF Konikoff, Jacob Brookmeyer, Ron Longosz, Andrew F. Cousins, Matthew M. Celum, Connie Buchbinder, Susan P. Seage, George R., III Kirk, Gregory D. Moore, Richard D. Mehta, Shruti H. Margolick, Joseph B. Brown, Joelle Mayer, Kenneth H. Koblin, Beryl A. Justman, Jessica E. Hodder, Sally L. Quinn, Thomas C. Eshleman, Susan H. Laeyendecker, Oliver TI Performance of a Limiting-Antigen Avidity Enzyme Immunoassay for Cross-Sectional Estimation of HIV Incidence in the United States SO PLOS ONE LA English DT Article ID INCIDENCE RATES; TYPE-1 SEROCONVERSION; INFECTION; COHORT; ASSAYS; CHALLENGES; ACCURACY; EPIDEMIC; THERAPY; PLASMA AB Background: A limiting antigen avidity enzyme immunoassay (HIV-1 LAg-Avidity assay) was recently developed for cross-sectional HIV incidence estimation. We evaluated the performance of the LAg-Avidity assay alone and in multi-assay algorithms (MAAs) that included other biomarkers. Methods and Findings: Performance of testing algorithms was evaluated using 2,282 samples from individuals in the United States collected 1 month to >8 years after HIV seroconversion. The capacity of selected testing algorithms to accurately estimate incidence was evaluated in three longitudinal cohorts. When used in a single-assay format, the LAg-Avidity assay classified some individuals infected >5 years as assay positive and failed to provide reliable incidence estimates in cohorts that included individuals with long-term infections. We evaluated >500,000 testing algorithms, that included the LAg-Avidity assay alone and MAAs with other biomarkers (BED capture immunoassay [BED-CEIA], BioRad-Avidity assay, HIV viral load, CD4 cell count), varying the assays and assay cutoffs. We identified an optimized 2-assay MAA that included the LAg-Avidity and BioRad-Avidity assays, and an optimized 4-assay MAA that included those assays, as well as HIV viral load and CD4 cell count. The two optimized MAAs classified all 845 samples from individuals infected >5 years as MAA negative and estimated incidence within a year of sample collection. These two MAAs produced incidence estimates that were consistent with those from longitudinal follow-up of cohorts. A comparison of the laboratory assay costs of the MAAs was also performed, and we found that the costs associated with the optimal two assay MAA were substantially less than with the four assay MAA. Conclusions: The LAg-Avidity assay did not perform well in a single-assay format, regardless of the assay cutoff. MAAs that include the LAg-Avidity and BioRad-Avidity assays, with or without viral load and CD4 cell count, provide accurate incidence estimates. C1 [Konikoff, Jacob; Brookmeyer, Ron; Laeyendecker, Oliver] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Longosz, Andrew F.] NIAID, NIH, Bethesda, MD 20892 USA. [Cousins, Matthew M.; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Celum, Connie] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Celum, Connie] Univ Washington, Dept Med, Seattle, WA USA. [Buchbinder, Susan P.] San Francisco Dept Hlth, San Francisco, CA USA. [Laeyendecker, Oliver] UCSF, Dept Epidemiol, San Francisco, CA USA. [Laeyendecker, Oliver] UCSF, Dept Med, San Francisco, CA USA. [Seage, George R., III] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kirk, Gregory D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Moore, Richard D.; Mehta, Shruti H.; Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Margolick, Joseph B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Brown, Joelle] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Mayer, Kenneth H.] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Koblin, Beryl A.] New York Blood Ctr, New York, NY 10021 USA. [Justman, Jessica E.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Hodder, Sally L.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, Newark, NJ 07103 USA. [Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. RP Laeyendecker, O (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. EM olaeyen1@jhmi.edu OI Laeyendecker, Oliver/0000-0002-6429-4760 FU HIV Prevention Trials Network (HPTN); National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH); Office of AIDS Research of the National Institutes of Health (NIH), Department of Health and Human Services [UM1-AI068613, R01-AI095068]; Division of Intramural Research, NIAID, NIH; HIV Network for Prevention Trials (HIVNET); NIAID, NIH, DHHS [N01-AI35176, N01-AI-45200, AI-45202]; NIDA [R01-DA-04334, R01-DA12568, R01-DA011602]; NIAID; National Cancer Institute; National Heart, Lung and Blood Institute [U01-AI35042, U01-AI35043, U01-AI35039, U01-AI35040, U01-AI35041, UL1-RR025005]; National Institute of Alcohol Abuse and Alcoholism [R01-AA016893]; NIH [UM1-AI068613, HPTN 061, HPTN 064, UM1-AI068619, UM1-AI068617] FX This work was supported by: (1) the HIV Prevention Trials Network (HPTN) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and the Office of AIDS Research of the National Institutes of Health (NIH), Department of Health and Human Services (UM1-AI068613 to SE); (2) R01-AI095068 (to SE and RB); and (3) the Division of Intramural Research, NIAID, NIH. The funders had no role in the design and conduct of the study, data collection and analysis, preparation of the manuscript, or the decision to publish. Support for the studies that provided samples for this project was as follows: the HIVNET 001/001.1 study was funded by the HIV Network for Prevention Trials (HIVNET) and sponsored by the NIAID, NIH, DHHS (N01-AI35176, N01-AI-45200, and AI-45202); the ALIVE study is funded by NIDA (R01-DA-04334 and R01-DA12568; the MACS is funded by the NIAID, with additional supplemental funding from the National Cancer Institute and the National Heart, Lung and Blood Institute (U01-AI35042, U01-AI35043, U01-AI35039, U01-AI35040, U01-AI35041, and UL1-RR025005); the JHHCC is funded by NIDA (R01-DA011602 to RDM) and the National Institute of Alcohol Abuse and Alcoholism (R01-AA016893 to RDM); HPTN 061 and HPTN 064 were funded by the NIH (see above; UM1-AI068619, UM1-AI068617, and UM1-AI068613). Role of the funders: None of the funders had a role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review, or approval of the manuscript. NR 40 TC 17 Z9 17 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 DEC 27 PY 2013 VL 8 IS 12 AR e82772 DI 10.1371/journal.pone.0082772 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281RE UT WOS:000329117900015 PM 24386116 ER PT J AU Steuerwald, NM Foureau, DM Norton, HJ Zhou, J Parsons, JC Chalasani, N Fontana, RJ Watkins, PB Lee, WM Reddy, KR Stolz, A Talwalkar, J Davern, T Saha, D Bell, LN Barnhart, H Gu, JZ Serrano, J Bonkovsky, HL AF Steuerwald, Nury M. Foureau, David M. Norton, H. James Zhou, Jie Parsons, Judith C. Chalasani, Naga Fontana, Robert J. Watkins, Paul B. Lee, William M. Reddy, K. Rajender Stolz, Andrew Talwalkar, Jayant Davern, Timothy Saha, Dhanonjoy Bell, Lauren N. Barnhart, Huiman Gu, Jiezhun Serrano, Jose Bonkovsky, Herbert L. TI Profiles of Serum Cytokines in Acute Drug-Induced Liver Injury and Their Prognostic Significance SO PLOS ONE LA English DT Article ID SEVERE ALCOHOLIC HEPATITIS; UNITED-STATES; THERAPY; FAILURE; INTERLEUKIN-10; HEPATOTOXICITY; IL-10; POLYMORPHISMS; BIOMARKERS; FEATURES AB Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN) and compared with 40 healthy controls. Immune analytes (14 cytokines, 7 chemokines and 6 growth factors) were measured by BioPlex multiplex ELISA at DILI onset and after 6 months. A modeling process utilizing immune principles was used to select a final set of variables among 27 immune analytes and several additional clinical lab values for prediction of early death (within 6 months of DILI onset). Nineteen of the 27 immune analytes were differentially expressed among healthy control, DILI onset and 6-month cohorts. Disparate patterns of immune responses, especially innate and adaptive cellular (mostly TH17) immunity were evident. Low values of four immune analytes (IL-9, IL-17, PDGF-bb and RANTES) and serum albumin are predictive of early death [PPV = 88% (95% CI, 65%-100%), NPV = 97% (95% CI, 93%-100%), accuracy = 96% (95% CI, 92%-100%)]. Conclusions: Acute DILI is associated with robust and varying immune responses. High levels of expression of cytokines associated with innate immunity are associated with a poor prognosis, whereas high levels of expression of adaptive cytokines are associated with good long-term prognosis and eventual recovery. Serum immune analyte profiles at DILI onset appear to be of prognostic, and perhaps, diagnostic significance. C1 [Steuerwald, Nury M.; Foureau, David M.; Norton, H. James; Zhou, Jie; Parsons, Judith C.; Saha, Dhanonjoy; Bonkovsky, Herbert L.] Carolinas Med Ctr, Liver Biliary Pancreat Ctr, Charlotte, NC 28203 USA. [Steuerwald, Nury M.; Foureau, David M.; Norton, H. James; Zhou, Jie; Parsons, Judith C.; Saha, Dhanonjoy; Bonkovsky, Herbert L.] Carolinas Med Ctr, Dept Internal Med, Charlotte, NC 28203 USA. [Steuerwald, Nury M.; Foureau, David M.; Norton, H. James; Zhou, Jie; Parsons, Judith C.; Saha, Dhanonjoy; Bonkovsky, Herbert L.] Carolinas Med Ctr, Dept Gen Surg, Charlotte, NC 28203 USA. [Steuerwald, Nury M.; Foureau, David M.; Norton, H. James; Zhou, Jie; Parsons, Judith C.; Saha, Dhanonjoy; Bonkovsky, Herbert L.] Carolinas Med Ctr, Dept Res, Charlotte, NC 28203 USA. [Steuerwald, Nury M.; Foureau, David M.; Norton, H. James; Zhou, Jie; Parsons, Judith C.; Saha, Dhanonjoy; Bonkovsky, Herbert L.] Carolinas Med Ctr, Dept Dickson Adv Analyt, Charlotte, NC 28203 USA. [Chalasani, Naga; Bell, Lauren N.] IUPUI, Dept Internal Med, Indianapolis, IN USA. [Fontana, Robert J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Watkins, Paul B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Watkins, Paul B.] Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. [Lee, William M.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Reddy, K. Rajender] Univ Penn, Dept Internal Med, Philadelphia, PA 19104 USA. [Stolz, Andrew] Univ So Calif, Dept Internal Med, Los Angeles, CA USA. [Talwalkar, Jayant] Mayo Clin, Dept Internal Med, Rochester, MN USA. [Davern, Timothy] Pacific Med Ctr, Dept Internal Med, San Francisco, CA USA. [Barnhart, Huiman; Gu, Jiezhun] Duke Clin Res Inst, Durham, NC USA. [Serrano, Jose] NIDDK, NIH, Bethesda, MD 20892 USA. RP Steuerwald, NM (reprint author), Carolinas Med Ctr, Liver Biliary Pancreat Ctr, Charlotte, NC 28203 USA. EM nury.steuerwald@carolinas.org FU National Institute of Diabetes and Digestive and Kidney Diseases [1U01DK065193, U01DK065211, U01DK065238, U01DK065184, U01DK065201, U01DK83023, U01DK083020, U01DK08992, U01DK083027] FX Supported by The DILIN (Drug Induced Liver Injury Network) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Numbers of the cooperative agreements are as follows: 1U01DK065193, U01DK065211, U01DK065238, U01DK065184, U01DK065201, U01DK83023, U01DK083020, U01DK08992, U01DK083027. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 19 Z9 20 U1 1 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 DEC 27 PY 2013 VL 8 IS 12 AR UNSP e81974 DI 10.1371/journal.pone.0081974 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281RE UT WOS:000329117900007 PM 24386086 ER PT J AU Bies, J Sramko, M Wolff, L AF Bies, Juraj Sramko, Marek Wolff, Linda TI Stress-induced Phosphorylation of Thr(486) in c-Myb by p38 Mitogen-activated Protein Kinases Attenuates Conjugation of SUMO-2/3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Apoptosis; p38 MAPK; Phosphorylation; Protein Degradation; Protein Stability; Stress; Sumoylation; Transcription; Myb ID NEGATIVE REGULATORY DOMAIN; INDUCED TRANSCRIPTION ACTIVATION; T-CELL DEVELOPMENT; V-MYB; LEUKEMIA; PROLIFERATION; DEGRADATION; GENE; DIFFERENTIATION; INTEGRATION AB c-Myb plays an essential role in regulation of properly balanced hematopoiesis through transcriptional regulation of genes directly controlling cellular processes such as proliferation, differentiation, and apoptosis. The transcriptional activity and protein levels of c-Myb are strictly controlled through post-translational modifications such as phosphorylation, acetylation, ubiquitination, and SUMOylation. Conjugation of small ubiquitin-like modifier (SUMO) proteins has been shown to suppress the transcriptional activity of c-Myb. SUMO-1 modifies c-Myb under physiological conditions, whereas SUMO-2/3 conjugation was reported in cells under stress. Because stress also activates several cellular protein kinases, we investigated whether phosphorylation of c-Myb changes in stressed cells and whether a mutual interplay exists between phosphorylation and SUMOylation of c-Myb. Here we show that several types of environmental stress induce a rapid change in c-Myb phosphorylation. Interestingly, the phosphorylation of Thr(486), located in close proximity to SUMOylation site Lys(499) of c-Myb, is detected preferentially in nonSUMOylated protein and has a negative effect on stress-induced SUMOylation of c-Myb. Stress-activated p38 MAPKs phosphorylate Thr(486) in c-Myb, attenuate its SUMOylation, and increase its proteolytic turnover. Stressed cells expressing a phosphorylation-deficient T486A mutant demonstrate decreased expression of c-Myb target genes Bcl-2 and Bcl-xL and accelerated apoptosis because of increased SUMOylation of the mutant protein. These results suggest that phosphorylation-dependent modulation of c-Myb SUMOylation may be important for proper response of cells to stress. In summary, we have identified a novel regulatory interplay between phosphorylation and SUMOylation of c-Myb that regulates its activity in stressed cells. C1 [Bies, Juraj; Sramko, Marek; Wolff, Linda] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bies, J (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bldg 37-4124,37 Convent Dr,MSC 4263, Bethesda, MD 20892 USA. EM biesj@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health FX This work was supported, in whole or in part, by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. NR 54 TC 1 Z9 1 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 27 PY 2013 VL 288 IS 52 BP 36983 EP 36993 DI 10.1074/jbc.M113.500264 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 282RH UT WOS:000329189700020 PM 24257756 ER PT J AU Quintero, OA Unrath, WC Stevens, SM Manor, U Kachar, B Yengo, CM AF Quintero, Omar A. Unrath, William C. Stevens, Stanley M., Jr. Manor, Uri Kachar, Bechara Yengo, Christopher M. TI Myosin 3A Kinase Activity Is Regulated by Phosphorylation of the Kinase Domain Activation Loop SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Actin; Hearing; Molecular Motors; Myosin; Phosphorylation ID CLASS-III MYOSIN; PROTEIN-KINASE; STATISTICAL-MODEL; ATPASE ACTIVITY; MST1 KINASE; ACTIN; MECHANISM; AUTOPHOSPHORYLATION; LOCALIZATION; MOTOR AB Class III myosins are unique members of the myosin superfamily in that they contain both a motor and kinase domain. We have found that motor activity is decreased by autophosphorylation, although little is known about the regulation of the kinase domain. We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919). The kinase activity of MYO3A 2IQ with the phosphomimic (T184E) or phosphoblock (T184A) mutations demonstrates that kinase activity is reduced 30-fold as a result of the T184A mutation, although the Thr-178 site only had a minor impact on kinase activity. Interestingly, the actin-activated ATPase activity of MYO3A 2IQ is slightly reduced as a result of the T178A and T184A mutations suggesting coupling between motor and kinase domains. Full-length GFP-tagged T184A and T184E MYO3A constructs transfected into COS7 cells do not disrupt the ability of MYO3A to localize to filopodia structures. In addition, we demonstrate that T184E MYO3A reduces filopodia elongation in the presence of espin-1, whereas T184A enhances filopodia elongation in a similar fashion to kinase-dead MYO3A. Our results suggest that as MYO3A accumulates at the tips of actin protrusions, autophosphorylation of Thr-184 enhances kinase activity resulting in phosphorylation of the MYO3A motor and reducing motor activity. The differential regulation of the kinase and motor activities allows for MYO3A to precisely self-regulate its concentration in the actin bundle-based structures of cells. C1 [Quintero, Omar A.; Unrath, William C.; Yengo, Christopher M.] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. [Stevens, Stanley M., Jr.] Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL 33620 USA. [Manor, Uri; Kachar, Bechara] NIDCD, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20894 USA. RP Yengo, CM (reprint author), Penn State Coll Med, Dept Cellular & Mol Physiol, 500 Univ Dr, Hershey, PA 17033 USA. EM cmy11@psu.edu OI Quintero, Omar/0000-0002-9314-1704 FU National Institutes of Health [EY0181416, K01CA160667]; Penn State College of Medicine FX This work was supported, in whole or in part, by National Institutes of Health Grants EY0181416 (to C. M. Y.) and K01CA160667 (to O. A. Q.). This work was also supported by start-up funds from Penn State College of Medicine. NR 54 TC 10 Z9 10 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 27 PY 2013 VL 288 IS 52 BP 37126 EP 37137 DI 10.1074/jbc.M113.511014 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 282RH UT WOS:000329189700032 PM 24214986 ER PT J AU Shinomiya, K Sato, K Yoshida, K Tokura, K Maruyama, H Yanagidaira, K Ito, Y AF Shinomiya, Kazufusa Sato, Kazuki Yoshida, Kazunori Tokura, Koji Maruyama, Hiroshi Yanagidaira, Kazuhiro Ito, Yoichiro TI Partition efficiencies of newly fabricated universal high-speed counter-current chromatograph for separation of two different types of sugar derivatives with organic-aqueous two-phase solvent systems SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Counter-current chromatography; Instrumentation; Sugar derivatives ID COIL PLANET CENTRIFUGE; POLYMER PHASE SYSTEMS; COLUMN; PURIFICATION; PERFORMANCE; PROTEINS AB A new design of universal high-speed counter-current chromatograph (HSCCC) was fabricated in our laboratory. It holds a set of four column holders symmetrically around the rotary frame at a distance of 11.2 cm from the central axis. By engaging the stationary gear on the central axis of the centrifuge to the planetary gears on the column holder shaft through a set of idle gears, two pairs of diagonally located column holders simultaneously rotate about their own axes in the opposite directions: one forward (type-J planetary motion) and the other backward (type-I planetary motion) each synchronously with the revolution. Using the eccentric coil assembly, partition efficiencies produced by these two planetary motions were compared on the separation of two different types of sugar derivatives (4-methylumbelliferyl and 5-bromo-4-chloro-3-indoxyl sugar derivatives) using organic-aqueous two-phase solvent systems composed of n-hexane/ethyl acetate/1-butanol/methanollwater and aqueous 0.1 M sodium tetraborate, respectively. With lower phase mobile, better peak resolution was obtained by the type-J forward rotation for both samples probably due to higher retention of the stationary phase. With upper phase mobile, however, similar peak resolutions were obtained between these two planetary motions for both sugar derivatives. The overall results indicate that the present universal HSCCC is useful for counter-current chromatographic separation since each planetary motion has its specific applications: e.g., vortex CCC by the type-I planetary motion and HSCCC by the type-J planetary motion both for separation of various natural and synthetic products. (C) 2013 Elsevier B.V. All rights reserved. C1 [Shinomiya, Kazufusa; Sato, Kazuki] Nihon Univ, Sch Pharm, Funabashi, Chiba 2748555, Japan. [Yoshida, Kazunori; Tokura, Koji; Maruyama, Hiroshi; Yanagidaira, Kazuhiro] Nihon Univ, Coll Sci & Technol, Funabashi, Chiba 2748501, Japan. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Shinomiya, K (reprint author), Nihon Univ, Sch Pharm, 7-7-1 Narashinodai, Funabashi, Chiba 2748555, Japan. EM shinomiya.kazufusa@nihon-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan FX The present study was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 18 TC 9 Z9 9 U1 0 U2 36 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD DEC 27 PY 2013 VL 1322 BP 74 EP 80 DI 10.1016/j.chroma.2013.10.096 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 275ZF UT WOS:000328717200010 PM 24267319 ER PT J AU Pena-Cruz, V Etemad, B Chatziandreou, N Nyein, PH Stock, S Reynolds, SJ Laeyendecker, O Gray, RH Serwadda, D Lee, SJ Quinn, TC Sagar, M AF Pena-Cruz, Victor Etemad, Behzad Chatziandreou, Nikolaos Phyu Hninn Nyein Stock, Shannon Reynolds, Steven J. Laeyendecker, Oliver Gray, Ronald H. Serwadda, David Lee, Sandra J. Quinn, Thomas C. Sagar, Manish TI HIV-1 envelope replication and alpha 4 beta 7 utilization among newly infected subjects and their corresponding heterosexual partners SO RETROVIROLOGY LA English DT Article DE HIV-1; Envelope; Transmission; Receptor; Replication; Alpha4 beta7; Dendritic cells; Langerhans cells; Selection ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN LANGERHANS CELLS; FUSION INHIBITOR T-20; DENDRITIC CELLS; T-CELLS; CORECEPTOR USAGE; TRANS-INFECTION; GENITAL-TRACT; NEUTRALIZATION SENSITIVITY; INTEGRIN ALPHA(4)BETA(7) AB Background: Previous studies suggest that active selection limits the number of HIV-1 variants acquired by a newly infected individual from the diverse variants circulating in the transmitting partner. We compared HIV-1 envelopes from 9 newly infected subjects and their linked transmitting partner to explore potential mechanisms for selection. Results: Recipient virus envelopes had significant genotypic differences compared to those present in the transmitting partner. Recombinant viruses incorporating pools of recipient and transmitter envelopes showed no significant difference in their sensitivity to receptor and fusion inhibitors, suggesting they had relatively similar entry capacity in the presence of low CD4 and CCR5 levels. Aggregate results in primary cells from up to 4 different blood or skin donors showed that viruses with envelopes from the transmitting partner as compared to recipient envelopes replicated more efficiently in CD4+ T cells, monocyte derived dendritic cell (MDDC) - CD4+ T cell co-cultures, Langerhans cells (LCs) - CD4+ T cell co-cultures and CD4+ T cells expressing high levels of the gut homing receptor, alpha 4 beta 7, and demonstrated greater binding to alpha 4 beta 7 high / CD8+ T cells. These transmitter versus recipient envelope virus phenotypic differences, however, were not always consistent among the primary cells from all the different blood or skin donation volunteers. Conclusion: Although genotypically unique variants are present in newly infected individuals compared to the diverse swarm circulating in the chronically infected transmitting partner, replication in potential early target cells and receptor utilization either do not completely dictate this genetic selection, or these potential transmission phenotypes are lost very soon after HIV-1 acquisition. C1 [Pena-Cruz, Victor; Etemad, Behzad; Chatziandreou, Nikolaos; Phyu Hninn Nyein; Sagar, Manish] Boston Univ, Dept Med, Div Infect Dis, Boston, MA 02215 USA. [Stock, Shannon] Coll Holy Cross, Dept Math & Comp Sci, Worcester, MA 01610 USA. [Reynolds, Steven J.; Laeyendecker, Oliver; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Reynolds, Steven J.; Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Gray, Ronald H.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Lee, Sandra J.] Dana Farber Canc Ctr, Dept Biostat, Boston, MA USA. [Lee, Sandra J.] Dana Farber Canc Ctr, Dept Computat Biol, Boston, MA USA. [Sagar, Manish] Boston Univ, Boston, MA 02118 USA. RP Sagar, M (reprint author), Boston Univ, Dept Med, Div Infect Dis, Boston, MA 02215 USA. EM msagar@bu.edu OI Laeyendecker, Oliver/0000-0002-6429-4760 FU NIH [AI077473]; Division of Intramural Research, NIAID, NIH FX We thank all the subjects who have contributed samples for these studies as part of the Rakai Health Sciences Program. We thank Drs. Andrew Redd, James Arthos, and Suryaram Gummuluru for insightful comments on the manuscript. This study was supported by NIH grants AI077473 (MS) and by the Division of Intramural Research, NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 112 TC 10 Z9 10 U1 2 U2 5 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 DEC 26 PY 2013 VL 10 AR 162 DI 10.1186/1742-4690-10-162 PG 16 WC Virology SC Virology GA AB3OC UT WOS:000331699100001 PM 24369910 ER PT J AU Claxton, JS Sandoval, PC Liu, G Chou, CL Hoffert, JD Knepper, MA AF Claxton, J'Neka S. Sandoval, Pablo C. Liu, Gary Chou, Chung-Lin Hoffert, Jason D. Knepper, Mark A. TI Endogenous Carbamylation of Renal Medullary Proteins SO PLOS ONE LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; HEMOGLOBIN CARBAMYLATION; WATER DIURESIS; IN-VIVO; UREA; IDENTIFICATION; ACETYLATION; EXCRETION; PEPTIDES; UREMIA AB Protein carbamylation is a post-translational modification that can occur in the presence of urea. In solution, urea is in equilibrium with ammonium cyanate, and carbamylation occurs when cyanate ions react with the amino groups of lysines, arginines, protein N-termini, as well as sulfhydryl groups of cysteines. The concentration of urea is elevated in the renal inner medulla compared with other tissues. Due to the high urea concentration, we hypothesized that carbamylation can occur endogenously within the rat inner medulla. Using immunoblotting of rat kidney cortical and medullary homogenates with a carbamyl-lysine specific antibody, we showed that carbamylation is present in a large number of inner medullary proteins. Using protein mass spectrometry (LC-MS/MS) of rat renal inner medulla, we identified 456 unique carbamylated sites in 403 proteins, including many that play important physiological roles in the renal medulla [Data can be accessed at https://helixweb.nih.gov/ESBL/Database/Carbamylation/Carbamylation_peptide_sorted.html]. We conclude that protein carbamylation occurs endogenously in the kidney, modifying many physiologically important proteins. C1 [Claxton, J'Neka S.; Sandoval, Pablo C.; Liu, Gary; Chou, Chung-Lin; Hoffert, Jason D.; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov FU Intramural budget of NHLBI [ZO1-HL001285] FX This work was supported by the Intramural budget of NHLBI (Project ZO1-HL001285, M. A. K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 3 Z9 4 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 DEC 26 PY 2013 VL 8 IS 12 AR e82655 DI 10.1371/journal.pone.0082655 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281QS UT WOS:000329116700011 PM 24386107 ER PT J AU Shindo, S Moore, R Flake, G Negishi, M AF Shindo, Sawako Moore, Rick Flake, Gordon Negishi, Masahiko TI Serine 216 Phosphorylation of Estrogen Receptor alpha in Neutrophils: Migration and Infiltration into the Mouse Uterus SO PLOS ONE LA English DT Article ID LACTOFERRIN; EXPRESSION; GENE; RAT AB Background: Whereas estrogen receptors are present in immune cells, it is not known if they are phosphorylated to regulate immune cell functions. Here we determined the phosphorylation status of estrogen receptor alpha (ER alpha) at residue serine 216 in mouse neutrophils and examined its role in migration and infiltration. Serine 216 is the conserved phosphorylation site within the DNA binding domains found in the majority of nuclear receptors. Methodology/Principal Findings: A phospho-peptide antibody specific to phosphorylated serine 216 and ER alpha KO mice were utilized in immunohistochemistry, double immuno-staining or Western blot to detect phosphorylation of ER alpha in peripheral blood as well as infiltrating neutrophils in the mouse uterus. Transwell assays were performed to examine migration of neutrophils. An anti-Ly6G antibody identified neutrophils. About 20% of neutrophils expressed phosphorylated ER alpha at serine 216 in peripheral white blood cells (WBC) from C3H/HeNCrIBR females. Phosphorylation was additively segregated between C3H/HeNCrIBR and C57BL/6 females. Only neutrophils that expressed phosphorylated ER alpha migrated in Transwell assays as well as infiltrated the mouse uterus during normal estrous cycles. Conclusions/Significance: ER alpha was phosphorylated at serine 216 in about 20% of mouse peripheral blood neutrophils. Only those that express phosphorylated ER alpha migrate and infiltrate the mouse uterus. This phosphorylation was the first to be characterized in endogenous ER alpha found in normal tissues and cells. Phosphorylated ER alpha may have opened a novel research direction for biological roles of phosphorylation in ER alpha actions and can be developed as a drug target for treatment of immune-related diseases. C1 [Shindo, Sawako; Moore, Rick; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Flake, Gordon] NIEHS, Pathol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health [Z01ES1005-01] FX This study was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health: Z01ES1005-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 4 Z9 4 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 DEC 26 PY 2013 VL 8 IS 12 AR e84462 DI 10.1371/journal.pone.0084462 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281QS UT WOS:000329116700109 PM 24386386 ER PT J AU Yu, Y Walia, V Elble, RC AF Yu, Yang Walia, Vijay Elble, Randolph C. TI Loss of CLCA4 Promotes Epithelial-to-Mesenchymal Transition in Breast Cancer Cells SO PLOS ONE LA English DT Article ID STEM-CELLS; TUMOR PROGRESSION; EXPRESSION; METASTASIS; PROTEIN; FAMILY; METALLOPROTEASE; PROLIFERATION; INVASIVENESS; CHANNELS AB The epithelial to mesenchymal transition (EMT) is a developmental program in which epithelial cells downregulate their cell-cell junctions, acquire spindle cell morphology and exhibit cellular motility. In breast cancer, EMT facilitates invasion of surrounding tissues and correlates closely with cancer metastasis and relapse. We found previously that the candidate tumor suppressor CLCA2 is expressed in differentiated, growth-arrested mammary epithelial cells but is downregulated during tumor progression and EMT. We further demonstrated that CLCA2 is a p53-inducible proliferation-inhibitor whose loss indicates an increased risk of metastasis. We show here that another member of the CLCA gene family, CLCA4, is expressed in mammary epithelial cells and is similarly downregulated in breast tumors and in breast cancer cell lines. Like CLCA2, the gene is stress-inducible, and ectopic expression inhibits colony formation. Transcriptional profiling studies revealed that CLCA4 and CLCA2 together are markers for mammary epithelial differentiation, and both are downregulated by TGF beta. Moreover, knockdown of CLCA4 in immortalized cells by shRNAs caused downregulation of epithelial marker E-cadherin and CLCA2, while mesenchymal markers N-cadherin, vimentin, and fibronectin were upregulated. Double knockdown of CLCA2 and CLCA4 enhanced the mesenchymal profile. These findings suggest that CLCA4 and CLCA2 play complementary but distinct roles in epithelial differentiation. Clinically, low expression of CLCA4 signaled lower relapse-free survival in basal and luminal B breast cancers. C1 [Walia, Vijay; Elble, Randolph C.] So Illinois Univ, Sch Med, Dept Pharmacol, Springfield, IL 62794 USA. [Yu, Yang; Walia, Vijay; Elble, Randolph C.] So Illinois Univ, Sch Med, Simmons Canc Inst, Springfield, IL USA. [Walia, Vijay] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21701 USA. RP Elble, RC (reprint author), So Illinois Univ, Sch Med, Dept Pharmacol, Springfield, IL 62794 USA. EM relble2@siumed.edu FU NIH [R15CA151094]; Department of Defense [W81XWH-10-1-0402] FX This work was supported by NIH grant R15CA151094 and Department of Defense grant number W81XWH-10-1-0402 to RCE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 10 Z9 10 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 DEC 26 PY 2013 VL 8 IS 12 AR e83943 DI 10.1371/journal.pone.0083943 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281QS UT WOS:000329116700090 PM 24386311 ER PT J AU Parkman, HP Van Natta, ML Abell, TL McCallum, RW Sarosiek, I Nguyen, L Snape, WJ Koch, KL Hasler, WL Farrugia, G Lee, L Unalp-Arida, A Tonascia, J Hamilton, F Pasricha, PJ AF Parkman, Henry P. Van Natta, Mark L. Abell, Thomas L. McCallum, Richard W. Sarosiek, Irene Nguyen, Linda Snape, William J. Koch, Kenneth L. Hasler, William L. Farrugia, Gianrico Lee, Linda Unalp-Arida, Aynur Tonascia, James Hamilton, Frank Pasricha, Pankaj J. TI Effect of Nortriptyline on Symptoms of Idiopathic Gastroparesis The NORIG Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID DOUBLE-BLIND; GASTROINTESTINAL DISORDERS; TRICYCLIC ANTIDEPRESSANTS; FUNCTIONAL DYSPEPSIA; MOTILIN AGONIST; SEVERITY; MULTICENTER; VALIDATION; MANAGEMENT; SATIATION AB IMPORTANCE Gastroparesis remains a challenging syndrome to manage, with few effective treatments and a lack of rigorously controlled trials. Tricyclic antidepressants are often used to treat refractory symptoms of nausea, vomiting, and abdominal pain. Evidence from well-designed studies for this use is lacking. OBJECTIVE To determine whether treatment with nortriptyline results in symptomatic improvement in patients with idiopathic gastroparesis. DESIGN, SETTING, AND PARTICIPANTS The NORIG (Nortriptyline for Idiopathic Gastroparesis) trial, a 15-week multicenter, parallel-group, placebo-controlled, double-masked, randomized clinical trial from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC), comparing nortriptyline with placebo for symptomatic relief in idiopathic gastroparesis. One hundred thirty patients with idiopathic gastroparesis were enrolled between March 2009 and June 2012 at 7 US academic medical centers. Patient follow-up was completed in October 2012. Inclusion criteria included delayed gastric emptying and moderate to severe symptom scores using the Gastroparesis Cardinal Symptom Index (GCSI). INTERVENTIONS Nortriptyline vs placebo. Study drug dose was increased at 3-week intervals (10, 25, 50, 75 mg) up to 75 mg at 12 weeks. MAIN OUTCOMES AND MEASURES The primary outcome measure of symptomatic improvement was a decrease from the patient's baseline GCSI score of at least 50% on 2 consecutive 3-week GCSI assessments during 15 weeks of treatment. RESULTS The primary symptomatic improvement outcome did not differ between 65 patients randomized to nortriptyline vs 65 patients randomized to placebo: 15 (23% [95% CI, 14%-35%]) in the nortriptyline group vs 14 (21% [95% CI, 12%-34%]) in the placebo group (P = .86). Treatment was stopped more often in the nortriptyline group (19 [29% {95% CI, 19%-42%}]) than in the placebo group (6 [9%] {95% CI, 3%-19%}]) (P = .007), but numbers of adverse events were not different (27 [95% CI, 18-39] vs 28 [95% CI, 19-40]) (P = .89). CONCLUSIONS AND RELEVANCE Among patients with idiopathic gastroparesis, the use of nortriptyline compared with placebo for 15 weeks did not result in improvement in overall symptoms. These findings do not support the use of nortriptyline for idiopathic gastroparesis. C1 [Parkman, Henry P.] Temple Univ, Philadelphia, PA 19140 USA. [Van Natta, Mark L.; Lee, Linda; Unalp-Arida, Aynur; Tonascia, James] Johns Hopkins Univ, Baltimore, MD USA. [Abell, Thomas L.] Univ Louisville, Louisville, KY 40292 USA. [McCallum, Richard W.; Sarosiek, Irene] Texas Tech Univ, El Paso, TX USA. [Nguyen, Linda] Stanford Univ, Palo Alto, CA 94304 USA. [Snape, William J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Koch, Kenneth L.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Hasler, William L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Farrugia, Gianrico] Mayo Clin, Rochester, MN USA. [Hamilton, Frank] NIDDK, Bethesda, MD 20892 USA. [Pasricha, Pankaj J.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. RP Parkman, HP (reprint author), Temple Univ, Sch Med, Gastroenterol Sect, Parkinson Pavil,8th Floor,3401 N Broad St, Philadelphia, PA 19140 USA. EM henry.parkman@temple.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008] FX The Gastroparesis Clinical Research Consortium (GpCRC) is supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, and U01DK074008. NR 30 TC 28 Z9 28 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 25 PY 2013 VL 310 IS 24 BP 2640 EP 2649 DI 10.1001/jama.2013.282833 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 277KN UT WOS:000328818000016 PM 24368464 ER PT J AU Noskov, SY Rostovtseva, TK Bezrukov, SM AF Noskov, Sergei Yu. Rostovtseva, Tatiana K. Bezrukov, Sergey M. TI ATP Transport through VDAC and the VDAC-Tubulin Complex Probed by Equilibrium and Nonequilibrium MD Simulations SO BIOCHEMISTRY LA English DT Article ID DEPENDENT ANION CHANNEL; OUTER MITOCHONDRIAL-MEMBRANE; SCALABLE MOLECULAR-DYNAMICS; FREE-ENERGY SIMULATIONS; ION CHANNELS; BINDING; CONDUCTION; PERMEATION; SELECTIVITY; PROTEIN AB Voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane, serves as a principal pathway for ATP, ADP, and other respiratory substrates across this membrane. Using umbrella-sampling simulations, we established the thermodynamic and kinetic components governing ATP transport across the VDAC1 channel. We found that there are several low-affinity binding sites for ATP along the translocation pathway and that the main barrier for ATP transport is located around the center of the channel and is formed predominantly by residues in the N-terminus. The binding affinity of ATP to an open channel was found to be in the millimolar to micromolar range. However, we show that this weak binding increases the ATP translocation probability by about 10-fold compared with the VDAC pore in which attractive interactions were artificially removed. Recently, it was found that free dimeric tubulin induces a highly efficient, reversible blockage of VDAC reconstituted into planar lipid membranes. It was proposed that by blocking VDAC permeability for ATP/ADP and other mitochondrial respiratory substrates tubulin controls mitochondrial respiration. Using the Rosetta protein-protein docking algorithm, we established a tentative structure of the VDAC-tubulin complex. An extensive set of equilibrium and nonequilibrium (under applied electric field) molecular dynamics (MD) simulations was used to establish the conductance of the open and blocked channel. It was found that the presence of the unstructured C-terminal tail of tubulin in the VDAC pore decreases its conductance by more than 40% and switches its selectivity from anionic to cationic. The subsequent ID potential of mean force (PMF) computations for the VDAC-tubulin complex show that the state renders ATP transport virtually impossible. A number of residues pivotal for tubulin binding to the channel were identified that help to clarify the molecular details of VDAC-tubulin interaction and to provide new insight into the mechanism of the control of mitochondria respiration by VDAC. C1 [Noskov, Sergei Yu.] Univ Calgary, Dept Biol Sci, Ctr Mol Simulat, Calgary, AB T2N 1N4, Canada. [Rostovtseva, Tatiana K.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Noskov, SY (reprint author), Univ Calgary, Dept Biol Sci, Ctr Mol Simulat, 2500 Univ Dr 1 NW, Calgary, AB T2N 1N4, Canada. EM snoskov@ucalgary.ca FU NICHD; National Sciences and Engineering Research Council [RGPIN-315019]; Alberta Innovates Technology Futures New Faculty; Canadian Foundation for Innovation FX This work was supported with intramural funding from NICHD and the National Sciences and Engineering Research Council (discovery grant RGPIN-315019 to S.Y.N.). S.Y.N. is an Alberta Innovates Technology Futures New Faculty, Canadian Institute for Health Research New Investigator, and an Alberta Innovates Health Solutions Scholar. Computations were performed on the West-Grid/Compute Canada facilities and the University of Calgary TNK cluster supported by the Canadian Foundation for Innovation. NR 65 TC 14 Z9 14 U1 4 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 24 PY 2013 VL 52 IS 51 BP 9246 EP 9256 DI 10.1021/bi4011495 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 281YP UT WOS:000329137200016 PM 24245503 ER PT J AU Lee, JE Wang, CC Xu, SLY Cho, YW Wang, LF Feng, XS Baldridge, A Sartorelli, V Zhuang, LN Peng, WQ Ge, K AF Lee, Ji-Eun Wang, Chaochen Xu, Shiliyang Cho, Young-Wook Wang, Lifeng Feng, Xuesong Baldridge, Anne Sartorelli, Vittorio Zhuang, Lenan Peng, Weiqun Ge, Kai TI H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation SO ELIFE LA English DT Article ID HISTONE-MODIFYING GENES; EMBRYONIC STEM-CELLS; PPAR-GAMMA; TRANSCRIPTION FACTORS; HUMAN GENOME; LYSINE 4; ADIPOGENESIS; EXPRESSION; IDENTIFICATION; METHYLATION AB Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for H3K4me1/2 on enhancers remain elusive. Furthermore, how these enzymes function on enhancers to regulate cell-type-specific gene expression is unclear. In this study, we identify MLL4 (KMT2D) as a major mammalian H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3 (KMT2C). Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of Mll4 markedly decreases H3K4me1/2, H3K27ac, Mediator and Polymerase II levels on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Together, these findings identify MLL4 as a major mammalian H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation. C1 [Lee, Ji-Eun; Wang, Chaochen; Xu, Shiliyang; Cho, Young-Wook; Wang, Lifeng; Baldridge, Anne; Zhuang, Lenan; Ge, Kai] NIDDK, Adipocyte Biol & Gene Regulat Sect, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Xu, Shiliyang; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Cho, Young-Wook] Korea Basic Sci Inst, Chuncheon Ctr, Chunchon, South Korea. [Feng, Xuesong; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Peng, Weiqun] George Washington Univ, Dept Anat & Regenerat Biol, Washington, DC USA. RP Ge, K (reprint author), NIDDK, Adipocyte Biol & Gene Regulat Sect, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. EM wpeng@gwu.edu; kaig@niddk.nih.gov RI Wang, Lifeng/I-4888-2012; Lee, Ji-Eun/F-7891-2011; OI Wang, Lifeng/0000-0003-4752-6547; Lee, Ji-Eun/0000-0002-3768-7016; Ge, Kai/0000-0002-7442-5138 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [1ZIADK075003]; National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health [1ZIAAR041126] FX National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health 1ZIADK075003 Ji-Eun Lee, Chaochen Wang, Shiliyang Xu, Lifeng Wang, Anne Baldridge, Lenan Zhuang, Weiqun Peng, Kai Ge; National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health 1ZIAAR041126 Xuesong Feng, Vittorio Sartorelli NR 62 TC 78 Z9 79 U1 3 U2 19 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD DEC 24 PY 2013 VL 2 AR e01503 DI 10.7554/eLife.01503 PG 25 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 280MC UT WOS:000329033300006 PM 24368734 ER PT J AU Jenkinson, SR Williams, JA Jeon, H Zhang, JJ Nitta, T Ohigashi, I Kruhlak, M Zuklys, S Sharrow, S Adams, A Granger, L Choi, Y Siebenlist, U Bishop, GA Hollander, GA Takahama, Y Hodes, RJ AF Jenkinson, S. Rhiannon Williams, Joy A. Jeon, Hyein Zhang, Jingjing Nitta, Takeshi Ohigashi, Izumi Kruhlak, Michael Zuklys, Saulius Sharrow, Susan Adams, Anthony Granger, Larry Choi, Yongwon Siebenlist, Ulrich Bishop, Gail A. Hollander, Georg A. Takahama, Yousuke Hodes, Richard J. TI TRAF3 enforces the requirement for T cell cross-talk in thymic medullary epithelial development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SELF-TOLERANCE; NF-KAPPA-B2 P100; GENE-EXPRESSION; RECEPTOR; MICE; ALPHA; AIRE; RANK; MICROENVIRONMENT; ORGANOGENESIS AB Induction of self-tolerance in developing T cells depends on medullary thymic epithelial cells (mTECs), whose development, in turn, requires signals from single-positive (SP) thymocytes. Thus, the absence of SP thymocytes in Tcra(-/-) mice results in a profound deficiency in mTECs. Here, we have probed the mechanism that underlies this requirement for cross-talk with thymocytes in medullary development. Previous studies have implicated nonclassical NF-kappa B as a pathway important in the development of mTECs, because mice lacking RelB, NIK, or IKK alpha, critical components of this pathway, have an almost complete absence of mTECs, with resulting autoimmune pathology. We therefore assessed the effect of selective deletion in TEC of TNF receptor-associated factor 3 (TRAF3), an inhibitor of nonclassical NF-kappa B signaling. Deletion of TRAF3 in thymic epithelial cells allowed RelB-dependent development of normal numbers of AIRE-expressing mTECs in the complete absence of SP thymocytes. Thus, mTEC development can occur in the absence of cross-talk with SP thymocytes, and signals provided by SP T cells are needed to overcome TRAF3-imposed arrest in mTEC development mediated by inhibition of nonclassical NF-kappa B. We further observed that TRAF3 deletion is also capable of overcoming all requirements for LT beta R and CD40, which are otherwise necessary for mTEC development, but is not sufficient to overcome the requirement for RANKL, indicating a role for RANKL that is distinct from the signals provided by SP thymocytes. We conclude that TRAF3 plays a central role in regulation of mTEC development by imposing requirements for SP T cells and costimulation-mediated cross-talk in generation of the medullary compartment. C1 [Jenkinson, S. Rhiannon; Williams, Joy A.; Jeon, Hyein; Zhang, Jingjing; Kruhlak, Michael; Sharrow, Susan; Adams, Anthony; Granger, Larry; Hodes, Richard J.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Nitta, Takeshi; Ohigashi, Izumi; Takahama, Yousuke] Univ Tokushima, Inst Genome Res, Div Expt Immunol, Tokushima 7708503, Japan. [Zuklys, Saulius; Hollander, Georg A.] Univ Basel, Dept Med, CH-4058 Basel, Switzerland. [Choi, Yongwon] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Siebenlist, Ulrich] NIAID, Lab Immunoregulat, Bethesda, MD 20892 USA. [Bishop, Gail A.] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. [Bishop, Gail A.] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Bishop, Gail A.] Univ Iowa, Vet Affairs Med Ctr, Iowa City, IA 52242 USA. [Hollander, Georg A.] Univ Oxford, Dept Pediat, Oxford OX1 3DW, England. RP Hodes, RJ (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM richard_hodes@nih.gov RI Takahama, Yousuke/A-5863-2010 FU NIAID NIH HHS [R01 AI064909] NR 41 TC 10 Z9 11 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 24 PY 2013 VL 110 IS 52 BP 21107 EP 21112 DI 10.1073/pnas.1314859111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 277ZW UT WOS:000328858800062 PM 24324158 ER PT J AU Sumner, AE Furtado, JD Courville, AB Ricks, M Younger-Coleman, N Tulloch-Reid, MK Sacks, FM AF Sumner, Anne E. Furtado, Jeremy D. Courville, Amber B. Ricks, Madia Younger-Coleman, Novie Tulloch-Reid, Marshall K. Sacks, Frank M. TI ApoC-III and visceral adipose tissue contribute to paradoxically normal triglyceride levels in insulin-resistant African-American women SO NUTRITION & METABOLISM LA English DT Article DE ApoC-III; Visceral adipose tissue; Triglyceride; Apoliprotein C-III; Visceral adiposity; Insulin resistance; African-Americans; Health disparities ID APOLIPOPROTEIN-C-III; LOW-DENSITY LIPOPROTEINS; METABOLIC SYNDROME; ETHNIC-DIFFERENCES; CORONARY EVENTS; RISK; CIII; LDL; HYPERTRIGLYCERIDEMIA; MEN AB Background: African-Americans are more insulin-resistant than whites but have lower triglyceride (TG) concentrations. The metabolic basis for this is unknown. Our goal was to determine in a cross-sectional study the effect of insulin resistance, visceral adipose tissue (VAT) and the apolipoproteins, B, C-III and E, on race differences in TG content of very low density lipoproteins (VLDL). Methods: The participants were 31 women (16 African-American, 15 white) of similar age (37 +/- 9 vs. 38 +/- 11y (mean +/- SD), P = 0.72) and BMI (32.4 +/- 7.2 vs. 29.3 +/- 6.0 kg/m(2), P = 0.21). A standard diet (33% fat, 52% carbohydrate, 15% protein) was given for 7 days followed by a test meal (40% fat, 40% carbohydrate, 20% protein) on Day 8. Insulin sensitivity index (SI) was calculated from the minimal model. VAT was measured at L2-3. The influence of race, S-1, VAT and apolipoproteins on the TG content of VLDL was determined by random effects models (REM). Results: African-Americans were more insulin-resistant (SI: 3.6 +/- 1.3 vs. 5.6 +/- 2.6 mU/L-1. min(-1), P < 0.01) with less VAT (75 +/- 59 vs. 102 +/- 71 cm(2), P < 0.01). TG, apoB and apoC-III content of light and dense VLDL were lower in African-Americans (all P < 0.05 except for apoC-III in light VLDL, P = 0.11). ApoE content did not vary by race. In REM, VAT but not SI influenced the TG concentration of VLDL. In models with race, SI, VAT and all apolipoproteins entered, race was not significant but apoC-III and VAT remained significant determinants of TG concentration in light and dense VLDL. Conclusions: Low concentrations of apoC-III and VAT in African-Americans contribute to race differences in TG concentrations. C1 [Sumner, Anne E.; Ricks, Madia] Natl Inst Diabet Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. [Furtado, Jeremy D.; Sacks, Frank M.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Courville, Amber B.] NIH, Ctr Clin, Dept Nutr, Bethesda, MD 20892 USA. [Younger-Coleman, Novie; Tulloch-Reid, Marshall K.] Univ W Indies, Res Inst Trop Med, Kingston 7, Jamaica. RP Sumner, AE (reprint author), Natl Inst Diabet Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. EM AnneS@intra.niddk.nih.gov FU Intramural Program of NIDDK; NIH Clinical Center; NIH [HL073286] FX Anne E. Sumner and Madia Ricks are supported by the Intramural Program of NIDDK. Amber B. Courville is supported by the NIH Clinical Center. The grant was also funded by the NIH Bench to Bedside Program with a supplement to HL073286 (Frank M. Sacks). NR 33 TC 4 Z9 4 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-7075 J9 NUTR METAB JI Nutr. Metab. PD DEC 23 PY 2013 VL 10 AR 73 DI 10.1186/1743-7075-10-73 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 285NA UT WOS:000329399500001 PM 24365086 ER PT J AU Huang, P Lin, J Li, WW Rong, PF Wang, Z Wang, SJ Wang, XP Sun, XL Aronova, M Niu, G Leapman, RD Nie, ZH Chen, XY AF Huang, Peng Lin, Jing Li, Wanwan Rong, Pengfei Wang, Zhe Wang, Shouju Wang, Xiaoping Sun, Xiaolian Aronova, Maria Niu, Gang Leapman, Richard D. Nie, Zhihong Chen, Xiaoyuan TI Biodegradable Gold Nanovesicles with an Ultrastrong Plasmonic Coupling Effect for Photoacoustic Imaging and Photothermal Therapy SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE biodegradable block copolymers; gold nanovesicles; photoacoustic imaging; photothermal therapy; plasmonic coupling ID IN-VIVO; PHOTODYNAMIC THERAPY; CANCER-CELLS; NANOPARTICLES; NANOCRYSTALS; GRAPHENE; NANORODS; AGENT; NANOCOMPOSITES; THERANOSTICS AB The hierarchical assembly of gold nanoparticles (GNPs) allows the localized surface plasmon resonance peaks to be engineered to the near-infrared (NIR) region for enhanced photothermal therapy (PTT). Herein we report a novel theranostic platform based on biodegradable plasmonic gold nanovesicles for photoacoustic (PA) imaging and PTT. The disulfide bond at the terminus of a PEG-b-PCL block-copolymer graft enables dense packing of GNPs during the assembly process and induces ultrastrong plasmonic coupling between adjacent GNPs. The strong NIR absorption induced by plasmon coupling and very high photothermal conversion efficiency (=37%) enable simultaneous thermal/PA imaging and enhanced PTT efficacy with improved clearance of the dissociated particles after the completion of PTT. The assembly of various nanocrystals with tailored optical, magnetic, and electronic properties into vesicle architectures opens new possibilities for the construction of multifunctional biodegradable platforms for biomedical applications. C1 [Huang, Peng; Li, Wanwan; Rong, Pengfei; Wang, Zhe; Wang, Shouju; Wang, Xiaoping; Sun, Xiaolian; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD USA. [Lin, Jing; Nie, Zhihong] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Aronova, Maria; Leapman, Richard D.] NIBIB, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. [Wang, Zhe] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Nie, ZH (reprint author), Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. EM znie@umd.edu; shawn.chen@nih.gov RI Huang, Peng/H-9985-2013; Nie, Zhihong/D-7495-2011; Huang, Peng/R-2480-2016 OI Nie, Zhihong/0000-0001-9639-905X; Huang, Peng/0000-0003-3651-7813 FU University of Maryland; NIBIB; NIH; National Key Basic Research Program (973 Project) [2010CB933901, 2013CB733802, 2014CB744503]; National Science Foundation of China [81272987, 31170961, 51102258, 81371596]; Chinese Academy of Sciences [2011T2J06] FX This research was supported by the startup funds of the University of Maryland, the Intramural Research Program (IRP) of the NIBIB, the NIH, the National Key Basic Research Program (973 Project; 2010CB933901, 2013CB733802, 2014CB744503), the National Science Foundation of China (81272987, 31170961, 51102258, 81371596), and a Chinese Academy of Sciences Professorship for Senior International Scientists (2011T2J06). NR 41 TC 138 Z9 140 U1 39 U2 342 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD DEC 23 PY 2013 VL 52 IS 52 BP 13958 EP 13964 DI 10.1002/anie.201308986 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 273JM UT WOS:000328531100010 PM 24318645 ER PT J AU Liu, DB Wang, ZT Jin, A Huang, XL Sun, XL Wang, F Yan, Q Ge, SX Xia, NS Niu, G Liu, G Walker, ARH Chen, XY AF Liu, Dingbin Wang, Zhantong Jin, Albert Huang, Xinglu Sun, Xiaolian Wang, Fu Yan, Qiang Ge, Shengxiang Xia, Ningshao Niu, Gang Liu, Gang Walker, A. R. Hight Chen, Xiaoyuan TI Acetylcholinesterase-Catalyzed Hydrolysis Allows Ultrasensitive Detection of Pathogens with the Naked Eye SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE acetylcholinesterase; analytical methods; gold; hydrolysis; nanoparticles ID GOLD NANOPARTICLES; COLORIMETRIC DETECTION; ENTEROVIRUS 71; RAPID DETECTION; DNA; GLUCOSE; POINT; CARE C1 [Liu, Dingbin; Huang, Xinglu; Sun, Xiaolian; Wang, Fu; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Wang, Zhantong; Yan, Qiang; Ge, Shengxiang; Xia, Ningshao] Xiamen Univ, Sch Publ Hlth, Natl Inst Diagnost & Vaccine Dev Infect Dis, Xiamen 361102, Peoples R China. [Wang, Zhantong; Liu, Gang] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. [Jin, Albert] NIBIB, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Walker, A. R. Hight] NIST, Opt Technol Div, Phys Lab, Gaithersburg, MD 20899 USA. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov RI Hight Walker, Angela/C-3373-2009; OI Hight Walker, Angela/0000-0003-1385-0672; Jin, Albert/0000-0003-3826-1081; Wang, Fu/0000-0001-9222-0833 FU Major State Basic Research Development Program of China (973 Program) [2013CB733802, 2014CB744503]; National Science Foundation of China (NSFC) [81101101, 51273165, 81201086, 81201190, 81371596]; Key Project of the Chinese Ministry of Education [212149]; Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); NIH-NIBIB/NIST NRC FX This work was supported in part the Major State Basic Research Development Program of China (973 Program; 2013CB733802 and 2014CB744503), the National Science Foundation of China (NSFC; 81101101, 51273165, 81201086, 81201190, and 81371596), a Key Project of the Chinese Ministry of Education (212149), the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and the National Institutes of Health (NIH). D. L. was supported by a postdoctoral fellowship from NIH-NIBIB/NIST NRC. NR 36 TC 46 Z9 47 U1 20 U2 163 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD DEC 23 PY 2013 VL 52 IS 52 BP 14065 EP 14069 DI 10.1002/anie.201307952 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA 273JM UT WOS:000328531100031 PM 24155243 ER PT J AU Nogueira, LM Sampson, JN Chu, LW Yu, K Andriole, G Church, T Stanczyk, FZ Koshiol, J Hsing, AW AF Nogueira, Leticia M. Sampson, Joshua N. Chu, Lisa W. Yu, Kai Andriole, Gerald Church, Timothy Stanczyk, Frank Z. Koshiol, Jill Hsing, Ann W. TI Individual Variations in Serum Melatonin Levels through Time: Implications for Epidemiologic Studies SO PLOS ONE LA English DT Article ID BREAST-CANCER RISK; NIGHT-SHIFT WORK; URINARY 6-SULFATOXYMELATONIN LEVELS; LIFE-STYLE FACTORS; LIGHT-AT-NIGHT; SLEEP DURATION; CIRCADIAN DISRUPTION; PROSTATE-CANCER; NURSES HEALTH; POSTMENOPAUSAL WOMEN AB Melatonin, a marker for the circadian rhythm with serum levels peaking between 2AM and 5AM, is hypothesized to possess anti-cancer properties, making it a mechanistic candidate for the probable carcinogenic effect of circadian rhythm disruption. In order to weigh epidemiologic evidence on the association of melatonin with cancer, we must first understand the laboratory and biological sources of variability in melatonin levels measured in samples. Participants for this methodological study were men enrolled in the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO). We measured serum melatonin levels over a five year period in 97 individuals to test if melatonin levels are steady over time. The Pearson correlation coefficient between two measures separated by 1 year was 0.87, while the correlation between two measures separated by 5 years was to 0.70. In an additional cross-sectional study of 292 individuals, we used Analysis of Variance to identify differences in melatonin levels between different lifestyle and environmental characteristics. Serum melatonin levels were slightly higher in samples collected from 130 individuals during the winter, (6.36 +/- 0.59 pg/ml) than in samples collected from 119 individuals during the summer (4.83 +/- 0.62 pg/ml). Serum melatonin levels were lowest in current smokers (3.02 +/- 1.25 pg/ml, p = 0.007) compared to never (6.66 +/- 0.66 pg/ml) and former (5.59 +/- 0.50 pg/ml) smokers whereas BMI did not significantly affect serum melatonin levels in this study. In conclusion, the high 5 year correlation of melatonin levels implies that single measurements may be used to detect population level associations between melatonin and risk of cancer. Furthermore, our results reiterate the need to record season of sample collection, and individual characteristics in order to maximize study power and prevent confounding. C1 [Nogueira, Leticia M.; Sampson, Joshua N.; Yu, Kai; Koshiol, Jill] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chu, Lisa W.; Hsing, Ann W.] Canc Prevent Inst Calif, Fremont, CA USA. [Andriole, Gerald] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Church, Timothy] Univ Minnesota, Sch Publ Hlth, Dept Environm Hlth Sci, Minneapolis, MN USA. [Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Obstet Gynecol & Prevent Med, Los Angeles, CA 90033 USA. RP Nogueira, LM (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM leticia.nogueira@nih.gov OI Church, Timothy R./0000-0003-3292-5035 FU Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 98 TC 4 Z9 4 U1 1 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 DEC 23 PY 2013 VL 8 IS 12 AR e83208 DI 10.1371/journal.pone.0083208 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 278IG UT WOS:000328882000069 PM 24376664 ER PT J AU Nonoguchi, H Izumi, Y Nakayama, Y Matsuzaki, T Yasuoka, Y Inoue, T Inoue, H Mouri, T Kawahara, K Saito, H Tomita, K AF Nonoguchi, Hiroshi Izumi, Yuichiro Nakayama, Yushi Matsuzaki, Takanobu Yasuoka, Yukiko Inoue, Takeaki Inoue, Hideki Mouri, Tomohiko Kawahara, Katsumasa Saito, Hideyuki Tomita, Kimio TI Effects of Atrial Natriuretic Peptide on Bicarbonate Transport in Long- and Short-Looped Medullary Thick Ascending Limbs of Rats SO PLOS ONE LA English DT Article ID CYCLIC ADENOSINE-MONOPHOSPHATE; CORTICAL COLLECTING DUCT; V2 VASOPRESSIN RECEPTOR; DOWN-REGULATION; CHLORIDE REABSORPTION; ANTIDIURETIC-HORMONE; NA+/H+ EXCHANGER; HCO3-ABSORPTION; BRATTLEBORO RAT; KIDNEY AB Atrial natriuretic peptide (ANP) is known to influence NaCl transport in the medullary thick ascending limbs (MAL), where the largest NaCl reabsorption occurs among distal nephron segments in response to arginine vasopressin (AVP). In the present study, we investigated the effect of ANP on bicarbonate (HCO3-) transport in the MAL using an isolated tubule perfusion technique. The HCO3- concentration was measured using free-flow ultramicro-fluorometer. We first observed basal HCO3- reabsorption in both long-and short-looped MALs (lMALs, and sMALs, respectively). AVP inhibited HCO3- reabsorption in both lMALs and sMALs, whereas ANP did not change HCO3- transport. However, in the presence of AVP, ANP restored the HCO3- reabsorption inhibited by AVP both in lMAL and sMAL. The effects of ANP on HCO3- transport was mimicked by cyclic GMP. The mRNA expression level of the vasopressin V2 receptor in lMALs was significantly higher than in sMALs, whereas expression of the V1a receptor was unchanged. In summary, AVP inhibits HCO3- transport, and ANP counteracts the action of AVP on HCO3- transport both in lMALs and sMALs. C1 [Nonoguchi, Hiroshi] Kitasato Univ, Med Ctr, Dept Internal Med, Kitamoto, Saitama, Japan. [Nonoguchi, Hiroshi] Kitasato Univ, Med Ctr, Educ & Res Ctr, Kitamoto, Saitama, Japan. [Izumi, Yuichiro] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Nakayama, Yushi; Inoue, Takeaki; Inoue, Hideki; Mouri, Tomohiko; Tomita, Kimio] Kumamoto Univ, Grad Sch Med Sci, Dept Nephrol, Kumamoto, Japan. [Matsuzaki, Takanobu; Saito, Hideyuki] Kumamoto Univ Hosp, Dept Pharm, Kumamoto, Japan. [Yasuoka, Yukiko; Kawahara, Katsumasa] Kitasato Univ, Sch Med, Dept Physiol, Sagamihara, Kanagawa 228, Japan. RP Nonoguchi, H (reprint author), Kitasato Univ, Med Ctr, Dept Internal Med, Kitamoto, Saitama, Japan. EM nono@insti.kitasato-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan [21591034, 21591064, 24591244]; Science Research Promotion Fund from the promotion and Mutual Aid Corporation for Private Schools of Japan FX This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (21591034, 21591064, 24591244) and by the Science Research Promotion Fund from the promotion and Mutual Aid Corporation for Private Schools of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 1 Z9 1 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 23 PY 2013 VL 8 IS 12 AR e83146 DI 10.1371/journal.pone.0083146 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 278IG UT WOS:000328882000066 PM 24376658 ER PT J AU Su, WH Shugart, YY Chang, KP Tsang, NM Tse, KP Chang, YS AF Su, Wen-Hui Shugart, Yin Yao Chang, Kai-Ping Tsang, Ngan-Ming Tse, Ka-Po Chang, Yu-Sun TI How Genome-Wide SNP-SNP Interactions Relate to Nasopharyngeal Carcinoma Susceptibility SO PLOS ONE LA English DT Article ID GENE-GENE INTERACTION; MISSING HERITABILITY; COMPLEX DISEASES; CLASS-I; ASSOCIATION; PROSTATE; LOCI; STRATEGIES; EPISTASIS; RISK AB This study is the first to use genome-wide association study (GWAS) data to evaluate the multidimensional genetic architecture underlying nasopharyngeal cancer. Since analysis of data from GWAS confirms a close and consistent association between elevated risk for nasopharyngeal carcinoma (NPC) and major histocompatibility complex class 1 genes, our goal here was to explore lesser effects of gene-gene interactions. We conducted an exhaustive genome-wide analysis of GWAS data of NPC, revealing two-locus interactions occurring between single nucleotide polymorphisms (SNPs), and identified a number of suggestive interaction loci which were missed by traditional GWAS analyses. Although none of the interaction pairs we identified passed the genome-wide Bonferroni-adjusted threshold for significance, using independent GWAS data from the same population (Stage 2), we selected 66 SNP pairs in 39 clusters with P < 0.01. We identified that in several chromosome regions, multiple suggestive interactions group to form a block-like signal, effectively reducing the rate of false discovery. The strongest cluster of interactions involved the CREB5 gene and a SNP rs1607979 on chromosome 17q22 (P = 9.86 x 10(-11)) which also show trans-expression quantitative loci (eQTL) association in Chinese population. We then detected a complicated cis-interaction pattern around the NPC-associated HLA-B locus, which is immediately adjacent to copy-number variations implicated in male susceptibility for NPC. While it remains to be seen exactly how and to what degree SNP-SNP interactions such as these affect susceptibility for nasopharyngeal cancer, future research on these questions holds great promise for increasing our understanding of this disease's genetic etiology, and possibly also that of other gene-related cancers. C1 [Su, Wen-Hui] Chang Gung Univ, Dept Biomed Sci, Tao Yuan, Taiwan. [Su, Wen-Hui] Chang Gung Univ, Coll Med, Grad Inst Biomed Sci, Tao Yuan, Taiwan. [Su, Wen-Hui; Tse, Ka-Po; Chang, Yu-Sun] Chang Gung Univ, Chang Gung Mol Med Res Ctr, Tao Yuan, Taiwan. [Shugart, Yin Yao] NIMH, Genom Res Branch, Div Neurosci & Behav Sci, NIH, Bethesda, MD 20892 USA. [Shugart, Yin Yao] Johns Hopkins Med Sch, Dept Gastroenterol, Baltimore, MD USA. [Chang, Kai-Ping] Chang Gung Mem Hosp Lin Kou, Dept Otolaryngol Head & Neck Surg, Tao Yuan, Taiwan. [Tsang, Ngan-Ming] Chang Gung Mem Hosp Lin Kou, Dept Radiat Oncol, Tao Yuan, Taiwan. RP Su, WH (reprint author), Chang Gung Univ, Dept Biomed Sci, Tao Yuan, Taiwan. EM whsu@mail.cgu.edu.tw; kay1yao@mail.nih.gov FU Ministry of Education (Chang Gung University); National Science Council [NSC 101-2314-B-182-051-MY3]; Chang Gung Memorial Hospital, Taiwan [CMRPD1A0381, CMRPD1A0382, CMRPD1A0383]; NIMH FX This work was supported by the Ministry of Education (Chang Gung University), the National Science Council (NSC 101-2314-B-182-051-MY3), and Chang Gung Memorial Hospital (CMRPD1A0381, CMRPD1A0382 and CMRPD1A0383), Taiwan. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr. Yin Yao Shugart was supported by the Intramural Research Program at NIMH. NR 43 TC 5 Z9 5 U1 1 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 DEC 23 PY 2013 VL 8 IS 12 AR e83034 DI 10.1371/journal.pone.0083034 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 278IG UT WOS:000328882000052 PM 24376627 ER PT J AU Prochazkova, M Terse, A Amin, ND Hall, B Utreras, E Pant, HC Kulkarni, AB AF Prochazkova, Michaela Terse, Anita Amin, Niranjana D. Hall, Bradford Utreras, Elias Pant, Harish C. Kulkarni, Ashok B. TI Activation of cyclin-dependent kinase 5 mediates orofacial mechanical hyperalgesia SO MOLECULAR PAIN LA English DT Article DE Cdk5; p35; Trigeminal ganglia; Orofacial pain; Mouse model ID DORSAL-ROOT GANGLION; CAPSAICIN RECEPTOR; FORMALIN TEST; NEUROTRANSMITTER RELEASE; NEUROPATHIC PAIN; TRIGEMINAL PAIN; SENSORY NEURONS; NMDA RECEPTORS; MICE LACKING; CDK5 AB Background: Cyclin-dependent kinase 5 (Cdk5) is a unique member of the serine/threonine kinase family. This kinase plays an important role in neuronal development, and deregulation of its activity leads to neurodegenerative disorders. Cdk5 also serves an important function in the regulation of nociceptive signaling. Our previous studies revealed that the expression of Cdk5 and its activator, p35, is upregulated in nociceptive neurons during peripheral inflammation. The aim of the present study was to characterize the involvement of Cdk5 in orofacial pain. Since mechanical hyperalgesia is the distinctive sign of many orofacial pain conditions, we adapted an existing orofacial stimulation test to assess the behavioral responses to mechanical stimulation in the trigeminal region of the transgenic mice with either reduced or increased Cdk5 activity. Results: Mice overexpressing or lacking p35, an activator of Cdk5, showed altered phenotype in response to noxious mechanical stimulation in the trigeminal area. Mice with increased Cdk5 activity displayed aversive behavior to mechanical stimulation as indicated by a significant decrease in reward licking events and licking time. The number of reward licking/facial contact events was significantly decreased in these mice as the mechanical intensity increased. By contrast, mice deficient in Cdk5 activity displayed mechanical hypoalgesia. Conclusions: Collectively, our findings demonstrate for the first time the important role of Cdk5 in orofacial mechanical nociception. Modulation of Cdk5 activity in primary sensory neurons makes it an attractive potential target for the development of novel analgesics that could be used to treat multiple orofacial pain conditions. C1 [Prochazkova, Michaela; Terse, Anita; Hall, Bradford; Utreras, Elias; Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Amin, Niranjana D.; Pant, Harish C.] Natl Inst Neurol Disorders & Stroke, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Utreras, Elias] Univ Chile, Fac Sci, Lab Cellular & Neuronal Dynam, Santiago, Chile. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM ak40m@nih.gov FU Divisions of Intramural Research, National Institute of Dental and Craniofacial Research; National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This work was supported by the Divisions of Intramural Research, National Institute of Dental and Craniofacial Research and the National Institute of Neurological Disorders and Stroke, National Institutes of Health. We would like to thank Drs. Michael Iadarola, Jason Keller, Santosh Mishra, and Varsha Shukla for their helpful discussions during the course of these studies, and Mr. Larry Jones for his expert editorial assistance. NR 66 TC 5 Z9 6 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD DEC 21 PY 2013 VL 9 AR 66 DI 10.1186/1744-8069-9-66 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 294MS UT WOS:000330051400001 PM 24359609 ER PT J AU Suryadevara, M Bonville, CA Rosenberg, HF Domachowske, JB AF Suryadevara, Manika Bonville, Cynthia A. Rosenberg, Helene F. Domachowske, Joseph B. TI Local production of CCL3, CCL11, and IFN-gamma correlates with disease severity in murine parainfluenza virus infection SO VIROLOGY JOURNAL LA English DT Article DE Sendai virus; Parainfluenza virus; CCL3; MIP-1a; CCL11; Eotaxin; Interferon-gamma ID RESPIRATORY SYNCYTIAL VIRUS; SENDAI-VIRUS; PNEUMOVIRUS INFECTION; LUNG PATHOLOGY; IN-VIVO; MICE; EXPRESSION; CHEMOKINES; DEXAMETHASONE; BRONCHIOLITIS AB Background: Using a murine model of parainfluenza virus infection (mPIV1 or Sendai virus; SeV), we compared the inflammatory responses to lethal and sub-lethal infections in inbred DBA/2 mice. Methods: Mice were intranasally inoculated with either 1.6x10(3) or 1.6x10(5) infectious units (IU) of SeV or diluent control. Clinical data including daily weights, oxygen saturation, and lung function via whole body plethysmography were collected on days 0, 3-7, and 9-14. Clarified whole lung homogenates were evaluated for inflammatory markers by enzyme-linked immunoassay (ELISA). Data were analyzed using ANOVA or Student t-tests, as appropriate. Results: Mice inoculated with 1.6x10(5) IU of SeV developed a lethal infection with 100% mortality by day 7, while mice inoculated with 1.6x10(3) IU developed a clinically significant infection, with universal weight loss but only 32% mortality. Interestingly, peak virus recovery from the lungs of mice inoculated with 1.6x10(5) IU of SeV did not differ substantially from that detected in mice that received the 100-fold lower inoculum. In contrast, concentrations of CCL5 (RANTES), CCL11 (eotaxin), interferon-gamma, CXCL10 (IP-10), and CCL3 (MIP-1a) were significantly higher in lung tissue homogenates from mice inoculated with 1.6x10(5) IU (p < 0.05). In the lethal infection, levels of CCL11, interferon-. and CCL3 all correlated strongly with disease severity. Conclusion: We observed that severity of SeV-infection in DBA/2 mice was not associated with virus recovery but rather with the levels of proinflammatory cytokines, specifically CCL11, interferon-. and CCL3, detected in lung tissue in response to SeV infection. C1 [Suryadevara, Manika; Bonville, Cynthia A.; Domachowske, Joseph B.] SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY 13210 USA. [Rosenberg, Helene F.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Suryadevara, M (reprint author), SUNY Upstate Med Univ, Dept Pediat, 750 E Adams St, Syracuse, NY 13210 USA. EM suryadem@upstate.edu NR 29 TC 2 Z9 2 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD DEC 21 PY 2013 VL 10 AR 357 DI 10.1186/1743-422X-10-357 PG 9 WC Virology SC Virology GA 294MX UT WOS:000330051900001 PM 24359540 ER PT J AU Lamart, S Imran, R Simon, SL Doi, K Morton, LM Curtis, RE Lee, C Drozdovitch, V Maass-Moreno, R Chen, CC Whatley, M Miller, DL Pacak, K Lee, C AF Lamart, Stephanie Imran, Rebecca Simon, Steven L. Doi, Kazutaka Morton, Lindsay M. Curtis, Rochelle E. Lee, Choonik Drozdovitch, Vladimir Maass-Moreno, Roberto Chen, Clara C. Whatley, Millie Miller, Donald L. Pacak, Karel Lee, Choonsik TI Prediction of the location and size of the stomach using patient characteristics for retrospective radiation dose estimation following radiotherapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID POSITION; THERAPY; CANCER AB Following cancer radiotherapy, reconstruction of doses to organs, other than the target organ, is of interest for retrospective health risk studies. Reliable estimation of doses to organs that may be partially within or fully outside the treatment field requires reliable knowledge of the location and size of the organs, e.g., the stomach, which is at risk from abdominal irradiation. The stomach location and size are known to be highly variable between individuals, but have been little studied. Moreover, for treatments conducted years ago, medical images of patients are usually not available in medical records to locate the stomach. In light of the poor information available to locate the stomach in historical dose reconstructions, the purpose of this work was to investigate the variability of stomach location and size among adult male patients and to develop prediction models for the stomach location and size using predictor variables generally available in medical records of radiotherapy patients treated in the past. To collect data on stomach size and position, we segmented the contours of the stomach and of the skeleton on contemporary computed tomography (CT) images for 30 male patients in supine position. The location and size of the stomach was found to depend on body mass index (BMI), ponderal index (PI), and age. For example, the anteroposterior dimension of the stomach was found to increase with increasing BMI (approximate to 0.25 cm kg(-1) m(2)) whereas its craniocaudal dimension decreased with increasing PI (approximate to-3.3 cm kg(-1) m(3)) and its transverse dimension increased with increasing PI (approximate to 2.5 cm kg(-1) m(3)). Using the prediction models, we generated three-dimensional computational stomach models from a deformable hybrid phantom for three patients of different BMI. Based on a typical radiotherapy treatment, we simulated radiotherapy treatments on the predicted stomach models and on the CT images of the corresponding patients. Those dose calculations demonstrated good agreement between predicted and actual stomachs compared with doses derived from a reference model of the body that might be used in the absence of individual CT scan data. C1 [Lamart, Stephanie; Imran, Rebecca; Simon, Steven L.; Doi, Kazutaka; Morton, Lindsay M.; Curtis, Rochelle E.; Drozdovitch, Vladimir; Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lee, Choonik] Univ Michigan Hosp, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Maass-Moreno, Roberto; Chen, Clara C.; Miller, Donald L.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Whatley, Millie] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, NIH, Bethesda, MD USA. RP Lamart, S (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM leechoonsik@mail.nih.gov RI Morton, Lindsay/B-5234-2015; Lee, Choonsik/C-9023-2015 OI Morton, Lindsay/0000-0001-9767-2310; Lee, Choonsik/0000-0003-4289-9870 FU National Cancer Institute FX This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). This work was supported by the National Cancer Institute's intramural research program. NR 16 TC 4 Z9 4 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD DEC 21 PY 2013 VL 58 IS 24 BP 8739 EP 8753 DI 10.1088/0031-9155/58/24/8739 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 266SG UT WOS:000328043400011 PM 24301086 ER PT J AU Huang, X Meng, B Iqbal, J Ding, BB Perry, AM Cao, WF Smith, LM Bi, CF Jiang, CS Greiner, TC Weisenburger, DD Rimsza, L Rosenwald, A Ott, G Delabie, J Campo, E Braziel, RM Gascoyne, RD Cook, JR Tubbs, RR Jaffe, ES Armitage, JO Vose, JM Staudt, LM McKeithan, TW Chan, WC Ye, BH Fu, K AF Huang, Xin Meng, Bin Iqbal, Javeed Ding, B. Belinda Perry, Anamarija M. Cao, Wenfeng Smith, Lynette M. Bi, Chengfeng Jiang, Chunsun Greiner, Timothy C. Weisenburger, Dennis D. Rimsza, Lisa Rosenwald, Andreas Ott, German Delabie, Jan Campo, Elias Braziel, Rita M. Gascoyne, Randy D. Cook, James R. Tubbs, Raymond R. Jaffe, Elaine S. Armitage, James O. Vose, Julie M. Staudt, Louis M. McKeithan, Timothy W. Chan, Wing C. Ye, B. Hilda Fu, Kai TI Activation of the STAT3 Signaling Pathway Is Associated With Poor Survival in Diffuse Large B-Cell Lymphoma Treated With R-CHOP SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MOLECULAR SUBTYPES; GASTRIC-CANCER; EXPRESSION; RITUXIMAB; PROGNOSIS; CHEMOTHERAPY; THERAPY; GENE; METALLOTHIONEIN; TRANSCRIPTION-3 AB Purpose We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether STAT3 activation can risk stratify patients with DLBCL. Patients and Methods By an immunohistochemical method, we investigated phosphotyrosine STAT3 (PY-STAT3) expression from 185 patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Cell line-based siRNA experiments were also performed to generate an 11-gene, PY-STAT3 activation signature, which was used to study a previously published cohort of 222 patients with DLBCL. The STAT3 activation status determined by these two methods and by STAT3 mRNA levels were then correlated with survival. Results PY-STAT3 was detected in 37% of DLBCL and enriched in ABC-DLBCL cases (P = .03). PY-STAT3 positivity significantly correlated with poor overall survival (OS; P = .01) and event-free survival (EFS; P = .006). Similar observations were made for high levels of STAT3 mRNA. In multivariable analysis, PY-STAT3 status (P = .02), International Prognostic Index (P = .02), and BCL2 expression (P = .046) were independent prognosticators of OS in this cohort. Among the cell-of-origin subgroups, PY-STAT3 was associated with poor EFS among non-germinal center B-cell DLBCL cases only (P = .027). Similarly, the 11-gene STAT3 activation signature correlated with poor survival in the entire DLBCL cohort (OS, P < .001; EFS, P < .001) as well as the ABC-DLBCL subgroup (OS, P = .029; EFS, P = .025). Conclusion STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype. C1 [Huang, Xin; Meng, Bin; Cao, Wenfeng; Fu, Kai] Tianjin Med Univ, Canc Inst & Hosp, Natl Clin Res Ctr Canc, Tianjin, Peoples R China. [Bi, Chengfeng] Sichuan Univ, West China Sch Med, West China Hosp, Chengdu 610064, Peoples R China. [Huang, Xin; Meng, Bin; Iqbal, Javeed; Perry, Anamarija M.; Cao, Wenfeng; Smith, Lynette M.; Bi, Chengfeng; Jiang, Chunsun; Greiner, Timothy C.; Weisenburger, Dennis D.; Armitage, James O.; Vose, Julie M.; McKeithan, Timothy W.; Chan, Wing C.; Fu, Kai] Univ Nebraska Med Ctr, Omaha, NE 68198 USA. [Ding, B. Belinda; Ye, B. Hilda] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Rimsza, Lisa] Univ Arizona, Tucson, AZ USA. [Rosenwald, Andreas] Univ Wurzburg, D-97070 Wurzburg, Germany. [Ott, German; Delabie, Jan] Univ Oslo, Rikshosp, Radiumhosp, Med Ctr, N-0027 Oslo, Norway. [Campo, Elias] Univ Barcelona, Hosp Clin, Barcelona, Spain. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Cook, James R.; Tubbs, Raymond R.] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44106 USA. [Jaffe, Elaine S.; Staudt, Louis M.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Fu, K (reprint author), Univ Nebraska Med Ctr, Dept Pathol & Microbiol, 983135 Nebraska Med Ctr, Omaha, NE 68198 USA. EM kfu@unmc.edu RI Huang, Xin/P-8103-2014; OI Huang, Xin/0000-0001-6778-8849; McKeithan, Timothy/0000-0003-2242-3074; Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301; Campo, elias/0000-0001-9850-9793 FU Lymphoma Research Foundation Career Development Award; National Institutes of Health Grant [R01 CA85573, U01 CA114778]; Leukemia & Lymphoma Society Translational Research Grant [62550]; Chinese Scholarship Council; National Institutes of Health Fogarty Grant [D43 TW0014290]; Lauri Strauss Leukemia Foundation FX Supported in part by a Lymphoma Research Foundation Career Development Award (K.F.); National Institutes of Health Grant No. R01 CA85573 (B.H.Y.) and U01 CA114778 (W.C.C.); Leukemia & Lymphoma Society Translational Research Grant No. 62550 (B.H.Y.); scholarship awards from the Chinese Scholarship Council (X. H. and C.B.); National Institutes of Health Fogarty Grant No. D43 TW0014290; and a fellowship grant from the Lauri Strauss Leukemia Foundation (B.B.D.). NR 45 TC 38 Z9 41 U1 1 U2 16 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 DEC 20 PY 2013 VL 31 IS 36 BP 4520 EP 4528 DI 10.1200/JCO.2012.45.6004 PG 9 WC Oncology SC Oncology GA 282QG UT WOS:000329186700008 PM 24220563 ER PT J AU Chaturvedi, AK Anderson, WF Lortet-Tieulent, J Curado, MP Ferlay, J Franceschi, S Rosenberg, PS Bray, F Gillison, ML AF Chaturvedi, Anil K. Anderson, William F. Lortet-Tieulent, Joannie Curado, Maria Paula Ferlay, Jacques Franceschi, Silvia Rosenberg, Philip S. Bray, Freddie Gillison, Maura L. TI Worldwide Trends in Incidence Rates for Oral Cavity and Oropharyngeal Cancers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; PERIOD-COHORT MODELS; HUMAN-PAPILLOMAVIRUS; NECK-CANCER; UNITED-STATES; PHARYNGEAL CANCER; HEAD; RISK; EPIDEMIOLOGY; POPULATION AB Purpose Human papillomavirus (HPV) has been identified as the cause of the increasing oropharyngeal cancer (OPC) incidence in some countries. To investigate whether this represents a global phenomenon, we evaluated incidence trends for OPCs and oral cavity cancers (OCCs) in 23 countries across four continents. Methods We used data from the Cancer Incidence in Five Continents database Volumes VI to IX (years 1983 to 2002). Using age-period-cohort modeling, incidence trends for OPCs were compared with those of OCCs and lung cancers to delineate the potential role of HPV vis-a-vis smoking on incidence trends. Analyses were country specific and sex specific. Results OPC incidence significantly increased during 1983 to 2002 predominantly in economically developed countries. Among men, OPC incidence significantly increased in the United States, Australia, Canada, Japan, and Slovakia, despite nonsignificant or significantly decreasing incidence of OCCs. In contrast, among women, in all countries with increasing OPC incidence (Denmark, Estonia, France, the Netherlands, Poland, Slovakia, Switzerland, and United Kingdom), there was a concomitant increase in incidence of OCCs. Although increasing OPC incidence among men was accompanied by decreasing lung cancer incidence, increasing incidence among women was generally accompanied by increasing lung cancer incidence. The magnitude of increase in OPC incidence among men was significantly higher at younger ages (< 60 years) than older ages in the United States, Australia, Canada, Slovakia, Denmark, and United Kingdom. Conclusion OPC incidence significantly increased during 1983 to 2002 predominantly in developed countries and at younger ages. These results underscore a potential role for HPV infection on increasing OPC incidence, particularly among men. C1 [Chaturvedi, Anil K.; Anderson, William F.; Rosenberg, Philip S.] NCI, Rockville, MD 20852 USA. [Gillison, Maura L.] Ohio State Univ, Columbus, OH 43210 USA. [Curado, Maria Paula] Int Prevent Res Inst, Lyon, France. RP Chaturvedi, AK (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Rockville, MD 20852 USA. EM chaturva@mail.nih.gov RI Chaturvedi, Anil/J-2024-2015; Curado, Maria Paula/M-6200-2013 OI Chaturvedi, Anil/0000-0003-2696-8899; Curado, Maria Paula/0000-0001-8172-2483 FU Intramural Research Program of the US National Cancer Institute; Institut National du Cancer (SPLIT project Grant) [2011/196] FX Supported in part by the Intramural Research Program of the US National Cancer Institute and by a grant from the Institut National du Cancer (SPLIT project Grant No. 2011/196). NR 37 TC 184 Z9 188 U1 6 U2 35 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 DEC 20 PY 2013 VL 31 IS 36 BP 4550 EP 4559 DI 10.1200/JCO.2013.50.3870 PG 10 WC Oncology SC Oncology GA 282QG UT WOS:000329186700012 PM 24248688 ER PT J AU Landrigan, PJ Wright, RO Birnbaum, LS AF Landrigan, Philip J. Wright, Robert O. Birnbaum, Linda S. TI Mercury Toxicity in Children SO SCIENCE LA English DT Letter ID FISH CONSUMPTION; PRENATAL EXPOSURE; HAIR MERCURY; METHYLMERCURY C1 [Landrigan, Philip J.; Wright, Robert O.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Birnbaum, Linda S.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Landrigan, PJ (reprint author), Icahn Sch Med Mt Sinai, New York, NY 10029 USA. EM phil.landrigan@mssm.edu NR 10 TC 4 Z9 4 U1 4 U2 30 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 DEC 20 PY 2013 VL 342 IS 6165 BP 1447 EP 1447 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 274ZI UT WOS:000328644300032 PM 24357301 ER PT J AU Kumar, V Kim, K Joseph, C Kourrich, S Yoo, SH Huang, HC Vitaterna, MH de Villena, FPM Churchill, G Bonci, A Takahashi, JS AF Kumar, Vivek Kim, Kyungin Joseph, Chryshanthi Kourrich, Said Yoo, Seung-Hee Huang, Hung Chung Vitaterna, Martha H. de Villena, Fernando Pardo-Manuel Churchill, Gary Bonci, Antonello Takahashi, Joseph S. TI C57BL/6N Mutation in Cytoplasmic FMRP interacting protein 2 Regulates Cocaine Response SO SCIENCE LA English DT Article ID NEURONAL CONNECTIVITY; SYNAPTIC PLASTICITY; LABORATORY MOUSE; ADDICTION; COMPLEX; SUBSTRAINS; KNOCKOUT; MEMORY; WAVE-1; GENOME AB The inbred mouse C57BL/6J is the reference strain for genome sequence and for most behavioral and physiological phenotypes. However, the International Knockout Mouse Consortium uses an embryonic stem cell line derived from a related C57BL/6N substrain. We found that C57BL/6N has a lower acute and sensitized response to cocaine and methamphetamine. We mapped a single causative locus and identified a nonsynonymous mutation of serine to phenylalanine (S968F) in Cytoplasmic FMRP interacting protein 2 (Cyfip2) as the causative variant. The S968F mutation destabilizes CYFIP2, and deletion of the C57BL/6N mutant allele leads to acute and sensitized cocaine-response phenotypes. We propose that CYFIP2 is a key regulator of cocaine response in mammals and present a framework to use mouse substrains to identify previously unknown genes and alleles regulating behavior. C1 [Kumar, Vivek; Kim, Kyungin; Joseph, Chryshanthi; Yoo, Seung-Hee; Huang, Hung Chung; Takahashi, Joseph S.] Univ Texas SW Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA. [Kumar, Vivek; Takahashi, Joseph S.] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [Kourrich, Said; Bonci, Antonello] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Vitaterna, Martha H.] Northwestern Univ, Dept Neurobiol, Evanston, IL 60208 USA. [de Villena, Fernando Pardo-Manuel] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Churchill, Gary] Jackson Lab, Bar Harbor, ME 04609 USA. RP Takahashi, JS (reprint author), Univ Texas SW Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA. EM joseph.takahashi@utsouthwestern.edu RI kourrich, said/M-3916-2014; Takahashi, Joseph/E-8482-2012 OI Takahashi, Joseph/0000-0003-0384-8878 FU National Research Service Award from NIDA [F32DA024556]; NIH [U01MH61915] FX We thank A. Khan and W. Khan for genotyping help; A. M. Wissman, J. Gibson, and K. Huber for help with diolistics; C. Olker for behavioral testing; C. Cowan for advice on sensitization; M. Strobel for C57BL/6 substrain DNA; S. Padrick, B. Chen, and M. Rosen for WRC reagents and advice; T. Keane (Sanger Centre) for access to sequencing data; N. Kumar and I. Kornblum for technical help; and O. Hermanson and P. Lowrey for advice on manuscript. V. K. was funded through National Research Service Award F32DA024556 from NIDA. NIH grant U01MH61915 funded J. S. T. J. S. T. is an Investigator and S.H.Y. and V. K. were associates in the Howard Hughes Medical Institute. NR 23 TC 36 Z9 36 U1 1 U2 6 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 DEC 20 PY 2013 VL 342 IS 6165 BP 1508 EP 1512 DI 10.1126/science.1245503 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 274ZI UT WOS:000328644300058 PM 24357318 ER PT J AU Sutherland, ML Fabre, KM Tagle, DA AF Sutherland, Margaret L. Fabre, Kristin M. Tagle, Danilo A. TI The National Institutes of Health Microphysiological Systems Program focuses on a critical challenge in the drug discovery pipeline INTRODUCTION SO STEM CELL RESEARCH & THERAPY LA English DT Editorial Material ID SPECIES-DIFFERENCES; COUMARIN; INHIBITION; METABOLISM AB The National Institutes of Health has partnered with the US Food and Drug Administration and the Defense Advanced Research Projects Agency to accelerate the development of human microphysiological systems (MPS) that address challenges faced in predictive toxicity assessment and efficacy analysis of new molecular entities during the preclinical phase of drug development. Use of human MPS could provide better models for predicting the efficacy of new molecular entities in clinical trials. It is also anticipated that improvements in predicting drug toxicities early in the drug development process through the use of MPS or human organs-on-a-chip will decrease the need to withdraw new therapies from the market and minimize or eliminate deaths due to unidentified drug toxicities. C1 [Sutherland, Margaret L.] NINDS, NIH, Bethesda, MD 20892 USA. [Fabre, Kristin M.; Tagle, Danilo A.] Natl Ctr Advancing Translat Sci, NIH, Bethesda, MD 20892 USA. RP Sutherland, ML (reprint author), NINDS, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM sutherlandm@ninds.nih.gov; fabrek@mail.nih.gov NR 13 TC 19 Z9 19 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD DEC 20 PY 2013 VL 4 SU 1 AR I1 DI 10.1186/scrt361 PG 5 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 286DG UT WOS:000329444700001 PM 24565163 ER PT J AU Tang, WK Xia, D AF Tang, Wai Kwan Xia, Di TI Altered Intersubunit Communication Is the Molecular Basis for Functional Defects of Pathogenic p97 Mutants SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE ATPases; Crystal Structure; Genetic Diseases; Molecular Chaperone; Mutant; ATPase Activity; IBMPFD; Communication; p97; VCP; Prebound ADP ID VALOSIN-CONTAINING PROTEIN; DISEASE-RELATED MUTANTS; ATPASE ACTIVITY; AAA ATPASE; FRONTOTEMPORAL DEMENTIA; PAGET-DISEASE; P97/VALOSIN-CONTAINING PROTEIN; CONFORMATIONAL-CHANGES; NUCLEOTIDE-BINDING; VCP DISEASE AB Background: Single-point mutations in AAA chaperone p97 cause multiple disorders, but the molecular basis remains unknown. Results: Significant differences in structural and biochemical properties between wild type and pathogenic p97 were revealed. Conclusion: Mutations altered the communication among subunits within a hexameric p97, resulting in p97 molecules with defective function. Significance: Mechanistic insights into the function of p97 are provided. The human AAA ATPase p97 is a molecular chaperone essential in cellular proteostasis. Single amino acid substitutions in p97 have been linked to a clinical multiple-disorder condition known as inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia. How the mutations affect the molecular mechanism that governs the function of p97 remains unclear. Here, we show that within the hexameric ring of a mutant p97, D1 domains fail to regulate their respective nucleotide-binding states, as evidenced by the lower amount of prebound ADP, weaker ADP binding affinity, full occupancy of adenosine-5-O-(3-thiotriphosphate) binding, and elevated overall ATPase activity, indicating a loss of communication among subunits. Defective communication between subunits is further illustrated by altered conformation in the side chain of residue Phe-360 that probes into the nucleotide-binding pocket from a neighboring subunit. Consequently, conformations of N domains in a hexameric ring of a mutant p97 become uncoordinated, thus impacting its ability to process substrate. C1 [Tang, Wai Kwan; Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Bldg 37,Rm 2122C, Bethesda, MD 20892 USA. EM xiad@mail.nih.gov FU National Institutes of Health Intramural Research Program (NCI, Center for Cancer Research) FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program (NCI, Center for Cancer Research). NR 45 TC 25 Z9 25 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 20 PY 2013 VL 288 IS 51 BP 36624 EP 36635 DI 10.1074/jbc.M113.488924 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278IQ UT WOS:000328883400042 PM 24196964 ER PT J AU Kuo, CL Zaykin, D AF Kuo, Chia-Ling Zaykin, Dmitri TI The Ranking Probability Approach and Its Usage in Design and Analysis of Large-Scale Studies SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; POSITIVE REPORT; FALSE; DISCOVERY AB In experiments with many statistical tests there is need to balance type I and type II error rates while taking multiplicity into account. In the traditional approach, the nominal a-level such as 0.05 is adjusted by the number of tests, K, i.e., as 0.05/K. Assuming that some proportion of tests represent "true signals'', that is, originate from a scenario where the null hypothesis is false, power depends on the number of true signals and the respective distribution of effect sizes. One way to define power is for it to be the probability of making at least one correct rejection at the assumed a-level. We advocate an alternative way of establishing how "well-powered'' a study is. In our approach, useful for studies with multiple tests, the ranking probability P-x,P-u is controlled, defined as the probability of making at least x correct rejections while rejecting hypotheses with u smallest P-values. The two approaches are statistically related. Probability that the smallest P-value is a true signal (i.e., P-1,P-1) is equal to the power at the level 0.5/K, to an very good excellent approximation. Ranking probabilities are also related to the false discovery rate and to the Bayesian posterior probability of the null hypothesis. We study properties of our approach when the effect size distribution is replaced for convenience by a single "typical'' value taken to be the mean of the underlying distribution. We conclude that its performance is often satisfactory under this simplification; however, substantial imprecision is to be expected when K is very large and u is small. Precision is largely restored when three values with the respective abundances are used instead of a single typical effect size value. C1 [Kuo, Chia-Ling] Univ Connecticut, Ctr Hlth, Ctr Quantitat Med, Farmington, CT USA. [Zaykin, Dmitri] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Zaykin, D (reprint author), NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM dmitri.zaykin@nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 11 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 DEC 20 PY 2013 VL 8 IS 12 AR e83079 DI 10.1371/journal.pone.0083079 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276IX UT WOS:000328745100086 PM 24376639 ER PT J AU Okamoto, KW Robert, MA Lloyd, AL Gould, F AF Okamoto, Kenichi W. Robert, Michael A. Lloyd, Alun L. Gould, Fred TI A Reduce and Replace Strategy for Suppressing Vector-Borne Diseases: Insights from a Stochastic, Spatial Model SO PLOS ONE LA English DT Article ID AEDES-AEGYPTI DIPTERA; LIFE TABLE MODEL; GENETIC-CONTROL; CULICIDAE PRODUCTION; MOSQUITO-CONTROL; DENGUE VECTOR; POPULATION; DISPERSAL; WOLBACHIA; IQUITOS AB Two basic strategies have been proposed for using transgenic Aedes aegypti mosquitoes to decrease dengue virus transmission: population reduction and population replacement. Here we model releases of a strain of Ae. aegypti carrying both a gene causing conditional adult female mortality and a gene blocking virus transmission into a wild population to assess whether such releases could reduce the number of competent vectors. We find this "reduce and replace" strategy can decrease the frequency of competent vectors below 50% two years after releases end. Therefore, this combined approach appears preferable to releasing a strain carrying only a female-killing gene, which is likely to merely result in temporary population suppression. However, the fixation of anti-pathogen genes in the population is unlikely. Genetic drift at small population sizes and the spatially heterogeneous nature of the population recovery after releases end prevent complete replacement of the competent vector population. Furthermore, releasing more individuals can be counterproductive in the face of immigration by wild-type mosquitoes, as greater population reduction amplifies the impact wildtype migrants have on the long-term frequency of the anti-pathogen gene. We expect the results presented here to give pause to expectations for driving an anti-pathogen construct to fixation by relying on releasing individuals carrying this two-gene construct. Nevertheless, in some dengue-endemic environments, a spatially heterogeneous decrease in competent vectors may still facilitate decreasing disease incidence. C1 [Okamoto, Kenichi W.; Gould, Fred] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Robert, Michael A.; Lloyd, Alun L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Robert, Michael A.; Lloyd, Alun L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. [Lloyd, Alun L.; Gould, Fred] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Okamoto, KW (reprint author), N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. EM kenichi_okamoto@ncsu.edu FU National Institutes of Health (NIH) [R01AI091980-01A1]; Foundation for the NIH through the Bill and Melinda Gates Foundation Grand Challenges in Global Health initiative; University of Pretoria North Carolina State University Strategic Collaboration Seed Grant FX This work is funded in part by National Institutes of Health (NIH) grant R01AI091980-01A1, a grant to the Regents of the University of California from the Foundation for the NIH through the Bill and Melinda Gates Foundation Grand Challenges in Global Health initiative, and in part by a University of Pretoria North Carolina State University Strategic Collaboration Seed Grant (to A. L. Lloyd). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 12 Z9 12 U1 9 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 DEC 20 PY 2013 VL 8 IS 12 AR e81860 DI 10.1371/journal.pone.0081860 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276IX UT WOS:000328745100010 PM 24376506 ER PT J AU Polizzotto, MN Uldrick, TS Wang, V Aleman, K Wyvill, KM Marshall, V Pittaluga, S O'Mahony, D Whitby, D Tosato, G Steinberg, SM Little, RF Yarchoan, R AF Polizzotto, Mark N. Uldrick, Thomas S. Wang, Victoria Aleman, Karen Wyvill, Kathleen M. Marshall, Vickie Pittaluga, Stefania O'Mahony, Deirdre Whitby, Denise Tosato, Giovanna Steinberg, Seth M. Little, Richard F. Yarchoan, Robert TI Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease SO BLOOD LA English DT Article ID PRIMARY EFFUSION LYMPHOMA; DNA-SEQUENCES; NODE HYPERPLASIA; GENE-EXPRESSION; HUMAN IL-6; B-CELLS; RECEPTOR; KSHV; RITUXIMAB; ANTIBODY AB Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder. Human (h) IL-6 and a KSHV-encoded homolog, viral IL-6, have been hypothesized to contribute to its pathogenesis, but their relative contributions to disease activity is not well understood. We prospectively characterized KSHV viral load (VL), viral (v) and hIL-6, and other cytokines during KSHV-MCD flare and remission in 21 patients with 34 flares and 20 remissions. KSHV-VL, vIL-6, hIL-6, IL-10, and to a lesser extent TNF-alpha, and IL-1 beta were each elevated during initial flares compared with remission. Flares fell into 3 distinct IL-6 profiles: those associated with elevations of vIL6-only (2 flares, 6%), hIL-6 elevations only (17 flares, 50%), and elevations in both hIL-6 and vIL-6 (13 flares, 38%). Compared with hIL-6-only flares, flares with elevated hIL-6 plus vIL-6 exhibited higher C-reactive protein (CRP) (P = .0009); worse hyponatremia (P = .02); higher KSHV VL (P = .016), and higher IL-10 (P = .012). This analysis shows vIL-6 and hIL-6 can independently or together lead to KSHV-MCD flares, and suggests that vIL-6 and hIL-6 may jointly contribute to disease severity. These findings have implications for the development of novel KSHV-MCD therapies targeting IL-6 and its downstream signaling. This trial was registered at clinicaltrials.gov as #NCT099073. C1 [Polizzotto, Mark N.; Uldrick, Thomas S.; Wang, Victoria; Aleman, Karen; Wyvill, Kathleen M.; O'Mahony, Deirdre; Little, Richard F.; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Marshall, Vickie; Whitby, Denise] Frederick Natl Lab Canc Res, Viral Oncol Sect, AIDS & Canc Virus Program, Frederick, MD USA. [Pittaluga, Stefania] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yarchoan, R (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Room 6N106,Bldg 10, Bethesda, MD 20892 USA. EM mark.polizzotto@nih.gov; robert.yarchoan@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 54 TC 37 Z9 38 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 19 PY 2013 VL 122 IS 26 BP 4189 EP 4198 DI 10.1182/blood-2013-08-519959 PG 10 WC Hematology SC Hematology GA 290FX UT WOS:000329741000013 PM 24174627 ER PT J AU Sheu, HL Kim, S Laane, J AF Sheu, Hong-Li Kim, Sunghwan Laane, Jaan TI Infrared, Raman, and Ultraviolet Absorption Spectra and Theoretical Calculations and Structure of 2,6-Difluoropyridine in Its Ground and Excited Electronic States SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID AB-INITIO CALCULATIONS; POTENTIAL-ENERGY FUNCTION; LASER-INDUCED FLUORESCENCE; VIBRATIONAL-SPECTRA; DFT CALCULATIONS; SPECTROSCOPIC DETERMINATION; 1,4-BENZODIOXAN; PYRIDINE; MODES; 1,4-DIHYDRONAPHTHALENE AB The infrared and Raman spectra of 2,6-difluoropyridine (26DFPy) along with ab initio and DFT computations have been used to assign the vibrations of the molecule in its S-0 electronic ground state and to calculate its structure. The ultraviolet absorption spectrum showed the electronic transition to the S-1(pi pi*) state to be at 37 820.2 cm(-1). With the aid of ab initio computations the vibrational frequencies for this excited state were also determined. TD-B3LYP and CASSCF computations for the excited states were carried out to calculate the structures for the S-1(pi pi*) and S-2(pi pi*) excited states. The CASSCF results predict that the S-1(pi pi*) state is planar and that the S-2(pi pi*) state has a barrier to planarity of 256 cm(-1). The TD-B3LYP computations predict a barrier of 124 cm-1 for the S-1(pi pi*) state, but the experimental results support the planar structure. Hypothetical models for the ring-puckering potential energy function were calculated for both electronic excited states to show the predicted quantum states. The changes in the vibrational frequencies in the two excited states reflect the weaker pi bonding within the pyridine ring. C1 [Sheu, Hong-Li; Laane, Jaan] Texas A&M Univ, Dept Chem, College Stn, TX 77843 USA. [Kim, Sunghwan] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, US Dept HHS, Bethesda, MD 20894 USA. RP Laane, J (reprint author), Texas A&M Univ, Dept Chem, College Stn, TX 77843 USA. EM laane@chem.tamu.edu RI Kim, Sunghwan/A-6738-2008; Laane, Jaan/O-4379-2014; Sheu, Hong-Li/B-4889-2016 OI Kim, Sunghwan/0000-0001-9828-2074; Laane, Jaan/0000-0003-4423-6122; FU Robert A. Welch Foundation [A-0396]; Intramural Research Program of the NIH, National Library of Medicine; National Science Foundation [CHE-0541587]; Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD FX This article is dedicated to Terry A. Miller and his contributions to the field of molecular spectroscopy. The authors wish to thank the Robert A. Welch Foundation (Grant A-0396) for financial support. This research was also supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Calculations were carried out on the Texas A&M Department of Chemistry Medusa computer system funded by the National Science Foundation, Grant No. CHE-0541587, and the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 33 TC 3 Z9 3 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD DEC 19 PY 2013 VL 117 IS 50 BP 13596 EP 13604 DI 10.1021/jp407592r PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 278WI UT WOS:000328920200044 PM 24070189 ER PT J AU Weinrich, M Worcester, DL AF Weinrich, Michael Worcester, David L. TI Xenon and Other Volatile Anesthetics Change Domain Structure in Model Lipid Raft Membranes SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID X-RAY; GENERAL-ANESTHESIA; PHASE-DIAGRAM; BILAYERS; ISOFLURANE; CHOLESTEROL; DIFFRACTION; HALOTHANE; MECHANISM; PRESSURE AB Inhalation anesthetics have been in clinical use for over 160 years, but the molecular mechanisms of action continue to be investigated. Direct interactions with ion channels received much attention after it was found that anesthetics do not change the structure of homogeneous model membranes. However, it was recently found that halothane, a prototypical anesthetic, changes domain structure of a binary lipid membrane. The noble gas xenon is an excellent anesthetic and provides a pivotal test of the generality of this finding, extended to ternary lipid raft mixtures. We report that xenon and conventional anesthetics change the domain equilibrium in two canonical ternary lipid raft mixtures. These findings demonstrate a membrane-mediated mechanism whereby inhalation anesthetics can affect the lipid environment of transmembrane proteins. C1 [Weinrich, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Weinrich, Michael; Worcester, David L.] NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA. [Worcester, David L.] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92697 USA. [Worcester, David L.] Univ Missouri, Div Biol, Columbia, MO 65211 USA. RP Weinrich, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. EM mw287k@nih.gov FU US National Institute of Health [GM86685] FX We thank Drs. Sergey Bezrukov and Hirsh Nanda for their comments, Dr. David Sandstrom for the use of his gas chromatograph, and Dr. Jason Simmons for his assistance with the X-ray diffractometer. D.W. was supported by US National Institute of Health Grant GM86685 (to Stephen H. White). The Center for Neutron Research provided facilities for neutron and X-ray diffraction.. The identification of any commercial product or trade name does not imply any endorsement or recommendation by the National Institute of Standards and Technology. NR 42 TC 12 Z9 12 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD DEC 19 PY 2013 VL 117 IS 50 BP 16141 EP 16147 DI 10.1021/jp411261g PG 7 WC Chemistry, Physical SC Chemistry GA 278WM UT WOS:000328920600023 PM 24299622 ER PT J AU Cook, MB Matthews, CE Gunja, MZ Abid, Z Freedman, ND Abnet, CC AF Cook, Michael B. Matthews, Charles E. Gunja, Munira Z. Abid, Zaynah Freedman, Neal D. Abnet, Christian C. TI Physical Activity and Sedentary Behavior in Relation to Esophageal and Gastric Cancers in the NIH-AARP Cohort SO PLOS ONE LA English DT Article ID BODY-MASS INDEX; SQUAMOUS-CELL CARCINOMA; POPULATION-BASED COHORT; NATIONAL DEATH INDEX; SOCIOECONOMIC-STATUS; BARRETTS-ESOPHAGUS; MASTER FILE; LIFE-STYLE; RISK; OBESITY AB Introduction: Body mass index is known to be positively associated with an increased risk of adenocarcinomas of the esophagus, yet there is there limited evidence on whether physical activity or sedentary behavior affects risk of histology- and site-specific upper gastrointestinal cancers. We used the NIH-AARP Diet and Health Study to assess these exposures in relation to esophageal adenocarcinoma (EA), esophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma (GCA), and gastric non-cardia adenocarcinoma (GNCA). Methods: Self-administered questionnaires were used to elicit physical activity and sedentary behavior exposures at various age periods. Cohort members were followed via linkage to the US Postal Service National Change of Address database, the Social Security Administration Death Master File, and the National Death Index. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95 percent confidence intervals (95% CI) Results: During 4.8 million person years, there were a total of 215 incident ESCCs, 631 EAs, 453 GCAs, and 501 GNCAs for analysis. Strenuous physical activity in the last 12 months (HR>(5times/week vs.never)=0.58, 95% CI: 0.39, 0.88) and typical physical activity and sports during ages 15-18 years (p for trend=0.01) were each inversely associated with GNCA risk. Increased sedentary behavior was inversely associated with EA (HR5-6 hrs/day vs. <1 hr=0.57, 95% CI: 0.36, 0.92). There was no evidence that BMI was a confounder or effect modifier of any relationship. After adjustment for multiple testing, none of these results were deemed to be statistically significant at p<0.05. Conclusions: We find evidence for an inverse association between physical activity and GNCA risk. Associations between body mass index and adenocarcinomas of the esophagus do not appear to be related to physical activity and sedentary behavior. C1 [Cook, Michael B.; Matthews, Charles E.; Gunja, Munira Z.; Abid, Zaynah; Freedman, Neal D.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Cook, MB (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM michael.cook@nih.gov RI Cook, Michael/A-5641-2009; Abnet, Christian/C-4111-2015; matthews, Charles/E-8073-2015; Freedman, Neal/B-9741-2015 OI Cook, Michael/0000-0002-0533-7302; Abnet, Christian/0000-0002-3008-7843; matthews, Charles/0000-0001-8037-3103; Freedman, Neal/0000-0003-0074-1098 NR 46 TC 1 Z9 1 U1 0 U2 13 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 DEC 19 PY 2013 VL 8 IS 12 AR UNSP e84805 DI 10.1371/journal.pone.0084805 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276HY UT WOS:000328741900068 PM 24367697 ER PT J AU Kieffer-Kwon, KR Tang, ZH Mathe, E Qian, JS Sung, MH Li, GL Resch, W Baek, S Pruett, N Grontved, L Vian, L Nelson, S Zare, H Hakim, O Reyon, D Yamane, A Nakahashi, H Kovalchuk, AL Zou, JZ Joung, JK Sartorelli, V Wei, CL Ruan, XA Hager, GL Ruan, YJ Casellas, R AF Kieffer-Kwon, Kyong-Rim Tang, Zhonghui Mathe, Ewy Qian, Jason Sung, Myong-Hee Li, Guoliang Resch, Wolfgang Baek, Songjoon Pruett, Nathanael Grontved, Lars Vian, Laura Nelson, Steevenson Zare, Hossein Hakim, Ofir Reyon, Deepak Yamane, Arito Nakahashi, Hirotaka Kovalchuk, Alexander L. Zou, Jizhong Joung, J. Keith Sartorelli, Vittorio Wei, Chia-Lin Ruan, Xiaoan Hager, Gordon L. Ruan, Yijun Casellas, Rafael TI Interactome Maps of Mouse Gene Regulatory Domains Reveal Basic Principles of Transcriptional Regulation SO CELL LA English DT Article ID ACTIVATION-INDUCED DEAMINASE; EMBRYONIC STEM-CELLS; LONG NONCODING RNAS; HUMAN GENOME; CHROMATIN INTERACTIONS; AID EXPRESSION; ENHANCERS; LYMPHOCYTES; ELEMENTS; RECOMBINATION AB A key finding of the ENCODE project is that the enhancer landscape of mammalian cells undergoes marked alterations during ontogeny. However, the nature and extent of these changes are unclear. As part of the NIH Mouse Regulome Project, we here combined DNaseI hypersensitivity, ChIP-seq, and ChIA-PET technologies to map the promoter-enhancer interactomes of pluripotent ES cells and differentiated B lymphocytes. We confirm that enhancer usage varies widely across tissues. Unexpectedly, we find that this feature extends to broadly transcribed genes, including Myc and Pim1 cell-cycle regulators, which associate with an entirely different set of enhancers in ES and B cells. By means of high-resolution CpG methylomes, genome editing, and digital footprinting, we show that these enhancers recruit lineage-determining factors. Furthermore, we demonstrate that the turning on and off of enhancers during development correlates with promoter activity. We propose that organisms rely on a dynamic enhancer landscape to control basic cellular functions in a tissue-specific manner. C1 [Kieffer-Kwon, Kyong-Rim; Mathe, Ewy; Qian, Jason; Resch, Wolfgang; Pruett, Nathanael; Vian, Laura; Nelson, Steevenson; Yamane, Arito; Nakahashi, Hirotaka; Casellas, Rafael] NIAMS, NIH, Bethesda, MD 20892 USA. [Tang, Zhonghui; Li, Guoliang; Ruan, Xiaoan; Ruan, Yijun] Univ Connecticut, Jackson Lab Genom Med, Farmington, CT 06030 USA. [Tang, Zhonghui; Li, Guoliang; Ruan, Xiaoan; Ruan, Yijun] Univ Connecticut, Dept Genet & Dev Biol, Farmington, CT 06030 USA. [Sung, Myong-Hee; Baek, Songjoon; Grontved, Lars; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Zare, Hossein; Sartorelli, Vittorio] NIAMS, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Hakim, Ofir] Bar Ilan Univ, IL-5290002 Ramat Gan, Israel. [Reyon, Deepak; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Mol Pathol Unit, Charlestown, MA 02129 USA. [Reyon, Deepak; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Reyon, Deepak; Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Kovalchuk, Alexander L.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Zou, Jizhong] NIAMS, Lab Stem Cell Biol, NIH, Bethesda, MD 20892 USA. [Wei, Chia-Lin] DOE Joint Genome Inst, Walnut Creek, CA 94598 USA. [Casellas, Rafael] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Casellas, R (reprint author), NIAMS, NIH, Bethesda, MD 20892 USA. EM rafael.casellas@nih.gov RI Li, Guoliang/I-1494-2015; OI Li, Guoliang/0000-0003-1601-6640; Grontved, Lars/0000-0002-6735-8483 FU Intramural Research Program of NIAMS; NCI; internal Jackson Laboratory fund [JAX19020120]; NIH [DP1 GM105378, P50 HG005550]; Defense Advanced Research Projects Agency [W911NF-11-2-0056]; Jim and Ann Orr Massachusetts General Hospital Research Scholar Award; NIH UGSP program FX We thank Kefei Yu for CH12 cells and protocols; J. Simone and J. Lay for cell sorting; G. Gutierrez for technical assistance with Illumina analyzer. This work was supported by the Intramural Research Program of NIAMS and NCI, and internal Jackson Laboratory fund JAX19020120 to Y.R. J.K.J. was supported by NIH grants DP1 GM105378 and P50 HG005550, the Defense Advanced Research Projects Agency grant W911NF-11-2-0056 and The Jim and Ann Orr Massachusetts General Hospital Research Scholar Award. J. Q. was supported by the NIH UGSP program. All animal experiments were performed according to NIH guidelines. High-performance computation was performed using NIH Helix Systems (http://helix.nih.gov). J. K. J. has a financial interest in Transposagen Biopharmaceuticals. J.K.J.'s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. NR 49 TC 116 Z9 120 U1 3 U2 44 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 DEC 19 PY 2013 VL 155 IS 7 BP 1507 EP 1520 DI 10.1016/j.cell.2013.11.039 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 275QW UT WOS:000328693300008 PM 24360274 ER PT J AU Gomes, AP Price, NL Ling, AJY Moslehi, JJ Montgomery, MK Rajman, L White, JP Teodor, JS Wrann, CD Hubbard, BP Mercken, EM Palmeira, CM de Cabo, R Rolo, AP Turner, N Bell, EL Sinclair, DA AF Gomes, Ana P. Price, Nathan L. Ling, Alvin J. Y. Moslehi, Javid J. Montgomery, Magdalene K. Rajman, Luis White, James P. Teodor, Joao S. Wrann, Christiane D. Hubbard, Basil P. Mercken, Evi M. Palmeira, Carlos M. de Cabo, Rafael Rolo, Anabela P. Turner, Nigel Bell, Eric L. Sinclair, David A. TI Declining NAD(+) Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging SO CELL LA English DT Article ID INDUCIBLE FACTOR 1-ALPHA; CANCER-CELL METABOLISM; FATTY-ACID OXIDATION; GLUCOSE-HOMEOSTASIS; LIFE-SPAN; C-MYC; NICOTINAMIDE MONONUCLEOTIDE; CALORIE RESTRICTION; ENERGY-EXPENDITURE; SIRT1 DEACETYLASE AB Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1 alpha/beta-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1 alpha under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1 alpha/beta-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible. C1 [Gomes, Ana P.; Price, Nathan L.; Ling, Alvin J. Y.; Rajman, Luis; Hubbard, Basil P.; Sinclair, David A.] Harvard Univ, Sch Med, Dept Genet, Glenn Labs Biol Mech Aging, Boston, MA 02115 USA. [Gomes, Ana P.; Teodor, Joao S.; Palmeira, Carlos M.; Rolo, Anabela P.] Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal. [Gomes, Ana P.; Teodor, Joao S.; Palmeira, Carlos M.] Univ Coimbra, Fac Sci & Technol, Dept Life Sci, P-3004517 Coimbra, Portugal. [Moslehi, Javid J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med Oncol, Boston, MA 02115 USA. [Moslehi, Javid J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Moslehi, Javid J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med,Dept Med, Boston, MA 02115 USA. [Montgomery, Magdalene K.; Turner, Nigel; Sinclair, David A.] Univ New S Wales, Sch Med Sci, Dept Pharmacol, Sydney, NSW 2052, Australia. [White, James P.; Wrann, Christiane D.] Harvard Univ, Sch Med, Dept Cell Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mercken, Evi M.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Rolo, Anabela P.] Univ Aveiro, Dept Biol, P-3810193 Aveiro, Portugal. [Bell, Eric L.] MIT, Dept Biol, Paul F Glenn Lab Sci Aging, Cambridge, MA 02139 USA. RP Sinclair, DA (reprint author), Harvard Univ, Sch Med, Dept Genet, Glenn Labs Biol Mech Aging, Boston, MA 02115 USA. EM david_sinclair@hms.harvard.edu RI Teodoro, Joao/F-5432-2011; de Cabo, Rafael/J-5230-2016; Turner, Nigel/H-7176-2013; OI Teodoro, Joao/0000-0002-1244-275X; de Cabo, Rafael/0000-0002-3354-2442; Turner, Nigel/0000-0002-0119-9328; Sinclair, David/0000-0002-9936-436X; , rafael/0000-0003-2830-5693 FU NIH/NIA; Glenn Foundation for Medical Research; United Mitochondrial Disease Foundation; Juvenile Diabetes Research Foundation; Portuguese Foundation for Science and Technology [SFRH/BD/44674/2008]; NSERC PGS-D fellowship; Australian Research Council Future Fellowship FX The Sinclair lab is supported by the NIH/NIA, the Glenn Foundation for Medical Research, the United Mitochondrial Disease Foundation, the Juvenile Diabetes Research Foundation, and a gift from the Schulak family. A. P. G. was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/44674/2008) and B. P. H. by an NSERC PGS-D fellowship. N.T. is supported by an Australian Research Council Future Fellowship. We are grateful to Michael Bonkowski, Carlos Daniel de Magalhaes Filho, Meghan Rego, Nikolina Dioufa, and David Zhang for technical advice and experimental assistance; William Kaelin Jr. for kindly providing the EglN1 KO mice; Daniel Kelly, John Rumsay, and Teresa Leone for unpublished PGC-1 alpha/beta KO myoblasts and advice; Bruce Spiegelman for PGC-1 alpha null myoblasts and advice; and Pere Puigserver and Zachary Gerhart-Hines for a SIRT1 adenovirus. D. A. S. is a consultant to Cohbar, OvaScience, HorizonScience, Segterra, MetroBiotech, and GlaxoSmithKline. Cohbar, MetroBiotech, and GlaxoSmithKline work on mitochondrially derived peptides, NAD+, and sirtuin modulation, respectively. NR 55 TC 253 Z9 258 U1 11 U2 97 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 DEC 19 PY 2013 VL 155 IS 7 BP 1624 EP 1638 DI 10.1016/j.cell.2013.11.037 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 275QW UT WOS:000328693300017 PM 24360282 ER PT J AU Collins, FS Hamburg, MA AF Collins, Francis S. Hamburg, Margaret A. TI First FDA Authorization for Next-Generation Sequencer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material AB The FDA has granted marketing authorization for a high-throughput genomic sequencer, Illumina's MiSeqDx, which will allow the development of innumerable new genome-based tests. Access to genomic data may transform research, clinical care, and patient engagement. This year marks 60 years since James Watson and Francis Crick described the structure of DNA and 10 years since the complete sequencing of the human genome. Fittingly, today the Food and Drug Administration (FDA) has granted marketing authorization for the first high-throughput (next-generation) genomic sequencer, Illumina's MiSeqDx, which will allow the development and use of innumerable new genome-based tests. When a global team of researchers sequenced that first human genome, it took more than a decade and cost hundreds of millions of dollars. Today, because of federal and private investment, sequencing technologies have advanced dramatically, and a human genome ... C1 [Collins, Francis S.] NIH, Off Director, Bethesda, MD 20892 USA. [Hamburg, Margaret A.] US Dept HHS, US FDA, Off Commissioner, Silver Spring, MD USA. RP Collins, FS (reprint author), NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 86 Z9 91 U1 2 U2 6 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 DEC 19 PY 2013 VL 369 IS 25 BP 2369 EP 2371 DI 10.1056/NEJMp1314561 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 274DQ UT WOS:000328586000003 PM 24251383 ER PT J AU Yaffe, K Falvey, C Harris, TB Newman, A Satterfield, S Koster, A Ayonayon, H Simonsick, E AF Yaffe, Kristine Falvey, Cherie Harris, Tamara B. Newman, Anne Satterfield, Suzanne Koster, Annemarie Ayonayon, Hilsa Simonsick, Eleanor CA Hlth ABC Study TI Effect of socioeconomic disparities on incidence of dementia among biracial older adults: prospective study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID MILD COGNITIVE IMPAIRMENT; AFRICAN-AMERICANS; RACIAL-DIFFERENCES; ALZHEIMER-DISEASE; WHITE DIFFERENCES; LIMITED LITERACY; BODY-COMPOSITION; TEST-PERFORMANCE; TEST-SCORES; LIFE-COURSE AB Objective To examine whether observed differences in dementia rates between black and white older people living in the community could be explained by measures of socioeconomic status (income, financial adequacy, education, and literacy) and health related factors. Design Prospective cohort study. Setting General community from two clinic sites in the United States (Pittsburgh, Pennsylvania and Memphis, Tennessee). Participants 2457 older people (mean age 73.6 years; 1019 (41.5%) black; 1233 (50.2%) women), dementia-free at baseline, in the Health, Aging, and Body Composition study. Main outcome measure Dementia was determined over 12 years (ending January 2011) by prescribed dementia drugs, hospital records, and decline in global cognitive scores. The influence of socioeconomic status and health related factors on dementia rates was examined in a series of Cox proportional hazard models in which these variables were added sequentially in covariate blocks. Results Over follow-up, 449 (18.3%) participants developed dementia. Black participants were more likely than white participants to develop dementia (211 (20.7%) v 238 (16.6%), P<0.001; unadjusted hazard ratio 1.44, 95% confidence interval 1.20 to 1.74). The hazard ratio lessened somewhat after adjustment for demographics, apolipoprotein E e4, comorbidities, and lifestyle factors (1.37, 1.12 to 1.67) but was greatly reduced and no longer statistically significant when socioeconomic status was added (1.09, 0.87 to 1.37). Conclusion These findings suggest that differences in the burden of risk factors, especially socioeconomic status, may contribute to the higher rates of dementia seen among black compared with white older people. Strategies aimed at reducing these disparities may favorably affect the incidence of dementia. C1 [Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94121 USA. [Falvey, Cherie] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Newman, Anne] Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Koster, Annemarie] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Maastricht, Netherlands. [Simonsick, Eleanor] NIA, Clin Res Branch, Harbor Hosp, Baltimore, MD 21225 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, 4150 Clement St,Box 181, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu RI Koster, Annemarie/E-7438-2010; Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; NINR [R01-NR012459]; NIH, National Institute on Aging; American Health Assistance Foundation [A201-0029] FX National Institute on Aging (NIA) contract Nos N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; NIA grant No R01-AG028050; NINR grant No R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, and a grant from the American Health Assistance Foundation, grant number A201-0029. The Intramural Research Program of the NIA participated in the design and conduct of the study. NR 47 TC 20 Z9 20 U1 3 U2 22 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD DEC 19 PY 2013 VL 347 AR f7051 DI 10.1136/bmj.f7051 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 277MS UT WOS:000328824300003 PM 24355614 ER PT J AU Kline, C Ndjomou, J Franks, T Kiser, R Coalter, V Smedley, J Piatak, M Mellors, JW Lifson, JD Ambrose, Z AF Kline, Christopher Ndjomou, Jean Franks, Tamera Kiser, Rebecca Coalter, Vicky Smedley, Jeremy Piatak, Michael, Jr. Mellors, John W. Lifson, Jeffrey D. Ambrose, Zandrea TI Persistence of Viral Reservoirs in Multiple Tissues after Antiretroviral Therapy Suppression in a Macaque RT-SHIV Model SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE INHIBITORS; HIV-POSITIVE PATIENTS; CD4(+) T-LYMPHOCYTES; RALTEGRAVIR INTENSIFICATION; LIFELONG PERSISTENCE; CONTROLLED-TRIAL; DRUG-RESISTANCE; RHESUS MACAQUES; GENITAL-TRACT AB Although antiretroviral therapy (ART) can suppress HIV-1 replication sufficiently to eliminate measurable plasma viremia, infected cells remain and ensure viral recrudescence after discontinuation of ART. We used a macaque model of HIV-1/AIDS to evaluate the location of infected cells during ART. Twelve macaques were infected with RT-SHIVmne, a SIV containing HIV-1 reverse transcriptase, conferring sensitivity to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Ten to fourteen weeks post-infection, 6 animals were treated with 3 or 4 antiretroviral drugs for 17-20 weeks; 6 control animals remained untreated. Viral DNA (vDNA) and RNA (vRNA) were measured in peripheral blood mononuclear cells (PBMC) and at necropsy in multiple tissues by quantitative PCR and RT-PCR. The majority of virally infected cells were located in lymphoid tissues with variable levels in the gastrointestinal tract of both treated and untreated animals. Tissue viral DNA levels correlated with week 1 plasma viremia, suggesting that tissues that harbor proviral DNA are established within the first week of infection. PBMC vDNA levels did not correlate with plasma viremia or tissue levels of vDNA. vRNA levels were high in lymphoid and gastrointestinal tissues of the untreated animals; animals on ART had little vRNA expressed in tissues and virus could not be cultured from lymph node resting CD4+ cells after 17-20 weeks on ART, indicating little or no ongoing viral replication. Strategies for eradication of HIV-1 will need to target residual virus in ART suppressed individuals, which may not be accurately reflected by frequencies of infected cells in blood. C1 [Kline, Christopher; Ndjomou, Jean; Franks, Tamera; Mellors, John W.; Ambrose, Zandrea] Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. [Kiser, Rebecca; Coalter, Vicky; Piatak, Michael, Jr.; Lifson, Jeffrey D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Smedley, Jeremy] Leidos Biomed Res Inc, Lab Anim Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Ambrose, Z (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. EM zaa4@pitt.edu OI Smedley, Jeremy/0000-0003-3369-4662 FU American Foundation for AIDS Research (amfAR) [107149-44-RGRL]; Merck Co., Inc. [33665]; National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E] FX This work was supported by grants 107149-44-RGRL from the American Foundation for AIDS Research (amfAR) and 33665 from Merck & Co., Inc. (Z.A.) and with federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract HHSN261200800001E (J.D.L.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 15 Z9 15 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 DEC 18 PY 2013 VL 8 IS 12 AR e84275 DI 10.1371/journal.pone.0084275 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276HL UT WOS:000328740300135 PM 24367650 ER PT J AU Samji, H Cescon, A Hogg, RS Modur, SP Althoff, KN Buchacz, K Burchell, AN Cohen, M Gebo, KA Gill, MJ Justice, A Kirk, G Klein, MB Korthuis, PT Martin, J Napravnik, S Rourke, SB Sterling, TR Silverberg, MJ Deeks, S Jacobson, LP Bosch, RJ Kitahata, MM Goedert, JJ Moore, R Gange, SJ AF Samji, Hasina Cescon, Angela Hogg, Robert S. Modur, Sharada P. Althoff, Keri N. Buchacz, Kate Burchell, Ann N. Cohen, Mardge Gebo, Kelly A. Gill, M. John Justice, Amy Kirk, Gregory Klein, Marina B. Korthuis, P. Todd Martin, Jeff Napravnik, Sonia Rourke, Sean B. Sterling, Timothy R. Silverberg, Michael J. Deeks, Stephen Jacobson, Lisa P. Bosch, Ronald J. Kitahata, Mari M. Goedert, James J. Moore, Richard Gange, Stephen J. CA North Amer AIDS Cohort TI Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada SO PLOS ONE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; INJECTING DRUG-USERS; INFECTED PERSONS; INCOME COUNTRIES; COHORT; INEQUALITIES; MORTALITY; SURVIVAL; TIME AB Background: Combination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United States (U. S.) and Canada, but gains in life expectancy for this region have not been well characterized. We aim to estimate temporal changes in life expectancy among HIV-positive adults on ART from 2000-2007 in the U. S. and Canada. Methods: Participants were from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), aged >= 20 years and on ART. Mortality rates were calculated using participants' person-time from January 1, 2000 or ART initiation until death, loss to follow-up, or administrative censoring December 31, 2007. Life expectancy at age 20, defined as the average number of additional years that a person of a specific age will live, provided the current age-specific mortality rates remain constant, was estimated using abridged life tables. Results: The crude mortality rate was 19.8/1,000 person-years, among 22,937 individuals contributing 82,022 person-years and 1,622 deaths. Life expectancy increased from 36.1 [standard error (SE) 0.5] to 51.4 [SE 0.5] years from 2000-2002 to 2006-2007. Men and women had comparable life expectancies in all periods except the last (2006-2007). Life expectancy was lower for individuals with a history of injection drug use, non-whites, and in patients with baseline CD4 counts <350 cells/mm(3). Conclusions: A 20-year-old HIV-positive adult on ART in the U. S. or Canada is expected to live into their early 70 s, a life expectancy approaching that of the general population. Differences by sex, race, HIV transmission risk group, and CD4 count remain. C1 [Samji, Hasina; Cescon, Angela; Hogg, Robert S.] British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Hogg, Robert S.] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. [Modur, Sharada P.; Althoff, Keri N.; Gebo, Kelly A.; Kirk, Gregory; Jacobson, Lisa P.; Moore, Richard; Gange, Stephen J.] Johns Hopkins Univ, Baltimore, MD USA. [Buchacz, Kate] Ctr Dis Control & Prevent, Atlanta, GA USA. [Burchell, Ann N.; Rourke, Sean B.] Ontario HIV Treatment Network, Toronto, ON, Canada. [Cohen, Mardge] Bur Hlth Serv Cook Cty, Core Ctr, Chicago, IL USA. [Gill, M. John] Univ Calgary, Calgary, AB, Canada. [Justice, Amy] Vet Adm Connecticut Healthcare Syst, West Haven, CT USA. [Justice, Amy] Yale Univ, West Haven, CT USA. [Klein, Marina B.] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Martin, Jeff] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Napravnik, Sonia] Univ N Carolina, Chapel Hill, NC USA. [Sterling, Timothy R.] Vanderbilt Univ, Nashville, TN 37235 USA. [Silverberg, Michael J.] Kaiser Permanente No Calif, Oakland, CA USA. [Deeks, Stephen] Univ Calif San Francisco, San Francisco Gen Hosp, San Francisco, CA USA. [Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Kitahata, Mari M.] Univ Washington, Seattle, WA 98195 USA. [Goedert, James J.] NCI, Rockville, MD USA. RP Hogg, RS (reprint author), British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. EM rhogg@sfu.ca RI Gill, John/G-7083-2016; OI Gill, John/0000-0002-8546-8790; Gange, Stephen/0000-0001-7842-512X; Hogg, Robert/0000-0003-3463-5488 FU National Institutes of Health [U01-AI069918, U10-AA13566, U01-AI31834, U01-AI34989, U01-AI34993, U01-AI34994, U01-AI35004, U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, U01-AI35043, U01-AI37613, U01-AI37984, U01-AI38855, U01-AI38858, U01-AI42590, U01-AI68634, U01-AI68636, U01-HD32632, U10-EY08057, U10-EY08052, U10-EY08067, UL1-RR024131, M01-RR-00052, M01-RR00071, M01-RR00079, M01-RR00083, M01-RR00722, M01-RR025747, P30-AI27757, P30-AI27767, P30-AI27763, P30-AI50410, P30-AI54999, R01-DA04334, R01-DA12568, R01-DA11602, R01-AA16893, R24-AI067039, Z01-CP010176, AHQ290-01-0012, N02-CP55504, AI-69432, AI-69434, K01-AI071725, K23-AI610320, K23-EY013707, K24-DA00432, K24 AI65298, K01-AI093197]; Agency for Healthcare Research and Quality [290-01-0012]; CDC [CDC200-2006-18797]; Canadian Institutes of Health Research [TGF-96118, HCP-97105, CBR-86906, CBR-94036, KRS-86251, 169621]; Canadian HIV Trials Network [24]; government of British Columbia FX This work was supported by grants U01-AI069918, U10-AA13566, U01-AI31834, U01-AI34989, U01-AI34993, U01-AI34994, U01-AI35004, U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, U01-AI35043, U01-AI37613, U01-AI37984, U01-AI38855, U01-AI38858, U01-AI42590, U01-AI68634, U01-AI68636, U01-HD32632, U10-EY08057, U10-EY08052, U10-EY08067, UL1-RR024131, UL1-RR024131, M01-RR-00052, M01-RR00071, M01-RR00079, M01-RR00083, M01-RR00722, M01-RR025747, P30-AI27757, P30-AI27767, P30-AI27763, P30-AI50410, P30-AI54999, R01-DA04334, R01-DA12568, R01-DA11602, R01-AA16893, R24-AI067039, Z01-CP010176, AHQ290-01-0012, N02-CP55504, AI-69432, AI-69434, K01-AI071725, K23-AI610320, K23-EY013707, K24-DA00432, K24 AI65298 and K01-AI093197 from the National Institutes of Health; contract 290-01-0012 from the Agency for Healthcare Research and Quality; contract CDC200-2006-18797 from the CDC; grants TGF-96118, HCP-97105, CBR-86906, CBR-94036, KRS-86251, and 169621 from the Canadian Institutes of Health Research; the Canadian HIV Trials Network, project 24; and the government of British Columbia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 240 Z9 241 U1 2 U2 15 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 DEC 18 PY 2013 VL 8 IS 12 AR e81355 DI 10.1371/journal.pone.0081355 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276HL UT WOS:000328740300004 PM 24367482 ER PT J AU Simpson, EA Paukner, A Sclafani, V Suomi, SJ Ferrari, PF AF Simpson, Elizabeth A. Paukner, Annika Sclafani, Valentina Suomi, Stephen J. Ferrari, Pier F. TI Lipsmacking Imitation Skill in Newborn Macaques Is Predictive of Social Partner Discrimination SO PLOS ONE LA English DT Article ID NEONATAL IMITATION; MEMORY AB Newborn rhesus macaques imitate facial gestures even after a delay, revealing the flexible nature of their early communicative exchanges. In the present study we examined whether newborn macaques are also sensitive to the identities of the social partners with whom they are interacting. We measured infant monkeys' (n = 90) lipsmacking and tongue protrusion gestures in a face-to-face interaction task with a human experimenter in the first week of life. After a one-minute delay, the same person who previously presented gestures or a different person returned and presented a still face to infants. We had two primary predictions: (1) infants would demonstrate higher rates of overall gesturing, and especially lipsmacking-an affiliative gesture-to a familiar person, compared to a novel person, and (2) infants' imitative skills would positively correlate with gestures to familiar, but not unfamiliar, social partners, as both abilities may reflect a strong general social interest. We found that overall infants did not produce more gestures or more lipsmacking when approached by a familiar person compared to a novel person; however, we did find individual differences in infants' social responsiveness: lipsmacking imitation was positively correlated with lipsmacking during the return period when the person was the same (p =.025), but not when the person was novel (p =.44). These findings are consistent with the notion that imitative skill is reflective of infants' more general interest in social interactions. C1 [Simpson, Elizabeth A.; Paukner, Annika; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, Poolesville, MD USA. [Simpson, Elizabeth A.; Sclafani, Valentina; Ferrari, Pier F.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. RP Simpson, EA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, Poolesville, MD USA. EM simpsonea@mail.nih.gov OI Simpson, Elizabeth/0000-0003-2715-2533 FU Division of Intramural Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Eunice Kennedy Shriver National Institute of Child Health and Human Development [P01 HD064653] FX This research was supported by the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development. EAS, VS, and PFF were supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development P01 HD064653. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 16 TC 5 Z9 5 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 DEC 18 PY 2013 VL 8 IS 12 AR e82921 DI 10.1371/journal.pone.0082921 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276HL UT WOS:000328740300080 PM 24367569 ER PT J AU Chen, HH Anstrom, KJ Givertz, MM Stevenson, LW Semigran, MJ Goldsmith, SR Bart, BA Bull, DA Stehlik, J LeWinter, MM Konstam, MA Huggins, GS Rouleau, JL O'Meara, E Tang, WHW Starling, RC Butler, J Deswal, A Felker, GM O'Connor, CM Bonita, RE Margulies, KB Cappola, TP Ofili, EO Mann, DL Davila-Roman, VG McNulty, SE Borlaug, BA Velazquez, EJ Lee, KL Shah, MR Hernandez, AF Braunwald, E Redfield, MM AF Chen, Horng H. Anstrom, Kevin J. Givertz, Michael M. Stevenson, Lynne W. Semigran, Marc J. Goldsmith, Steven R. Bart, Bradley A. Bull, David A. Stehlik, Josef LeWinter, Martin M. Konstam, Marvin A. Huggins, Gordon S. Rouleau, Jean L. O'Meara, Eileen Tang, W. H. Wilson Starling, Randall C. Butler, Javed Deswal, Anita Felker, G. Michael O'Connor, Christopher M. Bonita, Raphael E. Margulies, Kenneth B. Cappola, Thomas P. Ofili, Elizabeth O. Mann, Douglas L. Davila-Roman, Victor G. McNulty, Steven E. Borlaug, Barry A. Velazquez, Eric J. Lee, Kerry L. Shah, Monica R. Hernandez, Adrian F. Braunwald, Eugene Redfield, Margaret M. CA NHLBI Heart Failure Clin Res Netwo TI Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction The ROSE Acute Heart Failure Randomized Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RELAX-AHF; SERELAXIN AB IMPORTANCE Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 mu g/kg/min) or low-dose nesiritide (0.005 mu g/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m(2)), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. C1 [Chen, Horng H.; Borlaug, Barry A.; Redfield, Margaret M.] Mayo Clin, Rochester, MN 55905 USA. [Anstrom, Kevin J.; McNulty, Steven E.; Lee, Kerry L.; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Givertz, Michael M.; Stevenson, Lynne W.; Braunwald, Eugene] Brigham & Womens Hosp, Boston, MA 02115 USA. [Semigran, Marc J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Goldsmith, Steven R.; Bart, Bradley A.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Bull, David A.; Stehlik, Josef] Univ Utah, Salt Lake City, UT USA. [LeWinter, Martin M.] Univ Vermont, Burlington, VT 05405 USA. [Konstam, Marvin A.; Huggins, Gordon S.] Tufts Med Ctr, Boston, MA USA. [Rouleau, Jean L.; O'Meara, Eileen] Univ Montreal, Montreal, PQ, Canada. [Rouleau, Jean L.; O'Meara, Eileen] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Tang, W. H. Wilson; Starling, Randall C.] Cleveland Clin, Cleveland, OH 44106 USA. [Butler, Javed] Emory Univ, Atlanta, GA 30322 USA. [Deswal, Anita] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Deswal, Anita] Baylor Coll Med, Houston, TX USA. [Felker, G. Michael; O'Connor, Christopher M.; Velazquez, Eric J.] Duke Univ, Med Ctr, Durham, NC USA. [Felker, G. Michael; O'Connor, Christopher M.; Velazquez, Eric J.] Duke Heart Ctr, Durham, NC USA. [Bonita, Raphael E.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Margulies, Kenneth B.; Cappola, Thomas P.] Univ Penn, Philadelphia, PA 19104 USA. [Ofili, Elizabeth O.] Morehouse Sch Med, Atlanta, GA 30310 USA. [Mann, Douglas L.; Davila-Roman, Victor G.] Washington Univ, Sch Med, St Louis, MO USA. [Shah, Monica R.] NHLBI, Bethesda, MD 20892 USA. RP Chen, HH (reprint author), Mayo Clin Cardiovasc Res, Guggenheim 9,Mayo Clin,200 1st St SW, Rochester, MN 55905 USA. EM chen.horng@mayo.edu RI Hernandez, Adrian F./A-7818-2016; OI Patel, Ayan/0000-0003-1984-1400; Hernandez, Adrian F./0000-0003-3387-9616; Mann, Douglas /0000-0002-2516-0145 FU National Heart, Lung, and Blood Institute (NHLBI) [U10 HL084904, U01 HL084861, U10 HL110312, U109 HL110337, U01 HL084889, U01 HL084890, U01 HL084891, U10 HL110342, U10 HL110262, U01 HL084931, U10 HL110297, U10 HL110302, U10 HL110309, U10 HL110336, U10 HL110338]; National Center for Advancing Translational Sciences [UL1TR000454, UL1TR000135, UL1RR025008, UL1TR000439]; National Institute on Minority Health and Health Disparities [8 U54 MD007588] FX This work was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) (coordinating center: U10 HL084904; regional clinical centers: U01 HL084861, U10 HL110312, U109 HL110337, U01 HL084889, U01 HL084890, U01 HL084891, U10 HL110342, U10 HL110262, U01 HL084931, U10 HL110297, U10 HL110302, U10 HL110309, U10 HL110336, U10 HL110338). This work is also supported by the National Center for Advancing Translational Sciences (UL1TR000454, UL1TR000135, UL1RR025008, UL1TR000439) and the National Institute on Minority Health and Health Disparities (8 U54 MD007588). NR 26 TC 117 Z9 121 U1 2 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 18 PY 2013 VL 310 IS 23 BP 2533 EP 2543 DI 10.1001/jama.2013.282190 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 272ZZ UT WOS:000328503600023 PM 24247300 ER PT J AU Gerfen, CR Paletzki, R Heintz, N AF Gerfen, Charles R. Paletzki, Ronald Heintz, Nathaniel TI GENSAT BAG Cre-Recombinase Driver Lines to Study the Functional Organization of Cerebral Cortical and Basal Ganglia Circuits SO NEURON LA English DT Article ID MOTOR CORTEX; CORTICOSTRIATAL NEURONS; PROJECTION NEURONS; PYRAMIDAL NEURONS; GENE-EXPRESSION; TRANSGENIC MICE; NEURAL CIRCUITS; RAT; CONNECTIVITY; PATHWAY AB Recent development of molecular genetic techniques are rapidly advancing understanding of the functional role of brain circuits in behavior. Critical to this approach is the ability to target specific neuron populations and circuits. The collection of over 250 BAC Cre-recombinase driver lines produced by the GENSAT project provides a resource for such studies. Here we provide characterization of GENSAT BAG-Cre driver lines with expression in specific neuroanatomical pathways within the cerebral cortex and basal ganglia. C1 [Gerfen, Charles R.; Paletzki, Ronald] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. [Heintz, Nathaniel] Rockefeller Univ, Howard Hughes Med Inst, Mol Biol Lab, New York, NY 10021 USA. RP Gerfen, CR (reprint author), NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. EM gerfenc@mail.nih.gov FU NIMH IRP [MH002497-24]; GENSAT [NIH/NINDS N271200723701C]; NIH/NINDS MMRRC [201224636]; NIH/NIDA [1P30 DA035756-01]; NIH/NIMH [P50 MH090963 P2]; Howard Hughes Medical Institute FX We acknowledge the excellent technical support and expertise of Michelle Tenace, Scott Stavrou, Laura Kus, Shiaoching Gong, and Nicholas Didkovsky. We also thank the NINDS GENSAT staff, Laura Mamounas, Coryse St. Hillaire-Clarke, and Amelia Gubitz for their assistance. This study was supported by grants to C.R.G: (NIMH IRP project MH002497-24) and N.H. (GENSAT contract NIH/NINDS N271200723701C, NIH/NINDS MMRRC subaward 201224636, NIH/NIDA 1P30 DA035756-01, NIH/NIMH P50 MH090963 P2, and Howard Hughes Medical Institute Investigator Award). NR 37 TC 81 Z9 81 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD DEC 18 PY 2013 VL 80 IS 6 BP 1368 EP 1383 DI 10.1016/j.neuron.2013.10.016 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 278VY UT WOS:000328919200007 PM 24360541 ER PT J AU Rudebeck, PH Mitz, AR Chacko, RV Murray, EA AF Rudebeck, Peter H. Mitz, Andrew R. Chacko, Ravi V. Murray, Elisabeth A. TI Effects of Amygdala Lesions on Reward-Value Coding in Orbital and Medial Prefrontal Cortex SO NEURON LA English DT Article ID ANTERIOR CINGULATE CORTEX; PRIMATE ORBITOFRONTAL CORTEX; MAJOR DEPRESSIVE DISORDER; DECISION-MAKING; BASOLATERAL AMYGDALA; NEURONAL-ACTIVITY; FRONTAL-CORTEX; SINGLE NEURONS; ECONOMIC VALUE; BEHAVIOR AB We examined the contribution of the amygdala to value signals within orbital prefrontal cortex (OFC) and medial prefrontal cortex (MFC). On each trial, monkeys chose between two stimuli that were associated with different quantities of reward. In intact monkeys, as expected, neurons in both OFC and MFC signaled the reward quantity associated with stimuli. Contrasted with MFC, OFC contained a larger proportion of neurons encoding reward quantity and did so with faster response latencies. Removing the amygdala eliminated these differences, mainly by decreasing value coding in OFC. Similar decreases occurred in OFC immediately before and after reward delivery. Although the amygdala projects to both OFC and MFC, we found that it has its greatest influence over reward-value coding in OFC. Notably, amygdala lesions did not abolish value coding in OFC, which shows that OFC's representations of the value of objects, choices, and outcomes depends, in large part, on other sources. C1 [Rudebeck, Peter H.; Mitz, Andrew R.; Chacko, Ravi V.; Murray, Elisabeth A.] NIMH, Neuropsychol Lab, Sect Neurobiol Learning & Memory, Bethesda, MD 20892 USA. RP Rudebeck, PH (reprint author), NIMH, Neuropsychol Lab, Sect Neurobiol Learning & Memory, Bldg 49,Suite 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM rudebeckp@mail.nih.gov OI Rudebeck, Peter/0000-0002-1411-7555; Murray, Elisabeth/0000-0003-1450-1642 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 Kevin Blomstrom, Kevin Fomalont, and Joshua Ripple for assistance with data collection and James Fellows, Ping Yu Chen, and David Yu for help with surgery and histology. We are indebted to Steven Wise and Bruno Averbeck for comments on analyses and an earlier version of the manuscript. NR 50 TC 31 Z9 32 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD DEC 18 PY 2013 VL 80 IS 6 BP 1519 EP 1531 DI 10.1016/j.neuron.2013.09.036 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 278VY UT WOS:000328919200018 PM 24360550 ER PT J AU Sheliga, BM Quaia, C FitzGibbon, EJ Cumming, BG AF Sheliga, B. M. Quaia, C. FitzGibbon, E. J. Cumming, B. G. TI Retinal visual processing constrains human ocular following response SO VISION RESEARCH LA English DT Article DE Visual motion; Retinal ganglion cells; Contrast gain control; Surround inhibition ID LATERAL GENICULATE-NUCLEUS; MACAQUE V1 NEURONS; RECEPTIVE-FIELD PROPERTIES; VERGENCE EYE-MOVEMENTS; GANGLION-CELLS; CONTRAST SENSITIVITY; PRIMATE RETINA; CAT RETINA; SPATIAL SUMMATION; ORIENTATION BIAS AB Ocular following responses (OFRs) are the initial tracking eye movements elicited at ultra-short latency by sudden motion of a textured pattern. We wished to evaluate quantitatively the impact that subcortical stages of visual processing might have on the OFRs. In three experiments we recorded the OFRs of human subjects to brief horizontal motion of 1D vertical sine-wave gratings restricted to an elongated horizontal aperture. Gratings were composed of a variable number of abutting horizontal strips where alternate strips were in counterphase. In one of the experiments we also utilized gratings occupying a variable number of horizontal strips separated vertically by mean-luminance gaps. We modeled retinal center/surround receptive fields as a difference of two 2-D Gaussian functions. When the characteristics of such local filters were selected in accord with the known properties of primate retinal ganglion cells, a single-layer model was capable to quantitatively account for the observed changes in the OFR amplitude for stimuli composed of counterphase strips of different heights (Experiment 1), for a wide range of stimulus contrasts (Experiment 2) and spatial frequencies (Experiment 3). A similar model using oriented filters that resemble cortical simple cells was also able to account for these data. Since similar filters can be constructed from the linear summation of retinal filters, and these filters alone can explain the data, we conclude that retinal processing determines the response to these stimuli. Thus, with appropriately chosen stimuli, OFRs can be used to study visual spatial integration processes as early as in the retina. Published by Elsevier Ltd. C1 [Sheliga, B. M.; Quaia, C.; FitzGibbon, E. J.; Cumming, B. G.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Sheliga, BM (reprint author), NIH, Sensorimotor Res Lab, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. EM bms@lsr.nei.nih.gov FU Intramural Research Program of the National Eye Institute at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Eye Institute at the National Institutes of Health. NR 50 TC 4 Z9 4 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 EI 1878-5646 J9 VISION RES JI Vision Res. PD DEC 18 PY 2013 VL 93 BP 29 EP 42 DI 10.1016/j.visres.2013.10.002 PG 14 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 261SY UT WOS:000327686100004 PM 24125703 ER PT J AU Yamamizu, K Piao, YL Sharov, AA Zsiros, V Yu, H Nakazawa, K Schlessinger, D Ko, MSH AF Yamamizu, Kohei Piao, Yulan Sharov, Alexei A. Zsiros, Veronika Yu, Hong Nakazawa, Kazu Schlessinger, David Ko, Minoru S. H. TI Identification of Transcription Factors for Lineage-Specific ESC Differentiation SO STEM CELL REPORTS LA English DT Article ID EMBRYONIC STEM-CELLS; COUP-TFI; DIRECT CONVERSION; HUMAN FIBROBLASTS; DEFINED FACTORS; MOUSE EMBRYOS; GENE; EXPRESSION; RECEPTOR; NEURONS AB A network of transcription factors (TFs) determines cell identity, but identity can be altered by overexpressing a combination of TFs. However, choosing and verifying combinations of TFs for specific cell differentiation have been daunting due to the large number of possible combinations of similar to 2,000 TFs. Here, we report the identification of individual TFs for lineage-specific cell differentiation based on the correlation matrix of global gene expression profiles. The overexpression of identified TFs-Myod1, Mef2c, Esx1, Foxa1, Hnf4a, Gata2, Gata3, Myc, Elf5, Irf2, Elf1, Sfpi1, Ets1, Smad7, Nr2f1, Sox11, Dmrt1, Sox9, Foxg1, Sox2, or Ascl1-can direct efficient, specific, and rapid differentiation into myocytes, hepatocytes, blood cells, and neurons. Furthermore, transfection of synthetic mRNAs of TFs generates their appropriate target cells. These results demonstrate both the utility of this approach to identify potent TFs for cell differentiation, and the unanticipated capacity of single TFs directly guides differentiation to specific lineage fates. C1 [Yamamizu, Kohei; Piao, Yulan; Sharov, Alexei A.; Yu, Hong; Schlessinger, David; Ko, Minoru S. H.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Zsiros, Veronika; Nakazawa, Kazu] NIMH, Unit Genet Cognit & Behav, NIH, Bethesda, MD 20892 USA. [Ko, Minoru S. H.] Keio Univ, Dept Syst Med, Sch Med, Sakaguchi Lab, Tokyo 1608582, Japan. [Ko, Minoru S. H.] Japan Sci & Technol Agcy, CREST, Tokyo 1608528, Japan. RP Ko, MSH (reprint author), NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. EM kom@z7.keio.jp RI Nakazawa, Kazutoshi/J-6195-2015; OI Nakazawa, Kazutoshi/0000-0001-5699-9093; Ko, Minoru/0000-0002-3530-3015 FU Intramural Research Program of the NIH, National Institute on Aging; Japan Science and Technology Agency, CREST program; Kanae Foundation, Japan; Uehara Memorial Foundation, Japan; Naito Foundation, Japan; Japan Society for Promotion of Science FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. This research was also supported in part by the Japan Science and Technology Agency, CREST program. K.Y. was supported by the postdoctoral fellowships from the Kanae Foundation, Japan, Uehara Memorial Foundation, Japan, Naito Foundation, Japan, and the Japan Society for Promotion of Science. NR 58 TC 16 Z9 16 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD DEC 17 PY 2013 VL 1 IS 6 BP 545 EP 559 DI 10.1016/j.stemcr.2013.10.006 PG 15 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AI1WY UT WOS:000336647100008 PM 24371809 ER PT J AU Lombaert, IMA Abrams, SR Li, L Eswarakumar, VP Sethi, AJ Witt, RL Hoffman, MP AF Lombaert, Isabelle M. A. Abrams, Shaun R. Li, Li Eswarakumar, Veraragavan P. Sethi, Aditya J. Witt, Robert L. Hoffman, Matthew P. TI Combined KIT and FGFR2b Signaling Regulates Epithelial Progenitor Expansion during Organogenesis SO STEM CELL REPORTS LA English DT Article ID RECEPTOR TYROSINE KINASES; STEM-CELL; C-KIT; PARASYMPATHETIC INNERVATION; EMBRYONIC LUNG; MAMMARY-GLAND; SELF-RENEWAL; MOUSE; EXPRESSION; MORPHOGENESIS AB Organ formation and regeneration require epithelial progenitor expansion to engineer, maintain, and repair the branched tissue architecture. Identifying the mechanisms that control progenitor expansion will inform therapeutic organ (re) generation. Here, we discover that combined KIT and fibroblast growth factor receptor 2b (FGFR2b) signaling specifically increases distal progenitor expansion during salivary gland organogenesis. FGFR2b signaling upregulates the epithelial KIT pathway so that combined KIT/FGFR2b signaling, via separate AKT and mitogen-activated protein kinase (MAPK) pathways, amplifies FGFR2b-dependent transcription. Combined KIT/FGFR2b signaling selectively expands the number of KIT+K14+SOX10+ distal progenitors, and a genetic loss of KIT signaling depletes the distal progenitors but also unexpectedly depletes the K5+ proximal progenitors. This occurs because the distal progenitors produce neurotrophic factors that support gland innervation, which maintains the proximal progenitors. Furthermore, a rare population of KIT+FGFR2b+ cells is present in adult glands, in which KIT signaling also regulates epithelial-neuronal communication during homeostasis. Our findings provide a framework to direct regeneration of branched epithelial organs. C1 [Lombaert, Isabelle M. A.; Abrams, Shaun R.; Hoffman, Matthew P.] Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Sethi, Aditya J.] Natl Inst Dent & Craniofacial Res, Dev Mech Sect, NIH, Bethesda, MD 20892 USA. [Li, Li; Eswarakumar, Veraragavan P.] Yale Univ, Sch Med, Dept Orthoped & Rehabil, New Haven, CT 06520 USA. [Witt, Robert L.] Helen F Graham Canc Ctr Christiana Care, Head & Neck Multidisciplinary Clin, Newark, DE 19713 USA. RP Hoffman, MP (reprint author), Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM mhoffman@mail.nih.gov OI Eswarakumar, Jacob/0000-0003-0784-0507 FU Dutch Niels Stensen Stichting Award for young Dutch academics to gain experience abroad; Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, DHHS FX We thank Dr. P. McCoy and Dr. A. Williams from the NHLBI Flow Cytometry Core for technical support, Dr H. Ye (YU) for technical assistance with the L6 cells, Dr. S. Pradhan Bhatt (UD) for assistance with human samples, and Dr. S. Gutkind (NIDCR) and Dr. G. Martin (UCSF) for providing the K14Cre and RosamTmG reporter mice. I.M.A.L. received a Dutch Niels Stensen Stichting Award for young Dutch academics to gain experience abroad. This study was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, DHHS. NR 46 TC 22 Z9 22 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD DEC 17 PY 2013 VL 1 IS 6 BP 604 EP 619 DI 10.1016/j.stemcr.2013.10.013 PG 16 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AI1WY UT WOS:000336647100012 PM 24371813 ER PT J AU Lamas, GA Boineau, R Goertz, C Mark, DB Rosenberg, Y Stylianou, M Rozema, T Nahin, RL Lindblad, L Lewis, EF Drisko, J Lee, KL AF Lamas, Gervasio A. Boineau, Robin Goertz, Christine Mark, Daniel B. Rosenberg, Yves Stylianou, Mario Rozema, Theodore Nahin, Richard L. Lindblad, Lauren Lewis, Eldrin F. Drisko, Jeanne Lee, Kerry L. CA TACT Trial Assess Chelation TI Oral High-Dose Multivitamins and Minerals After Myocardial Infarction A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CARDIOVASCULAR-DISEASE; BETA-CAROTENE; ANTIOXIDANT VITAMINS; CLINICAL-TRIALS; LUNG-CANCER; PREVENTION; METAANALYSIS; COMBINATION; MORTALITY; RISK AB Background: Whether high-dose multivitamins are effective for secondary prevention of atherosclerotic disease is unknown. Objective: To assess whether oral multivitamins reduce cardiovascular events and are safe. Design: Double-blind, placebo-controlled, 2 x 2 factorial, multi-center, randomized trial. (ClinicalTrials.gov: NCT00044213) Setting: 134 U.S. and Canadian academic and clinical sites. Patients: 1708 patients aged 50 years or older who had myocardial infarction (MI) at least 6 weeks earlier and had serum creatinine levels of 176.8 mu mol/L (2.0 mg/dL) or less. Intervention: Patients were randomly assigned to an oral, 28-component, high-dose multivitamin and multimineral mixture or placebo. Measurements: The primary end point was time to total death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. Results: The median age was 65 years, and 18% of patients were women. The qualifying MI occurred a median of 4.6 years (inter-quartile range [IQR], 1.6 to 9.2 years) before enrollment. Median follow-up was 55 months (IQR, 26 to 60 months). Patients received vitamins for a median of 31 months (IQR, 13 to 59 months) in the vitamin group and 35 months (IQR, 13 to 60 months) in the placebo group (P = 0.65). Totals of 645 (76%) and 646 (76%) patients in the vitamin and placebo groups, respectively, completed at least 1 year of oral therapy (P = 0.98), and 400 (47%) and 426 (50%) patients, respectively, completed at least 3 years (P = 0.23). Totals of 394 (46%) and 390 (46%) patients in the vitamin and placebo groups, respectively, discontinued the vitamin regimen (P = 0.67), and 17% of patients withdrew from the study. The primary end point occurred in 230 (27%) patients in the vitamin group and 253 (30%) in the placebo group (hazard ratio, 0.89 [95% CI, 0.75 to 1.07]; P = 0.21). No evidence suggested harm from vitamin therapy in any category of adverse events. Limitation: There was considerable nonadherence and withdrawal, limiting the ability to draw firm conclusions (particularly about safety). Conclusion: High-dose oral multivitamins and multiminerals did not statistically significantly reduce cardiovascular events in patients after MI who received standard medications. However, this conclusion is tempered by the nonadherence rate. C1 Mt Sinai Med Ctr, Miami Beach, FL 33140 USA. NHLBI, Bethesda, MD 20892 USA. Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. Palmer Ctr Chiropract Res, Davenport, IA USA. Duke Clin Res Inst, Durham, NC USA. Biogenesis Med Ctr, Landrum, SC USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. RP Lamas, GA (reprint author), Columbia Univ, Div Cardiol, Mt Sinai Med Ctr, 4300 Alton Rd, Miami Beach, FL 33140 USA. EM gervasio.lamas@msmc.com OI Mark, Daniel/0000-0001-6340-8087 FU National Institutes of Health FX Primary Funding Source: National Institutes of Health. NR 25 TC 19 Z9 19 U1 0 U2 6 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 17 PY 2013 VL 159 IS 12 BP 797 EP + DI 10.7326/0003-4819-159-12-201312170-00004 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 290ED UT WOS:000329735300012 PM 24490264 ER PT J AU Krause, PR Bialek, SR Boppana, SB Griffiths, PD Laughlin, CA Ljungman, P Mocarski, ES Pass, RF Read, JS Schleiss, MR Plotkin, SA AF Krause, Philip R. Bialek, Stephanie R. Boppana, Suresh B. Griffiths, Paul D. Laughlin, Catherine A. Ljungman, Per Mocarski, Edward S. Pass, Robert F. Read, Jennifer S. Schleiss, Mark R. Plotkin, Stanley A. TI Priorities for CMV vaccine development SO VACCINE LA English DT Review DE Cytomegalovirus; Congenital CMV; Viruses; Clinical trial endpoints; Meeting report ID CONGENITAL CYTOMEGALOVIRUS-INFECTION; ORGAN TRANSPLANT RECIPIENTS; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; GLYCOPROTEIN-B VACCINE; DOUBLE-BLIND; ADVISORY-COMMITTEE; HEARING-LOSS; DISEASE; IMMUNIZATION AB A multidisciplinary meeting addressed priorities related to development of vaccines against cytomegalovirus (CMV), the cause of congenital CMV (cCMV) disease and of serious disease in the immunocompromised. Participants discussed optimal uses of a CMV vaccine, aspects of clinical study design, and the value of additional research. A universal childhood CMV vaccine could potentially rapidly reduce cCMV disease, as infected children are sources of viral transmission to seronegative and seropositive mothers. A vaccine administered to adolescents or adult women could also reduce cCMV disease by making them immune prior to pregnancy. Clinical trials of CMV vaccines in women should evaluate protection against cCMV infection, an essential precursor of cCMV disease, which is a more practical and acceptable endpoint for assessing vaccine effects on maternal-fetal transmission. Clinical trials of vaccines to evaluate prevention of CMV disease in stem cell transplant recipients could use CMV viremia at a level triggering pre-emptive antiviral therapy as an endpoint, because widespread use of pre-emptive and prophylactic antivirals has rendered CMV-induced disease too rare to be a practical endpoint for clinical trials. In solid organ transplant patients, CMV-associated disease is sufficiently common for use as a primary endpoint. Additional research to advance CMV vaccine development should include identifying factors that predict fetal loss due to CMV, determining age-specific incidence and transmission rates, defining the mechanism and relative contributions of maternal reactivation and reinfection to cCMV disease, developing assays that can distinguish between reactivation and re-infection in seropositive vaccinees, further defining predictors of sequelae from cCMV infection, and identifying clinically relevant immune response parameters to CMV (including developing validated assays that could assess CMV antibody avidity) that could lead to the establishment of immune correlates of protection. Published by Elsevier Ltd. C1 [Krause, Philip R.] US FDA, Off Vaccines Res & Review, CBER, Bethesda, MD 20014 USA. [Bialek, Stephanie R.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Boppana, Suresh B.; Pass, Robert F.] Univ Alabama Birmingham, Birmingham, AL USA. [Griffiths, Paul D.] UCL, London WC1E 6BT, England. [Laughlin, Catherine A.] NIAID, NIH, Bethesda, MD USA. [Ljungman, Per] Karolinska Inst, Stockholm, Sweden. [Mocarski, Edward S.] Emory Univ, Atlanta, GA 30322 USA. [Read, Jennifer S.] Natl Vaccine Program Off, Washington, DC USA. [Schleiss, Mark R.] Univ Minnesota, Minneapolis, MN USA. [Plotkin, Stanley A.] Univ Penn, Philadelphia, PA 19104 USA. RP Krause, PR (reprint author), US FDA, Off Vaccines Res & Review, CBER, 29 Lincoln Dr, Bethesda, MD 20014 USA. EM philip.krause@fda.hhs.gov; zqg7@cdc.gov; sboppana@peds.uab.edu; p.griffiths@ucl.ac.uk; CLaughlin@niaid.nih.gov; Per.Ljungman@ki.se; mocarski@emory.edu; RPass@peds.uab.edu; Jennifer.Read@fda.hhs.gov; schleiss@umn.edu; stanley.plotkin@vaxconsult.com OI Krause, Philip/0000-0002-1045-7536 FU Food and Drug Administration; National Institutes of Health; Centers for Disease Control and Prevention; National Vaccine Program Office FX We acknowledge the Food and Drug Administration, the National Institutes of Health, the Centers for Disease Control and Prevention, and the National Vaccine Program Office for sponsorship of the CMV Vaccine Workshop, held in Bethesda, MD on the NIH Campus on January 11-12, 2012. We also thank the presenters and participants at the meeting for excellent discussions that enabled a highly productive meeting. NR 55 TC 36 Z9 37 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 17 PY 2013 VL 32 IS 1 BP 4 EP 10 DI 10.1016/j.vaccine.2013.09.042 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 289LT UT WOS:000329684700003 PM 24129123 ER PT J AU Yorkin, M Spaccarotella, K Martin-Biggers, J Quick, V Byrd-Bredbenner, C AF Yorkin, Meredith Spaccarotella, Kim Martin-Biggers, Jennifer Quick, Virginia Byrd-Bredbenner, Carol TI Accuracy and consistency of weights provided by home bathroom scales SO BMC PUBLIC HEALTH LA English DT Article DE Body weight; Body mass index; Validity ID PRESCHOOL-CHILDREN; BODY-WEIGHT; OVERWEIGHT; HEIGHT; POPULATION; OBESITY; PREVALENCE; BMI AB Background: Self-reported body weight is often used for calculation of Body Mass Index because it is easy to collect. Little is known about sources of error introduced by using bathroom scales to measure weight at home. The objective of this study was to evaluate the accuracy and consistency of digital versus dial-type bathroom scales commonly used for self-reported weight. Methods: Participants brought functioning bathroom scales (n = 18 dial-type, n = 43 digital-type) to a central location. Trained researchers assessed accuracy and consistency using certified calibration weights at 10 kg, 25 kg, 50 kg, 75 kg, 100 kg, and 110 kg. Data also were collected on frequency of calibration, age and floor surface beneath the scale. Results: All participants reported using their scale on hard surface flooring. Before calibration, all digital scales displayed 0, but dial scales displayed a mean absolute initial weight of 0.95 (1.9 SD) kg. Digital scales accurately weighed test loads whereas dial-type scale weights differed significantly (p < 0.05). Imprecision of dial scales was significantly greater than that of digital scales at all weights (p < 0.05). Accuracy and precision did not vary by scale age. Conclusions: Digital home bathroom scales provide sufficiently accurate and consistent weights for public health research. Reminders to zero scales before each use may further improve accuracy of self-reported weight. C1 [Yorkin, Meredith; Spaccarotella, Kim; Martin-Biggers, Jennifer; Byrd-Bredbenner, Carol] Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08901 USA. [Quick, Virginia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. RP Martin-Biggers, J (reprint author), Rutgers State Univ, Dept Nutr Sci, 26 Nichol Ave,Davison Hall, New Brunswick, NJ 08901 USA. EM jmartin@njaes.rutgers.edu RI Byrd-Bredbenner, Carol/F-8064-2015; OI Byrd-Bredbenner, Carol/0000-0002-8010-3987; Martin-Biggers, Jennifer/0000-0001-8857-6386; Quick, Virginia/0000-0002-4338-963X FU United States Department of Agriculture, National Institute of Food and Agriculture [2011-68001-30170]; Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Training Award FX MY, KS, JMB, VQ and CBB received funding from the United States Department of Agriculture, National Institute of Food and Agriculture, Grant Number 2011-68001-30170. VQ also received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Training Award. NR 23 TC 3 Z9 3 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD DEC 17 PY 2013 VL 13 AR UNSP 1194 DI 10.1186/1471-2458-13-1194 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 286XL UT WOS:000329502500001 PM 24341761 ER PT J AU Li, FH Tan, H Singh, J Yang, J Xia, XF Bao, JG Ma, JW Zhan, M Wong, STC AF Li, Fuhai Tan, Hua Singh, Jaykrishna Yang, Jian Xia, Xiaofeng Bao, Jiguang Ma, Jinwen Zhan, Ming Wong, Stephen T. C. TI A 3D multiscale model of cancer stem cell in tumor development SO BMC SYSTEMS BIOLOGY LA English DT Article; Proceedings Paper CT 6th International Conference on Computational Systems Biology (ISB) CY AUG 18-20, 2012 CL Xian, PEOPLES R CHINA ID NONLINEAR SIMULATION; MATHEMATICAL-MODEL; WNT ACTIVITY; GROWTH; INVASION; ANGIOGENESIS; METASTASIS; MORPHOLOGY; BIOLOGY AB Background: Recent reports indicate that a subgroup of tumor cells named cancer stem cells (CSCs) or tumor initiating cells (TICs) are responsible for tumor initiation, growth and drug resistance. This subgroup of tumor cells has self-renewal capacity and could differentiate into heterogeneous tumor cell populations through asymmetric proliferation. The idea of CSC provides informative insights into tumor initiation, metastasis and treatment. However, the underlying mechanisms of CSCs regulating tumor behaviors are unclear due to the complex cancer system. To study the functions of CSCs in the complex tumor system, a few mathematical modeling studies have been proposed. Whereas, the effect of microenvironment (mE) factors, the behaviors of CSCs, progenitor tumor cells (PCs) and differentiated tumor cells (TCs), and the impact of CSC fraction and signaling heterogeneity, are not adequately explored yet. Methods: In this study, a novel 3D multi-scale mathematical modeling is proposed to investigate the behaviors of CSCsin tumor progressions. The model integrates CSCs, PCs, and TCs together with a few essential mE factors. With this model, we simulated and investigated the tumor development and drug response under different CSC content and heterogeneity. Results: The simulation results shown that the fraction of CSCs plays a critical role in driving the tumor progression and drug resistance. It is also showed that the pure chemo-drug treatment was not a successful treatment, as it resulted in a significant increase of the CSC fraction. It further shown that the self-renew heterogeneity of the initial CSC population is a cause of the heterogeneity of the derived tumors in terms of the CSC fraction and response to drug treatments. Conclusions: The proposed 3D multi-scale model provides a new tool for investigating the behaviors of CSC in CSC-initiated tumors, which enables scientists to investigate and generate testable hypotheses about CSCs in tumor development and drug response under different microenvironments and drug perturbations. C1 [Li, Fuhai; Tan, Hua; Singh, Jaykrishna; Yang, Jian; Xia, Xiaofeng; Ma, Jinwen; Zhan, Ming; Wong, Stephen T. C.] Cornell Univ, Weill Med Coll, Dept Syst Med & Bioengn, Methodist Hosp,Res Inst,NCI Ctr Modeling Canc Dev, Houston, TX 77030 USA. [Tan, Hua; Bao, Jiguang] Beijing Normal Univ, Lab Math & Complex Syst, Minist Educ, Sch Math Sci, Beijing 100875, Peoples R China. [Ma, Jinwen] Peking Univ, Sch Math Sci, Dept Informat Sci, Beijing 100871, Peoples R China. [Ma, Jinwen] Peking Univ, LMAM, Beijing 100871, Peoples R China. RP Zhan, M (reprint author), Cornell Univ, Weill Med Coll, Dept Syst Med & Bioengn, Methodist Hosp,Res Inst,NCI Ctr Modeling Canc Dev, Houston, TX 77030 USA. EM mzhan@tmhs.org FU NCI NIH HHS [NIH U54CA149169] NR 33 TC 6 Z9 6 U1 1 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD DEC 17 PY 2013 VL 7 SU 2 AR S12 DI 10.1186/1752-0509-7-S2-S12 PG 12 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 286BR UT WOS:000329440000004 PM 24564919 ER PT J AU Kiggundu, VL O'Meara, WP Musoke, R Nalugoda, FK Kigozi, G Baghendaghe, E Lutalo, T Achienge, MK Reynolds, SJ Makumbi, F Serwadda, D Gray, RH Wools-Kaloustian, KK AF Kiggundu, Valerian L. O'Meara, Wendy P. Musoke, Richard Nalugoda, Fred K. Kigozi, Godfrey Baghendaghe, Enos Lutalo, Tom Achienge, Marion K. Reynolds, Steven J. Makumbi, Fred Serwadda, David Gray, Ronald H. Wools-Kaloustian, Kara K. TI High Prevalence of Malaria Parasitemia and Anemia among Hospitalized Children in Rakai, Uganda SO PLOS ONE LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; TRANSMISSION INTENSITY; MORTALITY; MORBIDITY; MISDIAGNOSIS; VACCINES; SITES; KENYA AB Background: There is a paucity of data on malaria among hospitalized children in malaria endemic areas. We determined the prevalence, presentation and treatment outcomes of malaria and anemia among children in two hospitals in Rakai, Uganda. Methods: Children under five years hospitalized in Kalisizo hospital or Bikira health center in Rakai district, Uganda between May 2011 and May 2012 were enrolled and followed-up until discharge, death or referral. Data were collected on social-demographic characteristics, current and past illnesses and clinical signs and symptoms. Blood smears, hemoglobin (Hgb) levels and HIV testing were performed from finger/heel prick blood. The associations between malaria infection and other factors were estimated using log-binomial regression to estimate adjusted prevalence risk ratios (aPRR) and 95% confidence intervals (CIs), controlling for clustering at health facilities. Results: 2471 children were enrolled. The most common medical presentations were fever (96.2%), cough (61.7%), vomiting (44.2%), diarrhea (20.8%), and seizures (16.0%). The prevalence of malaria parasitemia was 54.6%. Children with malaria were more likely to present with a history of fever (aPRR 2.23; CI 1.18-4.24) and seizures (aPRR 1.12; CI 1.09-1.16). Confirmed malaria was significantly lower among girls than boys (aPRR 0.92; CI 0.91-0.93), HIV infected children (aPRR 0.60 CI 0.52-0.71), and children with diarrhea (aPRR 0.76; CI 0.65-0.90). The overall prevalence of anemia (Hgb, 10 g/dl) was 56.3% and severe anemia (Hgb, 6 g/dL) was 17.8%. Among children with severe anemia 76.8% had malaria parasitemia, of whom 93.1% received blood transfusion. Malaria associated mortality was 0.6%. Conclusion: There was a high prevalence of malaria parasitemia and anemia among inpatient children under five years. Malaria prevention is a priority in this population. C1 [Kiggundu, Valerian L.; Musoke, Richard; Nalugoda, Fred K.; Kigozi, Godfrey; Baghendaghe, Enos; Lutalo, Tom; Reynolds, Steven J.; Makumbi, Fred; Serwadda, David] Kalisizo Stn, Rakai Hlth Sci Program, Kalisizo, Rakai, Uganda. [O'Meara, Wendy P.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [O'Meara, Wendy P.] Duke Global Hlth Inst, Durham, NC USA. [Achienge, Marion K.] Makerere Univ, Coll Hlth Sci, East African IeDEA Int Epidemiol Data Bases Evalu, Kampala, Uganda. [Achienge, Marion K.] Makerere Univ, Coll Hlth Sci, Infect Dis Inst, Kampala, Uganda. [Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Makumbi, Fred; Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Gray, Ronald H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wools-Kaloustian, Kara K.] Indiana Univ Sch Med, Dept Med, Div Infect Dis, Indianapolis, IN 46202 USA. RP Kiggundu, VL (reprint author), Kalisizo Stn, Rakai Hlth Sci Program, Kalisizo, Rakai, Uganda. EM valerian@rhsp.org FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 A1069911]; National Institute of Child Health and Human Development (NICHD); National Cancer Institute (NCI) and National Institute of Health (NIH) through Indiana University and East Africa IeDEA FX The project described was supported by grant No. U01 A1069911 from the National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Child Health and Human Development (NICHD); National Cancer Institute (NCI) and National Institute of Health (NIH) through Indiana University and East Africa IeDEA (international epidemiological data bases to evaluate AIDs). The contents of this project are solely the responsibility of the authors and do not necessarily represent the official view of the National Institute of Allergy and Infectious Disease (NIAID); National Institute of Child Health and Human Development (NICHD); National Cancer Institute (NCI) or National Institute of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 4 Z9 4 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 DEC 17 PY 2013 VL 8 IS 12 AR e82455 DI 10.1371/journal.pone.0082455 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276GT UT WOS:000328737700017 PM 24358185 ER PT J AU Thameem, F Igo, RP Freedman, BI Langefeld, C Hanson, RL Schelling, JR Elston, RC Duggirala, R Nicholas, SB Goddard, KAB Divers, J Guo, XQ Ipp, E Kimmel, PL Meoni, LA Shah, VO Smith, MW Winkler, CA Zager, PG Knowler, WC Nelson, RG Pahl, MV Parekh, RS Kao, WHL Rasooly, RS Adler, SG Abboud, HE Iyengar, SK Sedor, JR AF Thameem, Farook Igo, Robert P., Jr. Freedman, Barry I. Langefeld, Carl Hanson, Robert L. Schelling, Jeffrey R. Elston, Robert C. Duggirala, Ravindranath Nicholas, Susanne B. Goddard, Katrina A. B. Divers, Jasmin Guo, Xiuqing Ipp, Eli Kimmel, Paul L. Meoni, Lucy A. Shah, Vallabh O. Smith, Michael W. Winkler, Cheryl A. Zager, Philip G. Knowler, William C. Nelson, Robert G. Pahl, Madeline V. Parekh, Rulan S. Kao, W. H. Linda Rasooly, Rebekah S. Adler, Sharon G. Abboud, Hanna E. Iyengar, Sudha K. Sedor, John R. CA Family Invest Nephropathy & Diabet TI A Genome-Wide Search for Linkage of Estimated Glomerular Filtration Rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND) SO PLOS ONE LA English DT Article ID CHRONIC KIDNEY-DISEASE; RENAL-FUNCTION; MEXICAN-AMERICANS; GENETIC-VARIANTS; SERUM CREATININE; IDENTIFIES 6; ASSOCIATION; LOCI; ALBUMINURIA; TRAITS AB Objective: Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR. Methods: Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula. Results: The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4x10(-5)) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5x10(-4)) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5x10(-4)) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome. Conclusion: The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN. C1 [Thameem, Farook; Abboud, Hanna E.] Univ Texas San Antonio, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. [Igo, Robert P., Jr.; Elston, Robert C.; Iyengar, Sudha K.; Sedor, John R.] Case Western Reserve Univ, Dept Biostat & Epidemiol, Cleveland, OH 44106 USA. [Freedman, Barry I.; Langefeld, Carl; Divers, Jasmin] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Hanson, Robert L.; Knowler, William C.; Nelson, Robert G.] Natl Inst Diabet & Digest & Kidney Dis, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Schelling, Jeffrey R.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Duggirala, Ravindranath] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Nicholas, Susanne B.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Goddard, Katrina A. B.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. [Guo, Xiuqing] Harbor Univ Calif Los Angeles, Med Ctr, Dept Pediat, Torrance, CA USA. [Ipp, Eli; Adler, Sharon G.] Harbor Univ Calif Los Angeles, Med Ctr, Dept Med, Torrance, CA USA. [Kimmel, Paul L.; Rasooly, Rebekah S.] Natl Inst Diabet Digest & Kidney Dis, NIH, Bethesda, MD USA. [Meoni, Lucy A.; Parekh, Rulan S.; Kao, W. H. Linda] Johns Hopkins Univ, Dept Epidemiol & Med, Baltimore, MD USA. [Shah, Vallabh O.; Zager, Philip G.] Univ New Mexico, Albuquerque, NM 87131 USA. [Smith, Michael W.] NHGRI, NIH, Bethesda, MD 20892 USA. [Winkler, Cheryl A.] NCI, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Pahl, Madeline V.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Parekh, Rulan S.] Univ Toronto, Dept Pediat, Toronto, ON, Canada. RP Iyengar, SK (reprint author), Case Western Reserve Univ, Dept Biostat & Epidemiol, Cleveland, OH 44106 USA. EM ski@case.edu RI Hanson, Robert/O-3238-2015; OI Hanson, Robert/0000-0002-4252-7068; Rasooly, Rebekah/0000-0002-6357-5528 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK57292-05]; Intramural Research Program of the NIDDK; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors thank all the FIND participants. This study was supported by the research grant U01DK57292-05 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The study was also supported in part by the Intramural Research Program of the NIDDK. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 15 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 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 17 PY 2013 VL 8 IS 12 AR e81888 DI 10.1371/journal.pone.0081888 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276GT UT WOS:000328737700002 PM 24358131 ER PT J AU Zhao, HY Lomash, S Glasser, C Mayer, ML Schuckl, P AF Zhao, Huaying Lomash, Suvendu Glasser, Carla Mayer, Mark L. Schuckl, Peter TI Analysis of High Affinity Self-Association by Fluorescence Optical Sedimentation Velocity Analytical Ultracentrifugation of Labeled Proteins: Opportunities and Limitations SO PLOS ONE LA English DT Article ID N-TERMINAL DOMAIN; DETECTED SEDIMENTATION; MACROMOLECULES; BINDING; ACCURACY AB Sedimentation velocity analytical ultracentrifugation (SV) is a powerful first-principle technique for the study of protein interactions, and allows a rigorous characterization of binding stoichiometry and affinities. A recently introduced commercial fluorescence optical detection system (FDS) permits analysis of high-affinity interactions by SV. However, for most proteins the attachment of an extrinsic fluorophore is an essential prerequisite for analysis by FDS-SV. Using the glutamate receptor GluA2 amino terminal domain as a model system for high-affinity homo-dimerization, we demonstrate how the experimental design and choice of fluorescent label can impact both the observed binding constants as well as the derived hydrodynamic parameter estimates for the monomer and dimer species. Specifically, FAM (5,6-carboxyfluorescein) was found to create different populations of artificially high-affinity and low-affinity dimers, as indicated by both FDS-SV and the kinetics of dimer dissociation studied using a bench-top fluorescence spectrometer and Forster Resonance Energy Transfer. By contrast, Dylight488 labeled GluA2, as well as GluA2 expressed as an EGFP fusion protein, yielded results consistent with estimates for unlabeled GluA2. Our study suggests considerations for the choice of labeling strategies, and highlights experimental designs that exploit specific opportunities of FDS-SV for improving the reliability of the binding isotherm analysis of interacting systems. C1 [Zhao, Huaying; Schuckl, Peter] Natl Inst Biomed Imaging & Bioengn, NIH, Lab Cellular Imaging & Macromol Biophys, Dynam Macromol Assembly Sect, Bethesda, MD USA. [Lomash, Suvendu; Glasser, Carla; Mayer, Mark L.] NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM mayerm@mail.nih.gov; schuckp@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering; National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering and the 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 32 TC 12 Z9 12 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 DEC 17 PY 2013 VL 8 IS 12 AR e83439 DI 10.1371/journal.pone.0083439 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276GT UT WOS:000328737700057 PM 24358283 ER PT J AU Simon-Manso, Y Lowenthal, MS Kilpatrick, LE Sampson, ML Telu, KH Rudnick, PA Mallard, WG Bearden, DW Schock, TB Tchekhovskoi, DV Blonder, N Yan, XJ Liang, YX Zheng, YF Wallace, WE Neta, P Phinney, KW Remaley, AT Stein, SE AF Simon-Manso, Yamil Lowenthal, Mark S. Kilpatrick, Lisa E. Sampson, Maureen L. Telu, Kelly H. Rudnick, Paul A. Mallard, W. Gary Bearden, Daniel W. Schock, Tracey B. Tchekhovskoi, Dmitrii V. Blonder, Niksa Yan, Xinjian Liang, Yuxue Zheng, Yufang Wallace, William E. Neta, Pedatsur Phinney, Karen W. Remaley, Alan T. Stein, Stephen E. TI Metabolite Profiling of a NIST Standard Reference Material for Human Plasma (SRM 1950): GC-MS, LC-MS, NMR, and Clinical Laboratory Analyses, Libraries, and Web-Based Resources SO ANALYTICAL CHEMISTRY LA English DT Article ID HUMAN BLOOD-PLASMA; MASS-SPECTROMETRY; ELECTROSPRAY-IONIZATION; CHROMATOGRAPHY/MASS SPECTROMETRY; COMPOUND IDENTIFICATION; SAMPLE PREPARATION; SERUM; SPECTROSCOPY; METABOLOMICS; SUPPRESSION AB Recent progress in metabolomics and the development of increasingly sensitive analytical techniques have renewed interest in global profiling, i.e., semiquantitative monitoring of all chemical constituents of biological fluids. In this work, we have performed global profiling of NIST SRM 1950, "Metabolites in Human Plasma", using GC-MS, LC-MS, and NMR Metabolome coverage, difficulties, and reproducibility of the experiments on each platform are discussed. A total of 353 metabolites have been identified in this material. GC-MS provides 65 unique identifications, and most of the identifications from NMR overlap with the LC-MS identifications, except for some small sugars that are not directly found by LC-MS. Also, repeatability and intermediate precision analyses show that the SRM 1950 profiling is reproducible enough to consider this material as a good choice to distinguish between analytical and biological variability. Clinical laboratory data shows that most results are within the reference ranges for each assay. In-house computational tools have been developed or modified for MS data processing and interactive web display: All data and programs are freely available online at http://peptide.nist.gov/ and http://srmd.nist.gov/. C1 [Simon-Manso, Yamil; Lowenthal, Mark S.; Kilpatrick, Lisa E.; Rudnick, Paul A.; Mallard, W. Gary; Tchekhovskoi, Dmitrii V.; Blonder, Niksa; Yan, Xinjian; Liang, Yuxue; Zheng, Yufang; Neta, Pedatsur; Phinney, Karen W.; Stein, Stephen E.] NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. [Sampson, Maureen L.; Remaley, Alan T.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Telu, Kelly H.; Wallace, William E.] NIST, Div Chem Sci, Gaithersburg, MD 20899 USA. [Bearden, Daniel W.; Schock, Tracey B.] NIST, Hollings Marine Lab, Div Chem Sci, Charleston, SC 29412 USA. RP Simon-Manso, Y (reprint author), 100 Bur Dr,M-S 8362, Gaithersburg, MD 20899 USA. EM ysimon@nist.gov RI Tchekhovskoi, Dmitrii/J-2319-2014; OI Mallard, Wm. Gary/0000-0003-2158-5098 NR 32 TC 28 Z9 28 U1 6 U2 70 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD DEC 17 PY 2013 VL 85 IS 24 BP 11725 EP 11731 DI 10.1021/ac402503m PG 7 WC Chemistry, Analytical SC Chemistry GA 277CV UT WOS:000328797200011 PM 24147600 ER PT J AU Phinney, KW Ballihaut, G Bedner, M Benford, BS Camara, JE Christopher, SJ Davis, WC Dodder, NG Eppe, G Lang, BE Long, SE Lowenthal, MS McGaw, EA Murphy, KE Nelson, BC Prendergast, JL Reiner, JL Rimmer, CA Sander, LC Schantz, MM Sharpless, KE Sniegoski, LT Tai, SSC Thomas, JB Vetter, TW Welch, MJ Wise, SA Wood, LJ Guthrie, WF Hagwood, CR Leigh, SD Yen, JH Zhang, NF Chaudhary-Webb, M Chen, HP Fazili, Z LaVoie, DJ McCoy, LF Momin, SS Paladugula, N Pendergrast, EC Pfeiffer, CM Powers, CD Rabinowitz, D Rybak, ME Schleicher, RL Toombs, BMH Xu, M Zhang, M Castle, AL AF Phinney, Karen W. Ballihaut, Guillaume Bedner, Mary Benford, Brandi S. Camara, Johanna E. Christopher, Steven J. Davis, W. Clay Dodder, Nathan G. Eppe, Gauthier Lang, Brian E. Long, Stephen E. Lowenthal, Mark S. McGaw, Elizabeth A. Murphy, Karen E. Nelson, Bryant C. Prendergast, Jocelyn L. Reiner, Jessica L. Rimmer, Catherine A. Sander, Lane C. Schantz, Michele M. Sharpless, Katherine E. Sniegoski, Lorna T. Tai, Susan S. -C. Thomas, Jeanice B. Vetter, Thomas W. Welch, Michael J. Wise, Stephen A. Wood, Laura J. Guthrie, William F. Hagwood, Charles R. Leigh, Stefan D. Yen, James H. Zhang, Nien-Fan Chaudhary-Webb, Madhu Chen, Huiping Fazili, Zia LaVoie, Donna J. McCoy, Leslie F. Momin, Shahzad S. Paladugula, Neelima Pendergrast, Elizabeth C. Pfeiffer, Christine M. Powers, Carissa D. Rabinowitz, Daniel Rybak, Michael E. Schleicher, Rosemary L. Toombs, Bridgette M. H. Xu, Mary Zhang, Mindy Castle, Arthur L. TI Development of a Standard Reference Material for Metabolomics Research SO ANALYTICAL CHEMISTRY LA English DT Article ID HUMAN PLASMA; MASS-SPECTROMETRY; HUMAN URINE; METABONOMIC ANALYSIS; DIABETES-MELLITUS; ACID-METABOLISM; HPLC-MS; DISEASE; SPECTROSCOPY; PERFORMANCE AB The National Institute of Standards and Technology (NIST), in collaboration with the National Institutes of Health (NTH), has developed a Standard Reference Material (SRM) to support technology development in metabolomics research. SRM 1950 Metabolites in Human Plasma is intended to have metabolite concentrations that are representative of those found in adult human plasma. The plasma used in the preparation of SRM 1950 was collected from both male and female donors, and donor ethnicity targets were selected based upon the ethnic makeup of the U.S. population. Metabolomics research is diverse in terms of both instrumentation and scientific goals. This SRM was designed to apply broadly to the field, not toward specific applications. Therefore, concentrations of approximately 100 analytes, including amino acids, fatty acids, trace elements, vitamins, hormones, selenoproteins, clinical markers, and perfluorinated compounds (PFCs), were determined. Value assignment measurements were performed by NIST and the Centers for Disease Control and Prevention (CDC). SRM 1950 is the first reference material developed specifically for metabolomics research. C1 [Phinney, Karen W.; Lowenthal, Mark S.] NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. [Ballihaut, Guillaume; Bedner, Mary; Benford, Brandi S.; Camara, Johanna E.; Christopher, Steven J.; Davis, W. Clay; Dodder, Nathan G.; Eppe, Gauthier; Long, Stephen E.; McGaw, Elizabeth A.; Murphy, Karen E.; Prendergast, Jocelyn L.; Reiner, Jessica L.; Rimmer, Catherine A.; Sander, Lane C.; Schantz, Michele M.; Sharpless, Katherine E.; Sniegoski, Lorna T.; Tai, Susan S. -C.; Thomas, Jeanice B.; Vetter, Thomas W.; Welch, Michael J.; Wise, Stephen A.; Wood, Laura J.] NIST, Div Chem Sci, Gaithersburg, MD 20899 USA. [Lang, Brian E.; Nelson, Bryant C.] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Guthrie, William F.; Hagwood, Charles R.; Leigh, Stefan D.; Yen, James H.; Zhang, Nien-Fan] NIST, Stat Engn Div, Gaithersburg, MD 20899 USA. [Chaudhary-Webb, Madhu; Chen, Huiping; Fazili, Zia; LaVoie, Donna J.; McCoy, Leslie F.; Momin, Shahzad S.; Paladugula, Neelima; Pendergrast, Elizabeth C.; Pfeiffer, Christine M.; Powers, Carissa D.; Rabinowitz, Daniel; Rybak, Michael E.; Schleicher, Rosemary L.; Toombs, Bridgette M. H.; Xu, Mary; Zhang, Mindy] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. [Castle, Arthur L.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Phinney, KW (reprint author), NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. EM karen.phinney@nist.gov RI Dodder, Nathan/C-7971-2015; OI Dodder, Nathan/0000-0001-5913-1767; Rybak, Michael/0000-0003-1650-8581 FU Intramural CDC HHS [CC999999] NR 62 TC 21 Z9 21 U1 7 U2 54 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD DEC 17 PY 2013 VL 85 IS 24 BP 11732 EP 11738 DI 10.1021/ac402689t PG 7 WC Chemistry, Analytical SC Chemistry GA 277CV UT WOS:000328797200012 PM 24187941 ER PT J AU Best, RB AF Best, Robert B. TI Folding and Binding: When the Force is Against You SO BIOPHYSICAL JOURNAL LA English DT News Item ID PROTEIN; CALMODULIN; LANDSCAPE; KINETICS C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertbe@helix.nih.gov RI Best, Robert/H-7588-2016 OI Best, Robert/0000-0002-7893-3543 NR 11 TC 0 Z9 0 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD DEC 17 PY 2013 VL 105 IS 12 BP 2611 EP 2612 DI 10.1016/j.bpj.2013.10.035 PG 2 WC Biophysics SC Biophysics GA 274HM UT WOS:000328597400002 PM 24359729 ER PT J AU Chen, HH Borlaug, BA Anstrom, KJ Felker, GM Givertz, MM Deswal, A Bart, BA Stevenson, LW Rouleau, JL O'Meara, E LeWinter, MM Bull, DA Stehlik, J Semigran, MJ Goldsmith, SR Ofili, EO O'Connor, CM Tang, WHW Starling, RC Butler, J Whellan, DJ Margulies, KB Cappola, TP Konstam, MA Mann, DL Davila-Roman, V McNulty, SE Velazquez, EJ Lee, KL Shah, MR Hernandez, AF Braunwald, E Redfield, MM AF Chen, Horng H. Borlaug, Barry A. Anstrom, Kevin J. Felker, G. M. Givertz, Michael M. Deswal, Anita Bart, Bradley A. Stevenson, Lynne W. Rouleau, Jean L. O'Meara, Eileen LeWinter, Martin M. Bull, David A. Stehlik, Josef Semigran, Marc J. Goldsmith, Steven R. Ofili, Elizabeth O. O'Connor, Christopher M. Tang, W. H. Wilson Starling, Randall C. Butler, Javed Whellan, David J. Margulies, Kenneth B. Cappola, Thomas P. Konstam, Marvin A. Mann, Douglas L. Davila-Roman, Victor McNulty, Steven E. Velazquez, Eric J. Lee, Kerry L. Shah, Monica R. Hernandez, Adrian F. Braunwald, Eugene Redfield, Magaret M. TI Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE AHF) Trial SO CIRCULATION LA English DT Meeting Abstract DE Acute heart failure; Renal function; Cardiovascular therapeutics; Catecholamines; Natriuretic peptide C1 [Chen, Horng H.; Borlaug, Barry A.; Redfield, Magaret M.] Mayo Clin, Rochester, MN USA. [Anstrom, Kevin J.; McNulty, Steven E.; Lee, Kerry L.; Hernandez, Adrian F.] Duke Clin Rsch Inst, Durham, NC USA. [Felker, G. M.] Duke Univ, Sch Med, Duke Heart Cntr, Durham, NC USA. [Givertz, Michael M.; Stevenson, Lynne W.; Braunwald, Eugene] Brigham & Womens Hosp, Boston, MA 02115 USA. [Deswal, Anita] Baylor Coll Med, Houston, TX 77030 USA. [Deswal, Anita] Baylor Clin, Houston, TX 77030 USA. [Bart, Bradley A.; Goldsmith, Steven R.] Univ Minnesota, Minneapolis, MN USA. [Rouleau, Jean L.; O'Meara, Eileen] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [LeWinter, Martin M.] Univ Vermont, Burlington, VT USA. [Bull, David A.; Stehlik, Josef] Univ Utah, Hlth Sci Cntr, Salt Lake City, UT USA. [Semigran, Marc J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ofili, Elizabeth O.] Morehouse Sch Med, Atlanta, GA 30310 USA. [O'Connor, Christopher M.; Velazquez, Eric J.] Duke Univ, Sch Med, Durham, NC USA. [O'Connor, Christopher M.; Velazquez, Eric J.] Duke Heart Cntr, Durham, NC USA. [Tang, W. H. Wilson; Starling, Randall C.] Cleveland Clin, Cleveland, OH 44106 USA. [Butler, Javed] Emory Univ, Atlanta, GA 30322 USA. [Whellan, David J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Margulies, Kenneth B.; Cappola, Thomas P.] Univ Penn, Philadelphia, PA 19104 USA. [Konstam, Marvin A.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Mann, Douglas L.; Davila-Roman, Victor] Washington Univ, St Louis, MO USA. [Shah, Monica R.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 17 PY 2013 VL 128 IS 24 BP 2707 EP 2708 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 271SB UT WOS:000328410800031 ER PT J AU Acker, MA Parides, MK Perrault, LP Moskowitz, AJ Voisine, P Smith, PK Gelijns, AC Hung, JW Blackstone, E Puskas, J Argenziano, M Gammie, JS Mack, M Ascheim, DD Bagiella, E Ferguson, TB Horvath, K Geller, NL Miller, MA Woo, JY D'Alessandro, DA Ailawadi, G Dagenais, F Gardner, TJ O'Gara, PT Michler, R Kron, IL AF Acker, Michael A. Parides, Michael K. Perrault, Louis P. Moskowitz, Alan J. Voisine, Pierre Smith, Peter K. Gelijns, Annetine C. Hung, Judy W. Blackstone, Eugene Puskas, John Argenziano, Michael Gammie, James S. Mack, Michael Ascheim, Deborah D. Bagiella, Emilia Ferguson, T. Bruce Horvath, Keith Geller, Nancy L. Miller, Marissa A. Woo, Joseph Y. D'Alessandro, David A. Ailawadi, Gorav Dagenais, Franois Gardner, Timothy J. O'Gara, Patrick T. Michler, Robert Kron, Irving L. TI Severe Ischemic Mitral Regurgitation: Is it Better to Repair or Replace the Valve? SO CIRCULATION LA English DT Meeting Abstract C1 [Acker, Michael A.] Hosp Univ Penn, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Parides, Michael K.; Moskowitz, Alan J.; Gelijns, Annetine C.; Ascheim, Deborah D.; Bagiella, Emilia] Icahn Sch Med Mt Sinai, New York, NY USA. [Perrault, Louis P.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Voisine, Pierre] Inst Univ Cardiol Quebec, Div Cardiac Surg, Quebec City, PQ, Canada. [Smith, Peter K.] Duke Univ, Durham, NC USA. [Hung, Judy W.] Massachusetts Gen Hosp, Echocardiog Core Lab, Boston, MA 02114 USA. [Blackstone, Eugene; Ailawadi, Gorav] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Puskas, John] Emory Univ Hosp Midtown, Atlanta, GA USA. [Argenziano, Michael] Columbia Univ, Med Cntr, New York, NY USA. [Gammie, James S.] Univ Maryland, Div Cardiac Surg, Baltimore, MD 21201 USA. [Mack, Michael] Baylor Res Inst, Plano, TX USA. [Ferguson, T. Bruce] ECU, East Carolina Heart Inst, Greenville, NC USA. [Horvath, Keith] NIH, Heart Cntr, Suburban Hosp, Bethesda, MD 20892 USA. [Geller, Nancy L.; Miller, Marissa A.] NHLBI, NIH, Bethesda, MD 20892 USA. [Woo, Joseph Y.] Hosp Univ Penn, Div Cardiothorac Surg, Philadelphia, PA 19104 USA. [D'Alessandro, David A.; Michler, Robert] Montefiore Einstein Heart Cntr, Bronx, NY USA. [Ailawadi, Gorav; Kron, Irving L.] Univ Virginia Hlth Syst, Charlottesville, VA USA. [Dagenais, Franois] Inst Univ Cardiol Quebec, Dept Cardiol, Quebec City, PQ, Canada. [Gardner, Timothy J.] Christiana Care Hlth Syst, Cardiovasc Med, Newark, DE USA. [O'Gara, Patrick T.] Brigham & Womens Hosp, Boston, MA 02115 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 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 17 PY 2013 VL 128 IS 24 BP 2708 EP 2708 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 271SB UT WOS:000328410800032 ER PT J AU Cooper, CJ Murphy, TP Cutlip, DE D'Agostino, R Jamerson, K Matsumoto, AH Jaff, MR Michael, S Solomon, S Cohen, D Tuttle, KR Rundback, JH Shapiro, JI Reid, D Henrich, W Dworklin, L AF Cooper, Christopher J. Murphy, Timothy P. Cutlip, Donald E. D'Agostino, Ralph Jamerson, Kenneth Matsumoto, Alan H. Jaff, Michael R. Michael, Steffes Solomon, Scott Cohen, David Tuttle, Katherine R. Rundback, John H. Shapiro, Joseph I. Reid, Diane Henrich, William Dworklin, Lance TI A Randomized Multicenter Clinical Trial of Renal Artery Stenting in Preventing Cardiovascular and Renal Events: Results of the CORAL Study SO CIRCULATION LA English DT Meeting Abstract DE Renal circulation; Stent; Clinical trials C1 [Cooper, Christopher J.] Univ Toledo, Toledo, OH 43606 USA. [Murphy, Timothy P.; Dworklin, Lance] Brown Univ, Rhode Isl Hosp, Sch Med, Providence, RI 02903 USA. [Cutlip, Donald E.] Harvard Univ, Sch Med, Beth Israel Deaconess Hosp, Boston, MA 02215 USA. [D'Agostino, Ralph] Boston Univ, Boston, MA 02215 USA. [Jamerson, Kenneth] Univ Michigan, Med Cntr, Ann Arbor, MI 48109 USA. [Matsumoto, Alan H.] Univ Virginia, Charlottesville, VA USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Michael, Steffes] Univ Minnesota, Minneapolis, MN USA. [Solomon, Scott] Brigham & Womens Hosp, Noninvas Cardiac Lab, Boston, MA 02115 USA. [Cohen, David] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Tuttle, Katherine R.] Providence Med Rsch Cntr, Spokane, WA USA. [Rundback, John H.] Inst Clin Rsch, Intervent Inst, Teaneck, NJ USA. [Shapiro, Joseph I.] Marshall Univ, Huntington, WV USA. [Reid, Diane] NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. [Henrich, William] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 17 PY 2013 VL 128 IS 24 BP 2710 EP 2710 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 271SB UT WOS:000328410800037 ER PT J AU Kimmel, SE French, B Kasner, SE Johnson, JA Anderson, JL Gage, BF Rosenberg, YD Geller, NL Eby, CS Madigan, R Goldberg, S McBane, RD Abdel-Rahman, S Stevens, SM Yale, S Mohler, ER Fang, MC Shah, V Horenstein, RB Limdi, NA Muldowney, JS Delafontaine, P Gujral, JS Desnick, RJ Halperin, JL Ortel, TL Billett, HH Pendleton, RC Goldhaber, SZ Caldwell, MD Califf, RM Ellenberg, J AF Kimmel, Stephen E. French, Benjamin Kasner, Scott E. Johnson, Julie A. Anderson, Jeffrey L. Gage, Brian F. Rosenberg, Yves D. Geller, Nancy L. Eby, Charles S. Madigan, Rosemary Goldberg, Suzanne McBane, Robert D. Abdel-Rahman, Sherif Stevens, Scott M. Yale, Steven Mohler, Emile R., III Fang, Margaret C. Shah, Vinay Horenstein, Richard B. Limdi, Nita A. Muldowney, James S., III Delafontaine, Patrice Gujral, Jaspal S. Desnick, Robert J. Halperin, Jonathan L. Ortel, Thomas L. Billett, Henny H. Pendleton, Robert C. Goldhaber, Samuel Z. Caldwell, Michael D. Califf, Robert M. Ellenberg, Jonas TI The Clarification of Optimal Anticoagulation through Genetics (COAG) Trial SO CIRCULATION LA English DT Meeting Abstract DE Anticoagulants; Pharmacogenetics; Anticoagulation; Genetics C1 [Kimmel, Stephen E.; French, Benjamin; Ellenberg, Jonas] Univ PA Sch Med, Cntr Clin Epidemiol & Biostat, Philadelphia, PA USA. [Kasner, Scott E.] Univ PA Sch Med, Hosp Univ Penn, Philadelphia, PA USA. [Johnson, Julie A.] Univ Florida, Dept Pharmacotherapy & Translat Rsch, Gainesville, FL USA. [Anderson, Jeffrey L.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Gage, Brian F.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Rosenberg, Yves D.; Goldberg, Suzanne] NHLBI, NIH, Bethesda, MD 20892 USA. [Geller, Nancy L.] NIH, Cntr Clin Epidemiol & Biostat, Bethesda, MD 20892 USA. [Eby, Charles S.] Washington Univ, Sch Med, Dept Med Hematol Div, St Louis, MO USA. [Madigan, Rosemary] Univ PA Sch Med, CRCU, Philadelphia, PA USA. [McBane, Robert D.] Mayo Clin, Coll Med, Div Internal Medciine & Cardiovasc Dis, Rochester, MN USA. [Abdel-Rahman, Sherif] Univ Texas, Dept Prevent Med & Community Hlth, Galveston, TX USA. [Stevens, Scott M.] Intermt Med Cntr, Murray, UT USA. [Yale, Steven] Marshfield Clin Rsch Fdn, Clin Rsch Cntr, Marshfiled, WI USA. [Mohler, Emile R., III] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Fang, Margaret C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Shah, Vinay] Henry Ford Hosp, Detroit, MI 48202 USA. [Horenstein, Richard B.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Limdi, Nita A.] Univ Alabama Birmingham, Birmingham, AL USA. [Muldowney, James S., III] Vanderbilt Univ, Div Cardiovasc Med, Nashville, TN 37235 USA. [Delafontaine, Patrice] Tulane Univ, Hlth Sci Cetner, Heart & Vasc Inst, New Orleans, LA 70118 USA. [Gujral, Jaspal S.] Georgia Regents Univ, Anticoagulat Cln, Augusta, GA USA. [Desnick, Robert J.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Halperin, Jonathan L.] Mt Sinai Sch Med, Dept Med Cardiol, New York, NY USA. [Ortel, Thomas L.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Billett, Henny H.] Montefiore Med Cntr, Bronx, NY USA. [Pendleton, Robert C.] Univ Utah Hlth Care, Div Gen Internal Med, Salt Lake City, UT USA. [Goldhaber, Samuel Z.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Caldwell, Michael D.] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. [Califf, Robert M.] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 17 PY 2013 VL 128 IS 24 BP 2711 EP 2711 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 271SB UT WOS:000328410800040 ER PT J AU Ascheim, DD Naka, Y Smidera, NG Moye, LA Lee, S Klodell, CT Szady, A Parides, MK Jeffries, N Skerret, D Taylor, DA Margulies, K Milano, C Rogers, JG Dewey, T Eichorn, E Sun, B Feldman, D Goldstein, D O'Gara, PT Simari, RD Skarlatos, S Taddei-Peters, W Miller, M Bagiella, E Gelijns, AC Woo, JY AF Ascheim, Deborah D. Naka, Yoshifumi Smidera, Nicholas G. Moye, Lemuel A. Lee, Sangjin Klodell, Charles T. Szady, Anita Parides, Michael K. Jeffries, Neal Skerret, Donna Taylor, Doris A. Margulies, Kenneth Milano, Carmelo Rogers, Joseph G. Dewey, Todd Eichorn, Eric Sun, Benjamin Feldman, David Goldstein, Daniel O'Gara, Patrick T. Simari, Robert D. Skarlatos, Sonia Taddei-Peters, Wendy Miller, Marissa Bagiella, Emilia Gelijns, Annetine C. Woo, Joseph Y. TI Intramyocardial Injection of Allogeneic Mesenchymal Precursor Cells in Left Ventricular Assist Device Patients SO CIRCULATION LA English DT Meeting Abstract DE Stem cell therapy; Heart failure; Ventricular assist devices; NHLBI C1 [Ascheim, Deborah D.; Parides, Michael K.; Bagiella, Emilia; Gelijns, Annetine C.] Icahn Sch Med Mt Sinai, New York, NY USA. [Naka, Yoshifumi] Columbia Univ, Med Cntr, New York, NY USA. [Smidera, Nicholas G.; Lee, Sangjin] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Moye, Lemuel A.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Klodell, Charles T.; Szady, Anita] Univ Florida, Gainesville, FL USA. [Jeffries, Neal; Skarlatos, Sonia; Taddei-Peters, Wendy; Miller, Marissa] NHLBI, NIH, Bethesda, MD 20892 USA. [Skerret, Donna] Mesoblast Ltd, New York, NY USA. [Taylor, Doris A.] Texas Heart Insititute, Houston, TX USA. [Margulies, Kenneth; Woo, Joseph Y.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Milano, Carmelo; Rogers, Joseph G.] Duke Univ, Durham, NC USA. [Dewey, Todd; Eichorn, Eric] Baylor Healthcare Syst, Dallas, TX USA. [Sun, Benjamin; Feldman, David] Minneapolis Heart Inst, Minneapolis, MN USA. [Goldstein, Daniel] Montefiore Einstein Med Cntr, Bronx, NY USA. [O'Gara, Patrick T.] Brigham & Womens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Simari, Robert D.] Mayo Clin, Rochester, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 17 PY 2013 VL 128 IS 24 BP 2713 EP 2714 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 271SB UT WOS:000328410800044 ER PT J AU Traverse, JH Henry, TD Pepine, CJ Willerson, JT Zhao, DX Ellis, SG Lai, D Perin, EC Penn, MS Hatzopoulos, AK Chambers, J Baran, KW Raveendran, G Lambert, C Lerman, A Simon, DI Gee, AP Forder, JR Taylor, DA Cogle, CR Olson, RE Skarlatos, SI Skarlatos, SI Ebert, RF Moye, LA Simari, RD AF Traverse, Jay H. Henry, Timothy D. Pepine, Carl J. Willerson, James T. Zhao, David X. Ellis, Stephen G. Lai, Dejian Perin, Emerson C. Penn, Marc S. Hatzopoulos, Antonis K. Chambers, Jeffrey Baran, Kenneth W. Raveendran, Ganesh Lambert, Charles Lerman, Amir Simon, Daniel I. Gee, Adrian P. Forder, John R. Taylor, Doris A. Cogle, Christopher R. Olson, Rachel E. Skarlatos, Sonia I. Skarlatos, Sonia I. Ebert, Ray F. Moye, Lemuel A. Simari, Robert D. TI The NHLBI TIME Trial: One-Year Results SO CIRCULATION LA English DT Meeting Abstract DE Stem cell therapy; STEMI; Cardiac MRI; Infarct size C1 [Traverse, Jay H.; Henry, Timothy D.; Olson, Rachel E.] Abbott NW Hosp, Minneapolis Heart Inst Fdn, Minneapolis, MN 55407 USA. [Pepine, Carl J.; Forder, John R.; Cogle, Christopher R.] Univ Florida, Coll Med, Gainesville, FL USA. [Willerson, James T.; Perin, Emerson C.; Taylor, Doris A.] St Lukes Episcopal Hosp, Texas Heart Inst, Houston, TX USA. [Zhao, David X.; Hatzopoulos, Antonis K.] Vanderbilt Univ, Sch Med, Minneapolis, MN USA. [Ellis, Stephen G.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Lai, Dejian; Moye, Lemuel A.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Penn, Marc S.] Summa Cardiovasc Inst, Rootstown, OH USA. [Chambers, Jeffrey] Mercy Hosp, Coon Rapids, MN USA. [Baran, Kenneth W.] United Hosp, St Paul Heart Clin, St Paul, MN USA. [Raveendran, Ganesh] Univ Minnesota, Lillehei Heart Inst, Minneapolis, MN USA. [Lambert, Charles] Pepin Heart Hosp, Patel Rsch Inst, Tampa, FL USA. [Lerman, Amir; Simari, Robert D.] Mayo Clin, Coll Med, Rochester, MN USA. [Simon, Daniel I.] Univ Hosp Case Med Cntr, Cleveland, OH USA. [Gee, Adrian P.] Baylor Coll Med, Houston, TX 77030 USA. [Skarlatos, Sonia I.; Skarlatos, Sonia I.; Ebert, Ray F.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 17 PY 2013 VL 128 IS 24 BP 2714 EP 2714 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 271SB UT WOS:000328410800045 ER PT J AU Huang, SYN Pommier, Y AF Huang, Shar-yin Naomi Pommier, Yves TI Cross-over of RNA 3'-phosphate ligase into the DNA world SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID SEQUENTIAL 2',3'-CYCLIC PHOSPHODIESTERASE; TOPOISOMERASE-I; RTCB; REPAIR; GUANYLYLATION; 3'-PHOSPHATE; MECHANISM; HSPC117; 5'-OH C1 [Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov NR 17 TC 2 Z9 2 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 17 PY 2013 VL 110 IS 51 BP 20354 EP 20355 DI 10.1073/pnas.1320033110 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273PR UT WOS:000328548600017 PM 24282304 ER PT J AU Vonk, FJ Casewell, NR Henkel, CV Heimberg, AM Jansen, HJ McCleary, RJR Kerkkamp, HME Vos, RA Guerreiro, I Calvete, JJ Wuster, W Woods, AE Logan, JM Harrison, RA Castoe, TA de Koning, APJ Pollock, DD Yandell, M Calderon, D Renjifo, C Currier, RB Salgado, D Pla, D Sanz, L Hyder, AS Ribeiro, JMC Arntzen, JW van den Thillart, GEEJM Boetzer, M Pirovano, W Dirks, RP Spaink, HP Duboule, D McGlinn, E Kini, RM Richardson, MK AF Vonk, Freek J. Casewell, Nicholas R. Henkel, Christiaan V. Heimberg, Alysha M. Jansen, Hans J. McCleary, Ryan J. R. Kerkkamp, Harald M. E. Vos, Rutger A. Guerreiro, Isabel Calvete, Juan J. Wuester, Wolfgang Woods, Anthony E. Logan, Jessica M. Harrison, Robert A. Castoe, Todd A. de Koning, A. P. Jason Pollock, David D. Yandell, Mark Calderon, Diego Renjifo, Camila Currier, Rachel B. Salgado, David Pla, Davinia Sanz, Libia Hyder, Asad S. Ribeiro, Jose M. C. Arntzen, Jan W. van den Thillart, Guido E. E. J. M. Boetzer, Marten Pirovano, Walter Dirks, Ron P. Spaink, Herman P. Duboule, Denis McGlinn, Edwina Kini, R. Manjunatha Richardson, Michael K. TI The king cobra genome reveals dynamic gene evolution and adaptation in the snake venom system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genomics; phylogenetics; serpentes ID SENSING ION CHANNELS; ACCELERATED EVOLUTION; MOLECULAR EVOLUTION; ANNOTATION PIPELINE; MICRORNA EXPRESSION; 3-FINGER TOXINS; HOX GENES; PROTEINS; MODEL; ALIGNMENT AB Snakes are limbless predators, and many species use venom to help overpower relatively large, agile prey. Snake venoms are complex protein mixtures encoded by several multilocus gene families that function synergistically to cause incapacitation. To examine venom evolution, we sequenced and interrogated the genome of a venomous snake, the king cobra (Ophiophagus hannah), and compared it, together with our unique transcriptome, microRNA, and proteome datasets from this species, with data from other vertebrates. In contrast to the platypus, the only other venomous vertebrate with a sequenced genome, we find that snake toxin genes evolve through several distinct co-option mechanisms and exhibit surprisingly variable levels of gene duplication and directional selection that correlate with their functional importance in prey capture. The enigmatic accessory venom gland shows a very different pattern of toxin gene expression from the main venom gland and seems to have recruited toxin-like lectin genes repeatedly for new nontoxic functions. In addition, tissue-specific microRNA analyses suggested the co-option of core genetic regulatory components of the venom secretory system from a pancreatic origin. Although the king cobra is limbless, we recovered coding sequences for all Hox genes involved in amniote limb development, with the exception of Hoxd12. Our results provide a unique view of the origin and evolution of snake venom and reveal multiple genome-level adaptive responses to natural selection in this complex biological weapon system. More generally, they provide insight into mechanisms of protein evolution under strong selection. C1 [Vonk, Freek J.; Vos, Rutger A.; Arntzen, Jan W.] Naturalis Biodivers Ctr, NL-2333 CR Leiden, Netherlands. [Vonk, Freek J.; Henkel, Christiaan V.; Kerkkamp, Harald M. E.; Hyder, Asad S.; Spaink, Herman P.; Richardson, Michael K.] Leiden Univ, Sylvius Lab, Inst Biol Leiden, NL-2300 RA Leiden, Netherlands. [Vonk, Freek J.; Casewell, Nicholas R.; Wuester, Wolfgang] Bangor Univ, Sch Biol Sci, Mol Ecol & Evolut Grp, Bangor LL57 2UW, Gwynedd, Wales. [Casewell, Nicholas R.; Harrison, Robert A.; Renjifo, Camila; Currier, Rachel B.] Univ Liverpool, Liverpool Sch Trop Med, Alistair Reid Venom Res Unit, Liverpool L3 5QA, Merseyside, England. [Henkel, Christiaan V.; Jansen, Hans J.; van den Thillart, Guido E. E. J. M.; Dirks, Ron P.; Spaink, Herman P.] ZF Screens BV, Bio Partner Ctr, NL-2333 CH Leiden, Netherlands. [Heimberg, Alysha M.; Salgado, David; McGlinn, Edwina] Monash Univ, Australian Regenerat Med Inst, European Mol Biol Lab Australia, Clayton, Vic 3800, Australia. [McCleary, Ryan J. R.; Kini, R. Manjunatha] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore. [Guerreiro, Isabel; Duboule, Denis] Univ Geneva, Dept Genet & Evolut, CH-1211 Geneva 4, Switzerland. [Calvete, Juan J.; Pla, Davinia; Sanz, Libia] Consejo Super Invest Cient Spain, Inst Biomed Valencia, Valencia 46010, Spain. [Woods, Anthony E.; Logan, Jessica M.] Univ S Australia, Sch Pharm & Med Sci, Adelaide, SA 5000, Australia. [Castoe, Todd A.; de Koning, A. P. Jason; Pollock, David D.] Univ Colorado, Sch Med, Dept Biochem & Mol Genet, Aurora, CO 80045 USA. [Castoe, Todd A.] Univ Texas, Dept Biol, Arlington, TX 76010 USA. [de Koning, A. P. Jason] Univ Calgary, Fac Med, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada. [de Koning, A. P. Jason] Alberta Childrens Prov Gen Hosp, Res Inst Child & Maternal Hlth, Calgary, AB T2N 4N1, Canada. [Yandell, Mark; Calderon, Diego] Univ Utah, Sch Med, Dept Human Genet, Salt Lake City, UT 84132 USA. [Salgado, David] Aix Marseille Univ, INSERM, GMGF UMR S910, F-13385 Marseille, France. [Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Boetzer, Marten; Pirovano, Walter] BaseClear BV, NL-2333 CC Leiden, Netherlands. RP Richardson, MK (reprint author), Leiden Univ, Sylvius Lab, Inst Biol Leiden, Sylviusweg 72, NL-2300 RA Leiden, Netherlands. EM M.K.Richardson@biology.leidenuniv.nl RI Casewell, Nicholas/C-3187-2014; Ribeiro, Jose/J-7011-2015; Vos, Rutger/H-9032-2012; Arntzen, Jan/E-7108-2016; Calvete, Juan/K-9619-2014; Pollock, David/M-4740-2016; SALGADO, David/A-1417-2014; OI Henkel, Christiaan/0000-0001-9838-8215; Pla, Davinia/0000-0002-9810-7556; Sanz, Libia/0000-0003-4991-9598; Casewell, Nicholas/0000-0002-8035-4719; McGlinn, Edwina/0000-0002-1829-986X; Ribeiro, Jose/0000-0002-9107-0818; Guerreiro, Isabel/0000-0003-1390-3535; Vos, Rutger/0000-0001-9254-7318; Arntzen, Jan/0000-0003-3229-5993; Calvete, Juan/0000-0001-5026-3122; Pollock, David/0000-0002-7627-4214; McCleary, Ryan/0000-0001-8232-9296 FU Naturalis Biodiversity Center; Netherlands Organization for Scientific Research; United Kingdom Natural Environment Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek; United Kingdom Biotechnology and Biological Sciences Research Council; Dutch Government FX We thank the following persons who helped us or contributed material used in this study: Austin Hughes, Nathan Dunstan, Danielle de Wijze, and Youri Lammers. We thank Bas Blankevoort for constructing Fig. 1. This work received funding from the following sources: internal funding from the Naturalis Biodiversity Center (F.J.V., J.W.A., and M. K. R.), a Rubicon Grant from the Netherlands Organization for Scientific Research (to F.J.V.), a research fellowship from the United Kingdom Natural Environment Research Council (to N.R.C.), an Netherlands Organization for Scientific Research Visitor's Travel Grant from Nederlandse Organisatie voor Wetenschappelijk Onderzoek (to R.J.R.M., R. M. K., and M. K. R.), a studentship from the United Kingdom Biotechnology and Biological Sciences Research Council (to R. B. C.), and a Smart Mix Grant from the Dutch Government (to M.K.R.). NR 57 TC 130 Z9 168 U1 20 U2 116 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 DEC 17 PY 2013 VL 110 IS 51 BP 20651 EP 20656 DI 10.1073/pnas.1314702110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273PR UT WOS:000328548600069 PM 24297900 ER PT J AU Kulkarni, S Qi, Y O'hUigin, C Pereyra, F Ramsuran, V McLaren, P Fellay, J Nelson, G Chen, HY Liao, W Bass, S Apps, R Gao, XJ Yuki, Y Lied, A Ganesan, A Hunt, PW Deeks, SG Wolinsky, S Walker, BD Carrington, M AF Kulkarni, Smita Qi, Ying O'hUigin, Colm Pereyra, Florencia Ramsuran, Veron McLaren, Paul Fellay, Jacques Nelson, George Chen, Haoyan Liao, Wilson Bass, Sara Apps, Richard Gao, Xiaojiang Yuki, Yuko Lied, Alexandra Ganesan, Anuradha Hunt, Peter W. Deeks, Steven G. Wolinsky, Steven Walker, Bruce D. Carrington, Mary TI Genetic interplay between HLA-C and MIR148A in HIV control and Crohn disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GENOME-WIDE ASSOCIATION; CELL-SURFACE EXPRESSION; HEAVY-CHAIN; DETERMINANTS; RNA; POLYMORPHISM; INFECTION; COHORT; NEF AB Variation in the 3' untranslated region (3'UTR) of the HLA-C locus determines binding of the microRNA Hsa-miR-148a, resulting in lower cell surface expression of alleles that bind miR-148a relative to those alleles that escape its binding. The HLA-C 3'UTR variant was shown to associate with HIV control, but like the vast majority of disease associations in a region dense with causal candidates, a direct effect of HLA-C expression level on HIV control was not proven. We demonstrate that a MIR148A insertion/deletion polymorphism associates with its own expression levels, affecting the extent to which HLA-C is down-regulated, the level of HIV control, and the risk of Crohn disease only among those carrying an intact miR-148a binding site in the HLA-C 3'UTR. These data illustrate a direct effect of HLA-C expression level on HIV control that cannot be attributed to other HLA loci in linkage disequilibrium with HLA-C and highlight the rich complexity of genetic interactions in human disease. C1 [Kulkarni, Smita; Qi, Ying; O'hUigin, Colm; Bass, Sara; Apps, Richard; Gao, Xiaojiang; Yuki, Yuko; Carrington, Mary] Frederick Natl Lab Canc Res, Sci Applicat Int Corp Frederick Inc, Ctr Canc Res Genet Core, Canc & Inflammat Program,Lab Expt Immunol, Frederick, MD 21702 USA. [Nelson, George] Frederick Natl Lab Canc Res, Sci Applicat Int Corp Frederick Inc, Ctr Canc Res Genet Core, Basic Res Program, Frederick, MD 21702 USA. [Kulkarni, Smita; Qi, Ying; Pereyra, Florencia; Ramsuran, Veron; Apps, Richard; Gao, Xiaojiang; Yuki, Yuko; Lied, Alexandra; Walker, Bruce D.; Carrington, Mary] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. [McLaren, Paul; Fellay, Jacques] Univ Lausanne, Ecole Polytech Fed Lausanne, Sch Life Sci, CH-1011 Lausanne, Switzerland. [McLaren, Paul; Fellay, Jacques] Univ Lausanne, Inst Microbiol, CH-1011 Lausanne, Switzerland. [Chen, Haoyan; Liao, Wilson] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94115 USA. [Chen, Haoyan] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Digest Dis, Dept Gastroenterol,Ren Ji Hosp, Shanghai 200001, Peoples R China. [Ganesan, Anuradha] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20817 USA. [Hunt, Peter W.; Deeks, Steven G.] Univ Calif San Francisco, San Francisco Gen Hosp, AIDS Div, San Francisco, CA 94110 USA. [Wolinsky, Steven] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. RP Carrington, M (reprint author), Frederick Natl Lab Canc Res, Sci Applicat Int Corp Frederick Inc, Ctr Canc Res Genet Core, Canc & Inflammat Program,Lab Expt Immunol, Frederick, MD 21702 USA. EM carringm@mail.nih.gov RI SHCS, int. coll. A/G-4083-2011; Fellay, Jacques/A-6681-2009; SHCS, all/G-4072-2011; OI Fellay, Jacques/0000-0002-8240-939X; Wolinsky, Steven/0000-0002-9625-6697 FU Swiss National Science Foundation [33CSC0-108787]; National Institute of Allergy and Infectious Diseases (NIAID); National Cancer Institute (NCI); National Heart, Lung and Blood Institute (NHLBI) [UO1-AI-35042, 5-MO1-RR-00722]; National Heart, Lung and Blood Institute (NHLBI) ([General Clinical Research Center]) [UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041]; IHCS; Bill and Melinda Gates Foundation; AIDS Healthcare Foundation; Harvard University Center for AIDS Research; National Institutes of Health (NIH) [P30 AI060354]; NIH, NIAID; NIH, NCI; NIH, National Institute of Child Health and Human Development; NIH, NHLBI; NIH, National Institute on Drug Abuse; NIH, National Institute of Mental Health; NIH, National Institute on Aging; NIH, Fogarty International Center; NIH, Office of AIDS Research; NCI, NIH [HHSN261200800001E, N02-CP-55504, R01-DA04334, R01-DA12568]; Mark and Lisa Schwartz Foundation; Ragon Institute; NIH NIAID Center for HIV/AIDS Vaccine Immunology [U01-AI-067854]; [RO1 AI087145]; [K24AI069994]; [P30 AI027763]; [UL1 RR024131]; [P30 MH62246]; [R24 AI067039] FX We thank Drs. David Goldstein and Paul de Bakker for helpful discussions and review of the manuscript. We also thank the patients and investigators contributing to samples studied in the Study of the Consequences of the Protease Inhibitor Era (SCOPE), International HIV Controllers Study (IHCS), Swiss HIV Cohort Study (SHCS), and US Military HIV Natural History Study (NHS). SHCS (supported by Swiss National Science Foundation Grant 33CSC0-108787), SCOPE (supported by Grants RO1 AI087145, K24AI069994, P30 AI027763, UL1 RR024131, P30 MH62246, and R24 AI067039), and Multicenter AIDS Cohort Study (MACS) cohorts [funded by the National Institute of Allergy and Infectious Diseases (NIAID), with supplemental funding from the National Cancer Institute (NCI) and the National Heart, Lung and Blood Institute (NHLBI) (Grants UO1-AI-35042, 5-MO1-RR-00722 [General Clinical Research Center], UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613 and UO1-AI-35041)] and the Infectious disease clinical research program HIV Working group for the NHS samples. This publication resulted in part from research supported by the IHCS, funded by the Bill and Melinda Gates Foundation, the AIDS Healthcare Foundation, and the Harvard University Center for AIDS Research, a program funded by National Institutes of Health (NIH) Grant P30 AI060354, which is supported by the following NIH Co-Funding and Participating Institutes and centers: NIAID, NCI, National Institute of Child Health and Human Development, NHLBI, National Institute on Drug Abuse, National Institute of Mental Health, National Institute on Aging, Fogarty International Center, and Office of AIDS Research. This project has been funded in part with federal funds from the NCI, NIH, under Contracts HHSN261200800001E, N02-CP-55504, R01-DA04334, and R01-DA12568. This research was supported in part by a grant from the Bill and Melinda Gates Foundation as part of the Collaboration for AIDS Vaccine Discovery, the Mark and Lisa Schwartz Foundation, the Ragon Institute, and the NIH NIAID Center for HIV/AIDS Vaccine Immunology (Grant U01-AI-067854). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services or the Department of Defense, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 29 TC 27 Z9 27 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 DEC 17 PY 2013 VL 110 IS 51 BP 20705 EP 20710 DI 10.1073/pnas.1312237110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273PR UT WOS:000328548600078 PM 24248364 ER PT J AU Bakhsheshian, J Wei, BR Chang, KE Shukla, S Ambudkar, SV Simpson, RM Gottesman, MM Hall, MD AF Bakhsheshian, Joshua Wei, Bih-Rong Chang, Ki-Eun Shukla, Suneet Ambudkar, Suresh V. Simpson, R. Mark Gottesman, Michael M. Hall, Matthew D. TI Bioluminescent imaging of drug efflux at the blood-brain barrier mediated by the transporter ABCG2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CANCER RESISTANCE PROTEIN; FIBRILLARY ACIDIC PROTEIN; CENTRAL-NERVOUS-SYSTEM; P-GLYCOPROTEIN; IN-VIVO; ACTIVE EFFLUX; RADIOLABELED SUBSTRATE; MULTIDRUG TRANSPORTER; TESTIS PENETRATION; FIREFLY LUCIFERASE AB ATP-binding cassette (ABC) transporters are a group of transmembrane proteins that maintain chemical homeostasis through efflux of compounds out of organelles and cells. Among other functions, ABC transporters play a key role in protecting the brain parenchyma by efflux of xenobiotics from capillary endothelial cells at the blood-brain barrier (BBB). They also prevent the entry of therapeutic drugs at the BBB, thereby limiting their efficacy. One of the key transporters playing this role is ABCG2. Although other ABC transporters can be studied through various imaging modalities, no specific probe exists for imaging ABCG2 function in vivo. Here we show that D-luciferin, the endogenous substrate of firefly luciferase, is a specific substrate for ABCG2. We hypothesized that ABCG2 function at the BBB could be evaluated by using bioluminescence imaging in transgenic mice expressing firefly luciferase in the brain. Bioluminescence signal in the brain of mice increased with co-administration of the ABCG2 inhibitors Ko143, gefitinib, and nilotinib, but not an ABCB1 inhibitor. This method for imaging ABCG2 function at the BBB will facilitate understanding of the function and pharmacokinetic inhibition of this transporter. C1 [Bakhsheshian, Joshua; Chang, Ki-Eun; Shukla, Suneet; Ambudkar, Suresh V.; Gottesman, Michael M.; Hall, Matthew D.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wei, Bih-Rong; Simpson, R. Mark] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU National Institutes of Health (NIH), National Cancer Institute; NIH FX We thank Mr. George Leiman for editorial assistance, Dr. Jeih-San Liow for training on tail vein injections, Dr. Michael Maurizi for fluorescence spectral analysis assistance, Ms. Karen Wolcott for FACS assistance, Ms. Susan Garfield for help with confocal microscopy, and Dr. Robert B. Innis and Dr. Victor W. Pike for helpful discussions. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute. J.B. and K.-E.C. are NIH Medical Research Scholars. The Medical Research Scholars Program is a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from Pfizer, the Leona M. and Harry B. Helmsley Charitable Trust, the Howard Hughes Medical Institute, as well as other private donors (listed at www.fnih.org/work/programs-development/medical-research-scholars-program ). NR 60 TC 15 Z9 17 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 DEC 17 PY 2013 VL 110 IS 51 BP 20801 EP 20806 DI 10.1073/pnas.1312159110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273PR UT WOS:000328548600094 PM 24297888 ER PT J AU Kerr, JP Ziman, AP Mueller, AL Muriel, JM Kleinhans-Welte, E Gumerson, JD Vogel, SS Ward, CW Roche, JA Bloch, RJ AF Kerr, Jaclyn P. Ziman, Andrew P. Mueller, Amber L. Muriel, Joaquin M. Kleinhans-Welte, Emily Gumerson, Jessica D. Vogel, Steven S. Ward, Christopher W. Roche, Joseph A. Bloch, Robert J. TI Dysferlin stabilizes stress-induced Ca2+ signaling in the transverse tubule membrane SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE excitation-contraction coupling; dihydropyridine receptor; triad junction; muscle injury ID SKELETAL-MUSCLE FIBERS; MUSCULAR-DYSTROPHY; OSMOTIC-STRESS; CELL-MEMBRANE; MDX MICE; REPAIR; MOUSE; PROTEIN; RECOVERY; ACTIVATION AB Dysferlinopathies, most commonly limb girdle muscular dystrophy 2B and Miyoshi myopathy, are degenerative myopathies caused by mutations in the DYSF gene encoding the protein dysferlin. Studies of dysferlin have focused on its role in the repair of the sarcolemma of skeletal muscle, but dysferlin's association with calcium (Ca2+) signaling proteins in the transverse (t-) tubules suggests additional roles. Here, we reveal that dysferlin is enriched in the t-tubule membrane of mature skeletal muscle fibers. Following experimental membrane stress in vitro, dysferlin-deficient muscle fibers undergo extensive functional and structural disruption of the t-tubules that is ameliorated by reducing external [Ca2+] or blocking L-type Ca2+ channels with diltiazem. Furthermore, we demonstrate that diltiazem treatment of dysferlin-deficient mice significantly reduces eccentric contraction-induced t-tubule damage, inflammation, and necrosis, which resulted in a concomitant increase in postinjury functional recovery. Our discovery of dysferlin as a t-tubule protein that stabilizes stress-induced Ca2+ signaling offers a therapeutic avenue for limb girdle muscular dystrophy 2B and Miyoshi myopathy patients. C1 [Kerr, Jaclyn P.; Ziman, Andrew P.; Mueller, Amber L.; Muriel, Joaquin M.; Kleinhans-Welte, Emily; Gumerson, Jessica D.; Roche, Joseph A.; Bloch, Robert J.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. [Vogel, Steven S.] NIAAA, Sect Cellular Biophoton, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Ward, Christopher W.] Univ Maryland, Sch Nursing, Baltimore, MD 21201 USA. RP Bloch, RJ (reprint author), Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. EM rbloch@umaryland.edu OI Vogel, Steven/0000-0002-3005-2667 FU Jain Foundation; Muscular Dystrophy Association; Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism; Kirschstein-National Research Service Award Individual Postdoctoral Fellowship [F32 AR057647]; Training Program in Cellular and Integrative Neuroscience [T32 NS007375]; Interdisciplinary Training Program in Muscle Biology [T32 AR07592] FX We thank W. Jonathan Lederer and Brian M. Hagen (University of Maryland School of Medicine, BioMET) for the use of confocal microscopy facilities and expertise. Dr. Gero Miesenbock (University of Oxford) provided the pHluorin construct. These studies were supported by the Jain Foundation (R.J.B., J.A.R., and S.S.V.) and the Muscular Dystrophy Association (R.J.B.). S.S.V. was supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism. A.P.Z. was supported by a Kirschstein-National Research Service Award Individual Postdoctoral Fellowship (F32 AR057647). J.P.K. was supported through the Training Program in Cellular and Integrative Neuroscience (T32 NS007375) and the Interdisciplinary Training Program in Muscle Biology (T32 AR07592). NR 51 TC 37 Z9 37 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 17 PY 2013 VL 110 IS 51 BP 20831 EP 20836 DI 10.1073/pnas.1307960110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273PR UT WOS:000328548600099 PM 24302765 ER PT J AU Blackwood, JC Streicker, DG Altizer, S Rohani, P AF Blackwood, Julie C. Streicker, Daniel G. Altizer, Sonia Rohani, Pejman TI Resolving the roles of immunity, pathogenesis, and immigration for rabies persistence in vampire bats SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Desmodus rotundus; zoonotic disease; host-pathogen dynamics; spatial processes; wildlife culling ID DESMODUS-ROTUNDUS; TRANSMITTED RABIES; INFECTION; EMERGENCE; CATTLE; VIRUS; ARGENTINA; HOST AB Bats are important reservoirs for emerging infectious diseases, yet the mechanisms that allow highly virulent pathogens to persist within bat populations remain obscure. In Latin America, vampire-bat-transmitted rabies virus represents a key example of how such uncertainty can impede efforts to prevent cross-species transmission. Despite decades of agricultural and human health losses, control efforts have had limited success. To establish persistence mechanisms of vampire-bat-transmitted rabies virus in Latin America, we use data from a spatially replicated, longitudinal field study of vampire bats in Peru to parameterize a series of mechanistic transmission models. We find that single-colony persistence cannot occur. Instead, dispersal of bats between colonies, combined with a high frequency of immunizing nonlethal infections, is necessary to maintain rabies virus at levels consistent with field observations. Simulations show that the strong spatial component to transmission dynamics could explain the failure of bat culls to eliminate rabies and suggests that geographic coordination of control efforts might reduce transmission to humans and domestic animals. These findings offer spatial dynamics as a mechanism for rabies persistence in bats that might be important for the understanding and control of other bat-borne pathogens. C1 [Blackwood, Julie C.; Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Blackwood, Julie C.; Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Blackwood, Julie C.] Williams Coll, Dept Math & Stat, Williamstown, MA 01267 USA. [Streicker, Daniel G.; Altizer, Sonia] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. [Streicker, Daniel G.] Univ Glasgow, Inst Biodivers Anim Hlth & Comparat Med, Glasgow G12 8QQ, Lanark, Scotland. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Blackwood, JC (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM jcb5@williams.edu OI Streicker, Daniel/0000-0001-7475-2705 FU National Science Foundation (NSF) [DEB-1020966]; University of Georgia (UGA)-CDC [FID-908]; NSF; UGA; National Geographic Committee for Research and Exploration; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank the P.R. laboratory and two anonymous reviewers for their feedback on earlier drafts of this manuscript. We also thank the Office of Epidemiology of the Ministry of Health of Peru, the National Service of Agricultural Health of the Ministry of Agriculture of Peru, and the Centers for Disease Control (CDC) Rabies Program for logistical support of field and lab work. This research was supported by National Science Foundation (NSF) Grant DEB-1020966 and a University of Georgia (UGA)-CDC Infectious Disease Seed Grant FID-908 to S.A. and P.R. In addition, D.G.S. was supported by an NSF Graduate Research Fellowship, a UGA Dissertation Completion Award, and a Young Explorers Grant from the National Geographic Committee for Research and Exploration. P.R. was supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 33 TC 20 Z9 21 U1 0 U2 64 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 DEC 17 PY 2013 VL 110 IS 51 BP 20837 EP 20842 DI 10.1073/pnas.1308817110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273PR UT WOS:000328548600100 PM 24297874 ER PT J AU Josefsson, L von Stockenstrom, S Faria, NR Sinclair, E Bacchetti, P Killian, M Epling, L Tan, A Ho, T Lemey, P Shao, W Hunt, PW Somsouk, M Wylie, W Douek, DC Loeb, L Custer, J Hoh, R Poole, L Deeks, SG Hecht, F Palmer, S AF Josefsson, Lina von Stockenstrom, Susanne Faria, Nuno R. Sinclair, Elizabeth Bacchetti, Peter Killian, Maudi Epling, Lorrie Tan, Alice Ho, Terence Lemey, Philippe Shao, Wei Hunt, Peter W. Somsouk, Ma Wylie, Will Douek, Daniel C. Loeb, Lisa Custer, Jeff Hoh, Rebecca Poole, Lauren Deeks, Steven G. Hecht, Frederick Palmer, Sarah TI The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; LOW-LEVEL VIREMIA; DRUG-RESISTANCE; RALTEGRAVIR INTENSIFICATION; INFECTED INDIVIDUALS; LYMPHOID-TISSUE; IN-VIVO; TYPE-1; REPLICATION AB The source and dynamics of persistent HIV-1 during long-term combinational antiretroviral therapy (cART) are critical to understanding the barriers to curing HIV-1 infection. To address this issue, we isolated and genetically characterized HIV-1 DNA from naive and memory T cells from peripheral blood and gut-associated lymphoid tissue (GALT) from eight patients after 4-12 y of suppressive cART. Our detailed analysis of these eight patients indicates that persistent HIV-1 in peripheral blood and GALT is found primarily in memory CD4(+) T cells [CD45RO(+)/CD27((+/-))]. The HIV-1 infection frequency of CD4(+) T cells from peripheral blood and GALT was higher in patients who initiated treatment during chronic compared with acute/early infection, indicating that early initiation of therapy results in lower HIV-1 reservoir size in blood and gut. Phylogenetic analysis revealed an HIV-1 genetic change between RNA sequences isolated before initiation of cART and intracellular HIV-1 sequences from the T-cell subsets after 4-12 y of suppressive cART in four of the eight patients. However, evolutionary rate analyses estimated no greater than three nucleotide substitutions per gene region analyzed during all of the 4-12 y of suppressive therapy. We also identified a clearly replication incompetent viral sequence in multiple memory T cells in one patient, strongly supporting asynchronous cell replication of a cell containing integrated HIV-1 DNA as the source. This study indicates that persistence of a remarkably stable population of infected memory cells will be the primary barrier to a cure, and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes. C1 [Josefsson, Lina; von Stockenstrom, Susanne; Palmer, Sarah] Swedish Inst Infect Dis Control, Dept Diagnost & Vaccinol, S-17182 Solna, Sweden. [Josefsson, Lina; von Stockenstrom, Susanne; Palmer, Sarah] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17182 Solna, Sweden. [Faria, Nuno R.; Lemey, Philippe] Katholieke Univ Leuven, Rega Inst, Dept Microbiol & Immunol, B-3000 Louvain, Belgium. [Sinclair, Elizabeth; Killian, Maudi; Epling, Lorrie; Tan, Alice; Ho, Terence; Hunt, Peter W.; Somsouk, Ma; Loeb, Lisa; Custer, Jeff; Hoh, Rebecca; Poole, Lauren; Deeks, Steven G.; Hecht, Frederick] Univ Calif San Francisco, Dept Med, San Francisco, CA 94110 USA. [Bacchetti, Peter] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Shao, Wei] NCI, Adv Biomed Comp Ctr, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Palmer, Sarah] Westmead Millennium Inst, Ctr Virus Res, Westmead, NSW 2145, Australia. [Palmer, Sarah] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. RP Josefsson, L (reprint author), Swedish Inst Infect Dis Control, Dept Diagnost & Vaccinol, S-17182 Solna, Sweden. EM Lina.Odevall@gmail.com RI Faria, Nuno/I-2975-2012; OI Faria, Nuno/0000-0001-8839-2798; Rodrigues Faria, Nuno/0000-0002-9747-8822 FU amfAR Research Consortium on HIV Eradication (ARCHE); Foundation for AIDS Research [amfAR 107857-48-RGRL]; Delaney AIDS Research Enterprise [U19 AI096109]; Swedish International Development Agency [SWE-2009-046]; Swedish Research Council [K2011-56X-21749-01-6]; National Institutes of Health (NIH) [AI071713, K24AI069994, K23 CA157929]; UCSF-Gladstone Institute of Virology and Immunology Center for AIDS Research [P30AI027763, P30 MH59037]; NIH/National Center for Research Resources UCSF Clinical and Translational Science Institute [UL1RR024131]; European Union Seventh Framework Programme [FP7/2007-2013, 278433-PREDEMICS]; European Research Council [260864]; Erik and Edith Fernstrom Foundation for Medical Research; Fundacao para a Ciencia e Tecnologia [SFRH/BD/64530/2009]; Karolinska Institutet alumni funds FX We thank the patients participating in this study. This work was primarily supported by an amfAR Research Consortium on HIV Eradication (ARCHE) Collaborative Research Grant from The Foundation for AIDS Research (amfAR 107857-48-RGRL) and Delaney AIDS Research Enterprise (U19 AI096109). The work was also supported by the Swedish International Development Agency (SWE-2009-046), The Swedish Research Council (K2011-56X-21749-01-6), the National Institutes of Health (NIH) [(AI071713, K24AI069994, and K23 CA157929), the UCSF-Gladstone Institute of Virology and Immunology Center for AIDS Research (P30AI027763 and P30 MH59037), the NIH/National Center for Research Resources UCSF Clinical and Translational Science Institute (UL1RR024131), the European Union Seventh Framework Programme [FP7/2007-2013] under Grant Agreement 278433-PREDEMICS, and European Research Council Grant Agreement 260864. L. J. was supported by the Erik and Edith Fernstrom Foundation for Medical Research and by Karolinska Institutet alumni funds. N. R. F. is supported by Fundacao para a Ciencia e Tecnologia under Grant Agreement SFRH/BD/64530/2009. NR 57 TC 64 Z9 65 U1 1 U2 15 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 DEC 17 PY 2013 VL 110 IS 51 BP E4987 EP E4996 DI 10.1073/pnas.1308313110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273PR UT WOS:000328548600010 PM 24277811 ER PT J AU Pepin, KM Lloyd-Smith, JO Webb, CT Holcomb, K Zhu, HC Guan, Y Riley, S AF Pepin, Kim M. Lloyd-Smith, James O. Webb, Colleen T. Holcomb, Karen Zhu, Huachen Guan, Yi Riley, Steven TI Minimizing the threat of pandemic emergence from avian influenza in poultry systems SO BMC INFECTIOUS DISEASES LA English DT Article DE Avian influenza; Live-bird markets; Efficacy of controls; Environmental transmission; Wholesale markets ID HONG-KONG; SOUTHERN CHINA; TRANSMISSION; VIRUSES; SURVEILLANCE; MARKETS; H9N2 AB Background: Live-animal markets are a culturally important feature of meat distribution chains in many populations, yet they provide an opportunity for the maintenance and transmission of potentially emergent zoonotic pathogens. The ongoing human outbreak of avian H7N9 in China highlights the need for increased surveillance and control in these live-bird markets (LBMs). Discussion: Closure of retail markets in affected areas rapidly decreased human cases to rare, sporadic occurrence, but little attention has been paid thus far to the role of upstream elements of the poultry distribution chain such as wholesale markets. This could partly explain why transmission in poultry populations has not been eliminated more broadly. We present surveillance data from both wholesale live-bird markets (wLBMs) and rLBMs in Shantou, China (from 2004-2006), and call on disease-dynamic theory to illustrate why closing rLBMs has only minor effects on the overall volume of transmission. We show that the length of time birds stay in rLBMs can severely limit transmission there, but that the system-wide effect may be reduced substantially by high levels of transmission upstream of retail markets. Summary: Management plans that minimize transmission throughout the entire poultry supply chain are essential for minimizing exposure to the public. These include reducing stay-time of birds in markets to 1 day, standardizing poultry supply chains to limit transmission in pre-retail settings, and monitoring strains with epidemiological traits that pose a high risk of emergence. These actions will further limit human exposure to extant viruses and reduce the likelihood of the emergence of novel strains by decreasing the overall volume of transmission. C1 [Pepin, Kim M.; Lloyd-Smith, James O.; Webb, Colleen T.; Riley, Steven] Fogarty Int Ctr, Res & Policy Dis Dynam Program, Bethesda, MD USA. [Pepin, Kim M.; Webb, Colleen T.; Holcomb, Karen] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA. [Zhu, Huachen; Guan, Yi] Univ Hong Kong, State Key Lab Emerging Infect Dis, Pokfulam, Hong Kong, Peoples R China. [Riley, Steven] Univ London Imperial Coll Sci Technol & Med, MRC Ctr Outbreak Anal & Dis Modelling, Dept Infect Dis Epidemiol, Sch Publ Hlth, London, England. RP Guan, Y (reprint author), Univ Hong Kong, State Key Lab Emerging Infect Dis, Pokfulam, Hong Kong, Peoples R China. EM yguan@hkucc.hku.hk RI Zhu, Huachen/A-8252-2017; Lloyd-Smith, James/K-4080-2012 OI Zhu, Huachen/0000-0003-2711-0501; Holcomb, Karen/0000-0002-9403-3756; Lloyd-Smith, James/0000-0001-7941-502X FU Research and Policy in Disease Dynamics (RAPIDD) program of the Science and Technology Directorate; U.S. Department of Homeland Security; Fogarty International Center, NIH; NIH [HSN266200700005C]; Li Ka Shing Foundation and Shenzhen Peacock Program [KQTD201203]; Wellcome Trust [093488/Z/10/Z]; Medical Research Council (UK) [MR/J008761/1] FX Thanks to the Research and Policy in Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center, NIH for funding this work. YG and HZ were also funded by NIH (HSN266200700005C), Li Ka Shing Foundation and Shenzhen Peacock Program (KQTD201203). SR was also funded by the Wellcome Trust (093488/Z/10/Z) and the Medical Research Council (UK, MR/J008761/1). NR 17 TC 5 Z9 5 U1 1 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD DEC 16 PY 2013 VL 13 AR 592 DI 10.1186/1471-2334-13-592 PG 6 WC Infectious Diseases SC Infectious Diseases GA 285DX UT WOS:000329374500002 PM 24341669 ER PT J AU Turner, JE Morrison, PJ Wilhelm, C Wilson, M Ahlfors, H Renauld, JC Panzer, U Helmby, H Stockinger, B AF Turner, Jan-Eric Morrison, Peter J. Wilhelm, Christoph Wilson, Mark Ahlfors, Helena Renauld, Jean-Christophe Panzer, Ulf Helmby, Helena Stockinger, Brigitta TI IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TRANSCRIPTION FACTOR GATA3; T-CELLS; GROWTH-FACTOR; IN-VIVO; AIRWAY HYPERREACTIVITY; EPITHELIAL-CELLS; TGF-BETA; EXPRESSION; IL-9; IMMUNITY AB IL-9 fate reporter mice established type 2 innate lymphoid cells (ILC2s) as major producers of this cytokine in vivo. Here we focus on the role of IL-9 and ILC2s during the lung stage of infection with Nippostrongylus brasiliensis, which results in substantial tissue damage. IL-9 receptor (IL-9R)-deficient mice displayed reduced numbers of ILC2s in the lung after infection, resulting in impaired IL-5, IL-13, and amphiregulin levels, despite undiminished numbers of Th2 cells. As a consequence, the restoration of tissue integrity and lung function was strongly impaired in the absence of IL-9 signaling. ILC2s, in contrast to Th2 cells, expressed high levels of the IL-9R, and IL-9 signaling was crucial for the survival of activated ILC2s in vitro. Furthermore, ILC2s in the lungs of infected mice required the IL-9R to up-regulate the antiapoptotic protein BCL-3 in vivo. This highlights a unique role for IL-9 as an autocrine amplifier of ILC2 function, promoting tissue repair in the recovery phase after helminth-induced lung inflammation. C1 [Turner, Jan-Eric; Morrison, Peter J.; Wilhelm, Christoph; Wilson, Mark; Ahlfors, Helena; Stockinger, Brigitta] Natl Inst Med Res, MRC, Divis Mol Immunol, London NW7 1AA, England. [Turner, Jan-Eric; Panzer, Ulf] Univ Klinikum Hamburg Eppendorf, Med Klin & Poliklin 3, D-20246 Hamburg, Germany. [Wilhelm, Christoph] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Renauld, Jean-Christophe] Catholic Univ Louvain, de Duve Inst, B-1200 Brussels, Belgium. [Renauld, Jean-Christophe] Ludwig Inst Canc Res, Brussels Branch, B-1200 Brussels, Belgium. [Helmby, Helena] Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England. RP Stockinger, B (reprint author), Natl Inst Med Res, MRC, Divis Mol Immunol, London NW7 1AA, England. EM bstocki@nimr.mrc.ac.uk OI Helmby, Helena/0000-0003-0761-7348 FU Medical Research Council UK [117512792, MC_UP_A253_1028]; Deutsche Forschungsgemeinschaft (DFG) [TU 316/1-1]; DGF (Klinische Forschergruppe 228 TP1) [PA 754/7] FX This work was supported by the Medical Research Council UK (grants U. 117512792 and MC_UP_A253_1028), a Research Fellowship from the Deutsche Forschungsgemeinschaft (DFG) to J.-E. Turner (TU 316/1-1), and a DGF grant to U. Panzer (Klinische Forschergruppe 228 TP1, PA 754/7). NR 58 TC 93 Z9 98 U1 1 U2 18 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD DEC 16 PY 2013 VL 210 IS 13 BP 2951 EP 2965 DI 10.1084/jem.20130071 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 276ID UT WOS:000328742600013 PM 24249111 ER PT J AU Chopin, M Seillet, C Chevrier, S Wu, L Wang, HS Morse, HC Belz, GT Nutt, SL AF Chopin, Michael Seillet, Cyril Chevrier, Stephane Wu, Li Wang, Hongsheng Morse, Herbert C., III Belz, Gabrielle T. Nutt, Stephen L. TI Langerhans cells are generated by two distinct PU.1-dependent transcriptional networks SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID DENDRITIC-CELL; IN-VIVO; HEMATOPOIETIC PROGENITORS; MYELOGENOUS LEUKEMIA; BLOOD MONOCYTES; STEADY-STATE; NULL MICE; EXPRESSION; PU.1; CD8-ALPHA(+) AB Langerhans cells (LCs) are the unique dendritic cells found in the epidermis. While a great deal of attention has focused on defining the developmental origins of LCs, reports addressing the transcriptional network ruling their differentiation remain sparse. We addressed the function of a group of key DC transcription factors-PU.1, ID2, IRF4, and IRF8-in the establishment of the LC network. We show that although steady-state LC homeostasis depends on PU.1 and ID2, the latter is dispensable for bone marrow-derived LCs. PU.1 controls LC differentiation by regulating the expression of the critical TGF-beta responsive transcription factor RUNX3. PU.1 directly binds to the Runx3 regulatory elements in a TGF-beta-dependent manner, whereas ectopic expression of RUNX3 rescued LC differentiation in the absence of PU.1 and promoted LC differentiation from PU.1-sufficient progenitors. These findings highlight the dual molecular network underlying LC differentiation, and show the central role of PU.1 in these processes. C1 [Chopin, Michael; Seillet, Cyril; Chevrier, Stephane; Wu, Li; Belz, Gabrielle T.; Nutt, Stephen L.] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. [Chopin, Michael; Seillet, Cyril; Chevrier, Stephane; Wu, Li; Belz, Gabrielle T.; Nutt, Stephen L.] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia. [Wu, Li] Tsinghua Univ, Tsinghua Peking Univ Joint Ctr Life Sci, Sch Med, Beijing 100084, Peoples R China. [Wang, Hongsheng; Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Nutt, SL (reprint author), Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. EM nutt@wehi.edu.au OI Morse, Herbert/0000-0002-9331-3705; Nutt, Stephen/0000-0002-0020-6637 FU National Health and Medical Research Council (NHRMC) of Australia [APP1048278, APP1023266]; Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infectious Diseases; Australian Research Council FX This work was supported by project grants (APP1048278 and APP1023266) and fellowships from the National Health and Medical Research Council (NHRMC) of Australia (to L. Wu, G. T. Belz, and S. L. Nutt), and the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (to H. C. Morse III). S. L. Nutt and G. T. Belz are supported by an Australian Research Council Future Fellowship. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIIS. NR 60 TC 23 Z9 23 U1 1 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD DEC 16 PY 2013 VL 210 IS 13 BP 2967 EP 2980 DI 10.1084/jem.20130930 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 276ID UT WOS:000328742600014 PM 24249112 ER PT J AU Hannas, BR Howdeshell, KL Furr, J Gray, LE AF Hannas, Bethany R. Howdeshell, Kembra L. Furr, Johnathan Gray, L. Earl, Jr. TI In utero phthalate effects in the female rat: A model for MRKH syndrome SO TOXICOLOGY LETTERS LA English DT Article DE Reproductive malformations; Uterine; Critical period ID MALE REPRODUCTIVE DEVELOPMENT; N-BUTYL PHTHALATE; DI(N-BUTYL) PHTHALATE; 2,4-DICHLOROPHENYL-PARA-NITROPHENYL ETHER; SEXUAL-DIFFERENTIATION; DIBUTYL PHTHALATE; PRENATAL EXPOSURE; LATE-GESTATION; MALFORMATIONS; TOXICITY AB Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is characterized by uterine and vaginal canal aplasia in normal karyotype human females and is a syndrome with poorly defined etiology. Reproductive toxicity of phthalate esters (PEs) occurs in rat offspring exposed in utero, a phenomenon that is better studied in male offspring than females. The current study reports female reproductive tract malformations in the Sprague-Dawley rat similar to those characteristic of MRKH syndrome, following in utero exposure to a mixture of 5 PEs. We determined that females are similar to 2-fold less sensitive to the effects of the 5-PE mixture than males for reproductive tract malformations. We were not fully successful in defining the critical exposure period for females; however, incidence of malformations was 88% following dosing from GD8 to 19 versus 22% and 0% for GD8-13 and GD14-19, respectively. Overall, this study provides valuable information regarding female vulnerability to in utero phthalate exposure and further characterizes a potential model for the human MRKH syndrome. Published by Elsevier Ireland Ltd. C1 [Hannas, Bethany R.; Furr, Johnathan; Gray, L. Earl, Jr.] US EPA, NHEERL, Toxicol Assessment Div, Reprod Toxicol Branch,Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Howdeshell, Kembra L.] NIEHS, Natl Toxicol Program, Off Hlth Assessment & Translat, Res Triangle Pk, NC 27709 USA. RP Gray, LE (reprint author), US EPA, NHEERL, RTD, MD 72, Res Triangle Pk, NC 27711 USA. EM Hannas.bethany@epa.gov; kembra.howdeshell@nih.gov; furr.johnathan@epa.gov; gray.earl@epa.gov FU National Toxicology Program at the National Institute of Environmental Health Sciences Interagency Agreement; U.S. Environmental Protection Agency [RW-75-92285501-1] FX National Toxicology Program at the National Institute of Environmental Health Sciences Interagency Agreement with the U.S. Environmental Protection Agency, Cooperative Agreement #RW-75-92285501-1. NR 25 TC 8 Z9 8 U1 0 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 EI 1879-3169 J9 TOXICOL LETT JI Toxicol. Lett. PD DEC 16 PY 2013 VL 223 IS 3 BP 315 EP 321 DI 10.1016/j.toxlet.2013.03.021 PG 7 WC Toxicology SC Toxicology GA 258XV UT WOS:000327492900009 PM 23542816 ER PT J AU Cleeland, CS Zhao, FM Chang, VT Sloan, JA O'Mara, AM Gilman, PB Weiss, M Mendoza, TR Lee, JW Fisch, MJ AF Cleeland, Charles S. Zhao, Fengmin Chang, Victor T. Sloan, Jeff A. O'Mara, Ann M. Gilman, Paul B. Weiss, Matthias Mendoza, Tito R. Lee, Ju-Whei Fisch, Michael J. TI The Symptom Burden of Cancer: Evidence for a Core Set of Cancer-Related and Treatment-Related Symptoms From the Eastern Cooperative Oncology Group Symptom Outcomes and Practice Patterns Study SO CANCER LA English DT Article DE symptoms; symptom assessment; cancer; symptom management; M. D. Anderson Symptom Inventory; MDASI ID MULTIPLE SYMPTOMS; METASTATIC CANCER; PAIN; SEVERITY; MODERATE; MILD; RECOMMENDATIONS; INTERFERENCE; OUTPATIENTS; PREVALENCE AB BACKGROUND: A set of common cancer-related and treatment-related symptoms has been proposed for quality of care assessment and clinical research. Using data from a large, multicenter, prospective study, the authors assessed the effects of disease site and stage on the percentages of patients rating these proposed symptoms as moderate to severe. METHODSThe severity of 13 symptoms proposed to represent core oncology symptoms was rated by 3106 ambulatory patients with cancer of the breast, prostate, colon/rectum, or lung, regardless of disease stage or phase of care; 2801 patients (90%) repeated the assessment 4 to 5 weeks later. RESULTSAt the time of the initial assessment, approximately 33% of the patients reported3 symptoms in the moderate-to-severe range; 11 of the 13 symptoms were rated as moderate to severe by at least 10% of all patients and 6 were rated as moderate to severe by at least 20% of those receiving active treatment. Fatigue/tiredness was the most severe symptom, followed by disturbed sleep, pain, dry mouth, and numbness/tingling. More patients with lung cancer and patients receiving active treatment reported moderate to severe symptoms. Percentages of symptomatic patients increased by disease stage, less adequate response to therapy, and declining Eastern Cooperative Oncology Group performance status. The percentages of patients reporting moderate to severe symptoms were stable across both assessments. CONCLUSIONSThe results of the current study support a core set of moderate to severe symptoms that are common across outpatients with solid tumors, that can guide consideration of progression-free survival as a trial outcome, and that should be considered in clinical care and in assessments of quality of care and treatment benefit. Cancer 2013;119:4333-4340. (c) 2013 American Cancer Society. C1 [Cleeland, Charles S.] Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, Houston, TX 77030 USA. [Zhao, Fengmin] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Chang, Victor T.] Rutgers Univ Med & Dent New Jersey, Vet Affairs New Jersey Hlth Care Syst, E Orange, NJ USA. [Sloan, Jeff A.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [O'Mara, Ann M.] NCI, Community Oncol & Prevent Trials Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Gilman, Paul B.] Main Line Hematol Oncol Associates, Lankenau Canc Ctr, Wynnewood, PA USA. [Weiss, Matthias] Marshfield Clin Fdn Med Res & Educ, Dept Hematol Oncol Northern Div, Marshfield, WI USA. [Fisch, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Gen Oncol, Houston, TX 77030 USA. RP Cleeland, CS (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, 1515 Holcombe Blvd,Unit 1450, Houston, TX 77030 USA. EM ccleeland@mdanderson.org FU National Cancer Institute/National Institutes of Health [CA37403, CA15488, CA13650, CA35412, CA063847]; MD Anderson Cancer Center Support Grant [P30 CA016672]; [R01 CA026582] FX Supported by grants from the National Cancer Institute/National Institutes of Health, including U10 grants CA37403, CA15488, CA13650, CA35412, and CA063847 to the Eastern Cooperative Oncology Group; R01 CA026582 to Dr. Cleeland; and MD Anderson Cancer Center Support Grant P30 CA016672. Neither the National Cancer Institute nor the National Institutes of Health had any role in the study design, data collection, analysis, interpretation, or preparation of this article. NR 20 TC 39 Z9 39 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD DEC 15 PY 2013 VL 119 IS 24 BP 4333 EP 4340 DI 10.1002/cncr.28376 PG 8 WC Oncology SC Oncology GA 295BP UT WOS:000330091900018 PM 24114037 ER PT J AU Winhusen, TM Adinoff, B Lewis, DF Brigham, GS Gardin, JG Sonne, SC Theobald, J Ghitza, U AF Winhusen, Theresa M. Adinoff, Bryon Lewis, Daniel F. Brigham, Gregory S. Gardin, John G., II Sonne, Susan C. Theobald, Jeff Ghitza, Udi TI A tale of two stimulants: Mentholated cigarettes may play a role in cocaine, but not methamphetamine, dependence SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Menthol; Cigarettes; Cocaine dependence; Methamphetamine dependence ID SMOKING-CESSATION; POTENTIAL IMPACT; CARBON-MONOXIDE; SUBSTANCE USE; DRUG-USE; SMOKERS; NONSMOKERS; ADDICTION; OUTCOMES; TRIAL AB Background: Research suggests that mentholated cigarettes may play a role in cocaine dependence. The purpose of the present study was to expand upon the research on mentholated cigarettes and cocaine dependence and to evaluate the role of mentholated cigarettes in methamphetamine dependence. Methods: Secondary analysis of a multisite, randomized trial evaluating the impact of smoking-cessation treatment in stimulant-dependent outpatients (N = 538). Participants' reasons for concurrent use of cigarettes and illicit stimulants were assessed via self-report. Stimulant-abstinence was measured by self-report and urine drug screens. Smoking cessation was assessed via self-report and carbon monoxide levels. Results: Of the 301 cocaine-dependent participants, 201 (67%) were menthol and 100 (33%) were non-menthol cigarette smokers. Cocaine-dependent participants who smoked menthol, compared to non-menthol, cigarettes were significantly more likely to report that cigarettes prolong their cocaine high (X-2(1) = 16.3, p < .0001, OR = 3.58 [95% CI: 1.88-6.79]) and were less likely to be stimulant abstinent during active treatment (W=3.6,p < 0.001, d=.39 [95% CI: 0.16-0.62]), at 3-month follow-up (X-2(1) = 14.4, p < 0.001, OR = .32 [95% CI: 0.17-0.581), and at 6-month follow-up (X-2(1) = 4.6, p = 0.03, OR = .53 [95% CI: 0.29-0.95]). No parallel differences were found between menthol and non-menthol methamphetamine-dependent smokers. The prevalence of Caucasian menthol smokers was significantly greater in the cocaine-dependent participants (37.2%) than in the methamphetamine-dependent participants (17.61%), (X-2(1) = 14.4, p < .001, OR = 2.77 [95% CI:1.62-4.731). Smoking cessation was not significantly associated with cigarette type for either cocaine- or methamphetamine-dependent participants. Conclusions: The present results suggest that mentholated cigarettes play a role in cocaine, but not methamphetamine, dependence. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Winhusen, Theresa M.; Lewis, Daniel F.; Brigham, Gregory S.; Theobald, Jeff] Univ Cincinnati, Coll Med, Dept Psychiat & Behav Neurosci, Cincinnati Addict Res Treatment & Educ Ctr CinART, Cincinnati, OH 45220 USA. [Adinoff, Bryon] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Adinoff, Bryon] Dallas VAMC, VA North Texas Hlth Care Syst, Dallas, TX 75216 USA. [Brigham, Gregory S.] Maryhaven, Columbus, OH 43207 USA. [Gardin, John G., II] ADAPT Inc, Roseburg, OR 97470 USA. [Sonne, Susan C.] Med Univ S Carolina, Charleston, SC 29425 USA. [Ghitza, Udi] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. RP Winhusen, TM (reprint author), Univ Cincinnati, Coll Med, Dept Psychiat & Behav Neurosci, Cincinnati Addict Res Treatment & Educ Ctr CinART, 3210 Jefferson Ave, Cincinnati, OH 45220 USA. EM winhusen@carc.uc.edu OI Winhusen, Theresa/0000-0002-3364-0739; Brigham, Gregory/0000-0003-1150-4493 FU National Institute on Drug Abuse (NIDA) Clinical Trials Network [U10-DA013732, U10-DA020036, U10-DA013720, U10-DA013045, U10-DA013727, U10-DA020024, U10-DA015815] FX Funding for this study was provided by the National Institute on Drug Abuse (NIDA) Clinical Trials Network: U10-DA013732 to University of Cincinnati (Dr. Winhusen); U10-DA020036 to University of Pittsburgh (Dr. Daley), U10-DA013720 to University of Miami School of Medicine (Drs. Szapocznik and Metsch); U10-DA013045 to University of California Los Angeles (Dr. Ling); U10-DA013727 to Medical University of South Carolina (Dr. Brady); U10-DA020024 to University of Texas Southwestern Medical Center (Dr. Trivedi);U10-DA015815 to University of California San Francisco (Drs. Sorensen and McCarty). The publications committee of the Clinical Trials Network (CTN) gave final approval of the analysis and interpretation of the data and approved the manuscript. NR 36 TC 5 Z9 5 U1 1 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD DEC 15 PY 2013 VL 133 IS 3 BP 845 EP 851 DI 10.1016/j.drugalcdep.2013.09.002 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 283VH UT WOS:000329274600007 PM 24075226 ER PT J AU Lavi, O Greene, JM Levy, D Gottesman, MM AF Lavi, Orit Greene, James M. Levy, Doron Gottesman, Michael M. TI The Role of Cell Density and Intratumoral Heterogeneity in Multidrug Resistance SO CANCER RESEARCH LA English DT Article ID INDUCED APOPTOSIS; DRUG-RESISTANCE; MUTATION-RATE; CANCER-CELLS; CHEMOTHERAPY; EVOLUTION; DYNAMICS; STATE AB Recent data have demonstrated that cancer drug resistance reflects complex biologic factors, including tumor heterogeneity, varying growth, differentiation, apoptosis pathways, and cell density. As a result, there is a need to find new ways to incorporate these complexities in the mathematical modeling of multidrug resistance. Here, we derive a novel structured population model that describes the behavior of cancer cells under selection with cytotoxic drugs. Our model is designed to estimate intratumoral heterogeneity as a function of the resistance level and time. This updated model of the multidrug resistance problem integrates both genetic and epigenetic changes, density dependence, and intratumoral heterogeneity. Our results suggest that treatment acts as a selection process, whereas genetic/epigenetic alteration rates act as a diffusion process. Application of our model to cancer treatment suggests that reducing alteration rates as a first step in treatment causes a reduction in tumor heterogeneity and may improve targeted therapy. The new insight provided by this model could help to dramatically change the ability of clinical oncologists to design new treatment protocols and analyze the response of patients to therapy. (C) 2013 AACR. C1 [Lavi, Orit; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Greene, James M.; Levy, Doron] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Greene, James M.; Levy, Doron] Univ Maryland, Ctr Sci Computat & Math Modeling CSCAMM, College Pk, MD 20742 USA. RP Lavi, O (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Room 2112, Bethesda, MD 20892 USA. EM orit.lavi@nih.gov FU Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute; UMD-NCI Partnership for Cancer Technology; NSF/NIGMS program [DMS-0758374]; National Cancer Institute [R01CA130817] FX The work was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute and was supported in part by a seed grant from the UMD-NCI Partnership for Cancer Technology. The work of D. Levy was supported in part by the joint NSF/NIGMS program under grant number DMS-0758374 and by grant number R01CA130817 from the National Cancer Institute. NR 24 TC 15 Z9 15 U1 2 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 IS 24 BP 7168 EP 7175 DI 10.1158/0008-5472.CAN-13-1768 PG 8 WC Oncology SC Oncology GA 279DB UT WOS:000328939200006 PM 24163380 ER PT J AU Pikor, LA Lockwood, WW Thu, KL Vucic, EA Chari, R Gazdar, AF Lam, S Lam, WL AF Pikor, Larissa A. Lockwood, William W. Thu, Kelsie L. Vucic, Emily A. Chari, Raj Gazdar, Adi F. Lam, Stephen Lam, Wan L. TI YEATS4 Is a Novel Oncogene Amplified in Non-Small Cell Lung Cancer That Regulates the p53 Pathway SO CANCER RESEARCH LA English DT Article ID PUTATIVE TRANSCRIPTION FACTOR; ARRAY CGH DATA; GENE AMPLIFICATION; HISTONE ACETYLTRANSFERASE; TUMOR-SUPPRESSOR; PROTEIN; GAS41; ADENOCARCINOMA; EXPRESSION; CARCINOMAS AB Genetic analyses of lung cancer have helped found new treatments in this disease. Weconducted an integrative analysis of gene expression and copy number in 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more specifically the YEATS4 gene as amplified and overexpressed in similar to 20% of the NSCLC cases examined. Overexpression of YEATS4 abrogated senescence in human bronchial epithelial cells. Conversely, RNAi-mediated attenuation of YEATS4 in human lung cancer cells reduced their proliferation and tumor growth, impairing colony formation and inducing cellular senescence. These effects were associated with increased levels of p21WAF1 and p53 and cleavage of PARP, implicating YEATS4 as a negative regulator of the p21-p53 pathway. We also found that YEATS4 expression affected cellular responses to cisplastin, with increased levels associated with resistance and decreased levels with sensitivity. Taken together, our findings reveal YEATS4 as a candidate oncogene amplified in NSCLC, and a novel mechanism contributing to NSCLC pathogenesis. (C) 2013 AACR. C1 [Pikor, Larissa A.; Thu, Kelsie L.; Vucic, Emily A.; Lam, Stephen; Lam, Wan L.] BC Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada. [Lockwood, William W.] NIH, Bethesda, MD 20892 USA. [Chari, Raj] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Gazdar, Adi F.] Univ Texas South Western, Hamon Ctr Therapeut, Dallas, TX USA. RP Pikor, LA (reprint author), BC Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada. EM lpikor@bccrc.ca OI Vucic, Emily/0000-0002-2728-8708 FU Canadian Institutes for Health Research [MOP 86731, 94867]; Canadian Cancer Society [CCS20485]; NCI Early Detection Research Network [U01CA0864021]; Canary Foundation; Vanier Canada Graduate Scholarship; CIHR Jean-Francois Saint Denis Fellowship in Cancer Research; CIHR Frederick Banting & Charles Best Canada Graduate Scholarship; Banting Postdoctoral Fellowship FX Funding for this work is provided by the Canadian Institutes for Health Research (MOP 86731, 94867), Canadian Cancer Society (CCS20485), NCI Early Detection Research Network (U01CA0864021), and the Canary Foundation. L. A. Pikor and K. L. Thu are supported by Vanier Canada Graduate Scholarship, W. W. Lockwood by CIHR Jean-Francois Saint Denis Fellowship in Cancer Research, E. A. Vucic by CIHR Frederick Banting & Charles Best Canada Graduate Scholarship, and R. Chari by Banting Postdoctoral Fellowship. NR 49 TC 9 Z9 9 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 IS 24 BP 7301 EP 7312 DI 10.1158/0008-5472.CAN-13-1897 PG 12 WC Oncology SC Oncology GA 279DB UT WOS:000328939200018 PM 24170126 ER PT J AU Greten, TF Duffy, AG Korangy, F AF Greten, Tim F. Duffy, Austin G. Korangy, Firouzeh TI Hepatocellular Carcinoma from an Immunologic Perspective SO CLINICAL CANCER RESEARCH LA English DT Review ID T-CELL RESPONSES; RADIOFREQUENCY THERMAL ABLATION; TARGETED ONCOLYTIC POXVIRUS; PHASE-I TRIAL; ANTITUMOR IMMUNITY; SUPPRESSOR-CELLS; CLINICAL-TRIAL; LIVER-CANCER; GLYPICAN-3; INFLAMMATION AB Hepatocellular carcinoma is the third most common cancer worldwide. It is an inflammation-associated cancer. Multiple investigators have demonstrated that analysis of the tumor microenvironment may be used to predict patient outcome, indicating the importance of local immune responses in this disease. In contrast with other types of cancer, in which surgery, radiation, and systemic cytotoxic chemotherapies dominate the treatment options, in hepatocellular carcinoma locoregional treatments are widely applied. Such treatments induce rapid tumor cell death and antitumor immune responses, which may favor or impair the patients' outcome. Recent immunotherapeutic studies demonstrating promising results include trials evaluating intratumoral injection of an oncolytic virus expressing granulocyte macrophage colony-stimulating factor, glypican-3 targeting treatments, and anti-CTLA4 treatment. Although some of these novel approaches may provide benefit as single agents, there is a clear opportunity in hepatocellular carcinoma to evaluate these in combination with the standard modalities to more effectively harness the immune response. (C)2013 AACR. C1 [Greten, Tim F.; Duffy, Austin G.; Korangy, Firouzeh] NCI, GI Malignancy Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, Bldg 10 Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was financially supported by grants from the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to T. F. Greten). NR 54 TC 17 Z9 18 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2013 VL 19 IS 24 BP 6678 EP 6685 DI 10.1158/1078-0432.CCR-13-1721 PG 8 WC Oncology SC Oncology GA 279CY UT WOS:000328938700006 PM 24030702 ER PT J AU Lee, JH Park, KS Alberobello, AT Kallakury, B Weng, MT Wang, Y Giaccone, G AF Lee, Jih-Hsiang Park, Kang-Seo Alberobello, Anna Teresa Kallakury, Bhaskar Weng, Meng-Tzu Wang, Yisong Giaccone, Giuseppe TI The Janus Kinases Inhibitor AZD1480 Attenuates Growth of Small Cell Lung Cancers In Vitro and In Vivo SO CLINICAL CANCER RESEARCH LA English DT Article ID PHASE-II; MYELOPROLIFERATIVE DISORDERS; SOLID TUMORS; DOUBLE-BLIND; JAK2; MUTATIONS; CYTOKINE; TRIAL; MYELOFIBROSIS; RUXOLITINIB AB Purpose: The prognosis of small cell lung cancer (SCLC) is poor, and there has been very little progress in the medical treatment of SCLC in the past two decades. We investigated the potential of Janus-activated kinases (JAK) inhibitor, AZD1480, for treatment of SCLC in vitro and in vivo. Experimental Design: JAK1 and JAK2 were inhibited by AZD1480 or siRNAs, and the effect of inhibition of JAK gene family on SCLC cell viability was evaluated. The effect of AZD1480 on cell-cycle distribution and apoptosis induction was studied. Antitumor effects of AZD1480 in tumor xenografts were assessed. Results: AZD1480 significantly inhibited growth of six out of 13 SCLC cells with IC(50)s ranging from 0.73 to 3.08 mu mol/L. Knocking down of JAK2 and JAK1 inhibited proliferation of Jak2-positive/Jak1-negative H82 cells and Jak1-positive/Jak2-negative GLC4 cells, respectively. Treatment of SCLC cells with AZD1480 for 24 hours resulted in an increase of 4N DNA content and histone 3 serine 10 phosphorylation, indicative of G(2)-M phase arrest. Moreover, SCLCs underwent apoptosis after AZD1480 treatment as exemplified by the downregulation of MCL1, the accumulation of cleaved caspase 3, cleaved PARP, and increase of annexin-V-positive cells. Finally, xenograft experiments showed that AZD1480 attenuated the growth of H82 and GLC4 tumors in mice, and we observed stronger apoptosis as well as decreased CD31-positive endothelial cells in H82 and GLC4 xenografts upon AZD1480 treatment. Conclusions: JAK inhibitor AZD1480 attenuated growth of SCLC cells in vitro and in vivo. Clinical development of anti-JAKs therapies in SCLC warrants further investigation. (C)2013 AACR. C1 [Lee, Jih-Hsiang; Park, Kang-Seo; Weng, Meng-Tzu; Wang, Yisong; Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Park, Kang-Seo; Alberobello, Anna Teresa; Kallakury, Bhaskar; Weng, Meng-Tzu; Wang, Yisong; Giaccone, Giuseppe] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Giaccone, G (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Res Bldg,Rm W503, Washington, DC 20007 USA. EM gg496@georgetown.edu RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU NIH FX The study was sponsored by the intramural grant of the NIH. NR 42 TC 13 Z9 13 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2013 VL 19 IS 24 BP 6777 EP 6786 DI 10.1158/1078-0432.CCR-13-1110 PG 10 WC Oncology SC Oncology GA 279CY UT WOS:000328938700015 PM 24158701 ER PT J AU Kreitman, RJ Wilson, W Calvo, KR Arons, E Roth, L Sapolsky, J Zhou, H Raffeld, M Stetler-Stevenson, M AF Kreitman, Robert J. Wilson, Wyndham Calvo, Katherine R. Arons, Evgeny Roth, Laura Sapolsky, Jeffrey Zhou, Hong Raffeld, Mark Stetler-Stevenson, Maryalice TI Cladribine with Immediate Rituximab for the Treatment of Patients with Variant Hairy Cell Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID MINIMAL RESIDUAL DISEASE; TERM-FOLLOW-UP; MARGINAL ZONE LYMPHOMA; VILLOUS LYMPHOCYTES; 2-CHLORODEOXYADENOSINE; DIAGNOSIS; FEATURES; IMMUNOGLOBULIN; PENTOSTATIN; DISORDERS AB Purpose: In contrast with the classic form, variant hairy cell leukemia (HCLv) responds poorly to single-agent purine analogs, expresses unmutated BRAF, has shorter overall survival, and lacks effective standard therapy. No treatment has achieved a high complete remission (CR) rate even in small series, and of 39 reported cases from six studies, overall response rate after cladribine was 44% with 8% CRs. Rituximab has been found to increase the sensitivity of malignant cells to cladribine, suggesting that combination with cladribine might improve response in HCLv. To test this hypothesis, patients with HCLv were treated with simultaneous cladribine and rituximab. Experimental Design: Patients with HCLv with 0 to 1 prior courses of cladribine received cladribine 0.15 mg/kg for days 1 to 5, with eight weekly doses of rituximab 375 mg/m(2) beginning day 1. Restaging was performed, and minimal residual disease (MRD) in blood and marrow was quantified using PCR, immunohistochemistry, and flow cytometry. Results: By 6 months, 9 (90%) of 10 patients achieved CR, compared with 3 (8%) of 39 reported cases treated with cladribine alone (P < 0.0001). Of the 9 CRs, 8 remain free of MRD at 12 to 48 (median 27) months of follow-up. No dose-limiting toxicities were observed when beginning cladribine and rituximab on the same day, although most patients required short-term steroids to prevent and treat rituximab infusion reactions. Cytopenias in CRs resolved in 7 to 211 (median 34) days without major infections. Conclusion: Although cladribine alone lacks effectiveness for early or relapsed HCLv, cladribine with immediate rituximab achieves CRs without MRD and is feasible to administer. (C)2013 AACR. C1 [Raffeld, Mark; Stetler-Stevenson, Maryalice] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wilson, Wyndham] NCI, Metab Branch, Bethesda, MD 20892 USA. [Calvo, Katherine R.] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), 37-5124b,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov OI Calvo, Katherine/0000-0002-0771-4191 FU Intramural Research Program; NCI; NIH; Hairy Cell Leukemia Foundation; Genentech FX This work was supported by the Intramural Research Program, NCI, NIH, and the Hairy Cell Leukemia Foundation. The rituximab for the trial was sponsored by Genentech. NR 47 TC 12 Z9 12 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2013 VL 19 IS 24 BP 6873 EP 6881 DI 10.1158/1078-0432.CCR-13-1752 PG 9 WC Oncology SC Oncology GA 279CY UT WOS:000328938700024 PM 24277451 ER PT J AU Guo, TL Germolec, DR Zhang, LX Auttachoat, W Smith, MJ White, KL AF Guo, T. L. Germolec, D. R. Zhang, Ling X. Auttachoat, W. Smith, M. J. White, K. L., Jr. TI Contact sensitizing potential of pyrogallol and 5-amino-o-cresol in female BALB/c mice SO TOXICOLOGY LA English DT Article DE Hair dyes; Pyrogallol; 5-Amino-o-cresol; Chemical hypersensitivity; Lymph node subpopulations ID LOCAL LYMPH-NODE; RISK-ASSESSMENT; CUMULATIVE IRRITATION; HELA-CELLS; ASSAY; ALLERGENS; SKIN; IRRITANTS; APOPTOSIS; CHEMICALS AB Hair dye components such as pyrogallol and cresol have been shown previously to promote allergic reactions such as rashes, dermal inflammation, irritation and dermatitis. The objective of this study was to determine the contact sensitization potential of pyrogallol (PYR) and 5-amino-o-cresol (AOC) when applied dermally to female BALB/c mice. Measurement of the contact hypersensitivity response was initially accomplished using the local lymph node assay. For PYR, significant increases in the proliferation of lymph node cells were observed at concentrations of 0.5% (w/v) and higher. For AOC, borderline increases, albeit significant, in auricular lymph node cell proliferation were observed at 5% and 10%. Results from the irritancy assay suggested that PYR, but not AOC, was an irritant. To further delineate whether PYR was primarily an irritant or a contact sensitizer, the mouse ear swelling test (MEST) was conducted. A significant increase in mouse ear thickness was observed at 72 h following challenge with 0.5% PYR in mice that had been sensitized with 5% PYR In contrast, no effects were observed in the MEST in mice sensitized and challenged with the highest achievable concentration of AOC (10%). Additional studies examining lymph node subpopulations and CD86 (B7.2) expression by B cells further support the indication that PYR was a sensitizer in BALB/c mice. The results demonstrate that PYR is both a sensitizer and an irritant in female BALB/c mice. However, the contact sensitization potential of AOC is minimal in this strain of mouse. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Guo, T. L.; Zhang, Ling X.; Auttachoat, W.; Smith, M. J.; White, K. L., Jr.] Univ Georgia, Coll Vet Med, Dept Vet Biosci & Diagnost Imaging, Athens, GA 30602 USA. [Germolec, D. R.] NIEHS, Div Natl Toxicol Program, RTP, Res Triangle Pk, NC 27709 USA. RP Guo, TL (reprint author), Univ Georgia, Coll Vet Med, Dept Vet Biosci & Diagnost Imaging, Athens, GA 30602 USA. EM tlguo1@uga.edu FU NIEHS [N01-ES-55538] FX This study was supported by the NIEHS contract N01-ES-55538. The authors would like to thank Dr. Steven D. Holladay at University of Georgia for his critical and editorial review, and D.L. Musgrove and R.D. Brown at Virginia Commonwealth University for their technical assistance. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. NR 51 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD DEC 15 PY 2013 VL 314 IS 2-3 BP 202 EP 208 DI 10.1016/j.tox.2013.10.006 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 280DH UT WOS:000329008400002 PM 24172597 ER PT J AU Ruhl, CE Everhart, JE AF Ruhl, Constance E. Everhart, James E. TI The Association of Low Serum Alanine Aminotransferase Activity With Mortality in the US Population SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alanine aminotransferase; body composition; mortality; National Health and Nutrition Examination Survey ID ALL-CAUSE MORTALITY; BODY-MASS INDEX; PHYSICAL PERFORMANCE BATTERY; LOWER-EXTREMITY FUNCTION; UNITED-STATES; CAFFEINE CONSUMPTION; PREDICT MORTALITY; SARCOPENIA; DISABILITY; RISK AB Elevated alanine aminotransferase (ALT) activity, an important marker of liver injury, has been associated inconsistently with higher mortality. We evaluated whether persons with nonelevated ALT levels are the most appropriate comparison group by examining the relationships of low ALT with mortality and body composition in the US National Health and Nutrition Examination Survey (NHANES). In NHANES 19881994, the mortality risk of persons in ALT deciles 1, 2, 3, and 10 was compared with that of persons in deciles 49 (mortality was relatively flat across these deciles) over an 18-year period (through 2006) among 14,950 viral-hepatitis-negative adults. In NHANES 19992006, low ALT was evaluated in association with dual-energy x-ray absorptiometry body composition measures among 15,028 adults. Multivariate-adjusted mortality was higher for decile 1 (hazard ratio (HR) 1.42, 95 confidence interval (CI): 1.24, 1.63), decile 2 (HR 1.27, 95 CI: 1.06, 1.53), and decile 3 (HR 1.25, 95 CI: 1.04, 1.50) and nonsignificantly higher for decile 10 (HR 1.21, 95 CI: 0.91, 1.61) than for deciles 49. Adjusted appendicular lean mass was decreased among the lowest ALT deciles. In the US population, low ALT was associated with higher mortality risk, possibly attributable to decreased appendicular lean mass. For mortality studies of elevated ALT levels, the most appropriate comparison group is persons in the middle range of ALT rather than all persons with nonelevated ALT. C1 [Ruhl, Constance E.] Social & Sci Syst Inc, Silver Spring, MD 20910 USA. [Everhart, James E.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Ruhl, CE (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM cruhl@s-3.com FU National Institute of Diabetes and Digestive and Kidney Diseases [HHSN2762012 00161U] FX This work was supported by a contract (HHSN2762012 00161U) from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 40 TC 10 Z9 11 U1 2 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 15 PY 2013 VL 178 IS 12 BP 1702 EP 1711 DI 10.1093/aje/kwt209 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 271IZ UT WOS:000328386500005 PM 24071009 ER PT J AU Lin, SW Abnet, CC AF Lin, Shih-Wen Abnet, Christian C. TI RE: "PROSPECTIVE STUDY OF ULTRAVIOLET RADIATION EXPOSURE AND MORTALITY RISK IN THE UNITED STATES" Reply SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID NONMELANOMA SKIN-CANCER; SUNLIGHT; TRENDS C1 [Lin, Shih-Wen; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Lin, SW (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM lins4@mail.nih.gov RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU Intramural NIH HHS NR 11 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 15 PY 2013 VL 178 IS 12 BP 1762 EP 1763 DI 10.1093/aje/kwt266 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 271IZ UT WOS:000328386500013 PM 24471178 ER PT J AU Taguchi, A Maruyama, H Nameta, M Yamamoto, T Matsuda, J Kulkarni, AB Yoshioka, H Ishii, S AF Taguchi, Atsumi Maruyama, Hiroki Nameta, Masaaki Yamamoto, Tadashi Matsuda, Junichiro Kulkarni, Ashok B. Yoshioka, Hidekatsu Ishii, Satoshi TI A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis SO BIOCHEMICAL JOURNAL LA English DT Article DE enzyme replacement therapy; Fabry disease; globotriaosylceramide synthesis; symptomatic mouse model ID ALPHA-GALACTOSIDASE-A; ENZYME REPLACEMENT THERAPY; NATURAL-HISTORY; DEFICIENT MICE; CHAPERONE THERAPY; AGALSIDASE-ALPHA; GAUCHER-DISEASE; KNOCKOUT MICE; ANIMAL-MODEL; CELL AB Fabry disease is a lysosomal storage disorder in which neutral glycosphingolipids, predominantly Gb3 (globotriaosylceramide), accumulate due to deficient alpha-Gal A (alpha-galactosidase A) activity. The GLAko (alpha-Gal A-knockout) mouse has been used as a model for Fabry disease, but it does not have any symptomatic abnormalities. In the present study, we generated a symptomatic mouse model (G3Stg/GLAko) by cross-breeding GLAko mice with transgenic mice expressing human Gb3 synthase. G3Stg/GLAko mice had high Gb3 levels in major organs, and their serum Gb3 level at 5-25 weeks of age was 6-10-fold higher than that in GLAko mice of the same age. G3Stg/GLAko mice showed progressive renal impairment, with albuminuria at 3 weeks of age, decreased urine osmolality at 5 weeks, polyuria at 10 weeks and increased blood urea nitrogen at 15 weeks. The urine volume and urinary albumin concentration were significantly reduced in the G3Stg/GLAko mice when human recombinant alpha-Gal A was administered intravenously. These data suggest that Gb3 accumulation is a primary pathogenic factor in the symptomatic phenotype of G3Stg/GLAko mice, and that this mouse line is suitable for studying the pathogenesis of Fabry disease and for preclinical studies of candidate therapies. C1 [Taguchi, Atsumi; Yoshioka, Hidekatsu; Ishii, Satoshi] Oita Univ, Fac Med, Dept Matrix Med, Oita 8795593, Japan. [Maruyama, Hiroki] Niigata Univ, Grad Sch Med & Dent Sci, Dept Clin Nephrosci, Niigata 9518120, Japan. [Nameta, Masaaki; Yamamoto, Tadashi] Niigata Univ, Electron Microscope Core Facil, Niigata 9518120, Japan. [Matsuda, Junichiro] Natl Inst Biomed Innovat, Lab Anim Models Human Dis, Osaka 5670085, Japan. [Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Ishii, Satoshi] GlycoPharma Corp, Biochem Lab, Oita 8700822, Japan. RP Ishii, S (reprint author), Oita Univ, Fac Med, Dept Matrix Med, Oita 8795593, Japan. EM ishiis01@oita-u.ac.jp FU Ministry of Education, Science and Culture of Japan [KM23390223] FX This work was supported by a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Science and Culture of Japan [grant number KM23390223 (to H.M. and S.I.)]. NR 45 TC 9 Z9 9 U1 0 U2 3 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD DEC 15 PY 2013 VL 456 BP 373 EP 383 DI 10.1042/BJ20130825 PN 3 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278GB UT WOS:000328876100006 PM 24094090 ER PT J AU Vang, AG Housley, W Dong, HL Basole, C Ben-Sasson, SZ Kream, BE Epstein, PM Clark, RB Brocke, S AF Vang, Amanda G. Housley, William Dong, Hongli Basole, Chaitali Ben-Sasson, Shlomo Z. Kream, Barbara E. Epstein, Paul M. Clark, Robert B. Brocke, Stefan TI Regulatory T-cells and cAMP suppress effector T-cells independently of PKA-CREM/ICER: a potential role for Epac SO BIOCHEMICAL JOURNAL LA English DT Article DE cyclic nucleotide phosphodiesterase; immune tolerance; immunosuppression; inducible cAMP early repressor (ICER); T-cell proliferation ID PROTEIN-KINASE-A; EARLY REPRESSOR ICER; CYCLIC-AMP; GENE-EXPRESSION; LEUKEMIC-CELLS; MESSENGER-RNA; LIPID RAFTS; TGF-BETA; IL-2; ACTIVATION AB cAMP signalling is both a major pathway as well as a key therapeutic target for inducing immune tolerance and is involved in Treg cell (regulatory T-cell) function. To achieve potent immunoregulation, cAMP can act through several downstream effectors. One proposed mechanism is that cAMP-mediated suppression, including immunosuppression by Treg cells, results from activation of PKA (protein kinase A) leading to the induction of the transcription factor ICER (inducible cAMP early repressor). In the present study, we examined CD4(+)CD25(-) Teff cell (effector T-cell) and CD4(+)CD25(+) Treg cell immune responses in Crem (cAMP-response-element modulator) gene-deficient mice which lack ICER (Crem(-/-)/ICER-deficient mice). ICER deficiency did not significantly alter the frequency or number of Treg cells and Teff cells. Treg cells or a pharmacological increase in cAMP suppressed Teff cells from Crem(+/+) and Crem(-/-) /ICER-deficient mice to an equivalent degree, demonstrating that ICER is dispensable in these functions. Additionally, activating the cAMP effector Epac (exchange protein directly activated by cAMP) suppressed Teff cells. Treg cells expressed low levels of all cyclic nucleotide Pde (phosphodiesterase) genes tested, but high levels of Epac. These data identify ICER as a redundant mediator of Treg cells and cAMP action on Teff cells and suggest that Epac may function as an alternative effector to promote cAMP-dependent Teff cell suppression. C1 [Vang, Amanda G.; Housley, William; Basole, Chaitali; Clark, Robert B.; Brocke, Stefan] Univ Connecticut, Ctr Hlth, Dept Immunol, Farmington, CT 06030 USA. [Vang, Amanda G.; Dong, Hongli; Epstein, Paul M.; Brocke, Stefan] Univ Connecticut, Ctr Hlth, Dept Pharmacol, Farmington, CT 06030 USA. [Dong, Hongli; Kream, Barbara E.; Epstein, Paul M.] Univ Connecticut, Ctr Hlth, Dept Cell Biol, Farmington, CT 06030 USA. [Ben-Sasson, Shlomo Z.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Kream, Barbara E.; Clark, Robert B.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT 06030 USA. [Kream, Barbara E.] Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT 06030 USA. RP Epstein, PM (reprint author), Univ Connecticut, Ctr Hlth, Dept Pharmacol, 263 Farmington Ave, Farmington, CT 06030 USA. EM epstein@nso1.uchc.edu; sbrocke@uchc.edu OI Basole, Chaitali/0000-0003-0644-7324 FU National Multiple Sclerosis Society [RG 4544A1/1, RG 4070A6]; institutional start-up funds; Connecticut Breast Health Initiative; CT Department of Public Health; Smart Family Foundation; Lea's Foundation for Leukemia Research; National Institutes of Health [1R56 A1072533-01 Al, R01 AR046542] FX This work was supported by the National Multiple Sclerosis Society [grant numbers RG 4544A1/1 (to S.B.) and RG 4070A6 (R.C.)], institutional start-up funds (to S.B.), the Connecticut Breast Health Initiative (to P.M.E. and S.B.), the CT Department of Public Health (to P.M.E. and S.B.), the Smart Family Foundation (to P.M.E. and S.B.), the Lea's Foundation for Leukemia Research (to P.M.E.) and the National Institutes of Health [grant numbers 1R56 A1072533-01 Al (to R.B.C.) and R01 AR046542 (to B.E.K.)]. NR 50 TC 10 Z9 10 U1 0 U2 5 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD DEC 15 PY 2013 VL 456 BP 463 EP 473 DI 10.1042/BJ20130064 PN 3 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278GB UT WOS:000328876100014 PM 24007532 ER PT J AU Battesti, A Hoskins, JR Tong, S Milanesio, P Mann, JM Kravats, A Tsegaye, YM Bougdour, A Wickner, S Gottesman, S AF Battesti, Aurelia Hoskins, Joel R. Tong, Song Milanesio, Paola Mann, Jessica M. Kravats, Andrea Tsegaye, Yodit M. Bougdour, Alexandre Wickner, Sue Gottesman, Susan TI Anti-adaptors provide multiple modes for regulation of the RssB adaptor protein SO GENES & DEVELOPMENT LA English DT Article DE RpoS; ClpX; IraP; response regulator; RsbP ID ESCHERICHIA-COLI; SIGMA(S) PROTEOLYSIS; PHOSPHORYLATION; RPOS; RECOGNITION; STABILITY; PHOSPHATE; PATHWAY; SITE; OMPR AB RpoS, an RNA polymerase sigma factor, controls the response of Escherichia coli and related bacteria to multiple stress responses. During nonstress conditions, RpoS is rapidly degraded by ClpXP, mediated by the adaptor protein RssB, a member of the response regulator family. In response to stress, RpoS degradation ceases. Small anti-adaptor proteins-IraP, IraM, and IraD, each made under a different stress condition-block RpoS degradation. RssB mutants resistant to either IraP or IraM were isolated and analyzed in vivo and in vitro. Each of the anti-adaptors is unique in its interaction with RssB and sensitivity to RssB mutants. One class of mutants defined an RssB N-terminal region close to the phosphorylation site and critical for interaction with IraP but unnecessary for IraM and IraD function. A second class, in the RssB C-terminal PP2C-like domain, led to activation of RssB function. These mutants allowed the response regulator to act in the absence of phosphorylation but did not abolish interaction with anti-adaptors. This class of mutants is broadly resistant to the anti-adaptors and bears similarity to constitutively activated mutants found in a very different PP2C protein. The mutants provide insight into how the anti-adaptors perturb RssB response regulator function and activation. C1 [Battesti, Aurelia; Hoskins, Joel R.; Tong, Song; Milanesio, Paola; Mann, Jessica M.; Kravats, Andrea; Tsegaye, Yodit M.; Bougdour, Alexandre; Wickner, Sue; Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM gottesms@helix.nih.gov RI Bougdour, Alexandre/K-3795-2014 OI Bougdour, Alexandre/0000-0002-5895-0020 FU Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; NIH undergraduate scholarship program FX We thank members of the laboratory, M. Galperin, M. Maurizi, and D. Dougan, for their comments on the manuscript. We thank A. Boulanger for discussions on using the Phos-tag method. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. J.M.M. was supported by the NIH undergraduate scholarship program. NR 32 TC 14 Z9 16 U1 0 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD DEC 15 PY 2013 VL 27 IS 24 BP 2722 EP 2735 DI 10.1101/gad.229617.113 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 278LW UT WOS:000328892800009 PM 24352426 ER PT J AU Chattopadhyay, G Shevach, EM AF Chattopadhyay, Gouri Shevach, Ethan M. TI Antigen-Specific Induced T Regulatory Cells Impair Dendritic Cell Function via an IL-10/MARCH1-Dependent Mechanism SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-II; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CUTTING EDGE; IN-VITRO; FOXP3(+); INTERLEUKIN-10; EXPRESSION; MATURATION; INDUCTION; CTLA-4 AB Foxp3(+) T regulatory cells (Tregs) are critically important for the maintenance of immunological tolerance, immune homeostasis, and prevention of autoimmunity. Dendritic cells (DCs) are one of the major targets of Treg-mediated suppression. Some studies have suggested that Treg-mediated suppression of DC function is mediated by the interaction of CTLA-4 on Tregs with CD80/CD86 on the DCs resulting in downregulation of CD80/CD86 expression and a decrease in costimulation. We have re-examined the effects of Tregs on mouse DC function in a model in which Ag-specific, induced Tregs (iTregs) are cocultured with DCs in the absence of T effector cells. iTreg-treated DCs are markedly defective in their capacity to activate naive T cells. iTregs from CTLA4-deficient mice failed to induce downregulation of CD80/CD86, but DCs treated with CTLA-4-deficient iTregs still exhibited impaired capacity to activate naive T cells. The iTreg-induced defect in DC function could be completely reversed by anti-IL-10, and IL-10-deficient iTregs failed to downregulate DC function. iTreg-treated DCs expressed high levels of MARCH1, an E3 ubiquitin ligase, recently found to degrade CD86 and MHC class II on the DCs and expressed lower levels of CD83, a molecule involved in neutralizing the function of MARCH1. Both the enhanced expression of MARCH1 and the decreased expression of CD83 were mediated by IL-10 produced by the iTregs. Taken together, these studies demonstrate that a major suppressive mechanism of DC function by iTregs is secondary to the effects of IL-10 on MARCH1 and CD83 expression. C1 [Chattopadhyay, Gouri; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, NIH, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. NR 38 TC 26 Z9 28 U1 0 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2013 VL 191 IS 12 BP 5875 EP 5884 DI 10.4049/jimmunol.1301693 PG 10 WC Immunology SC Immunology GA 272TM UT WOS:000328483900014 PM 24218453 ER PT J AU Zhang, XR Paun, A Claudio, E Wang, HS Siebenlist, U AF Zhang, Xiaoren Paun, Andrea Claudio, Estefania Wang, Hongshan Siebenlist, Ulrich TI The Tumor Promoter and NF-kappa B Modulator Bcl-3 Regulates Splenic B Cell Development SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MARGINAL-ZONE; CYCLIN D1; T-CELLS; LYMPHOMA; GENE; TRANSCRIPTION; EXPRESSION; PROLIFERATION; DEGRADATION; MACROPHAGES AB Bcl-3 is an atypical member of the family of I kappa B proteins. Unlike the classic members, Bcl-3 functions as a nuclear transcriptional cofactor that may, depending on context, promote or suppress genes via association with p50/NF-kappa B1 or p52/NF-kappa B2 homodimers. Bcl-3 is also an oncogene, because it is a partner in recurrent translocations in B cell tumors, resulting in deregulated expression. Bcl-3 functions, however, remain poorly understood. We have investigated the role of Bcl-3 in B cells and discovered a previously unknown involvement in the splenic development of these cells. Loss of Bcl-3 in B cells resulted in significantly more marginal zone (MZ) and fewer follicular (FO) B cells. Conversely, transgenic expression of Bcl-3 in B cells generated fewer MZ and more FO B cells. Both Bcl-3(-/-) FO and MZ B cells were more responsive to LPS stimulation compared with their wild-type counterparts, including increased proliferation. By contrast, Bcl-3(-/-) FO B cells were more prone to apoptosis upon BCR stimulation, also limiting their expansion. The data reveal Bcl-3 as a regulator of B cell fate determination, restricting the MZ path and favoring the FO pathway, at least in part, via increased signal-specific survival of the latter, a finding of relevance to its tumorigenic activity. C1 [Zhang, Xiaoren; Paun, Andrea; Claudio, Estefania; Wang, Hongshan; Siebenlist, Ulrich] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Zhang, Xiaoren] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Lab Stem Cell Biol, Shanghai 200031, Peoples R China. [Zhang, Xiaoren] Shanghai Jiao Tong Univ, Sch Med, Shanghai 200031, Peoples R China. RP Siebenlist, U (reprint author), NIH, Bldg 10,Room 11B15A, Bethesda, MD 20892 USA. EM xrzhang@sibs.ac.cn; usiebenlist@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Basic Research program [2014CB541904]; National Natural Science Foundation of China [31370881] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; the National Basic Research program (2014CB541904); and the National Natural Science Foundation of China (31370881). NR 49 TC 11 Z9 11 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2013 VL 191 IS 12 BP 5984 EP 5992 DI 10.4049/jimmunol.1300611 PG 9 WC Immunology SC Immunology GA 272TM UT WOS:000328483900025 PM 24244019 ER PT J AU Jaiswal, H Kaushik, M Sougrat, R Gupta, M Dey, A Verma, R Ozato, K Tailor, P AF Jaiswal, Hemant Kaushik, Monika Sougrat, Rachid Gupta, Monica Dey, Anup Verma, Rohit Ozato, Keiko Tailor, Prafullakumar TI Batf3 and Id2 Have a Synergistic Effect on Irf8-Directed Classical CD8 alpha(+) Dendritic Cell Development SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-PRODUCING CELLS; MYELOID PROGENITOR CELLS; SEQUENCE BINDING-PROTEIN; TRANSCRIPTION FACTOR; REGULATORY FACTOR-8; IN-VIVO; SUBSET DEVELOPMENT; M-CSF; MOUSE; EXPRESSION AB Dendritic cells (DCs) are heterogeneous cell populations represented by different subtypes, each varying in terms of gene expression patterns and specific functions. Recent studies identified transcription factors essential for the development of different DC subtypes, yet molecular mechanisms for the developmental program and functions remain poorly understood. In this study, we developed and characterized a mouse DC progenitor-like cell line, designated DC9, from Irf8(-/-) bone marrow cells as a model for DC development and function. Expression of Irf8 in DC9 cells led to plasmacytoid DCs and CD8 alpha(+) DC-like cells, with a concomitant increase in plasmacytoid DC-and CD8 alpha(+) DC-specific gene transcripts and induction of type I IFNs and IL12p40 following TLR ligand stimulation. Irf8 expression in DC9 cells led to an increase in Id2 and Batf3 transcript levels, transcription factors shown to be important for the development of CD8 alpha(+) DCs. We show that, without Irf8, expression of Id2 and Batf3 was not sufficient for directing classical CD8 alpha(+) DC development. When coexpressed with Irf8, Batf3 and Id2 had a synergistic effect on classical CD8 alpha(+) DC development. We demonstrate that Irf8 is upstream of Batf3 and Id2 in the classical CD8 alpha(+) DC developmental program and define the hierarchical relationship of transcription factors important for classical CD8 alpha(+) DC development. C1 [Jaiswal, Hemant; Kaushik, Monika; Verma, Rohit; Tailor, Prafullakumar] Natl Inst Immunol, Lab Innate Immun, New Delhi 110067, India. [Sougrat, Rachid] King Abdullah Univ Sci & Technol, Nanobiol Lab, Thuwal 239556900, Saudi Arabia. [Gupta, Monica; Dey, Anup; Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Tailor, P (reprint author), Natl Inst Immunol, Lab Innate Immun, Aruna Asaf Ali Marg, New Delhi 110067, India. EM tailorp@nii.ac.in OI Sougrat, Rachid/0000-0001-6476-1886 FU National Institute of Immunology Core Fund; Council for Scientific and Industrial Research, Government of India; Ramalingaswami Fellowship FX This work was supported by the National Institute of Immunology Core Fund. P.T. is a Ramalingaswami fellow, Department of Biotechnology, "Government of India" at National Institute of Immunology. H.J. and R.V. are supported by a fellowship from the Council for Scientific and Industrial Research, Government of India. M.K. is supported by a contingency grant of the Ramalingaswami Fellowship awarded to P.T. NR 57 TC 11 Z9 11 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2013 VL 191 IS 12 BP 5993 EP 6001 DI 10.4049/jimmunol.1203541 PG 9 WC Immunology SC Immunology GA 272TM UT WOS:000328483900026 PM 24227775 ER PT J AU Malachowa, N Kobayashi, SD Freedman, B Dorward, DW DeLeo, FR AF Malachowa, Natalia Kobayashi, Scott D. Freedman, Brett Dorward, David W. DeLeo, Frank R. TI Staphylococcus aureus Leukotoxin GH Promotes Formation of Neutrophil Extracellular Traps SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; IN-VIVO; GENE-EXPRESSION; INFECTION; LIPOPOLYSACCHARIDE; CONTRIBUTES; ACTIVATION; GENERATION; LEUCOCIDIN AB Staphylococcus aureus secretes numerous virulence factors that facilitate evasion of the host immune system. Among these molecules are pore-forming cytolytic toxins, including Panton-Valentine leukocidin (PVL), leukotoxin GH (LukGH; also known as LukAB), leukotoxin DE, and g-hemolysin. PVL and LukGH have potent cytolytic activity in vitro, and both toxins are proinflammatory in vivo. Although progress has been made toward elucidating the role of these toxins in S. aureus virulence, our understanding of the mechanisms that underlie the proinflammatory capacity of these toxins, as well as the associated host response toward them, is incomplete. To address this deficiency in knowledge, we assessed the ability of LukGH to prime human PMNs for enhanced bactericidal activity and further investigated the impact of the toxin on neutrophil function. We found that, unlike PVL, LukGH did not prime human neutrophils for increased production of reactive oxygen species nor did it enhance binding and/or uptake of S. aureus. Unexpectedly, LukGH promoted the release of neutrophil extracellular traps (NETs), which, in turn, ensnared but did not kill S. aureus. Furthermore, we found that electropermeabilization of human neutrophils, used as a separate means to create pores in the neutrophil plasma membrane, similarly induced formation of NETs, a finding consistent with the notion that NETs can form during nonspecific cytolysis. We propose that the ability of LukGH to promote formation of NETs contributes to the inflammatory response and host defense against S. aureus infection. C1 [Malachowa, Natalia; Kobayashi, Scott D.; Freedman, Brett; DeLeo, Frank R.] NIAID, Lab Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Dorward, David W.] NIAID, Microscopy Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 42 TC 27 Z9 27 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2013 VL 191 IS 12 BP 6022 EP 6029 DI 10.4049/jimmunol.1301821 PG 8 WC Immunology SC Immunology GA 272TM UT WOS:000328483900029 PM 24190656 ER PT J AU Munitic, I Torchia, MLG Meena, NP Zhu, GZ Li, CC Ashwell, JD AF Munitic, Ivana Torchia, Maria Letizia Giardino Meena, Netra Pal Zhu, Guozhi Li, Caiyi C. Ashwell, Jonathan D. TI Optineurin Insufficiency Impairs IRF3 but Not NF-kappa B Activation in Immune Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SEVERE LIVER DEGENERATION; OPEN-ANGLE GLAUCOMA; GENE-EXPRESSION; POLYUBIQUITIN BINDING; SIGNALING PATHWAY; VIRAL-INFECTION; MICE LACKING; NEURAL-TUBE; IKK-EPSILON; MYOSIN-VI AB Optineurin is a widely expressed polyubiquitin-binding protein that has been implicated in regulating cell signaling via its NF-kappa B essential modulator-homologous C-terminal ubiquitin (Ub)-binding region. Its functions are controversial, with in vitro studies finding that optineurin suppressed TNF-mediated NF-kappa B activation and virus-induced activation of IFN regulatory factor 3 (IRF3), whereas bone marrow-derived macrophages (BMDMs) from mice carrying an optineurin Ub-binding point mutation had normal TLR-mediated NF-kappa B activation and diminished IRF3 activation. We have generated a mouse model in which the entire Ub-binding C-terminal region is deleted (Optn(470T)). Akin to C-terminal optineurin mutations found in patients with certain neurodegenerative diseases, Optn(470T) was expressed at substantially lower levels than the native protein, allowing assessment not only of the lack of Ub binding, but also of protein insufficiency. Embryonic lethality with incomplete penetrance was observed for 129 x C57BL/6 Optn(470T)/(470T) mice, but after further backcrossing to C57BL/6, offspring viability was restored. Moreover, the mice that survived were indistinguishable from wild type littermates and had normal immune cell distributions. Activation of NF-kappa B in Optn(470T) BMDM and BM-derived dendritic cells with TNF or via TLR4, T cells via the TCR, and B cells with LPS or anti-CD40 was normal. In contrast, optineurin and/or its Ub-binding function was necessary for optimal TANK binding kinase 1 and IRF3 activation, and both Optn(470T) BMDMs and bone marrow-derived dendritic cells had diminished IFN-beta production upon LPS stimulation. Importantly, Optn(470T) mice produced less IFN-beta upon LPS challenge. Therefore, endogenous optineurin is dispensable for NF-kappa B activation but necessary for optimal IRF3 activation in immune cells. C1 [Munitic, Ivana; Torchia, Maria Letizia Giardino; Meena, Netra Pal; Zhu, Guozhi; Li, Caiyi C.; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. EM ivana.munitic@biotech.uniri.hr; jda@pop.nci.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 68 TC 20 Z9 21 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2013 VL 191 IS 12 BP 6231 EP 6240 DI 10.4049/jimmunol.1301696 PG 10 WC Immunology SC Immunology GA 272TM UT WOS:000328483900050 PM 24244017 ER PT J AU Lundqvist, A Smith, AL Takahashi, Y Wong, S Bahceci, E Cook, L Ramos, C Tawab, A McCoy, JP Read, EJ Khuu, HM Bolan, CD Joo, J Geller, N Leitman, SF Calandra, G Dunbar, C Kurlander, R Childs, RW AF Lundqvist, Andreas Smith, Aleah L. Takahashi, Yoshiyuki Wong, Susan Bahceci, Erkut Cook, Lisa Ramos, Catalina Tawab, Abdul McCoy, J. Philip, Jr. Read, Elizabeth J. Khuu, Hanh M. Bolan, Charles D. Joo, Jungnam Geller, Nancy Leitman, Susan F. Calandra, Gary Dunbar, Cynthia Kurlander, Roger Childs, Richard W. TI Differences in the Phenotype, Cytokine Gene Expression Profiles, and In Vivo Alloreactivity of T Cells Mobilized with Plerixafor Compared with G-CSF SO JOURNAL OF IMMUNOLOGY LA English DT Article ID VERSUS-HOST-DISEASE; BLOOD STEM-CELLS; HEMATOPOIETIC PROGENITOR CELLS; PERIPHERAL-BLOOD; BONE-MARROW; ALLOGENEIC TRANSPLANTATION; HEMATOLOGICAL MALIGNANCIES; HEALTHY-VOLUNTEERS; CXCR4 ANTAGONIST; RANDOMIZED-TRIAL AB Plerixafor (Mozobil) is a CXCR4 antagonist that rapidly mobilizes CD34(+) cells into circulation. Recently, plerixafor has been used as a single agent to mobilize peripheral blood stem cells for allogeneic hematopoietic cell transplantation. Although G-CSF mobilization is known to alter the phenotype and cytokine polarization of transplanted T cells, the effects of plerixafor mobilization on T cells have not been well characterized. In this study, we show that alterations in the T cell phenotype and cytokine gene expression profiles characteristic of G-CSF mobilization do not occur after mobilization with plerixafor. Compared with non-mobilized T cells, plerixafor-mobilized T cells had similar phenotype, mixed lymphocyte reactivity, and Foxp3 gene expression levels in CD4(+) T cells, and did not undergo a change in expression levels of 84 genes associated with Th1/Th2/Th3 pathways. In contrast with plerixafor, G-CSF mobilization decreased CD62L expression on both CD4 and CD8(+) T cells and altered expression levels of 16 cytokine-associated genes in CD3(+) T cells. To assess the clinical relevance of these findings, we explored a murine model of graft-versus-host disease in which transplant recipients received plerixafor or G-CSF mobilized allograft from MHC-matched, minor histocompatibility-mismatched donors; recipients of plerixafor mobilized peripheral blood stem cells had a significantly higher incidence of skin graft-versus-host disease compared with mice receiving G-CSF mobilized transplants (100 versus 50%, respectively, p = 0.02). These preclinical data show plerixafor, in contrast with G-CSF, does not alter the phenotype and cytokine polarization of T cells, which raises the possibility that T cell-mediated immune sequelae of allogeneic transplantation in humans may differ when donor allografts are mobilized with plerixafor compared with G-CSF. C1 [Lundqvist, Andreas; Smith, Aleah L.; Wong, Susan; Cook, Lisa; Ramos, Catalina; McCoy, J. Philip, Jr.; Dunbar, Cynthia; Childs, Richard W.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Lundqvist, Andreas] Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden. [Takahashi, Yoshiyuki] Nagoya Univ, Grad Sch Med, Nagoya, Aichi 4668550, Japan. [Bahceci, Erkut] Yale Univ, Sch Med, Sect Med Oncol, New Haven, CT 06520 USA. [Tawab, Abdul; Kurlander, Roger] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Read, Elizabeth J.; Khuu, Hanh M.; Bolan, Charles D.; Joo, Jungnam; Geller, Nancy; Leitman, Susan F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Calandra, Gary] Sanofi Oncol, Cambridge, MA 02139 USA. RP Childs, RW (reprint author), NHLBI, Hematol Branch, NIH, 10CRC,3-5330, Bethesda, MD 20892 USA. EM childsr@nhlbi.nih.gov OI Lundqvist, Andreas/0000-0002-9709-2970 FU National Institutes of Health, National Heart, Lung, and Blood Institute, Hematology Branch; Swedish and European Research Councils FX This work was supported by the intramural research program of the National Institutes of Health, National Heart, Lung, and Blood Institute, Hematology Branch and the Swedish and European Research Councils (A.L.). NR 45 TC 10 Z9 10 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2013 VL 191 IS 12 BP 6241 EP 6249 DI 10.4049/jimmunol.1301148 PG 9 WC Immunology SC Immunology GA 272TM UT WOS:000328483900051 PM 24244025 ER PT J AU Yaniv, Y AF Yaniv, Yael TI Cardiac troponin I phosphorylation and the force-length relationship SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material ID GENERATION; DEPENDENCE C1 Natl Inst Aging, Program, Biomed Res Ctr, Lab Cardiovascular Sci, Baltimore, MD USA. RP Yaniv, Y (reprint author), Natl Inst Aging, Program, Biomed Res Ctr, Lab Cardiovascular Sci, Baltimore, MD USA. EM yanivyael@gmail.com RI Yaniv, Yael/B-3311-2015 OI Yaniv, Yael/0000-0002-5183-6284 FU Intramural NIH HHS NR 9 TC 0 Z9 0 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD DEC 15 PY 2013 VL 591 IS 24 BP 6135 EP 6136 DI 10.1113/jphysiol.2013.265090 PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 274BI UT WOS:000328579700007 PM 24339151 ER PT J AU Seo, YJ Muench, L Reid, A Chen, JZ Kang, YN Hooker, JM Volkow, ND Fowler, JS Kim, SW AF Seo, Young Jun Muench, Lisa Reid, Alicia Chen, Jinzhu Kang, Yeona Hooker, Jacob M. Volkow, Nora D. Fowler, Joanna S. Kim, Sung Won TI Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Carbon-11; Positron emission tomography; SAHA; Brain; Epigenetics; Brain permeability ID TRICHOSTATIN-A; INHIBITORS; POTENT; RADIOSYNTHESIS; MECHANISMS; DISORDERS; EFFICIENT; ESTERS; MS-275 AB Histone deacetylases (HDACs) regulate gene expression by inducing conformational changes in chromatin. Ever since the discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA) stimulated the recent development of suberoylanilide (SAHA, Zolinza (R)), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study epigenetic regulation and HDAC engagement for drug development for diseases including cancer and disorders. 6-([F-18]Fluoroacetamido)-1-hexanoicanilide ([F-18]FAHA) was recently developed as a HDAC substrate and shows moderate blood-brain barrier (BBB) permeability and specific signal (by metabolic trapping/or deacetylation) but rapid metabolism. Here, we report the radiosynthesis of two carbon-11 labeled candidate radiotracers (substrate-and inhibitor-based radioligand) for HDAC and their evaluation in non-human primate brain. PET studies showed very low brain uptake and rapid metabolism of both labeled compounds but revealed a surprising enhancement of brain penetration by F for H substitution when comparing one of these to [F-18]FAHA. Further structural refinement is needed for the development of brain-penetrant, metabolically stable HDAC radiotracers and to understand the role of fluorine substitution on brain penetration. Published by Elsevier Ltd. C1 [Seo, Young Jun; Chen, Jinzhu; Kang, Yeona; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. [Seo, Young Jun] Chonbuk Natl Univ, Dept Chem, Jeonju 561756, South Korea. [Muench, Lisa; Volkow, Nora D.; Kim, Sung Won] NIAAA, Lab Neuroimaging, Bethesda, MD 20892 USA. [Reid, Alicia] CUNY Medgar Evers Coll, Dept Phys Environm & Comp Sci, Brooklyn, NY 11225 USA. [Hooker, Jacob M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA 02129 USA. [Volkow, Nora D.] NIDA, Rockville, MD 20852 USA. RP Hooker, JM (reprint author), NIAAA, 10 Ctr Dr,Rm B2L304, Bethesda, MD 20892 USA. EM hooker@nmr.mgh.harvard.edu; sunny.kim@nih.gov OI Hooker, Jacob/0000-0002-9394-7708 FU DOE [BR KP1503010]; NIH [1R01DA030321]; U.S. Department of Energy [DEAC02-98CH10886]; National Institute on Alcohol Abuse and Alcoholism FX This work was supported by DOE grant B&R KP1503010 and NIH grant 1R01DA030321. In addition, the work at Brookhaven National Laboratory was performed under contract DEAC02-98CH10886 with the U.S. Department of Energy, and with infrastructure support from its Office of Biological and Environmental Research. Salary support for SWK and LM was provided by the intramural program of the National Institute on Alcohol Abuse and Alcoholism. We are grateful to the PET radiotracer and imaging team at BNL (Dr. Michael Schueller, David Alexoff, Colleen Shea, Youwen Xu, Pauline Carter, Payton King, Barbara Hubbard and Don Warner) for carrying out primate imaging experiments. We used two computational chemistry programs available in the Center for Molecular Modeling (http://cmm.cit.nih.gov) and the Helix Systems (http://helix.nih.gov) at the National Institutes of Health, Bethesda, MD. NR 30 TC 10 Z9 10 U1 3 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD DEC 15 PY 2013 VL 23 IS 24 BP 6700 EP 6705 DI 10.1016/j.bmcl.2013.10.038 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 263DU UT WOS:000327787700033 PM 24210501 ER PT J AU Magill, SS Klompas, M Balk, R Burns, SM Deutschman, CS Diekema, D Fridkin, S Greene, L Guh, A Gutterman, D Hammer, B Henderson, D Hess, D Hill, NS Horan, T Kollef, M Levy, M Septimus, E VanAntwerpen, C Wright, D Lipsett, P AF Magill, Shelley S. Klompas, Michael Balk, Robert Burns, Suzanne M. Deutschman, Clifford S. Diekema, Daniel Fridkin, Scott Greene, Linda Guh, Alice Gutterman, David Hammer, Beth Henderson, David Hess, Dean Hill, Nicholas S. Horan, Teresa Kollef, Marin Levy, Mitchell Septimus, Edward VanAntwerpen, Carole Wright, Don Lipsett, Pamela TI Developing a New, National Approach to Surveillance for Ventilator-Associated Events: Executive Summary SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE ventilator-associated pneumonia; intensive care unit; epidemiology; public health; critical care; mechanical ventilation C1 [Magill, Shelley S.; Fridkin, Scott; Guh, Alice; Horan, Teresa] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30329 USA. [Klompas, Michael] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Klompas, Michael] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Klompas, Michael] Brigham & Womens Hosp, Infect Control Dept, Boston, MA 02115 USA. [Klompas, Michael] Soc Healthcare Epidemiol Amer, Arlington, VA USA. [Balk, Robert] Rush Univ, Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60612 USA. [Balk, Robert; Burns, Suzanne M.; Deutschman, Clifford S.; Gutterman, David; Hammer, Beth; Hill, Nicholas S.; Kollef, Marin; Levy, Mitchell; Lipsett, Pamela] Crit Care Soc Collaborat Amer Assoc Crit Care Nur, Charlottesville, VA USA. [Burns, Suzanne M.] Univ Virginia, Sch Nursing Crit & Acute Care, Charlottesville, VA USA. [Deutschman, Clifford S.] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Diekema, Daniel] Univ Iowa, Carver Coll Med, Div Infect Dis, Iowa City, IA USA. [Diekema, Daniel] Healthcare Infect Control Practices Advisory Comm, Atlanta, GA USA. [Greene, Linda] Rochester Gen Hlth Syst, Infect Prevent & Control Dept, Rochester, NY USA. [Greene, Linda] Assoc Profess Infect Control & Epidemiol, Washington, DC USA. [Gutterman, David] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Hammer, Beth] Zablocki VA Med Ctr, Dept Cardiol, Milwaukee, WI USA. [Henderson, David] NIH, Hosp Epidemiol & Qual Improvement, Ctr Clin, Bethesda, MD 20892 USA. [Hess, Dean] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Hess, Dean] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Hess, Dean] Amer Assoc Resp Care, Irving, TX USA. [Hill, Nicholas S.] Tufts Med Ctr, Div Pulm & Crit Care Med, Boston, MA USA. [Kollef, Marin] Washington Univ, Div Pulm & Crit Care Med, St Louis, MO USA. [Levy, Mitchell] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Pulm Crit Care & Sleep, Providence, RI 02903 USA. [Septimus, Edward] Texas A&M Hlth Sci Ctr, Dept Internal Med, College Stn, TX USA. [Septimus, Edward] Infect Dis Soc Amer, Arlington, VA USA. [VanAntwerpen, Carole] New York State Dept Hlth, Bur Healthcare Associated Infect, Albany, NY USA. [VanAntwerpen, Carole] Council State & Terr Epidemiologists, Atlanta, GA USA. [Wright, Don] US Dept HHS, Off Dis Prevent & Hlth Promot, Washington, DC 20201 USA. [Lipsett, Pamela] Johns Hopkins Univ, Sch Med, Dept Surg Anesthesiol & Crit Care Med, Baltimore, MD USA. RP Magill, SS (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, 1600 Clifton Rd,MS A-24, Atlanta, GA 30329 USA. EM smagill@cdc.gov NR 2 TC 12 Z9 13 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2013 VL 57 IS 12 BP 1742 EP 1746 DI 10.1093/cid/cit577 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 262FT UT WOS:000327720400013 PM 24280662 ER PT J AU Mullis, CE Laeyendecker, O Reynolds, SJ Ocama, P Quinn, J Boaz, I Gray, RH Kirk, GD Thomas, DL Quinn, TC Stabinski, L AF Mullis, Caroline E. Laeyendecker, Oliver Reynolds, Steven J. Ocama, Ponsiano Quinn, Jeffrey Boaz, Iga Gray, Ronald H. Kirk, Gregory D. Thomas, David L. Quinn, Thomas C. Stabinski, Lara TI High Frequency of False-Positive Hepatitis C Virus Enzyme-Linked Immunosorbent Assay in Rakai, Uganda SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE hepatitis C virus; ELISA; Africa ID HIV; EPIDEMIOLOGY; PREVALENCE; INFECTION; PERFORMANCE; ANTIBODIES; AFRICA AB The prevalence of hepatitis C virus (HCV) infection in sub-Saharan Africa remains unclear. We tested 1000 individuals from Rakai, Uganda, with the Ortho version 3.0 HCV enzyme-linked immunosorbent assay. All serologically positive samples were tested for HCV RNA. Seventy-six of the 1000 (7.6%) participants were HCV antibody positive; none were confirmed by detection of HCV RNA. C1 [Mullis, Caroline E.; Laeyendecker, Oliver; Reynolds, Steven J.; Quinn, Jeffrey; Thomas, David L.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Laeyendecker, Oliver; Reynolds, Steven J.; Quinn, Thomas C.; Stabinski, Lara] NIAID, Div Intramural Res, NIH, Baltimore, MD USA. [Ocama, Ponsiano] Makerere Univ, Dept Med, Kampala, Uganda. [Boaz, Iga] Rakai Hlth Sci Program, Entebbe, Uganda. [Gray, Ronald H.; Kirk, Gregory D.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Laeyendecker, O (reprint author), NIAID, LIR, NIH, 855 N Wolfe St,Rm 538A, Baltimore, MD USA. EM olaeyen1@jhmi.edu OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); HIV Prevention Trials Network; NIAID; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Mental Health; Office of AIDS Research, of the NIH; Department of Health and Human Services [UM1-AI068613, R37 DA 13806] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). Additional support was provided by the HIV Prevention Trials Network sponsored by the NIAID, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Mental Health, and the Office of AIDS Research, of the NIH, Department of Health and Human Services (UM1-AI068613 and R37 DA 13806). NR 11 TC 16 Z9 16 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2013 VL 57 IS 12 BP 1747 EP 1750 DI 10.1093/cid/cit602 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 262FT UT WOS:000327720400014 PM 24051866 ER PT J AU Platt, JL Rogers, BJ Rogers, KC Harwood, AJ Kimmel, AR AF Platt, James L. Rogers, Benjamin J. Rogers, Kelley C. Harwood, Adrian J. Kimmel, Alan R. TI Different CHD chromatin remodelers are required for expression of distinct gene sets and specific stages during development of Dictyostelium discoideum SO DEVELOPMENT LA English DT Article DE SNF2; Transcriptome profiling; RNA-seq; Chemotaxis; Growth; Differentiation ID CHARGE SYNDROME; SACCHAROMYCES-CEREVISIAE; SNF2 FAMILY; GROUP-SIZE; PROTEIN; CHEMOTAXIS; MUTATIONS; DOMAIN; CHROMODOMAINS; TRANSCRIPTION AB Control of chromatin structure is crucial for multicellular development and regulation of cell differentiation. The CHD (chromodomain-helicase-DNA binding) protein family is one of the major ATP-dependent, chromatin remodeling factors that regulate nucleosome positioning and access of transcription factors and RNA polymerase to the eukaryotic genome. There are three mammalian CHD subfamilies and their impaired functions are associated with several human diseases. Here, we identify three CHD orthologs (ChdA, ChdB and ChdC) in Dictyostelium discoideum. These CHDs are expressed throughout development, but with unique patterns. Null mutants lacking each CHD have distinct phenotypes that reflect their expression patterns and suggest functional specificity. Accordingly, using genome-wide (RNA-seq) transcriptome profiling for each null strain, we show that the different CHDs regulate distinct gene sets during both growth and development. ChdC is an apparent ortholog of the mammalian Class III CHD group that is associated with the human CHARGE syndrome, and GO analyses of aberrant gene expression in chdC nulls suggest defects in both cell-autonomous and non-autonomous signaling, which have been confirmed through analyses of chdC nulls developed in pure populations or with low levels of wild-type cells. This study provides novel insight into the broad function of CHDs in the regulation development and disease, through chromatin-mediated changes in directed gene expression. C1 [Platt, James L.; Rogers, Kelley C.; Kimmel, Alan R.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Platt, James L.; Rogers, Benjamin J.; Harwood, Adrian J.] Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales. RP Harwood, AJ (reprint author), Cardiff Univ, Sch Biosci, Museum Ave, Cardiff CF10 3AX, S Glam, Wales. EM harwoodaj@cf.ac.uk; alank@helix.nih.gov OI Harwood, Adrian/0000-0003-3124-5169 FU National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases; Wellcome Trust/NIH FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), the National Institute of Diabetes and Digestive and Kidney Diseases, and a Wellcome Trust/NIH Programme Studentship to J.L.P. Deposited in PMC for immediate release. NR 74 TC 3 Z9 3 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 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD DEC 15 PY 2013 VL 140 IS 24 BP 4926 EP 4936 DI 10.1242/dev.099879 PG 11 WC Developmental Biology SC Developmental Biology GA 264PR UT WOS:000327892200011 PM 24301467 ER PT J AU Sanders, AR Goring, HHH Duan, JB Drigalenko, EI Moy, W Freda, J He, DL Shi, JX Gejman, PV AF Sanders, Alan R. Goering, Harald H. H. Duan, Jubao Drigalenko, Eugene I. Moy, Winton Freda, Jessica He, Deli Shi, Jianxin Gejman, Pablo V. CA MGS TI Transcriptome study of differential expression in schizophrenia SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; FUNCTIONAL PROMOTER POLYMORPHISM; GLOBAL GENE-EXPRESSION; HISTONE MESSENGER-RNAS; OF-THE-LITERATURE; AUTOIMMUNE-DISEASES; BIPOLAR DISORDER; CELL-CYCLE; RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS AB Schizophrenia genome-wide association studies (GWAS) have identified common SNPs, rare copy number variants (CNVs) and a large polygenic contribution to illness risk, but biological mechanisms remain unclear. Bioinformatic analyses of significantly associated genetic variants point to a large role for regulatory variants. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines (LCLs) from 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate (FDR) of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, microRNA (miRNA) processing and immunity. This functional diversity is consistent with schizophrenia's likely significant pathophysiological heterogeneity. The overall enrichment of immune-related genes among those differentially expressed by affection status is consistent with hypothesized immune contributions to schizophrenia risk. The observed differential expression of extended major histocompatibility complex (xMHC) region histones (HIST1H2BD, HIST1H2BC, HIST1H2BH, HIST1H2BG and HIST1H4K) converges with the genetic evidence from GWAS, which find the xMHC to be the most significant susceptibility locus. Among the differentially expressed immune-related genes, B3GNT2 is implicated in autoimmune disorders previously tied to schizophrenia risk (rheumatoid arthritis and Graves' disease), and DICER1 is pivotal in miRNA processing potentially linking to miRNA alterations in schizophrenia (e. g. MIR137, the second strongest GWAS finding). Our analysis provides novel candidate genes for further study to assess their potential contribution to schizophrenia. C1 [Sanders, Alan R.; Duan, Jubao; Moy, Winton; Freda, Jessica; He, Deli; Gejman, Pablo V.] NorthShore Univ HealthSyst, Dept Psychiat & Behav Sci, Evanston, IL 60201 USA. [Sanders, Alan R.; Duan, Jubao; Gejman, Pablo V.] Univ Chicago, Dept Psychiat & Behav Sci, Chicago, IL 60637 USA. [Goering, Harald H. H.; Drigalenko, Eugene I.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX 78227 USA. [Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [MGS] Mol Genet Schizophrenia MGS Collaborat, Evanston, IL 60201 USA. RP Sanders, AR (reprint author), 1001 Univ Pl, Evanston, IL 60201 USA. EM alan.sanders.md@gmail.com FU National Institutes of Health (NIH) [RC2MH090030, R01MH067257, R01MH 059588, R01MH059571, R01MH059565, R01MH059587, R01MH060870, R01M H059566, R01MH059586, R01MH061675, R01MH060879, R01MH081800, U01MH046276, U01MH046289, U01MH046318, U01MH079469, U01MH079470, U54RR 020278, RR017515]; Genetic Association Information Network (GAIN); Paul Michael Donovan Charitable Foundation FX This work was supported primarily by the National Institutes of Health (NIH grant RC2MH090030 to A. R. S.); as well as for MGS by NIH grants (R01MH067257 to N.G.B., R01MH 059588 to B.J.M., R01MH059571 to P. V. G., R01MH059565 to R. F., R01MH059587 to F. A., R01MH060870 to W. F. B., R01M H059566 to D. W. B., R01MH059586 to J.M.S., R01MH061675 to D. F. L., R01MH060879 to C. R. C., R01MH081800 to P. V. G., U01MH046276 to C. R. C., U01MH046289 to C. Kaufmann, U01MH046318 to M. T. Tsuang, U01MH079469 to P. V. G. and U01MH079470 to D. F. L.), the Genetic Association Information Network (GAIN, for genotyping of half of the EA sample and almost all the AA sample), and The Paul Michael Donovan Charitable Foundation. Genotyping was carried out by the Center for Genotyping and Analysis at the Broad Institute of Harvard and MIT (S. G. and D. B. M.), supported by NIH grant U54RR 020278. Analyses done in San Antonio (E. I. D., H. H. H. G.) were conducted in facilities constructed with support from NIH grant RR017515, and a gift from the AT&T Foundation. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 173 TC 27 Z9 27 U1 5 U2 25 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD DEC 15 PY 2013 VL 22 IS 24 BP 5001 EP 5014 DI 10.1093/hmg/ddt350 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 259QY UT WOS:000327542600011 PM 23904455 ER PT J AU Wang, HS Haiman, CA Burnett, T Fortini, BK Kolonel, LN Henderson, BE Signorello, LB Blot, WJ Keku, TO Berndt, SI Newcomb, PA Pande, M Amos, CI West, DW Casey, G Sandler, RS Haile, R Stram, DO Le Marchand, L AF Wang, Hansong Haiman, Christopher A. Burnett, Terrilea Fortini, Barbara K. Kolonel, Laurence N. Henderson, Brian E. Signorello, Lisa B. Blot, William J. Keku, Temitope O. Berndt, Sonja I. Newcomb, Polly A. Pande, Mala Amos, Christopher I. West, Dee W. Casey, Graham Sandler, Robert S. Haile, Robert Stram, Daniel O. Le Marchand, Loic TI Fine-mapping of genome-wide association study-identified risk loci for colorectal cancer in African Americans SO HUMAN MOLECULAR GENETICS LA English DT Article ID SUSCEPTIBILITY LOCI; GENETIC ASSOCIATION; CHINESE POPULATION; WINNERS CURSE; VARIANTS; METAANALYSIS; SCAN; 8Q24; PARAMETERS; ALLELES AB Genome-wide association studies of colorectal cancer (CRC) in Europeans and Asians have identified 21 risk susceptibility regions [ 29 index single-nucleotide polymorphisms (SNPs)]. Characterizing these risk regions in diverse racial groups with different linkage disequilibrium (LD) structure can help localize causal variants. We examined associations between CRC and all 29 index SNPs in 6597 African Americans (1894 cases and 4703 controls). Nine SNPs in eight regions(5q31.1, 6q26-q27, 8q23.3, 8q24.21, 11q13.4, 15q13.3, 18q21.1 and 20p12.3) formally replicated in our data with one-sided P-values <0.05 and the same risk directions as reported previously. We performed fine-mapping of the 21 risk regions(including 250 kb on both sides of the index SNPs) using genotyped and imputed markers at the density of the 1000 Genomes Project to search for additional or more predictive risk markers. Among the SNPs correlated with the index variants, two markers, rs12759486 (or rs7547751, a putative functional variant in perfect LD with it) in 1q41 and rs7252505 in 19q13.1, were more strongly and statistically significantly associated with CRC (P < 0.0006). The average per allele risk was improved using the replicated index variants and the two new markers (odds ratio 5 1.14, P = 6.5 x 10(-16)) in African Americans, compared with using all index SNPs (odds ratio = 1.07, P = 3.4 x 10(-10)). The contribution of the two new risk SNPs to CRC heritability was estimated to be 1.5% in African Americans. This study highlights the importance of fine-mapping in diverse populations. C1 [Wang, Hansong; Burnett, Terrilea; Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA. [Haiman, Christopher A.; Fortini, Barbara K.; Henderson, Brian E.; Casey, Graham; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Haiman, Christopher A.; Fortini, Barbara K.; Henderson, Brian E.; Casey, Graham; Stram, Daniel O.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Signorello, Lisa B.; Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Signorello, Lisa B.; Blot, William J.] Vanderbilt Univ, Dept Med, Div Epidemiol, Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Signorello, Lisa B.; Blot, William J.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Keku, Temitope O.; Sandler, Robert S.] Univ N Carolina, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC USA. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Pande, Mala] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Lebanon, NH 03756 USA. [West, Dee W.] Canc Prevent Inst Calif, Fremont, CA USA. [Haile, Robert] Stanford Canc Inst, Stanford, CA USA. RP Wang, HS (reprint author), Univ Hawaii, Ctr Canc, 701 Ilalo St, Honolulu, HI 96813 USA. EM hansongw@hawaii.edu FU National Cancer Institute (NCI) [R01CA126895, R01CA126895-S1, R01CA104132]; California Breast Cancer Research Program grant [15UB-8402]; NCI [UM1CA164973, R37CA54281, P01CA33619, R01CA 63464, U01CA074799, U01CA074794, U01CA074806, R01CA092447, U01CA93326, R01CA66635, K07CA160753]; MD Anderson University Cancer Fund; MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment; Center for Clinical and Translational Sciences of the University of Texas Health Science Center at Houston; NCI Cancer Center Support Grant [CA16672] FX This work was supported by National Cancer Institute (NCI) grants (R01CA126895, R01CA126895-S1 and R01CA104132) and California Breast Cancer Research Program grant (15UB-8402). The MEC study is funded by NCI grants (UM1CA164973, R37CA54281, P01CA33619 and R01CA 63464). The CCFR studies included were funded by NCI grants (U01CA074799 to Familial Colorectal Neoplasia Collaborative Group at University of Southern California, U01CA074794 to Seattle Colorectal Cancer Family Registry and U01CA074806 to University of Hawaii Colorectal Cancer Family Registry). The SCCS was funded by NCI grant (R01CA092447). UNC-CanCORS was funded by NCI grant (U01CA93326). The North Carolina Rectal Cancer study was funded by NCI grant (R01CA66635). The MD Anderson data collection was supported in part by the MD Anderson University Cancer Fund, the MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment, the Center for Clinical and Translational Sciences of the University of Texas Health Science Center at Houston, NCI Cancer Center Support Grant (CA16672) and NCI grant (K07CA160753). NR 33 TC 15 Z9 16 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD DEC 15 PY 2013 VL 22 IS 24 BP 5048 EP 5055 DI 10.1093/hmg/ddt337 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 259QY UT WOS:000327542600015 PM 23851122 ER PT J AU Amiri-Kordestani, L Mena, E Lindenberg, ML Kurdziel, K Choyke, P Patronas, N Frye, R Lin, N Bala, S Fojo, T Bates, S AF Amiri-Kordestani, L. Mena, E. Lindenberg, M. L. Kurdziel, K. Choyke, P. Patronas, N. Frye, R. Lin, N. Bala, S. Fojo, T. Bates, S. TI 18F-FLT-PET/CT for the prediction of response to ANG-1005 therapy in patients with brain metastases from breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA P4-01-09 DI 10.1158/0008-5472.SABCS13-P4-01-09 PG 1 WC Oncology SC Oncology GA V40RY UT WOS:000209496901265 ER PT J AU Anderson, WF AF Anderson, W. F. TI Divergent trends in breast cancer subtypes, a manifestation of cancer heterogeneity SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Anderson, W. F.] NCI, Bethesda, MD 20892 USA. NR 0 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 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA ES05-2 DI 10.1158/0008-5472.SABCS13-ES05-2 PG 2 WC Oncology SC Oncology GA V40RY UT WOS:000209496900020 ER PT J AU Berg, P Kirolikar, S Ginsburg, E Schwartz, A Simmens, S AF Berg, P. Kirolikar, S. Ginsburg, E. Schwartz, A. Simmens, S. TI BP1, a homeoprotein, regulates estrogen receptor alpha and induces estrogen independence SO CANCER RESEARCH LA English DT Meeting Abstract C1 George Washington Univ, Washington, DC USA. NCI, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Washington, DC 20037 USA. NR 0 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 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA P5-09-11 DI 10.1158/0008-5472.SABCS13-P5-09-11 PG 2 WC Oncology SC Oncology GA V40RY UT WOS:000209496902158 ER PT J AU Cortazar, P Zhang, L Untch, M Mehta, K Constantino, J Wolmark, N Bonnefoi, H Piccart, M Gianni, L Valagussa, P Zujewski, JA Justice, R Loibl, S Swain, SM Bogaerts, J Baselga, J Prowell, TM Rastogi, P Sridhara, R Tang, S Pazdur, R Mamounas, E von Minckwitz, G AF Cortazar, P. Zhang, L. Untch, M. Mehta, K. Constantino, J. Wolmark, N. Bonnefoi, H. Piccart, M. Gianni, L. Valagussa, P. Zujewski, J. A. Justice, R. Loibl, S. Swain, S. M. Bogaerts, J. Baselga, J. Prowell, T. M. Rastogi, P. Sridhara, R. Tang, S. Pazdur, R. Mamounas, E. von Minckwitz, G. TI A definition of a high-risk early-breast cancer population based on data from the collaborative trials in neoadjuvant breast cancer (CTNeoBC) meta-analysis SO CANCER RESEARCH LA English DT Meeting Abstract C1 HELIOS Klinikum Berlin Buch, D-13125 Berlin, Germany. GBG Forsch GmbH, Neu Isenburg, Germany. NSABP, Pittsburgh, PA USA. INSERM, U916, Inst Bergonie, F-75654 Paris 13, France. Inst Jules Bordet, B-1000 Brussels, Belgium. San Raffaele Sci Insitute, Milan, Italy. Fdn Michelangelo, Milan, Italy. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Medstar Washington Hosp Ctr, Washington, DC USA. EORTC Headquarters, Brussels, Belgium. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Orlando Hlth MD Anderson Canc Ctr, Houston, TX USA. NR 0 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 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA P5-17-01 DI 10.1158/0008-5472.SABCS13-P5-17-01 PG 2 WC Oncology SC Oncology GA V40RY UT WOS:000209496902235 ER PT J AU Goetz, MP Suman, VA Reid, JR Northfelt, DW Mahr, MA Dockter, T Haluska, PJ Kuffel, M Burhow, S Safgren, S McGovern, R Collins, J Streicher, H Hawse, JR Erlichman, C Ingle, JN Ames, MM AF Goetz, M. P. Suman, V. A. Reid, J. R. Northfelt, D. W. Mahr, M. A. Dockter, T. Haluska, P. J. Kuffel, M. Burhow, S. Safgren, S. McGovern, R. Collins, J. Streicher, H. Hawse, J. R. Erlichman, C. Ingle, J. N. Ames, M. M. TI A first-in-human phase I study of the tamoxifen (TAM) metabolite, Z-endoxifen hydrochloride (Z-Endx) in women with aromatase inhibitor (AI) refractory metastatic breast cancer (MBC) (NCT01327781) SO CANCER RESEARCH LA English DT Meeting Abstract C1 Mayo Clin, Rochester, MN USA. Mayo Clin, Scottsdale, AZ USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA PD3-4 DI 10.1158/0008-5472.SABCS13-PD3-4 PG 1 WC Oncology SC Oncology GA V40RY UT WOS:000209496903069 ER PT J AU Gucalp, A Morris, PG Zhou, XK Giri, DD Lyengar, NM Heckman-Stoddard, BM Dunn, B Garber, JE Crew, KD Hershman, DL Nangia, JR Cook, ED Brown, PH Dannenberg, AJ Hudis, CA AF Gucalp, A. Morris, P. G. Zhou, X. K. Giri, D. D. Lyengar, N. M. Heckman-Stoddard, B. M. Dunn, B. Garber, J. E. Crew, K. D. Hershman, D. L. Nangia, J. R. Cook, E. D. Brown, P. H. Dannenberg, A. J. Hudis, C. A. TI A multicenter phase II study of docosahexaenoic acid (DHA) in triple negative breast cancer (TNBC) survivors SO CANCER RESEARCH LA English DT Meeting Abstract C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Columbia Univ, Med Ctr, New York, NY USA. Baylor Coll Med, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Weill Cornell Med Coll, New York, NY USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. EM gucalpa@mskcc.org NR 0 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 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA OT3-3-01 DI 10.1158/0008-5472.SABCS13-OT3-3-01 PG 2 WC Oncology SC Oncology GA V40RY UT WOS:000209496900100 ER PT J AU Janosky, M Demaria, S Novik, Y Oratz, R Tiersten, A Goldberg, J Wang, E Marincola, F Fenton-Kerimian, M Maisonet, O Axelrod, D Sacris, E Levine, P Formenti, S Adams, S AF Janosky, M. Demaria, S. Novik, Y. Oratz, R. Tiersten, A. Goldberg, J. Wang, E. Marincola, F. Fenton-Kerimian, M. Maisonet, O. Axelrod, D. Sacris, E. Levine, P. Formenti, S. Adams, S. TI Novel combination of toll-like receptor (TLR)-7 agonist imiquimod and local radiotherapy in the treatment of breast cancer chest wall recurrences or skin metastases SO CANCER RESEARCH LA English DT Meeting Abstract C1 NYU, New York, NY 10003 USA. NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA OT2-1-02 DI 10.1158/0008-5472.SABCS13-OT2-1-02 PG 2 WC Oncology SC Oncology GA V40RY UT WOS:000209496900057 ER PT J AU Jassem, J Duchnowska, R Hua, E Qian, Y Biernat, W Sosinska-Mielcarek, K Gril, B Stark, A Hewitt, S Liewehr, DJ Steinberg, SM Palmieri, D Steeg, PS AF Jassem, J. Duchnowska, R. Hua, E. Qian, Y. Biernat, W. Sosinska-Mielcarek, K. Gril, B. Stark, A. Hewitt, S. Liewehr, D. J. Steinberg, S. M. Palmieri, D. Steeg, P. S. TI Profound prevention of experimental brain metastases of breast cancer by temozolomide in a MGMT-dependent manner SO CANCER RESEARCH LA English DT Meeting Abstract C1 Med Univ Gdansk, Gdansk, Poland. NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bthesda, MD USA. Mil Inst Med, Warsaw, Poland. Reg Canc Ctr, Gdansk, Poland. NCI, Lab Anim Sci Program, SAIC Frederick, NIH, Frederick, MD 21701 USA. UKSH Campus Kiel, Klin Neurochirurg, Kiel, Germany. NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA P6-11-04 DI 10.1158/0008-5472.SABCS13-P6-11-04 PG 1 WC Oncology SC Oncology GA V40RY UT WOS:000209496903026 ER PT J AU Julian, TB Anderson, SJ Krag, DN Weaver, DL Costantino, JP Ashikaga, T Harlow, SP Mamounas, EP Wolmark, N AF Julian, T. B. Anderson, S. J. Krag, D. N. Weaver, D. L. Costantino, J. P. Ashikaga, T. Harlow, S. P. Mamounas, E. P. Wolmark, N. TI 10-yr follow-up results of occult detected sentinel node disease: NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection (SNR) to conventional axillary dissection (AD) in clinically node-negative breast cancer patients SO CANCER RESEARCH LA English DT Meeting Abstract C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Allegheny Gen Hosp West Penn Allegheny Hlth Syst, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project Biostat, Pittsburgh, PA USA. Univ Vermont, Burlington, VT USA. MD Anderson Canc Ctr, Orlando, FL USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA S2-05 DI 10.1158/0008-5472.SABCS13-S2-05 PG 1 WC Oncology SC Oncology GA V40RY UT WOS:000209496903112 ER PT J AU Nielsen, TO Polley, MYC AF Nielsen, T. O. Polley, M-Y C. CA Int Ki67 Breast Canc Working Grp TI An international Ki67 reproducibility study: Harmonizing scoring methodology SO CANCER RESEARCH LA English DT Meeting Abstract C1 Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. NCI, Bethesda, MD 20892 USA. BIG NABCG Collaborat, Brussels, Belgium. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA S2-07 DI 10.1158/0008-5472.SABCS13-S2-07 PG 2 WC Oncology SC Oncology GA V40RY UT WOS:000209496903114 ER PT J AU Nussenzweig, A Callen, E AF Nussenzweig, A. Callen, E. TI 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Nussenzweig, A.; Callen, E.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA ES01-2 DI 10.1158/0008-5472.SABCS13-ES01-2 PG 2 WC Oncology SC Oncology GA V40RY UT WOS:000209496900012 ER PT J AU O'Sullivan, CC Holmes, E Spielmann, M Perez, EA Joensuu, H Costantino, JP Delaloge, S Rastogi, P Zardavas, D Ballman, KV de Azambuja, E Piccart-Gebhart, M Zujewski, JA Gelber, RD AF O'Sullivan, C. C. Holmes, E. Spielmann, M. Perez, E. A. Joensuu, H. Costantino, J. P. Delaloge, S. Rastogi, P. Zardavas, D. Ballman, K. V. de Azambuja, E. Piccart-Gebhart, M. Zujewski, J. A. Gelber, R. D. TI The prognosis of small HER2+breast cancers: A meta-analysis of the randomized trastuzumab trials SO CANCER RESEARCH LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. Frontier Sci Scotland, Kincraig, Inverness, Scotland. Inst Gustave Roussy, Villejuif, France. Inst Jules Bordet, B-1000 Brussels, Belgium. Mayo Clin, Jacksonville, FL 32224 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Helsinki, Cent Hosp, FIN-00014 Helsinki, Finland. Dana Farber Canc Inst, Boston, MA 02115 USA. Mayo Clin, Rochester, MN USA. NR 0 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 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA S6-03 DI 10.1158/0008-5472.SABCS13-S6-03 PG 1 WC Oncology SC Oncology GA V40RY UT WOS:000209496903138 ER PT J AU Park, IH Kong, SY Ro, JY Kwon, Y Kang, JH Mo, HJ Jung, SY Lee, S Lee, KS Kang, HS Lee, E Ro, J AF Park, I. H. Kong, S-Y Ro, J. Y. Kwon, Y. Kang, J. H. Mo, H. J. Jung, S-Y Lee, S. Lee, K. S. Kang, H-S Lee, E. Ro, J. TI Prognostic implications of tumor-infiltrating lymphocytes (TIL) in association with PD-L1 expression, and serum cytokine levels in early breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Natl Canc Ctr, Ctr Breast Canc, Bethesda, MD USA. Natl Canc Ctr, Breast & Endocrine Canc Branch, Res Inst, Bethesda, MD USA. Natl Canc Ctr, Bethesda, MD USA. Cornell Univ, Methodist Hosp, Houston, TX USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA P5-01-12 DI 10.1158/0008-5472.SABCS13-P5-01-12 PG 2 WC Oncology SC Oncology GA V40RY UT WOS:000209496902086 ER PT J AU Slamon, DJ Swain, SM Buyse, M Martin, M Geyer, CE Im, YH Pienkowski, T Kim, SB Robert, NJ Steger, G Crown, J Verma, S Eiermann, W Costantino, JP Im, SA Mamounas, EP Schwartzberg, L Paterson, A Mackey, JR Provencher, L Press, MF Thirlwell, M Bee-Munteanu, V Henschel, V Crepelle-Flechais, A Wolmark, N AF Slamon, D. J. Swain, S. M. Buyse, M. Martin, M. Geyer, C. E. Im, Y-H Pienkowski, T. Kim, S-B Robert, N. J. Steger, G. Crown, J. Verma, S. Eiermann, W. Costantino, J. P. Im, S-A Mamounas, E. P. Schwartzberg, L. Paterson, A. Mackey, J. R. Provencher, L. Press, M. F. Thirlwell, M. Bee-Munteanu, V. Henschel, V. Crepelle-Flechais, A. Wolmark, N. TI Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab +/- bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Los Angeles, CA USA. MedStar Washington Hosp Ctr, Washington, MD USA. IDDI, Louvain, Belgium. Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. Maria Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. Inst Oncol, Warsaw, Poland. Virginia Commonwealth Univ, Richmond, VA USA. Asan Med Ctr, Seoul, South Korea. US Oncol Res, Fairfax, VA USA. ABCSG, Vienna, Austria. ICORG, Dublin, Ireland. RotKreuzKlinikum, Munich, Germany. GEICAM, Madrid, Spain. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. F Hoffmann La Roche & Co Ltd, CH-4002 Basel, Switzerland. NSABP, Pittsburgh, PA USA. Seoul Natl Univ, Coll Med, Seoul, South Korea. Ottawa Hosp Reg Canc Ctr, Ottawa, ON, Canada. ACORN Res, Memphis, TN USA. Tom Baker Canc Clin, Calgary, AB, Canada. CHA Univ Quebec, Hop St Sacrement, Quebec City, PQ, Canada. TRIO, Edmonton, AB, Canada. Montreal Gen Hosp, Montreal, PQ H3G 1A4, Canada. MD Anderson Canc Ctr Orlando, Orlando, FL USA. Allegheny Canc Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 8 Z9 8 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA S1-03 DI 10.1158/0008-5472.SABCS13-S1-03 PG 2 WC Oncology SC Oncology GA V40RY UT WOS:000209496903102 ER PT J AU Somlo, G Frankel, P Luu, T Ma, C Arun, B Garcia, A Cigler, T Fleming, G Harvey, H Sparano, J Nanda, R Chew, H Moynihan, T Vahdat, L Goetz, M Hurria, A Mortimer, J Gandara, D Chen, A Weitzel, J AF Somlo, G. Frankel, P. Luu, T. Ma, C. Arun, B. Garcia, A. Cigler, T. Fleming, G. Harvey, H. Sparano, J. Nanda, R. Chew, H. Moynihan, T. Vahdat, L. Goetz, M. Hurria, A. Mortimer, J. Gandara, D. Chen, A. Weitzel, J. TI Efficacy of ABT-888 (veliparib) in patients with BRCA-associated breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 City Hope Canc Ctr, Duarte, CA USA. Washington Univ, Sch Med, St Louis, MO USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. Weill Cornell Med Coll, New York, NY USA. Alliance Clin Trials Oncol, Chicago, IL USA. Milton S Hershey Med Ctr, Hershey, PA USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Univ Chicago, Chicago, IL 60637 USA. Univ Calif, Davis Canc Ctr, Sacramento, CA USA. Mayo Clin, Rochester, MN USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2013 VL 73 SU 24 MA P2-16-05 DI 10.1158/0008-5472.SABCS13-P2-16-05 PG 1 WC Oncology SC Oncology GA V40RY UT WOS:000209496901054 ER PT J AU Lesniak, WG Jyoti, A Mishra, MK Louissaint, N Romero, R Chugani, DC Kannan, S Kannan, RM AF Lesniak, Wojciech G. Jyoti, Amar Mishra, Manoj K. Louissaint, Nicolette Romero, Roberto Chugani, Diane C. Kannan, Sujatha Kannan, Rangaramanujam M. TI Concurrent quantification of tryptophan and its major metabolites SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Kynurenine pathway; Serotonin; Kynurenic acid; Tryptophan metabolites; HPLC ID PERFORMANCE LIQUID-CHROMATOGRAPHY; KYNURENIC ACID; HUMAN SERUM; GASTROINTESTINAL-TRACT; FLUORESCENCE DETECTION; MASS-SPECTROMETRY; AMNIOTIC-FLUID; RABBIT BRAIN; AMINO-ACIDS; RAT PLASMA AB An imbalance in tryptophan (TRP) metabolites is associated with several neurological and inflammatory disorders. Therefore, analytical methods allowing for simultaneous quantification of TRP and its major metabolites would be highly desirable, and may be valuable as potential biomarkers. We have developed a HPLC method for concurrent quantitative determination of tryptophan, serotonin, 5-hydroxyindoleacetic acid, kynurenine, and kynurenic acid in tissue and fluids. The method utilizes the intrinsic spectroscopic properties of TRP and its metabolites that enable UV absorbance and fluorescence detection by HPLC, without additional labeling. The origin of the peaks related to analytes of interest was confirmed by UV-Vis spectral patterns using a PDA detector and mass spectrometry. The developed methods were validated in rabbit fetal brain and amniotic fluid at gestational day 29. Results are in excellent agreement with those reported in the literature for the same regions. This method allows for rapid quantification of tryptophan and four of its major metabolites concurrently. A change in the relative ratios of these metabolites can provide important insights in predicting the presence and progression of neuroinflammation in disorders such as cerebral palsy, autism, multiple sclerosis, Alzheimer disease, and schizophrenia. (C) 2013 Elsevier Inc. All rights reserved. C1 [Lesniak, Wojciech G.; Mishra, Manoj K.; Kannan, Rangaramanujam M.] Wayne State Univ, Childrens Hosp Michigan, Dept Chem Engn & Mat Sci, Detroit, MI 48202 USA. [Lesniak, Wojciech G.; Mishra, Manoj K.; Louissaint, Nicolette; Kannan, Rangaramanujam M.] Johns Hopkins Univ, Dept Ophthalmol, Ctr Nanomed, Sch Med, Baltimore, MD 21287 USA. [Lesniak, Wojciech G.; Jyoti, Amar; Mishra, Manoj K.; Romero, Roberto; Kannan, Rangaramanujam M.] NICHHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. [Lesniak, Wojciech G.; Jyoti, Amar; Mishra, Manoj K.; Romero, Roberto; Kannan, Rangaramanujam M.] NICHHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Jyoti, Amar; Kannan, Sujatha] Johns Hopkins Univ, Dept Anesthesiol & Crit Care Med, Sch Med, Baltimore, MD 21287 USA. [Chugani, Diane C.] Wayne State Univ, Childrens Hosp Michigan, Carman & Ann Adams Dept Pediat, Detroit, MI 48202 USA. RP Kannan, RM (reprint author), Johns Hopkins Sch Med, Dept Ophthalmol, Ctr Nanomed, Baltimore, MD 21218 USA. EM krangar1@jhmi.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH; NICHD [R01HD069562] FX This research was supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, and by R01HD069562, NICHD (S.K.). NR 36 TC 7 Z9 7 U1 8 U2 81 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD DEC 15 PY 2013 VL 443 IS 2 BP 222 EP 231 DI 10.1016/j.ab.2013.09.001 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 255ZQ UT WOS:000327279700017 PM 24036037 ER PT J AU Leibenluft, E Pine, DS AF Leibenluft, Ellen Pine, Daniel S. TI Resting State Functional Connectivity and Depression: In Search of a Bottom Line SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID CINGULATE CORTEX; MAJOR DEPRESSION; DISORDER; NETWORKS; MRI C1 [Leibenluft, Ellen; Pine, Daniel S.] NIMH, Emot & Dev Branch, Div Intramural Res Programs, Natl Inst Hlth,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Leibenluft, E (reprint author), Bldg 15K Room 210,MSC 2670,15K North Dr, Bethesda, MD 20892 USA. EM leibs@mail.nih.gov NR 10 TC 3 Z9 3 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 15 PY 2013 VL 74 IS 12 BP 868 EP 869 DI 10.1016/j.biopsych.2013.10.001 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 252DC UT WOS:000326983900007 PM 24246362 ER PT J AU Enjuanes, A Albero, R Clot, G Navarro, A Bea, S Pinyol, M Martin-Subero, JI Klapper, W Staudt, LM Jaffe, ES Rimsza, L Braziel, RM Delabie, J Cook, JR Tubbs, RR Gascoyne, R Connors, JM Weisenburger, DD Greiner, TC Chan, WC Lopez-Guillermo, A Rosenwald, A Ott, G Campo, E Jares, P AF Enjuanes, Anna Albero, Robert Clot, Guillem Navarro, Alba Bea, Silvia Pinyol, Magda Martin-Subero, Jose I. Klapper, Wolfram Staudt, Louis M. Jaffe, Elaine S. Rimsza, Lisa Braziel, Rita M. Delabie, Jan Cook, James R. Tubbs, Raymond R. Gascoyne, Randy Connors, Joseph M. Weisenburger, Dennis D. Greiner, Timothy C. Chan, Wing-Chung Lopez-Guillermo, Armando Rosenwald, Andreas Ott, German Campo, Elias Jares, Pedro TI Genome-wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE mantle cell lymphoma; genome-wide; hypermethylation; hypomethylation; pathogenesis ID CHRONIC LYMPHOCYTIC-LEUKEMIA; TUMOR-SUPPRESSOR GENES; DNA METHYLATION; FOLLICULAR LYMPHOMA; HYPERMETHYLATION; CANCER; EXPRESSION; PROLIFERATION; P16(INK4A); MICROARRAY AB Mantle cell lymphoma (MCL) is a B-cell neoplasm with an aggressive clinical behavior characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. To clarify the potential contribution of altered DNA methylation in the development and/or progression of MCL, we performed genome-wide methylation profiling of a large cohort of primary MCL tumors (n = 132), MCL cell lines (n = 6) and normal lymphoid tissue samples (n = 31), using the Infinium HumanMethylation27 BeadChip. DNA methylation was compared to gene expression, chromosomal alterations and clinicopathological parameters. Primary MCL displayed a heterogeneous methylation pattern dominated by DNA hypomethylation when compared to normal lymphoid samples. A total of 454 hypermethylated and 875 hypomethylated genes were identified as differentially methylated in at least 10% of primary MCL. Annotation analysis of hypermethylated genes recognized WNT pathway inhibitors and several tumor suppressor genes as frequently methylated, and a substantial fraction of these genes (22%) showed a significant downregulation of their transcriptional levels. Furthermore, we identified a subset of tumors with extensive CpG methylation that had an increased proliferation signature, higher number of chromosomal alterations and poor prognosis. Our results suggest that a subset of MCL displays a dysregulation of DNA methylation characterized by the accumulation of CpG hypermethylation highly associated with increased proliferation that may influence the clinical behavior of the tumors. C1 [Enjuanes, Anna] Univ Barcelona, Genom Unit, Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain. [Albero, Robert; Clot, Guillem; Navarro, Alba; Bea, Silvia; Pinyol, Magda; Campo, Elias; Jares, Pedro] Univ Barcelona, Dept Anat Pathol, Inst Invest Biomed August Pi & Sunyer, Hematopathol Sect,Hosp Clin, Barcelona, Spain. [Martin-Subero, Jose I.] Univ Barcelona, Dept Anat Pathol Pharmacol & Microbiol, Barcelona, Spain. [Klapper, Wolfram] Univ Hosp Schleswig Holstein, Hematopathol Sect, Kiel, Germany. [Klapper, Wolfram] Univ Hosp Schleswig Holstein, Lymph Node Registry, Dept Pathol, Kiel, Germany. [Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jaffe, Elaine S.] NCI, Hematopathol Dept, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Rimsza, Lisa] Univ Arizona, Coll Med, Dept Pathol, Tucson, AZ 85721 USA. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Delabie, Jan] Aker Univ Hosp, Rikshosp, Dept Pathol, Oslo, Norway. [Cook, James R.; Tubbs, Raymond R.] Dept Mol & Anat Pathol, Cleveland, OH USA. [Cook, James R.; Tubbs, Raymond R.] Dept Pathol, Cleveland, OH USA. [Cook, James R.; Tubbs, Raymond R.] Dept Lab Med Inst, Cleveland, OH USA. [Gascoyne, Randy; Connors, Joseph M.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Weisenburger, Dennis D.; Greiner, Timothy C.; Chan, Wing-Chung] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Lopez-Guillermo, Armando] Univ Barcelona, Hosp Clin, Dept Hematol, Barcelona, Spain. [Rosenwald, Andreas] Univ Wurzburg, Inst Pathol, Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. RP Jares, P (reprint author), Hosp Cln, Dept Anat Pathol, Villarroel 170, Barcelona 08036, Spain. EM pjares@clinic.ub.es RI Navarro, Alba/H-2611-2015; ENJUANES, Anna/H-3245-2015; Klapper, Wolfram/S-6314-2016; Bea, Silvia/K-7699-2014 OI Navarro, Alba/0000-0002-4041-0974; ENJUANES, Anna/0000-0002-4679-6687; Jaffe, Elaine/0000-0003-4632-0301; Martin-Subero, Jose Ignacio/0000-0001-8809-5195; Campo, elias/0000-0001-9850-9793; Delabie, Jan/0000-0001-5023-0689; Bea, Silvia/0000-0001-7192-2385 FU Lymphoma Research Foundation [LRF07168]; Asociacion Espanola Contra el Cancer (AECC) of Barcelona; Spanish Ministry of Science and Innovation [CICYT SAF 2008/03630]; Tematica de Investigacion Cooperativa en Cancer (RTICC) [RD06/0020/0039]; Instituto de Salud Carlos III (ISCIII); Spanish Ministry of Science and Innovation & European Regional Development Fund (ERDF) "Una manera de hacer Europa"; Generalitat de Catalunya [2009-SGR-992]; Formacion de personal de Investigacion [FPU11-3997]; Instituto de Salud Carlos III, Fondo Investigaciones Sanitarias [PI11/01177]; Formacion de Personal Investigador [BES-2007-16330]; Interdisciplinary Center for Clinical Research (IZKF); University of Wurzburg, Germany; Robert-Bosch-Stiftung FX Grant sponsor: Lymphoma Research Foundation; Grant number: LRF07168; Grant sponsor: The Asociacion Espanola Contra el Cancer (AECC) of Barcelona 2008; Grant sponsor: The CICYT SAF 2008/03630 from the Spanish Ministry of Science and Innovation; Grant sponsor: Red Tematica de Investigacion Cooperativa en Cancer (RTICC); Grant number: RD06/0020/0039; Grant sponsors Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation & European Regional Development Fund (ERDF) "Una manera de hacer Europa", Generalitat de Catalunya (2009-SGR-992); Grant sponsor: "Formacion de personal de Investigacion"; Grant number: FPU11-3997; Grant sponsor: "Instituto de Salud Carlos III, Fondo Investigaciones Sanitarias"; Grant number: PI11/01177; Grant sponsor: "Formacion de Personal Investigador"; Grant number: BES-2007-16330; Grant sponsors The Interdisciplinary Center for Clinical Research (IZKF), University of Wurzburg, Germany, The Robert-Bosch-Stiftung NR 50 TC 8 Z9 8 U1 2 U2 37 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD DEC 15 PY 2013 VL 133 IS 12 BP 2852 EP 2863 DI 10.1002/ijc.28321 PG 12 WC Oncology SC Oncology GA 233JW UT WOS:000325565600010 PM 23754783 ER PT J AU Koutros, S Baris, D Fischer, A Tang, W Garcia-Closas, M Karagas, MR Schwenn, M Johnson, A Figueroa, J Waddell, R Prokunina-Olsson, L Rothman, N Silverman, DT AF Koutros, Stella Baris, Dalsu Fischer, Alexander Tang, Wei Garcia-Closas, Montserrat Karagas, Margaret R. Schwenn, Molly Johnson, Alison Figueroa, Jonine Waddell, Richard Prokunina-Olsson, Ludmila Rothman, Nathaniel Silverman, Debra T. TI Differential urinary specific gravity as a molecular phenotype of the bladder cancer genetic association in the urea transporter gene, SLC14A1 SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE bladder cancer; urinary specific gravity; genome-wide association study; epidemiology ID GENOME-WIDE ASSOCIATION; FLUID INTAKE; RISK; CONSUMPTION; EXPRESSION; COHORT AB Genome-wide association studies (GWAS) identified associations between markers within the solute carrier family 14 (urea transporter), member 1 (SLC14A1) gene and risk of bladder cancer. SLC14A1 defines the Kidd blood groups in erythrocytes and is also involved in concentration of the urine in the kidney. We evaluated the association between a representative genetic variant (rs10775480) of SLC14A1 and urine concentration, as measured by urinary specific gravity (USG), in a subset of 275 population-based controls enrolled in the New England Bladder Cancer Study. Overnight urine samples were collected, and USG was measured using refractometry. Analysis of covariance was used to estimate adjusted least square means for USG in relation to rs10775480. We also examined the mRNA expression of both urea transporters, SLC14A1 and SLC14A2, in a panel of human tissues. USG was decreased with each copy of the rs10775480 risk T allele (p-trend=0.011) with a significant difference observed for CC vs. TT genotypes (p-value(tukey)=0.024). RNA-sequencing in the bladder tissue showed high expression of SLC14A1 and the absence of SLC14A2, while both transporters were expressed in the kidney. We suggest that the molecular phenotype of this GWAS finding is the genotype-specific biological activity of SLC14A1 in the bladder tissue. Our data suggest that SLC14A1 could be a unique urea transporter in the bladder that has the ability to influence urine concentration and that this mechanism might explain the increased bladder cancer susceptibility associated with rs10775480. C1 [Koutros, Stella; Baris, Dalsu; Fischer, Alexander; Tang, Wei; Garcia-Closas, Montserrat; Figueroa, Jonine; Prokunina-Olsson, Ludmila; Rothman, Nathaniel; Silverman, Debra T.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Epidemiol Sect, London SW3 6JB, England. [Garcia-Closas, Montserrat] Inst Canc Res, Genet Sect, London SW3 6JB, England. [Garcia-Closas, Montserrat] Breakthrough Breast Canc Res Ctr, London, England. [Karagas, Margaret R.; Waddell, Richard] Dartmouth Med Sch, Sect Biostat & Epidemiol, Dept Community & Family Med, Hanover, NH USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. RP Koutros, S (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, 9609 Med Ctr Dr,Room 6-E116,MSC 9771, Bethesda, MD 20892 USA. EM koutross@mail.nih.gov RI Garcia-Closas, Montserrat /F-3871-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics NR 29 TC 5 Z9 5 U1 2 U2 33 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD DEC 15 PY 2013 VL 133 IS 12 BP 3008 EP 3013 DI 10.1002/ijc.28325 PG 6 WC Oncology SC Oncology GA 233JW UT WOS:000325565600026 PM 23754249 ER PT J AU Cotten, M Watson, SJ Kellam, P Al-Rabeeah, AA Makhdoom, HQ Assiri, A Al-Tawfiq, JA Alhakeem, RF Madani, H AlRabiah, FA Al Hajjar, S Al-Nassir, WN Albarrak, A Flemban, H Balkhy, HH Alsubaie, S Palser, AL Gall, A Bashford-Rogers, R Rambaut, A Zumla, AI Memish, ZA AF Cotten, Matthew Watson, Simon J. Kellam, Paul Al-Rabeeah, Abdullah A. Makhdoom, Hatem Q. Assiri, Abdullah Al-Tawfiq, Jaffar A. Alhakeem, Rafat F. Madani, Hossam AlRabiah, Fahad A. Al Hajjar, Sami Al-Nassir, Wafa N. Albarrak, Ali Flemban, Hesham Balkhy, Hanan H. Alsubaie, Sarah Palser, Anne L. Gall, Astrid Bashford-Rogers, Rachael Rambaut, Andrew Zumla, Alimuddin I. Memish, Ziad A. TI Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study SO LANCET LA English DT Article ID HUMAN AIRWAY EPITHELIUM; PHYLOGENETIC ANALYSIS; SPIKE PROTEIN; ACTIVATION; RECEPTOR; INFECTIONS; INFERENCE; CLEAVAGE; TMPRSS2; SITES AB Background Since June, 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has, worldwide, caused 104 infections in people including 49 deaths, with 82 cases and 41 deaths reported from Saudi Arabia. In addition to confirming diagnosis, we generated the MERS-CoV genomic sequences obtained directly from patient samples to provide important information on MERS-CoV transmission, evolution, and origin. Methods Full genome deep sequencing was done on nucleic acid extracted directly from PCR-confirmed clinical samples. Viral genomes were obtained from 21 MERS cases of which 13 had 100%, four 85-95%, and four 30-50% genome coverage. Phylogenetic analysis of the 21 sequences, combined with nine published MERS-CoV genomes, was done. Findings Three distinct MERS-CoV genotypes were identified in Riyadh. Phylogeographic analyses suggest the MERS-CoV zoonotic reservoir is geographically disperse. Selection analysis of the MERS-CoV genomes reveals the expected accumulation of genetic diversity including changes in the S protein. The genetic diversity in the Al-Hasa cluster suggests that the hospital outbreak might have had more than one virus introduction. Interpretation We present the largest number of MERS-CoV genomes (21) described so far. MERS-CoV full genome sequences provide greater detail in tracking transmission. Multiple introductions of MERS-CoV are identified and suggest lower R 0 values. Transmission within Saudi Arabia is consistent with either movement of an animal reservoir, animal products, or movement of infected people. Further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed. C1 [Al-Rabeeah, Abdullah A.; Assiri, Abdullah; Alhakeem, Rafat F.; Zumla, Alimuddin I.; Memish, Ziad A.] Minist Hlth, Global Ctr Mass Gatherings Med, Riyadh 11176, Saudi Arabia. [Cotten, Matthew; Watson, Simon J.; Kellam, Paul; Palser, Anne L.; Gall, Astrid; Bashford-Rogers, Rachael] Wellcome Trust Sanger Inst, Hinxton, England. [Makhdoom, Hatem Q.; Madani, Hossam] Minist Hlth, Jeddah Reg Lab, Jeddah, Saudi Arabia. [Al-Tawfiq, Jaffar A.] Saudi Aramco Med Serv Org, Dhahran, Saudi Arabia. [Rambaut, Andrew] Ashworth Labs, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [AlRabiah, Fahad A.; Al Hajjar, Sami] King Faisal Specialist Hosp & Res Ctr, Riyadh, Saudi Arabia. [Al-Nassir, Wafa N.] Natl Guard Hlth Affairs Dammam, Imam Abdulrahman Bin Mohamed Hosp, Dammam, Saudi Arabia. [Albarrak, Ali] Prince Sultan Mil Med City, Riyadh, Saudi Arabia. [Flemban, Hesham] Alhada Mil Hosp, Riyadh, Saudi Arabia. [Balkhy, Hanan H.] King Abdul Aziz Med City, Riyadh, Saudi Arabia. [Alsubaie, Sarah] King Saud Univ, Riyadh 11451, Saudi Arabia. [Kellam, Paul; Zumla, Alimuddin I.] UCL, Div Infect & Immun, London, England. [Zumla, Alimuddin I.] UCL Hosp NHS Fdn Trust, London, England. RP Memish, ZA (reprint author), Minist Hlth, Global Ctr Mass Gatherings Med, Riyadh 11176, Saudi Arabia. EM zmemish@yahoo.com OI Assiri, Abdullah/0000-0002-5605-2876; Zumla, Alimuddin/0000-0002-5111-5735; Rambaut, Andrew/0000-0003-4337-3707 FU Saudi Arabian Ministry of Health; Wellcome Trust; European Community; National Institute of Health Research University College London Hospitals Biomedical Research Centre FX Funding Saudi Arabian Ministry of Health, Wellcome Trust, European Community, and National Institute of Health Research University College London Hospitals Biomedical Research Centre. NR 32 TC 94 Z9 107 U1 3 U2 37 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD DEC 14 PY 2013 VL 382 IS 9909 BP 1993 EP 2002 DI 10.1016/S0140-6736(13)61887-5 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 269EI UT WOS:000328223700026 PM 24055451 ER PT J AU Hsu, DC Sereti, I Ananworanich, J AF Hsu, Denise C. Sereti, Irini Ananworanich, Jintanat TI Serious Non-AIDS events: Immunopathogenesis and interventional strategies SO AIDS RESEARCH AND THERAPY LA English DT Review DE Serious non-AIDS events; Immune activation; HIV infection ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; HEPATITIS-C VIRUS; COMBINATION ANTIRETROVIRAL THERAPY; T-CELL-ACTIVATION; CORONARY-HEART-DISEASE; CARDIOVASCULAR RISK-FACTORS; REACTIVE PROTEIN-LEVELS; LIVER-RELATED MORTALITY; INDIVIDUAL PARTICIPANT METAANALYSIS AB Despite the major advances in the management of HIV infection, HIV-infected patients still have greater morbidity and mortality than the general population. Serious non-AIDS events (SNAEs), including non-AIDS malignancies, cardiovascular events, renal and hepatic disease, bone disorders and neurocognitive impairment, have become the major causes of morbidity and mortality in the antiretroviral therapy (ART) era. SNAEs occur at the rate of 1 to 2 per 100 person-years of follow-up. The pathogenesis of SNAEs is multifactorial and includes the direct effect of HIV and associated immunodeficiency, underlying co-infections and co-morbidities, immune activation with associated inflammation and coagulopathy as well as ART toxicities. A number of novel strategies such as ART intensification, treatment of co-infection, the use of anti-inflammatory drugs and agents that reduce microbial translocation are currently being examined for their potential effects in reducing immune activation and SNAEs. However, currently, initiation of ART before advanced immunodeficiency, smoking cessation, optimisation of cardiovascular risk factors and treatment of HCV infection are most strongly linked with reduced risk of SNAEs or mortality. Clinicians should therefore focus their attention on addressing these issues prior to the availability of further data. C1 [Hsu, Denise C.] Univ New S Wales, Kirby Inst Infect & Immun Soc, Sydney, NSW, Australia. [Sereti, Irini] NIAID, HIV Pathogenesis Unit, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Ananworanich, Jintanat] Red Cross AIDS Res Ctr, HIV Netherlands Australia Thailand Res Collaborat, Bangkok, Thailand. [Ananworanich, Jintanat] Red Cross AIDS Res Ctr, SEARCH, Bangkok, Thailand. RP Hsu, DC (reprint author), Univ New S Wales, Kirby Inst Infect & Immun Soc, Sydney, NSW, Australia. EM d.hsu@amr.org.au NR 224 TC 22 Z9 22 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PD DEC 13 PY 2013 VL 10 AR 29 DI 10.1186/1742-6405-10-29 PG 15 WC Infectious Diseases SC Infectious Diseases GA AB8FP UT WOS:000332025900002 PM 24330529 ER PT J AU Youn, A Simon, R AF Youn, Ahrim Simon, Richard TI Using passenger mutations to estimate the timing of driver mutations and identify mutator alterations SO BMC BIOINFORMATICS LA English DT Article DE Probabilistic modeling of tumor development; Estimating the order of mutations during tumorigenesis; Identifying mutator genes ID SOMATIC MUTATIONS; HUMAN CANCERS; DNA-REPAIR; TUMOR; TUMORIGENESIS; PPP2R2A; GENE AB Background: Recent developments in high-throughput genomic technologies make it possible to have a comprehensive view of genomic alterations in tumors on a whole genome scale. Only a small number of somatic alterations detected in tumor genomes are driver alterations which drive tumorigenesis. Most of the somatic alterations are passengers that are neutral to tumor cell selection. Although most research efforts are focused on analyzing driver alterations, the passenger alterations also provide valuable information about the history of tumor development. Results: In this paper, we develop a method for estimating the age of the tumor lineage and the timing of the driver alterations based on the number of passenger alterations. This method also identifies mutator genes which increase genomic instability when they are altered and provides estimates of the increased rate of alterations caused by each mutator gene. We applied this method to copy number data and DNA sequencing data for ovarian and lung tumors. We identified well known mutators such as TP53, PRKDC, BRCA1/2 as well as new mutator candidates PPP2R2A and the chromosomal region 22q13.33. We found that most mutator genes alter early during tumorigenesis and were able to estimate the age of individual tumor lineage in cell generations. Conclusions: This is the first computational method to identify mutator genes and to take into account the increase of the alteration rate by mutator genes, providing more accurate estimates of the tumor age and the timing of driver alterations. C1 [Youn, Ahrim; Simon, Richard] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, Bethesda, MD 20892 USA. EM rsimon@mail.nih.gov NR 32 TC 5 Z9 5 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD DEC 13 PY 2013 VL 14 AR 363 DI 10.1186/1471-2105-14-363 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA AC0QY UT WOS:000332201000001 PM 24330428 ER PT J AU Wang, Y Tjandra, N AF Wang, Yu Tjandra, Nico TI Structural Insights of tBid, the Caspase-8-activated Bid, and Its BH3 Domain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Apoptosis; Bcl-2; NMR; Protein Dynamics; Protein Structure; LPPG Micelles; tBid ID CYTOCHROME-C RELEASE; BCL-2 FAMILY-MEMBER; OUTER MITOCHONDRIAL-MEMBRANE; TRIPLE-RESONANCE NMR; CELL-DEATH; CONFORMATIONAL-CHANGES; BACKBONE DYNAMICS; INDUCE APOPTOSIS; PROTEIN FAMILY; BAX ACTIVATION AB Background: The membrane-associated tBid promotes Bax membrane insertion and activation. Results: tBid adopts an extended structure in 1-palmitoyl-2-hydroxy-sn-glycero-3-[phospho-RAC-(1-glycerol)] (LPPG) micelles with its six helices including the BH3 domain interacting with the micelles. Conclusion: An on the membrane binding mode was suggested for tBid interaction with Bax. Significance: Revealing tBid structure on the membrane is key to the understanding of tBid-mediated Bax activation. The Bcl-2 family proteins regulate mitochondria-mediated apoptosis through intricate molecular mechanisms. One of the pro-apoptotic proteins, tBid, can induce apoptosis by promoting Bax activation, Bax homo-oligomerization, and mitochondrial outer membrane permeabilization. Association of tBid on the mitochondrial outer membrane is key to its biological function. Therefore knowing the conformation of tBid on the membrane will be the first step toward understanding its crucial role in triggering apoptosis. Here, we present NMR characterization of the structure and dynamics of human tBid in 1-palmitoyl-2-hydroxy-sn-glycero-3-[phospho-RAC-(1-glycerol)] micelles. Our data showed that tBid is monomeric with six well defined -helices in the micelles. Compared with the full-length Bid structure, a longer flexible loop between tBid helix (4) and (5) was observed. Helices in tBid do not pack into a compact-fold but form an extended structure with a C-shape configuration in the micelles. All six tBid helices were shown to interact with LPPG micelles, with helix (6) and (7) being more embedded. Of note, the BH3-containing helix (3), which was previously believed to be exposed above the membrane surface, is also membrane associated, suggesting an on the membrane binding mode for tBid interaction with Bax. Our data provided structural details on the membrane-associated state of tBid and the functional implications of its membrane-associated BH3 domain. C1 [Wang, Yu; Tjandra, Nico] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU National Institutes of Health grant from the Intramural Research Program of the NHLBI FX This work was supported, in whole or in part, by a National Institutes of Health grant from the Intramural Research Program of the NHLBI (to N. T.). NR 79 TC 20 Z9 20 U1 3 U2 17 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 13 PY 2013 VL 288 IS 50 BP 35840 EP 35851 DI 10.1074/jbc.M113.503680 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 291FZ UT WOS:000329814700021 PM 24158446 ER PT J AU Chagas, AC Calvo, E Rios-Velasquez, CM Pessoa, FAC Medeiros, JF Ribeiro, JMC AF Chagas, Andrezza C. Calvo, Eric Rios-Velasquez, Claudia M. Pessoa, Felipe A. C. Medeiros, Jansen F. Ribeiro, Jose M. C. TI A deep insight into the sialotranscriptome of the mosquito, Psorophora albipes SO BMC GENOMICS LA English DT Article ID SALIVARY-GLAND TRANSCRIPTOME; FLY LUTZOMYIA-LONGIPALPIS; WEST NILE VIRUS; RNA-SEQ DATA; AEDES-AEGYPTI; YELLOW-FEVER; SEQUENCE ALIGNMENT; VECTOR COMPETENCE; IXODES-SCAPULARIS; ENZOOTIC STRAINS AB Background: Psorophora mosquitoes are exclusively found in the Americas and have been associated with transmission of encephalitis and West Nile fever viruses, among other arboviruses. Mosquito salivary glands represent the final route of differentiation and transmission of many parasites. They also secrete molecules with powerful pharmacologic actions that modulate host hemostasis, inflammation, and immune response. Here, we employed next generation sequencing and proteome approaches to investigate for the first time the salivary composition of a mosquito member of the Psorophora genus. We additionally discuss the evolutionary position of this mosquito genus into the Culicidae family by comparing the identity of its secreted salivary compounds to other mosquito salivary proteins identified so far. Results: Illumina sequencing resulted in 13,535,229 sequence reads, which were assembled into 3,247 contigs. All families were classified according to their in silico-predicted function/activity. Annotation of these sequences allowed classification of their products into 83 salivary protein families, twenty (24.39%) of which were confirmed by our subsequent proteome analysis. Two protein families were deorphanized from Aedes and one from Ochlerotatus, while four protein families were described as novel to Psorophora genus because they had no match with any other known mosquito salivary sequence. Several protein families described as exclusive to Culicines were present in Psorophora mosquitoes, while we did not identify any member of the protein families already known as unique to Anophelines. Also, the Psorophora salivary proteins had better identity to homologs in Aedes (69.23%), followed by Ochlerotatus (8.15%), Culex (6.52%), and Anopheles (4.66%), respectively. Conclusions: This is the first sialome (from the Greek sialo = saliva) catalog of salivary proteins from a Psorophora mosquito, which may be useful for better understanding the lifecycle of this mosquito and the role of its salivary secretion in arboviral transmission. C1 [Chagas, Andrezza C.; Calvo, Eric; Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Rios-Velasquez, Claudia M.; Pessoa, Felipe A. C.] Fiocruz MS, Inst Leonidas & Maria Deane, Biodivers Lab, Manaus, Amazonas, Brazil. [Medeiros, Jansen F.] Fiocruz Rondonia, Entomol Lab, Porto Velho, Rondonia, Brazil. RP Ribeiro, JMC (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM jribeiro@nih.gov RI Ribeiro, Jose/J-7011-2015; Rios Velasquez, Claudia Maria/K-2901-2015; OI Calvo, Eric/0000-0001-7880-2730; 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; Fundacao Oswaldo Cruz (Fiocruz) represented by Instituto Leonidas e Maria Deane (ILMD); FIOCRUZ/CNPq 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 and by Fundacao Oswaldo Cruz (Fiocruz) represented by Instituto Leonidas e Maria Deane (ILMD). We also thank the PAPES V program support FIOCRUZ/CNPq. We are grateful to Dr. Michalis Kotsyfakis for the critical reading of the manuscript and to Brenda Rae Marshall, DPSS, NIAID, for editing assistance. In addition, we thank Dr. Roberto Rocha (Fiocruz/Amazonia/Brazil) for his support. Because JMCR, EC, and ACC are government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license. NR 73 TC 11 Z9 11 U1 0 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 13 PY 2013 VL 14 AR 875 DI 10.1186/1471-2164-14-875 PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 285AE UT WOS:000329363900001 PM 24330624 ER PT J AU Akazawa, Y Isomoto, H Matsushima, K Kanda, T Minami, H Yamaghchi, N Taura, N Shiozawa, K Ohnita, K Takeshima, F Nakano, M Moss, J Hirayama, T Nakao, K AF Akazawa, Yuko Isomoto, Hajime Matsushima, Kayoko Kanda, Tsutomu Minami, Hitomi Yamaghchi, Naoyuki Taura, Naota Shiozawa, Ken Ohnita, Ken Takeshima, Fuminao Nakano, Masayuki Moss, Joel Hirayama, Toshiya Nakao, Kazuhiko TI Endoplasmic Reticulum Stress Contributes to Helicobacter Pylori VacA-Induced Apoptosis SO PLOS ONE LA English DT Article ID CYTOCHROME-C RELEASE; UNFOLDED PROTEIN RESPONSE; GASTRIC EPITHELIAL-CELLS; FATTY LIVER-DISEASE; VACUOLATING CYTOTOXIN; ER STRESS; MOLECULAR-MECHANISMS; UP-REGULATION; TOXIN VACA; DEATH AB Vacuolating cytotoxin A (VacA) is one of the important virulence factors produced by H. pylori. VacA induces apoptotic cell death, which is potentiated by ammonia. VacA also causes cell death by mitochondrial damage, via signaling pathways that are not fully defined. Our aim was to determine whether endoplasmic reticulum (ER) stress is associated with VacA-induced mitochondrial dysfunction and apoptosis. We found that C/EBP homologous protein (CHOP), a key signaling protein of ER stress-induced apoptosis, was transcriptionally up-regulated following incubation of gastric epithelial cells with VacA. The effect of VacA on CHOP induction was significantly enhanced by co-incubation with ammonium chloride. Phosphorylation of eukaryotic initiation factor 2 (eIF2)-alpha, which is known to occur downstream of the ER stress sensor PKR-like ER-localized eIF2-alpha kinase (PERK) and to regulate CHOP expression, was also observed following incubation with VacA in the presence of ammonium chloride. Knockdown of CHOP by siRNA resulted in inhibition of VacA-induced apoptosis. Further studies showed that silencing of the PERK gene with siRNA attenuated VacA-mediated phosphorylation of eIF2-alpha, CHOP induction, expression of BH3-only protein Bim and Bax activation, and cell death induced by VacA with ammonium chloride, indicating that ER stress may lead to mitochondrial dysfunction during VacA-induced toxicity. Activation of ER stress and up-regulation of BH3-only proteins were also observed in human H. pylori-infected gastric mucosa. Collectively, this study reveals a possible association between VacA-induced apoptosis in gastric epithelial cells, and activation of ER stress in H. pylori-positive gastric mucosa. C1 [Akazawa, Yuko; Isomoto, Hajime; Matsushima, Kayoko; Kanda, Tsutomu; Minami, Hitomi; Yamaghchi, Naoyuki; Taura, Naota; Shiozawa, Ken; Ohnita, Ken; Takeshima, Fuminao; Nakao, Kazuhiko] Nagasaki Univ Hosp, Dept Gastroenterol & Hepatol, Nagasaki, Japan. [Nakano, Masayuki; Hirayama, Toshiya] Nagasaki Univ, Dept Bacteriol, Inst Trop Med, Nagasaki 852, Japan. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Akazawa, Y (reprint author), Nagasaki Univ Hosp, Dept Gastroenterol & Hepatol, Nagasaki, Japan. EM akazaway@nagassaki-u.ac.jp FU MEXT/JSPS KAKENHI [22890138] FX This study was supported by MEXT/JSPS KAKENHI Grant Number 22890138. http://www.mext.go.jp/english/. 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 11 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 DEC 13 PY 2013 VL 8 IS 12 AR e82322 DI 10.1371/journal.pone.0082322 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276FP UT WOS:000328734200037 PM 24349255 ER PT J AU Varchetta, S Lusso, P Hudspeth, K Mikulak, J Mele, D Paolucci, S Cimbro, R Malnati, M Riva, A Maserati, R Mondelli, MU Mavilio, D AF Varchetta, Stefania Lusso, Paolo Hudspeth, Kelly Mikulak, Joanna Mele, Dalila Paolucci, Stefania Cimbro, Raffaello Malnati, Mauro Riva, Agostino Maserati, Renato Mondelli, Mario U. Mavilio, Domenico TI Sialic acid-binding Ig-like lectin-7 interacts with HIV-1 gp120 and facilitates infection of CD4(pos) T cells and macrophages SO RETROVIROLOGY LA English DT Article DE HIV-1 infection; Siglec-7; CD4+T cells; Macrophages; AIDS patients ID HUMAN-IMMUNODEFICIENCY-VIRUS; NATURAL-KILLER-CELLS; PSEUDOMONAS-AERUGINOSA; ALVEOLAR MACROPHAGES; TRANS-INFECTION; HUMAN-MONOCYTES; IMMUNE-SYSTEM; TROPIC HIV-1; TYPE-1 HIV-1; SIGLECS AB Background: Sialic acid-binding Ig-like lectin-7 (Siglec-7) expression is strongly reduced on natural killer (NK) cells from HIV-1 infected viremic patients. To investigate the mechanism(s) underlying this phenomenon, we hypothesized that Siglec-7 could contribute to the infection of CD4(pos) target cells following its interaction with HIV-1 envelope (Env) glycoprotein 120 (gp120). Results: The ability of Siglec-7 to bind gp120 Env in a sialic acid-dependent manner facilitates the infection of both T cells and monocyte-derived macrophages (MDMs). Indeed, pre-incubation of HIV-1 with soluble Siglec-7 (sSiglec-7) increases the infection rate of CD4(pos) T cells, which do not constitutively express Siglec-7. Conversely, selective blockade of Siglec-7 markedly reduces the degree of HIV-1 infection in Siglec-7(pos) MDMs. Finally, the sSiglec-7 amount is increased in the serum of AIDS patients with high levels of HIV-1 viremia and inversely correlates with CD4(pos) T cell counts. Conclusions: Our results show that Siglec-7 binds HIV-1 and contributes to enhance the susceptibility to infection of CD4(pos) T cells and MDMs. This phenomenon plays a role in HIV-1 pathogenesis and in disease progression, as suggested by the inverse correlation between high serum level of sSiglec-7 and the low CD4(pos) T cell count observed in AIDS patients in the presence of chronic viral replication. C1 [Varchetta, Stefania; Mele, Dalila; Mondelli, Mario U.] Policlin San Matteo, Res Labs, Dept Infect Dis, Fdn IRCCS, I-27100 Pavia, Italy. [Lusso, Paolo; Cimbro, Raffaello] NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. [Hudspeth, Kelly; Mikulak, Joanna; Mavilio, Domenico] Humanitas Clin & Res Ctr, Unit Clin & Expt Immunol, Milan, Italy. [Paolucci, Stefania] Fdn IRCCS Policlin San Matteo, SS Virol Mol, SC Virol & Microbiol, Pavia, Italy. [Malnati, Mauro] Ist Sci San Raffaele, Unit Human Virol, Div Immunol Transplantat & Infect Dis, I-20132 Milan, Italy. [Riva, Agostino] Univ Milan, Dipartimento Sci Clin DISC, L Sacco Hosp, Infect Dis & Immunopathol Sect, Milan, Italy. [Maserati, Renato] Fdn IRCCS Policlin San Matteo, HIV Outpatient Clin, Dept Infect Dis, Pavia, Italy. [Mondelli, Mario U.] Univ Pavia, Dept Internal Med, I-27100 Pavia, Italy. [Mavilio, Domenico] Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy. RP Mavilio, D (reprint author), Humanitas Clin & Res Ctr, Unit Clin & Expt Immunol, Milan, Italy. EM domenico.mavilio@humanitas.it OI Varchetta, Stefania/0000-0002-0289-2896; Mavilio, Domenico/0000-0001-6147-0952; Cimbro, Raffaello/0000-0002-6251-5160 FU Italian Ministry of Health, Ricerca Finalizzata, Bando ISS [RF-ICH-2009-1299677] FX This work was supported by the Italian Ministry of Health, Ricerca Finalizzata, Bando ISS, [Grant number RF-ICH-2009-1299677] to D. M., Ministero della Salute, by Ricerca Corrente Fondazione IRCCS Policlinico San Matteo: "Role of Innate Immune Response during Hepatitis C virus infection", and by the intramural research program of National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 62 TC 8 Z9 8 U1 0 U2 9 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 DEC 13 PY 2013 VL 10 AR 154 DI 10.1186/1742-4690-10-154 PG 13 WC Virology SC Virology GA 280SE UT WOS:000329050300002 PM 24330394 ER PT J AU Ryan, JF Pang, K Schnitzler, CE Nguyen, AD Moreland, RT Simmons, DK Koch, BJ Francis, WR Havlak, P Smith, SA Putnam, NH Haddock, SHD Dunn, CW Wolfsberg, TG Mullikin, JC Martindale, MQ Baxevanis, AD AF Ryan, Joseph F. Pang, Kevin Schnitzler, Christine E. Anh-Dao Nguyen Moreland, R. Travis Simmons, David K. Koch, Bernard J. Francis, Warren R. Havlak, Paul Smith, Stephen A. Putnam, Nicholas H. Haddock, Steven H. D. Dunn, Casey W. Wolfsberg, Tyra G. Mullikin, James C. Martindale, Mark Q. Baxevanis, Andreas D. CA NISC Comparative Sequencing Progra TI The Genome of the Ctenophore Mnemiopsis leidyi and Its Implications for Cell Type Evolution SO SCIENCE LA English DT Article ID NERVOUS-SYSTEM; HOMEOBOX GENES; METAZOAN; ORIGIN; EXPRESSION; REVEALS; TREE; ULTRASTRUCTURE; ORGANIZATION; INSIGHTS AB An understanding of ctenophore biology is critical for reconstructing events that occurred early in animal evolution. Toward this goal, we have sequenced, assembled, and annotated the genome of the ctenophore Mnemiopsis leidyi. Our phylogenomic analyses of both amino acid positions and gene content suggest that ctenophores rather than sponges are the sister lineage to all other animals. Mnemiopsis lacks many of the genes found in bilaterian mesodermal cell types, suggesting that these cell types evolved independently. The set of neural genes in Mnemiopsis is similar to that of sponges, indicating that sponges may have lost a nervous system. These results present a newly supported view of early animal evolution that accounts for major losses and/or gains of sophisticated cell types, including nerve and muscle cells. C1 [Ryan, Joseph F.; Schnitzler, Christine E.; Anh-Dao Nguyen; Moreland, R. Travis; Koch, Bernard J.; Wolfsberg, Tyra G.; Mullikin, James C.; Baxevanis, Andreas D.] NHGRI, Genome Technol Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Ryan, Joseph F.; Pang, Kevin] Univ Bergen, Sars Int Ctr Marine Mol Biol, N-5008 Bergen, Norway. [Simmons, David K.; Martindale, Mark Q.] Univ Florida, Whitney Lab Marine Biosci, St Augustine, FL 32080 USA. [Francis, Warren R.; Haddock, Steven H. D.] Monterey Bay Aquarium Res Inst, Moss Landing, CA 95039 USA. [Havlak, Paul; Putnam, Nicholas H.] Rice Univ, Dept Ecol & Evolutionary Biol, Houston, TX 77098 USA. [Mullikin, James C.; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr, NIH, Rockville, MD 20852 USA. [Smith, Stephen A.; Dunn, Casey W.] Brown Univ, Dept Ecol & Evolutionary Biol, Providence, RI 02912 USA. [Smith, Stephen A.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. RP Baxevanis, AD (reprint author), NHGRI, Genome Technol Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM andy@mail.nih.gov RI Putnam, Nicholas/B-9968-2008; OI Putnam, Nicholas/0000-0002-1315-782X; Dunn, Casey/0000-0003-0628-5150 FU National Human Genome Research Institute (NHGRI), NIH; NASA; NSF; Sars International Centre for Marine Molecular Biology; University of Bergen FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute (NHGRI), NIH. This work was also supported in part by NASA and NSF grants to M. Q. M. J.F.R. received additional support from the Sars International Centre for Marine Molecular Biology and the University of Bergen. We thank A. Young, B. Schmidt, N. Gurson, R. Legaspi, B. Novotny, and R. Blakesley, who were responsible for the sequencing performed at the NIH Intramural Sequencing Center (NISC); A. Prasad, D. Gildea, N. Trivedi, A. Yun, K. Siewert, D. Leja, S. Bond, and G. Bouffard at NHGRI; A. Hejnol, D. Chourrout, L. Leclere, G. Richards, F. Rentzsch, C. Martin, H. Hausen, S. Henriet, S. Church, and S9 at Sars; B. Vellutini for the photo of M. leidyi used in Fig. 1A; W. Browne for access to additional RNA-seq data from early developmental stages of M. leidyi; J. Lehmann for supplying an updated near intron pair matrix; C. Trapnell for help with the Bowtie short-read aligner and Cufflinks transcript assembly program; M. Srivastava for phylogenetic data sets and advice; I. Ruiz-Trillo and the Origins of Multicellularity Sequencing Project, Broad Institute of Harvard and MIT for use of their genomic data; D. Rokhsar and the Joint Genome Institute for use of their genomic data; and other researchers whose publicly available sequence data were used in this study. The views expressed in this paper do not necessarily reflect the views of those acknowledged. We dedicate this manuscript to the pioneering work of the late Sebastian Beroe of the Stazione Zoologica in Naples. The authors declare no competing financial interests. The genome sequence data can be accessed from GenBank as project accession AGCP00000000 and from http://research.nhgri.nih.gov/mnemiopsis/. Contributions are as follows: genome and RNA-seq sequencing and assembly: NISC and J. C. M.; annotation: J. F. R., K. P., C. E. S., P. H., N. H. P., A.-D.N., R. T. M., B. J. K., and T. G. W.; analysis: J. F. R., K. P., C. E. S., D. K. S., B. J. K., P. H., N. H. P., M. Q. M., and A. D. B.; additional ctenophore data: S. H. D. H. and W. R. F.; phylogenetics: J. F. R., S. A. S., and C. W. D.; writing: J. F. R., K. P., C. E. S., D. K. S., R. T. M., C. W. D., M. Q. M., and A. D. B.; project design and coordination: J. F. R., M. Q. M., and A.D.B. NR 53 TC 212 Z9 214 U1 12 U2 115 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 DEC 13 PY 2013 VL 342 IS 6164 BP 1336 EP + DI 10.1126/science.1242592 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 268UL UT WOS:000328196000040 ER PT J AU Hardy, RR Roederer, M AF Hardy, Richard R. Roederer, Mario TI Leonard Herzenberg (1931-2013): The Life of FACS Obituary SO IMMUNITY LA English DT Biographical-Item C1 [Hardy, Richard R.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Roederer, Mario] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Roederer, M (reprint author), NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM roederer@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD DEC 12 PY 2013 VL 39 IS 6 BP 989 EP 991 DI 10.1016/j.immuni.2013.11.008 PG 3 WC Immunology SC Immunology GA AA2UZ UT WOS:000330951000002 PM 24479158 ER PT J AU Lavender, KJ Pang, WW Messer, RJ Duley, AK Race, B Phillips, K Scott, D Peterson, KE Chan, CK Dittmer, U Dudek, T Allen, TM Weissman, IL Hasenkrug, KJ AF Lavender, Kerry J. Pang, Wendy W. Messer, Ronald J. Duley, Amanda K. Race, Brent Phillips, Katie Scott, Dana Peterson, Karin E. Chan, Charles K. Dittmer, Ulf Dudek, Timothy Allen, Todd M. Weissman, Irving L. Hasenkrug, Kim J. TI BLT-humanized C57BL/6 Rag2(-/-)gamma(-/-)(c)CD47(-/-) mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; SCID-HU MOUSE; REGULATORY PROTEIN ALPHA; RECEPTOR-GAMMA CHAIN; IN-VIVO; CORD BLOOD; ENGRAFTMENT; MODEL; IMMUNODEFICIENCY; RESPONSES AB The use of C57BL/6 Rag2(-/-)gamma(-/-)(c) mice as recipients for xenotransplantation with human immune systems (humanization) has been problematic because C57BL/6 SIRP alpha does not recognize human CD47, and such recognition is required to suppress macrophage-mediated phagocytosis of transplanted human hematopoietic stem cells (HSCs). We show that genetic inactivation of CD47 on the C57BL/6 Rag2(-/-)gamma(-/-)(c) background negates the requirement for CD47-signal recognition protein alpha (SIRP alpha) signaling and induces tolerance to transplanted human HSCs. These triple-knockout, bone marrow, liver, thymus (TKO-BLT) humanized mice develop organized lymphoid tissues including mesenteric lymph nodes, splenic follicles and gut-associated lymphoid tissue that demonstrate high levels of multilineage hematopoiesis. Importantly, these mice have an intact complement system and showed no signs of graft-versus-host disease (GVHD) out to 29 weeks after transplantation. Sustained, high-level HIV-1 infection was observed via either intrarectal or intraperitoneal inoculation. TKO-BLT mice exhibited hallmarks of human HIV infection including CD4(+) T-cell depletion, immune activation, and development of HIV-specific B-and T-cell responses. The lack of GVHD makes the TKO-BLT mouse a significantly improved model for long-term studies of pathogenesis, immune responses, therapeutics, and vaccines to human pathogens. C1 [Lavender, Kerry J.; Messer, Ronald J.; Duley, Amanda K.; Race, Brent; Phillips, Katie; Peterson, Karin E.; Hasenkrug, Kim J.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Pang, Wendy W.; Chan, Charles K.; Weissman, Irving L.] Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Pang, Wendy W.; Chan, Charles K.; Weissman, Irving L.] Stanford Univ, Sch Med, Ludwig Ctr Canc Cell Res, Stanford, CA 94305 USA. [Scott, Dana] NIAID, Rocky Mt Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. [Dittmer, Ulf] Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, Essen, Germany. [Dudek, Timothy; Allen, Todd M.] Ragon Inst Massachusetts Gen Hosp MIT & Harvard, Cambridge, MA USA. RP Hasenkrug, KJ (reprint author), Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59875 USA. EM kerry.lavender@nih.gov; khasenkrug@nih.gov RI Allen, Todd/F-5473-2011 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health HIVRAD grant [P01 AI104715]; Intramural Research Program of the Medical Faculty of the University Duisburg-Essen; Ludwig Foundation FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health HIVRAD grant P01 AI104715 (to T. M. A.), the Intramural Research Program of the Medical Faculty of the University Duisburg-Essen, and funding from the Ludwig Foundation. NR 38 TC 26 Z9 28 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 12 PY 2013 VL 122 IS 25 BP 4013 EP 4020 DI 10.1182/blood-2013-06-506949 PG 8 WC Hematology SC Hematology GA 290FH UT WOS:000329739100009 PM 24021673 ER PT J AU Ma, DY Mizurini, DM Assumpcao, TCF Li, Y Qi, YW Kotsyfakis, M Ribeiro, JMC Monteiro, RQ Francischetti, IMB AF Ma, Dongying Mizurini, Daniella M. Assumpcao, Teresa C. F. Li, Yuan Qi, Yanwei Kotsyfakis, Michail Ribeiro, Jose M. C. Monteiro, Robson Q. Francischetti, Ivo M. B. TI Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo SO BLOOD LA English DT Article ID FACTOR PATHWAY INHIBITOR; TISSUE FACTOR PATHWAY; FACTOR-XA; ARTERIAL THROMBOSIS; CAROTID-ARTERY; COAGULATION; PROTEIN; ACTIVATION; DOMAIN; PROTEASES AB The identity of vampire bat saliva anticoagulant remained elusive for almost a century. Sequencing the salivary gland genes from the vampire bat Desmodus rotundus identified Desmolaris as a novel 21.5-kDa naturally deleted (Kunitz 1-domainless) form of tissue factor pathway inhibitor. Recombinant Desmolaris was expressed in HEK293 cells and characterized as a slow, tight, and noncompetitive inhibitor of factor (F) XIa by a mechanism modulated by heparin. Desmolaris also inhibits FXa with lower affinity, independently of protein S. In addition, Desmolaris binds kallikrein and reduces bradykinin generation in plasma activated with kaolin. Truncated and mutated forms of Desmolaris determined that Arg32 in the Kunitz-1 domain is critical for protease inhibition. Moreover, Kunitz-2 and the carboxyl-terminus domains mediate interaction of Desmolaris with heparin and are required for optimal inhibition of FXIa and FXa. Notably, Desmolaris (100 mu g/kg) inhibited FeCl3-induced carotid artery thrombus without impairing hemostasis. These results imply that FXIa is the primary in vivo target for Desmolaris at antithrombotic concentrations. Desmolaris also reduces the polyphosphate-induced increase in vascular permeability and collagen-and epinephrine-mediated thromboembolism in mice. Desmolaris emerges as a novel anticoagulant targeting FXIa under conditions in which the coagulation activation, particularly the contact pathway, plays a major pathological role. C1 [Ma, Dongying; Assumpcao, Teresa C. F.; Li, Yuan; Ribeiro, Jose M. C.; Francischetti, Ivo M. B.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Mizurini, Daniella M.; Monteiro, Robson Q.] Univ Fed Rio de Janeiro, Inst Bioquim Med, Rio De Janeiro, Brazil. [Qi, Yanwei] NIAID, Malaria Funct Genom Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Kotsyfakis, Michail] Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, CR-37005 Ceske Budejovice, Czech Republic. RP Francischetti, IMB (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Twinbrook 3 Bldg,Room 2E-32C, Rockville, MD 20852 USA. EM ifrancischetti@niaid.nih.gov RI Kotsyfakis, Michail/G-9525-2014; ma, dongying/D-8623-2012; Monteiro, Robson/B-8007-2014; Ribeiro, Jose/J-7011-2015; OI Kotsyfakis, Michail/0000-0002-7526-1876; Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, NIAID, National Institutes of Health; Grant Agency of the Czech Republic [P502/12/2409] FX This work was supported by the Intramural Research Program of the Division of Intramural Research, NIAID, National Institutes of Health, and the Grant Agency of the Czech Republic (grant P502/12/2409) (M.K.). NR 50 TC 13 Z9 14 U1 0 U2 20 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 12 PY 2013 VL 122 IS 25 BP 4094 EP 4106 DI 10.1182/blood-2013-08-517474 PG 13 WC Hematology SC Hematology GA 290FH UT WOS:000329739100018 PM 24159172 ER PT J AU Kochenderfer, JN Dudley, ME Carpenter, RO Kassim, SH Rose, JJ Telford, WG Hakim, FT Halverson, DC Fowler, DH Hardy, NM Mato, AR Hickstein, DD Gea-Banacloche, JC Pavletic, SZ Sportes, C Maric, I Feldman, SA Hansen, BG Wilder, JS Blacklock-Schuver, B Jena, B Bishop, MR Gress, RE Rosenberg, SA AF Kochenderfer, James N. Dudley, Mark E. Carpenter, Robert O. Kassim, Sadik H. Rose, Jeremy J. Telford, William G. Hakim, Frances T. Halverson, David C. Fowler, Daniel H. Hardy, Nancy M. Mato, Anthony R. Hickstein, Dennis D. Gea-Banacloche, Juan C. Pavletic, Steven Z. Sportes, Claude Maric, Irina Feldman, Steven A. Hansen, Brenna G. Wilder, Jennifer S. Blacklock-Schuver, Bazetta Jena, Bipulendu Bishop, Michael R. Gress, Ronald E. Rosenberg, Steven A. TI Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation SO BLOOD LA English DT Article ID CHIMERIC-ANTIGEN-RECEPTOR; CHRONIC LYMPHOCYTIC-LEUKEMIA; GRAFT-VERSUS-LEUKEMIA; ADOPTIVE IMMUNOTHERAPY; INTERNATIONAL WORKSHOP; REDUCED-INTENSITY; CLINICAL-TRIAL; HOST-DISEASE; LYMPHOMA; THERAPY AB New treatments are needed for B-cell malignancies persisting after allogeneic hematopoietic stem cell transplantation (alloHSCT). We conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. T cells for genetic modification were obtained from each patient's alloHSCT donor. All patients had malignancy that persisted after alloHSCT and standard donor lymphocyte infusions (DLIs). Patients did not receive chemotherapy prior to the CAR T-cell infusions and were not lymphocyte depleted at the time of the infusions. The 10 treated patients received a single infusion of allogeneic anti-CD19-CAR T cells. Three patients had regressions of their malignancies. One patient with chronic lymphocytic leukemia (CLL) obtained an ongoing complete remission after treatment with allogeneic anti-CD19-CAR T cells, another CLL patient had tumor lysis syndrome as his leukemia dramatically regressed, and a patient with mantle cell lymphoma obtained an ongoing partial remission. None of the 10 patients developed graft-versus-host disease (GVHD). Toxicities included transient hypotension and fever. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. These results show for the first time that donor-derived allogeneic anti-CD19-CAR T cells can cause regression of B-cell malignancies resistant to standard DLIs without causing GVHD. This trial was registered at www.clinicaltrials.gov as #NCT01087294. C1 [Kochenderfer, James N.; Carpenter, Robert O.; Rose, Jeremy J.; Telford, William G.; Hakim, Frances T.; Halverson, David C.; Fowler, Daniel H.; Hardy, Nancy M.; Hickstein, Dennis D.; Gea-Banacloche, Juan C.; Pavletic, Steven Z.; Sportes, Claude; Hansen, Brenna G.; Blacklock-Schuver, Bazetta; Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Dudley, Mark E.; Kassim, Sadik H.; Feldman, Steven A.; Rosenberg, Steven A.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Mato, Anthony R.] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Maric, Irina] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Wilder, Jennifer S.] NCI, Clin Res Directorate Sci Applicat Int Corp Freder, Frederick, MD 21701 USA. [Jena, Bipulendu] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Bishop, Michael R.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. RP Kochenderfer, JN (reprint author), NIH, 10 Ctr Dr,CRC Room 3-3330, Bethesda, MD 20892 USA. EM kochendj@mail.nih.gov RI Jena, Bipulendu/G-8206-2014 FU National Institutes of Health National Cancer Institute, Center for Cancer Research; National Institutes of Health National Cancer Institute [HHSN261200800001E] FX This work was supported by intramural funding of the National Institutes of Health National Cancer Institute, Center for Cancer Research. This project has been funded in part with federal funds from the National Institutes of Health National Cancer Institute (contract no. HHSN261200800001E). NR 45 TC 161 Z9 170 U1 5 U2 39 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 12 PY 2013 VL 122 IS 25 BP 4129 EP 4139 DI 10.1182/blood-2013-08-519413 PG 11 WC Hematology SC Hematology GA 290FH UT WOS:000329739100022 PM 24055823 ER PT J AU Brady, OJ Johansson, MA Guerra, CA Bhatt, S Golding, N Pigott, DM Delatte, H Grech, MG Leisnham, PT Maciel-de-Freitas, R Styer, LM Smith, DL Scott, TW Gething, PW Hay, SI AF Brady, Oliver J. Johansson, Michael A. Guerra, Carlos A. Bhatt, Samir Golding, Nick Pigott, David M. Delatte, Helene Grech, Marta G. Leisnham, Paul T. Maciel-de-Freitas, Rafael Styer, Linda M. Smith, David L. Scott, Thomas W. Gething, Peter W. Hay, Simon I. TI Modelling adult Aedes aegypti and Aedes albopictus survival at different temperatures in laboratory and field settings SO PARASITES & VECTORS LA English DT Article DE Aedes; Survival; Temperature; Mortality; Longevity; Modelling; Mark-release-recapture; Dengue; Transmission; Generalised additive models ID DENGUE VIRUS TRANSMISSION; BLOOD PLUS SUGAR; RIO-DE-JANEIRO; DIPTERA-CULICIDAE; RELEASE-RECAPTURE; PUERTO-RICO; CONTAINER PRODUCTIVITY; LIFE TABLE; MORTALITY; MOSQUITOS AB Background: The survival of adult female Aedes mosquitoes is a critical component of their ability to transmit pathogens such as dengue viruses. One of the principal determinants of Aedes survival is temperature, which has been associated with seasonal changes in Aedes populations and limits their geographical distribution. The effects of temperature and other sources of mortality have been studied in the field, often via mark-release-recapture experiments, and under controlled conditions in the laboratory. Survival results differ and reconciling predictions between the two settings has been hindered by variable measurements from different experimental protocols, lack of precision in measuring survival of free-ranging mosquitoes, and uncertainty about the role of age-dependent mortality in the field. Methods: Here we apply generalised additive models to data from 351 published adult Ae. aegypti and Ae. albopictus survival experiments in the laboratory to create survival models for each species across their range of viable temperatures. These models are then adjusted to estimate survival at different temperatures in the field using data from 59 Ae. aegypti and Ae. albopictus field survivorship experiments. The uncertainty at each stage of the modelling process is propagated through to provide confidence intervals around our predictions. Results: Our results indicate that adult Ae. albopictus has higher survival than Ae. aegypti in the laboratory and field, however, Ae. aegypti can tolerate a wider range of temperatures. A full breakdown of survival by age and temperature is given for both species. The differences between laboratory and field models also give insight into the relative contributions to mortality from temperature, other environmental factors, and senescence and over what ranges these factors can be important. Conclusions: Our results support the importance of producing site-specific mosquito survival estimates. By including fluctuating temperature regimes, our models provide insight into seasonal patterns of Ae. aegypti and Ae. albopictus population dynamics that may be relevant to seasonal changes in dengue virus transmission. Our models can be integrated with Aedes and dengue modelling efforts to guide and evaluate vector control, better map the distribution of disease and produce early warning systems for dengue epidemics. C1 [Brady, Oliver J.; Guerra, Carlos A.; Bhatt, Samir; Golding, Nick; Pigott, David M.; Gething, Peter W.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Tinbergen Bldg,South Parks Rd, Oxford, England. [Johansson, Michael A.] Ctr Dis Control & Prevent, Dengue Branch, Div Vector Borne Dis, San Juan, PR USA. [Delatte, Helene] CIRAD, UMR PVBMT, St Piarre 97410, Reunion. [Grech, Marta G.] Univ Nacl Patagonia San Juan Bosco, FCN Sede, Lab Invest Ecol & Sistemat Anim, Esquel, Chubut, Argentina. [Leisnham, Paul T.] Univ Maryland, Dept Environm Sci & Technol, College Pk, MD 20742 USA. [Maciel-de-Freitas, Rafael] Fiocruz MS, Inst Oswaldo Cruz, Lab Transmissores Hematozoarios, BR-21045900 Rio De Janeiro, RJ, Brazil. [Styer, Linda M.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12208 USA. [Smith, David L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Smith, David L.; Scott, Thomas W.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Brady, OJ (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Tinbergen Bldg,South Parks Rd, Oxford, England. EM oliver.brady@zoo.ox.ac.uk RI Hay, Simon/F-8967-2015; OI Golding, Nick/0000-0001-8916-5570; Hay, Simon/0000-0002-0611-7272; Gething, Peter/0000-0001-6759-5449; Brady, Oliver/0000-0002-3235-2129; Pigott, David/0000-0002-6731-4034 FU BBSRC studentship; Department of Zoology at the University of Oxford; Medical Research Council (UK) Career Development Fellow [K00669X]; Bill and Melinda Gates Foundation [OPP1068048]; Bill AMP; Melinda Gates Foundation [OPP1053338]; Wellcome Trust [095066]; EU [21803]; RAPIDD program of the Science AMP; Technology Directorate; Department of Homeland Security; Fogarty International Center, National Institutes of Health FX O.J.B. is funded by a BBSRC studentship. DMP is funded by a Sir Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford. P.W.G is a Medical Research Council (UK) Career Development Fellow (#K00669X) and receives support from the Bill and Melinda Gates Foundation (#OPP1068048) which also supports S.B. N.G. is funded by a grant from the Bill & Melinda Gates Foundation (OPP1053338). S. I. H. is funded by a Senior Research Fellowship from the Wellcome Trust (095066). This study was partially funded by EU grant 21803 IDAMS (http://www.idams.eu). The contents of this publication are the sole responsibility of the authors and don't necessarily reflect the views of the European Commission. S.I.H. C.A.G. and T.W.S. also acknowledge funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 79 TC 56 Z9 56 U1 5 U2 58 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD DEC 12 PY 2013 VL 6 AR 351 DI 10.1186/1756-3305-6-351 PG 12 WC Parasitology SC Parasitology GA 277RW UT WOS:000328838000002 PM 24330720 ER PT J AU Biancotto, A Wank, A Perl, S Cook, W Olnes, MJ Dagur, PK Fuchs, JC Langweiler, M Wang, E McCoy, JP AF Biancotto, Angelique Wank, Abigail Perl, Shira Cook, Wendell Olnes, Matthew J. Dagur, Pradeep K. Fuchs, J. Christopher Langweiler, Marc Wang, Ena McCoy, J. Philip TI Baseline Levels and Temporal Stability of 27 Multiplexed Serum Cytokine Concentrations in Healthy Subjects SO PLOS ONE LA English DT Article ID BEAD ARRAY ASSAYS; ATHEROSCLEROSIS; ASSOCIATION; SENSITIVITY; EOTAXIN; PLASMA; RANTES; ALPHA AB Background: Cytokines are humoral molecules that elicit regulatory function in immunologic pathways. The level and type of cytokine production has become critical in distinguishing physiologic from pathologic immune conditions. Cytokine profiling has become an important biomarker discovery tool in monitoring of the immune system. However, the variations in cytokine levels in individual subjects over time in healthy individuals have not been extensively studied. In this study, we use multiplex bead arrays to evaluate 27 analytes in paired serum samples taken seven days apart from 144 healthy individuals in order to assess variations over a short time period. Methods: Fluorescent bead-based immunoassay (Luminex) was used to measure 27 analytes in serum samples. Measurements were performed on matched samples from 144 healthy donors. To assess inter-plate variability, one arbitrarily selected serum sample was analyzed on each of the first ten plates as bridge sample. Results: Using the bridge sample, we showed minimal inter-plate variations in the measurement of most analytes. In measurement of cytokines from the 144 patients at two time points, we found that three cytokines (IL-2, IL-15 and GM-CSF) were undetectable and five analytes (RANTES, MCP-1, VEGF, MIP-1 beta and PDGF-BB) showed significant difference in concentrations at Day 0 compared to Day 7. Conclusions: The current study demonstrated higher variations in cytokine levels among individuals than were observed for samples obtained one week apart from identical donors. These data suggest that a serum sample from each subject for use as a baseline measurement is a better control for clinical trials rather than sera from a paired cohort. C1 [Biancotto, Angelique; Wank, Abigail; Perl, Shira; Cook, Wendell; Olnes, Matthew J.; Dagur, Pradeep K.; Fuchs, J. Christopher; Langweiler, Marc; Wang, Ena; McCoy, J. Philip] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. RP McCoy, JP (reprint author), NIH, Ctr Human Immunol Autoimmun & Inflammat, Bldg 10, Bethesda, MD 20892 USA. EM Mccoyj@nhlbi.nih.gov FU NIH CHI FX This work was supported by the NIH CHI intramural research program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 23 Z9 24 U1 2 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 DEC 12 PY 2013 VL 8 IS 12 AR UNSP e76091 DI 10.1371/journal.pone.0076091 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276EU UT WOS:000328731800001 PM 24348989 ER PT J AU Kimmel, SE French, B Kasner, SE Johnson, JA Anderson, JL Gage, BF Rosenberg, YD Eby, CS Madigan, RA McBane, RB Abdel-Rahman, SZ Stevens, SM Yale, S Mohler, ER Fang, MC Shah, V Horenstein, RB Limdi, NA Muldowney, JAS Gujral, J Delafontaine, P Desnick, RJ Ortel, TL Billett, HH Pendleton, RC Geller, NL Halperin, JL Goldhaber, SZ Caldwell, MD Califf, RM Ellenberg, JH AF Kimmel, Stephen E. French, Benjamin Kasner, Scott E. Johnson, Julie A. Anderson, Jeffrey L. Gage, Brian F. Rosenberg, Yves D. Eby, Charles S. Madigan, Rosemary A. McBane, Robert B. Abdel-Rahman, Sherif Z. Stevens, Scott M. Yale, Steven Mohler, Emile R., III Fang, Margaret C. Shah, Vinay Horenstein, Richard B. Limdi, Nita A. Muldowney, James A. S., III Gujral, Jaspal Delafontaine, Patrice Desnick, Robert J. Ortel, Thomas L. Billett, Henny H. Pendleton, Robert C. Geller, Nancy L. Halperin, Jonathan L. Goldhaber, Samuel Z. Caldwell, Michael D. Califf, Robert M. Ellenberg, Jonas H. CA COAG Investigators TI A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GENETICS COAG TRIAL; OPTIMAL ANTICOAGULATION; ATRIAL-FIBRILLATION; THERAPY; CLARIFICATION; DISEASE; PREDICT AB BackgroundThe clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. MethodsWe randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. ResultsAt 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. ConclusionsGenotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.) In this trial, 1015 patients were assigned to the use of either a genotype-guided algorithm or a clinically guided algorithm for warfarin dosing during the first 5 days. At 4 weeks, there was no significant difference in the percentage of time in the therapeutic INR range. The need for clinical trials before widespread adoption of genotype-guided drug dosing and selection remains widely debated.(1)-(4) Warfarin therapy has served as a model for the potential for pharmacogenetics to improve patient care.(1) Observational studies have identified two genes, CYP2C9 and VKORC1, that are associated with variation in warfarin maintenance doses. However, the clinical utility of starting warfarin at the maintenance dose predicted by genotype-guided algorithms has been tested only in small trials, none of which were definitive.(5)-(8) In contrast, observational studies have suggested potential benefits from genotype-guided dosing.(9),(10) In addition, previous clinical trials could not determine ... C1 [Kimmel, Stephen E.; French, Benjamin; Kasner, Scott E.; Madigan, Rosemary A.; Mohler, Emile R., III; Ellenberg, Jonas H.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Johnson, Julie A.] Univ Florida, Gainesville, FL USA. [Anderson, Jeffrey L.; Stevens, Scott M.] Intermt Med Ctr, Murray, UT USA. [Gage, Brian F.; Eby, Charles S.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Rosenberg, Yves D.; Geller, Nancy L.] NHLBI, NIH, Bethesda, MD 20892 USA. [McBane, Robert B.] Mayo Clin, Coll Med, Rochester, MN USA. [Abdel-Rahman, Sherif Z.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Yale, Steven; Caldwell, Michael D.] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. [Fang, Margaret C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Shah, Vinay] Henry Ford Hosp, Detroit, MI 48202 USA. [Horenstein, Richard B.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Limdi, Nita A.] Univ Alabama Birmingham, Birmingham, AL USA. [Muldowney, James A. S., III] Vanderbilt Univ, Nashville, TN 37235 USA. [Gujral, Jaspal] Georgia Regents Med Ctr, Augusta, GA USA. [Delafontaine, Patrice] Tulane Univ, New Orleans, LA 70118 USA. [Desnick, Robert J.; Halperin, Jonathan L.] Mt Sinai Sch Med, New York, NY USA. [Billett, Henny H.] Montefiore Med Ctr, New York, NY USA. [Ortel, Thomas L.; Califf, Robert M.] Duke Univ, Med Ctr, Durham, NC USA. [Pendleton, Robert C.] Univ Utah Hlth Care, Provo, UT USA. [Goldhaber, Samuel Z.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Kimmel, SE (reprint author), Ctr Therapeut Effectiveness Res, 923 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM stevek@mail.med.upenn.edu OI Delafontaine, Patrice/0000-0003-3744-3617 FU National Heart, Lung, and Blood Institute [HHSN-268200800003C]; Pfizer; Janssen; Novartis; Merck; Medtronic; Photothera; AstraZeneca; Cardionet; W.L. Gore; Acorda; Daiichi Asubio; Boehringer Ingelheim; Siemens; serving on an advisory board for Instrumentation Laboratory; Iverson Genetics; MCG; Bristol-Myers Squibb; Theravasc; Bayer; Instrumentation Laboratory; Eisai; GlaxoSmithKline; Daiichi Sankyo; Daiichi SanIcyo; Baxter; Portola; Sanofi-Aventis; Daiichi Sanlcyo; EKOS; Johnson Johnson; Roche; Bristol-Myers Squibb Foundation; Regeneron; CV Sight; Eli Lilly; Gambro; Kowa; Genentech; Laboratoires Servier; Amylin; Merck/Schering Plough FX Supported under a contract (HHSN-268200800003C) with the National Heart, Lung, and Blood Institute. Bristol-Myers Squibb donated Coumadin (warfarin). GenMark Diagnostics and AutoGenomics loaned genotyping platforms to the clinical centers.; Dr. Kimmel reports receiving consulting fees from Pfizer and Janssen; Dr. Kasner, receiving personal fees from Novartis, Pfizer, Merck, Medtronic, Photothera, AstraZeneca, and Cardionet and grant support from W.L. Gore, Acorda, and Daiichi Asubio; Dr. Gage, receiving consulting fees from Boehringer Ingelheim; Dr. Eby, receiving grant support from Siemens and serving on an advisory board for Instrumentation Laboratory; Dr. Stevens, receiving grant support from Iverson Genetics; Dr. Muldowney, receiving consulting fees from MCG (formerly Milliman Care Guidelines), lecture fees from Bristol-Myers Squibb, Pfizer, and Boehringer Ingelheim, and grant support from Novartis and Theravasc; Dr. Ortel, receiving consulting fees from Boehringer Ingelheim, Bayer, and Instrumentation Laboratory and grant support from Eisai, GlaxoSmithKline, Pfizer, Daiichi Sankyo, and Instrumentation Laboratory; Dr. Goldhaber, receiving consulting fees from Bristol-Myers Squibb, Daiichi SanIcyo, Baxter, Boehringer Ingelheim, Eisai, Merck, Pfizer, Portola, and Sanofi-Aventis and grant support from Bristol-Myers Squibb, Daiichi Sanlcyo, EKOS, and Johnson & Johnson; Dr. Caldwell, holding a patent, issued to the Marshfield Clinic, on the use of CYP4F2 for warfarin dosing; Dr. Califf, serving as a board member at Portola, receiving consulting fees from Novartis, Johnson & Johnson, Bayer, Roche, Pfizer, Bristol-Myers Squibb Foundation, Regeneron, CV Sight, Daiichi Sankyo, Eli Lilly, Gambro, Kowa, Genentech, GlaxoSmithKline, Laboratoires Servier, and Portola, receiving grant support from Amylin, Johnson & Johnson, Merck/Schering Plough, Novartis, Bristol-Myers Squibb Foundation, and Eli Lilly, and having an equity interest in N30 Pharma; and Dr. Ellenberg, receiving consulting fees from Bristol-Myers Squibb. No other potential conflict of interest relevant to this article was reported. NR 30 TC 273 Z9 289 U1 1 U2 14 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 DEC 12 PY 2013 VL 369 IS 24 BP 2283 EP 2293 DI 10.1056/NEJMoa1310669 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 268FV UT WOS:000328156300006 PM 24251361 ER PT J AU Schiffman, M Solomon, D AF Schiffman, Mark Solomon, Diane TI Cervical-Cancer Screening with Human Papillomavirus and Cytologic Cotesting SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LIQUID-BASED CYTOLOGY; NEOPLASIA GRADE 2/3; COLLABORATIVE REANALYSIS; INDIVIDUAL DATA; CLINICAL-PRACTICE; AMERICAN SOCIETY; 5-YEAR RISKS; WOMEN; HPV; TESTS C1 [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Solomon, Diane] NCI, Canc Prevent Div, NIH, Rockville, MD 20850 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM schiffmm@exchange.nih.gov NR 54 TC 23 Z9 24 U1 1 U2 10 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 12 PY 2013 VL 369 IS 24 BP 2324 EP 2331 DI 10.1056/NEJMcp1210379 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 268FV UT WOS:000328156300010 PM 24328466 ER PT J AU Banala, AK Zhang, P Plenge, P Cyriac, G Kopajtic, T Katz, JL Loland, CJ Newman, AH AF Banala, Ashwini K. Zhang, Peng Plenge, Per Cyriac, George Kopajtic, Theresa Katz, Jonathan L. Loland, Claus Juul Newman, Amy Hauck TI Design and Synthesis of 1-(3-(Dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran- 5-carbonitrile (Citalopram) Analogues as Novel Probes for the Serotonin Transporter S1 and S2 Binding Sites SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HIGH-AFFINITY; NEUROTRANSMITTER TRANSPORTERS; NOREPINEPHRINE TRANSPORTERS; H-3 IMIPRAMINE; ALLOSTERIC MECHANISM; BACTERIAL HOMOLOG; 5-HT TRANSPORTER; ANTIDEPRESSANTS; LEUT; RECOGNITION AB The serotonin transporter (SERT) is the primary target for antidepressant drugs. The existence of a high affinity primary orthosteric binding site (S1) and a low affinity secondary site (S2) has been described, and their relation to antidepressant pharmacology has been debated. Herein, structural modifications to the N, 4, 5, and 4' positions of (+/-)citalopram (1) are reported. All of the analogues were SERT-selective and demonstrated that steric bulk was tolerated at the SERT Si site, including two dimeric ligands (15 and 51). In addition, eight analogues were identified with similar potencies to S-1 for decreasing the dissociation of [H-3]S-1 from the S1 site via allosteric modulation at S2. Both dimeric compounds had similar affinities for the SERT Si site (K-i = 19.7 and 30.2 nM, respectively), whereas only the N-substituted analogue, 51, was as effective as S-1 in allosterically modulating the binding of [H-3]S-1 via S2. C1 [Banala, Ashwini K.; Zhang, Peng; Cyriac, George; Newman, Amy Hauck] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Kopajtic, Theresa; Katz, Jonathan L.] NIDA, Psychobiol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Plenge, Per; Loland, Claus Juul] Univ Copenhagen, Mol Neuropharmacol Lab, Dept Neurosci & Pharmacol, Fac Hlth & Med Sci, DK-2200 Copenhagen N, Denmark. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM cllo@sund.ku.dk; anewman@intra.nida.nih.gov RI Loland, Claus/E-5975-2014; OI Loland, Claus/0000-0002-1773-1446; Katz, Jonathan/0000-0002-1068-1159 FU NIDA Intramural Research Program; Danish Independent Research Council - Sapere Aude; Lundbeck Foundation; NIH visiting postdoctoral fellowship; NIH Intramural Research Training Award (IRTA) postdoctoral fellowship; postbaccalaureate IRTA fellowship FX This work was supported by the NIDA Intramural Research Program (A.H.N. and J.L.K.), Danish Independent Research Council - Sapere Aude (C.J.L.), and the Lundbeck Foundation (C.J.L.). B.A.K. was supported by an NIH visiting postdoctoral fellowship, P.Z. was supported by an NIH Intramural Research Training Award (IRTA) postdoctoral fellowship, and G.C.C. was supported by a postbaccalaureate IRTA fellowship. The authors would like to thank Dr. Lei Shi, Weill Medical School of Cornell University, for advising us on the Si docking models in the design of Figure 1, Dr. Vivek Kumar (NIDA-IRP) for his critical reading of an earlier version of this manuscript, Dr. Dwight Williams (NIDA-IRP summer student) for his contributions to the synthesis of several intermediates described herein, and Bente Bennike (UC) for excellent technical assistance. NR 39 TC 11 Z9 11 U1 6 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD DEC 12 PY 2013 VL 56 IS 23 BP 9709 EP 9724 DI 10.1021/jm4014136 PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 273IY UT WOS:000328529700029 PM 24237160 ER PT J AU Cho, HS Schotte, F Dashdorj, N Kyndt, J Anfinrud, PA AF Cho, Hyun Sun Schotte, Friedrich Dashdorj, Naranbaatar Kyndt, John Anfinrud, Philip A. TI Probing Anisotropic Structure Changes in Proteins with Picosecond Time-Resolved Small-Angle X-ray Scattering SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID PHOTOACTIVE YELLOW PROTEIN; HALOPHILIC PHOTOTROPHIC BACTERIUM; ECTOTHIORHODOSPIRA-HALOPHILA; INFRARED-SPECTROSCOPY; QUANTUM YIELD; DYNAMICS; CRYSTALLOGRAPHY; PHOTOCYCLE; MYOGLOBIN; KINETICS AB We have exploited the principle of photoselection and the method of time-resolved small-angle X-ray scattering (SAXS) to investigate protein size and shape changes following photoactivation of photoactive yellow protein (PYP) in solution with similar to 150 ps time resolution. This study partially overcomes the orientational average intrinsic to solution scattering methods and provides structural information at a higher level of detail. Photoactivation of the p-coumaric acid (pCA) chromophore in PYP produces a highly contorted, short-lived, red-shifted intermediate (pR(0)), and triggers prompt, protein compaction of approximately 0.3% along the direction defined by the electronic transition dipole moment of the chromophore. Contraction along this dimension is accompanied by expansion along the orthogonal directions, with the net protein volume change being approximately -0.25%. More than half the strain arising from formation of pR(0) is relieved by the pR(0) to pR(1) structure transition (1.8 +/- 0.2 ns), with the persistent strain presumably contributing to the driving force needed to generate the spectroscopically blue-shifted pB signaling state. The results reported here are consistent with the near-atomic resolution structural dynamics reported in a recent time-resolved Laue crystallography study of PYP crystals and suggest that the early time structural dynamics in the crystalline state carry over to proteins in solution. C1 [Cho, Hyun Sun; Schotte, Friedrich; Dashdorj, Naranbaatar; Anfinrud, Philip A.] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. [Kyndt, John] Bellevue Univ, Coll Sci & Technol, Bellevue, NE 68005 USA. RP Anfinrud, PA (reprint author), NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM anfinrud@nih.gov FU National Center for Research Resources [5P41RR007707]; National Institute of General Medical Sciences from NIH [8P41GM103543]; U.S. DOE [DE-AC02-06CH11357]; National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX We thank Dr. Rob Henning and Dr. Irina Kosheleva for assistance preparing the 14-ID-B beamline for our studies and Bernard Howder, Jr. for machining many of the components required to pursue time-resolved x-ray studies on this beamline. We are grateful to the late Prof. Cusanovich for his early participation in this collaborative effort. Use of the BioCARS Sector 14 was supported by National Center for Research Resources Grant 5P41RR007707 and National Institute of General Medical Sciences Grant 8P41GM103543 from NIH. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by U.S. DOE Contract DE-AC02-06CH11357. The time-resolved setup at Sector 14 was funded in part through collaboration with P.A.A. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. VMD was developed by the Theoretical and Computational Biophysics Group in the Beckman Institute for Advanced Science and Technology at the University of Illinois at Urbana-Champaign. NR 40 TC 10 Z9 10 U1 1 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD DEC 12 PY 2013 VL 117 IS 49 SI SI BP 15825 EP 15832 DI 10.1021/jp407593j PG 8 WC Chemistry, Physical SC Chemistry GA 273IR UT WOS:000328529000060 PM 24125473 ER PT J AU Markovski, M Wickner, S AF Markovski, Monica Wickner, Sue TI Preventing Bacterial Suicide: A Novel Toxin-Antitoxin Strategy SO MOLECULAR CELL LA English DT Editorial Material ID REPLICATION; SYSTEMS AB In this issue of Molecular Cell, Aarke et al. (2013) identify a toxin-antitoxin system in Caulobacter crescentus that acts by a unique mechanism. The toxin, which blocks DNA replication, is constitutively degraded by CIpXP, and this degradation requires the antitoxin, a CIpXP adaptor. C1 [Markovski, Monica; Wickner, Sue] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM wickners@mail.nih.gov FU Intramural NIH HHS [ZIA BC008710-36] NR 10 TC 7 Z9 7 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD DEC 12 PY 2013 VL 52 IS 5 BP 611 EP 612 DI 10.1016/j.molcel.2013.11.018 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 274FI UT WOS:000328591800001 PM 24332174 ER PT J AU Hasson, SA Kane, LA Yamano, K Huang, CH Sliter, DA Buehler, E Wang, CX Heman-Ackah, SM Hessa, T Guha, R Martin, SE Youle, RJ AF Hasson, Samuel A. Kane, Lesley A. Yamano, Koji Huang, Chiu-Hui Sliter, Danielle A. Buehler, Eugen Wang, Chunxin Heman-Ackah, Sabrina M. Hessa, Tara Guha, Rajarshi Martin, Scott E. Youle, Richard J. TI High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy SO NATURE LA English DT Article ID PINK1; PATHWAY; MITOCHONDRIA; RECRUITMENT; SENSITIVITY; ACTIVATION; MUTATIONS; MEMBRANE; PROMOTES; COMPLEX AB An increasing body of evidence points to mitochondrial dysfunction as a contributor to the molecular pathogenesis of neurodegenerative diseases such as Parkinson's disease(1). Recent studies of the Parkinson's disease associated genes PINK1 (ref. 2) and parkin (PARK2, ref. 3) indicate that they may act in a quality control pathway preventing the accumulation of dysfunctional mitochondria(4-8). Here we elucidate regulators that have an impact on parkin translocation to damaged mitochondria with genome-wide small interfering RNA (siRNA) screens coupled to high-content microscopy. Screening yielded gene candidates involved in diverse cellular processes that were subsequently validated in low-throughput assays. This led to characterization of TOMM7 as essential for stabilizing PINK1 on the outer mitochondrial membrane following mitochondrial damage. We also discovered that HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation. The screens revealed that SIAH3, found to localize to mitochondria, inhibits PINK1 accumulation after mitochondrial insult, reducing parkin translocation. Overall, our screens provide a rich resource to understand mitochondrial quality control. C1 [Hasson, Samuel A.; Kane, Lesley A.; Yamano, Koji; Huang, Chiu-Hui; Sliter, Danielle A.; Wang, Chunxin; Hessa, Tara; Youle, Richard J.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Hasson, Samuel A.; Buehler, Eugen; Guha, Rajarshi; Martin, Scott E.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Heman-Ackah, Sabrina M.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov RI Wang, Chunxin/B-9312-2016 OI Wang, Chunxin/0000-0001-6015-6806 FU Japan Society for Promotion of Science; NIGMS Research Associate Program; NIH, NINDS; Trans-NIH RNAi initiative FX We thank P. Tuzmen for qRT-PCR assistance; C. Klumpp for automation; D. Maric for FACS sorting; C. Smith for microscopy assistance; H. Jaffe for mass spectrometry analyses; R. Fields (NINDS) for lentivirus assistance; N. Malik for iPS-derived neurons; the NINDS DNA Sequencing Facility; K. Mihara for the TOMM7 antibody and A. Koretsky and N. Caplen for support. Research was supported by the Japan Society for Promotion of Science Postdoctoral Fellowship for Research Abroad (K.Y.), the NIGMS Research Associate Program, the Intramural Research Program of the NIH, NINDS and the Trans-NIH RNAi initiative. NR 30 TC 93 Z9 101 U1 4 U2 50 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD DEC 12 PY 2013 VL 504 IS 7479 BP 291 EP + DI 10.1038/nature12748 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267TQ UT WOS:000328121500039 PM 24270810 ER PT J AU Courcoulas, AP Christian, NJ Belle, SH Berk, PD Flum, DR Garcia, L Horlick, M Kalarchian, MA King, WC Mitchell, JE Patterson, EJ Pender, JR Pomp, A Pories, WJ Thirlby, RC Yanovski, SZ Wolfe, BM AF Courcoulas, Anita P. Christian, Nicholas J. Belle, Steven H. Berk, Paul D. Flum, David R. Garcia, Luis Horlick, Mary Kalarchian, Melissa A. King, Wendy C. Mitchell, James E. Patterson, Emma J. Pender, John R. Pomp, Alfons Pories, Walter J. Thirlby, Richard C. Yanovski, Susan Z. Wolfe, Bruce M. CA Labs Consortium TI Weight Change and Health Outcomes at 3 Years After Bariatric Surgery Among Individuals With Severe Obesity SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ROUX-EN-Y; TYPE-2 DIABETES-MELLITUS; GASTRIC BYPASS; LONGITUDINAL ASSESSMENT; REPORTING WEIGHT; MEDICAL THERAPY; BLOOD-PRESSURE; RISK-FACTORS; HYPERTENSION; SAFETY AB IMPORTANCE Severe obesity (body mass index [BMI] >= 35) is associated with a broad range of health risks. Bariatric surgery induces weight loss and short-term health improvements, but little is known about long-term outcomes of these operations. OBJECTIVE To report 3-year change in weight and select health parameters after common bariatric surgical procedures. DESIGN AND SETTING The Longitudinal Assessment of Bariatric Surgery (LABS) Consortium is a multicenter observational cohort study at 10 US hospitals in 6 geographically diverse clinical centers. PARTICIPANTS AND EXPOSURE Adults undergoing first-time bariatric surgical procedures as part of routine clinical care by participating surgeons were recruited between 2006 and 2009 and followed up until September 2012. Participants completed research assessments prior to surgery and 6 months, 12 months, and then annually after surgery. MAIN OUTCOMES AND MEASURES Three years after Roux-en-Y gastric bypass (RYGB) or laparoscopic adjustable gastric banding (LAGB), we assessed percent weight change from baseline and the percentage of participants with diabetes achieving hemoglobin A(1c) levels less than 6.5% or fasting plasma glucose values less than 126 mg/dL without pharmacologic therapy. Dyslipidemia and hypertension resolution at 3 years was also assessed. RESULTS At baseline, participants (N = 2458) were 18 to 78 years old, 79% were women, median BMI was 45.9 (IQR, 41.7-51.5), and median weight was 129 kg (IQR, 115-147). For their first bariatric surgical procedure, 1738 participants underwent RYGB, 610 LAGB, and 110 other procedures. At baseline, 774 (33%) had diabetes, 1252 (63%) dyslipidemia, and 1601 (68%) hypertension. Three years after surgery, median actual weight loss for RYGB participants was 41 kg (IQR, 31-52), corresponding to a percentage of baseline weight lost of 31.5% (IQR, 24.6%-38.4%). For LAGB participants, actual weight loss was 20 kg (IQR, 10-29), corresponding to 15.9% (IQR, 7.9%-23.0%). The majority of weight loss was evident 1 year after surgery for both procedures. Five distinct weight change trajectory groups were identified for each procedure. Among participants who had diabetes at baseline, 216 RYGB participants (67.5%) and 28 LAGB participants (28.6%) experienced partial remission at 3 years. The incidence of diabetes was 0.9% after RYGB and 3.2% after LAGB. Dyslipidemia resolved in 237 RYGB participants (61.9%) and 39 LAGB participants (27.1%); remission of hypertension occurred in 269 RYGB participants (38.2%) and 43 LAGB participants (17.4%). CONCLUSIONS AND RELEVANCE Among participants with severe obesity, there was substantial weight loss 3 years after bariatric surgery, with the majority experiencing maximum weight change during the first year. However, there was variability in the amount and trajectories of weight loss and in diabetes, blood pressure, and lipid outcomes. C1 [Courcoulas, Anita P.] Univ Pittsburgh, Med Ctr, Dept Surg, Pittsburgh, PA 15213 USA. [Christian, Nicholas J.; Belle, Steven H.; King, Wendy C.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Berk, Paul D.] Columbia Univ, Med Ctr, Dept Med, New York, NY USA. [Flum, David R.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Garcia, Luis] Univ N Dakota, Sch Hlth Sci, Dept Surg, Grand Forks, ND 58201 USA. [Horlick, Mary; Yanovski, Susan Z.] NIDDK, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. [Kalarchian, Melissa A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Mitchell, James E.] Univ N Dakota, Sch Med & Hlth Sci, Dept Neurosci, Neuropsychiatr Res Inst, Grand Forks, ND 58201 USA. [Patterson, Emma J.] Legacy Good Samaritan Med Ctr, Dept Surg, Portland, OR USA. [Pender, John R.; Pories, Walter J.] E Carolina Univ, Brody Sch Med, Dept Surg, Greenville, NC USA. [Pomp, Alfons] Weill Cornell Med Coll, Dept Surg, New York, NY USA. [Thirlby, Richard C.] Virginia Mason Med Ctr, Dept Surg, Seattle, WA 98101 USA. [Wolfe, Bruce M.] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA. RP Courcoulas, AP (reprint author), Univ Pittsburgh, Med Ctr, Dept Surg, 3380 Blvd Allies,Ste 390, Pittsburgh, PA 15213 USA. EM courcoulasap@upmc.edu OI King, Wendy/0000-0002-0740-0029; Kalarchian, Melissa/0000-0003-2099-9299 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01 DK066557, U01-DK66667, UL1-RR024996, U01-DK66568, M01RR-00037, U01-DK66471, U01-DK66526, U01-DK66585, UL1-RR024153, U01-DK66555] FX LABS-2 was a cooperative agreement funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) with grants for the data coordinating center (U01 DK066557), Columbia University Medical Center (U01-DK66667) (in collaboration with Cornell University Medical Center Clinical and Translational Research Center [CTRC], grant UL1-RR024996), University of Washington (U01-DK66568) (in collaboration with CTRC, grant M01RR-00037), Neuropsychiatric Research Institute (U01-DK66471), East Carolina University (U01-DK66526), University of Pittsburgh Medical Center (U01-DK66585) (in collaboration with CTRC, grant UL1-RR024153), and Oregon Health and Science University (U01-DK66555). NR 36 TC 198 Z9 201 U1 6 U2 29 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 11 PY 2013 VL 310 IS 22 BP 2416 EP 2425 DI 10.1001/jama.2013.280928 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 266NN UT WOS:000328030900022 PM 24189773 ER PT J AU Christian, NJ King, WC Yanovski, SZ Courcoulas, AP Belle, SH AF Christian, Nicholas J. King, Wendy C. Yanovski, Susan Z. Courcoulas, Anita P. Belle, Steven H. TI Validity of Self-reported Weights Following Bariatric Surgery SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID BODY-MASS INDEX; HEIGHT C1 [Christian, Nicholas J.; King, Wendy C.; Belle, Steven H.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Yanovski, Susan Z.] NIDDKD, Bethesda, MD USA. [Courcoulas, Anita P.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. RP Christian, NJ (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, 130 DeSoto St,127 Parran Hall, Pittsburgh, PA 15261 USA. EM christiann@edc.pitt.edu OI King, Wendy/0000-0002-0740-0029 FU NCATS NIH HHS [UL1 TR000005, UL1 TR000457]; NCRR NIH HHS [M01 RR000037, M01RR-00037, UL1 RR024153, UL1 RR024996, UL1-RR024153, UL1-RR024996]; NIDDK NIH HHS [U01-DK66585, U01 DK066471, U01 DK066526, U01 DK066555, U01 DK066557, U01 DK066568, U01 DK066585, U01 DK066667, U01-DK66471, U01-DK66526, U01-DK66555, U01-DK66568, U01-DK66667] NR 6 TC 21 Z9 21 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 11 PY 2013 VL 310 IS 22 BP 2454 EP 2456 DI 10.1001/jama.2013.281043 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 266NN UT WOS:000328030900027 PM 24189698 ER PT J AU Forni, PE Bharti, K Flannery, EM Shimogori, T Wray, S AF Forni, Paolo Emanuele Bharti, Kapil Flannery, Ellen M. Shimogori, Tomomi Wray, Susan TI The Indirect Role of Fibroblast Growth Factor-8 in Defining Neurogenic Niches of the Olfactory/GnRH Systems SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; EPITHELIAL-MESENCHYMAL INTERACTIONS; NEURAL INDUCTION; CLEFT-LIP; KALLMANN-SYNDROME; FACIAL PRIMORDIA; PROGENITOR CELLS; BMP INHIBITION; GNRH-1 NEURONS; CHICK-EMBRYO AB Bone morphogenic protein-4 (BMP4) and fibroblast growth factor-8 (FGF8) are thought to have opposite roles in defining epithelial versus neurogenic fate in the developing olfactory/vomeronasal system. In particular, FGF8 has been implicated in specification of olfactory and gonadotropin releasing hormone-1 (GnRH) neurons, as well as in controlling olfactory stem cell survival. Using different knock-in mouse lines and Cre-lox-mediated lineage tracing, Fgf8 expression and cell lineage was analyzed in the developing nose in relation to the expression of Bmp4 and its antagonist Noggin (Nog). FGF8 is expressed by cells that acquire an epidermal, respiratory cell fate and not by stem cells that acquire neuronal olfactory or vomeronasal cell fate. Ectodermal and mesenchymal sources of BMP4 control the expression of BMP/TGF beta antagonist Nog, whereas mesenchymal sources of Nog define the neurogenic borders of the olfactory pit. Fgf8 hypomorph mouse models, Fgf8(neo/neo) and Fgf8(neo/null), displayed severe craniofacial defects together with overlapping defects in the olfactory pit including (1) lack of neuronal formation ventrally, where GnRH neurons normally form, and (2) altered expression of Bmp4 and Nog, with Nog ectopically expressed in the nasal mesenchyme and no longer defining the GnRH and vomeronasal neurogenic border. Together our data show that (1) FGF8 is not sufficient to induce ectodermal progenitors of the olfactory pit to acquire neural fate and (2) altered neurogenesis and lack of GnRH neuron specification after chronically reduced Fgf8 expression reflected dysgenesis of the nasal region and loss of a specific neurogenic permissive milieu that was defined by mesenchymal signals. C1 [Forni, Paolo Emanuele; Flannery, Ellen M.; Wray, Susan] Natl Inst Neurol Disorders & Stroke, Cellular & Dev Neurobiol Sect, Bethesda, MD 20892 USA. [Bharti, Kapil] NEI, Unit Ocular & Stem Cell Translat Res, NIH, Bethesda, MD 20892 USA. [Shimogori, Tomomi] RIKEN, Brain Sci Inst, Lab Mol Mech Thalamus Dev, Wako, Saitama 3510198, Japan. RP Wray, S (reprint author), NINDS, NIH, Bldg 35,Rm 3A-1012, Bethesda, MD 20892 USA. EM wrays@ninds.nih.gov RI Flannery, Ellen/D-3941-2014; OI wray, susan/0000-0001-7670-3915 FU Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke [NS002824-13] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke (NS002824-13). Several monoclonal antibodies used in these studies were obtained from the Developmental Studies Hybridoma Bank developed under National Institute of Child Health and Human Development and maintained by the University of Iowa, Department of Biology, Iowa City, Iowa. NR 70 TC 5 Z9 5 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 11 PY 2013 VL 33 IS 50 BP 19620 EP 19634 DI 10.1523/JNEUROSCI.3238-13.2013 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 274SP UT WOS:000328626800022 PM 24336726 ER PT J AU Sekerkova, G Kim, JA Nigro, MJ Becker, EBE Hartmann, J Birnbaumer, L Mugnaini, E Martina, M AF Sekerkova, Gabriella Kim, Jin-Ah Nigro, Maximiliano J. Becker, Esther B. E. Hartmann, Jana Birnbaumer, Lutz Mugnaini, Enrico Martina, Marco TI Early Onset of Ataxia in Moonwalker Mice Is Accompanied by Complete Ablation of Type II Unipolar Brush Cells and Purkinje Cell Dysfunction SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TRPC3 CHANNELS; CEREBELLUM; TRANSMISSION AB Transient receptor potential "canonical" cation channels (TRPC) are involved in many cellular activities, including neuronal synaptic transmission. These channels couple lipid metabolism, calcium homeostasis, and electrophysiological properties as they are calcium permeable and activated through the phospholipase C pathway and by diacylglycerol. The TRPC3 subunit is abundantly expressed in Purkinje cells (PCs), where it mediates slow metabotropic glutamate receptor-mediated synaptic responses. Recently, it has been shown that heterozygous moonwalker mice, which are a model of cerebellar ataxia, carry a dominant gain-of-function mutation (T635A) in the TRPC3 gene. This mutation leads to PC loss and dysmorphism, which have been suggested to cause the ataxia. However, the ataxic phenotype is present from a very early stage (before weaning), whereas PC loss does not appear until several months of age. Here we show that another class of cerebellar neurons, the type II unipolar brush cells (UBCs), express functional TRPC3 channels; intriguingly, these cells are ablated in moonwalker mice by 1 month of age. Additionally, we show that in moonwalker mice, intrinsic excitability of PCs is altered as early as 3 weeks after birth. We suggest that this altered excitability and the TRPC3-mediated loss of type II UBCs may both contribute to the ataxic phenotype of these mice and that different calcium handling in PCs and type II UBCs may account for the dramatic differences in sensitivity to the moonwalker mutation between these cell types. C1 [Sekerkova, Gabriella; Kim, Jin-Ah; Nigro, Maximiliano J.; Mugnaini, Enrico; Martina, Marco] Northwestern Univ, Dept Physiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Sekerkova, Gabriella; Mugnaini, Enrico] Northwestern Univ, Dept Cell & Mol Biol, Feinberg Sch Med, Chicago, IL 60611 USA. [Becker, Esther B. E.] Univ Oxford, Dept Physiol Anat & Genet, MRC, Funct Genom Unit, Oxford OX1 3PT, England. [Hartmann, Jana] Tech Univ Munich, Inst Neurosci, D-80802 Munich, Germany. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Durham, NC 27709 USA. RP Martina, M (reprint author), Northwestern Univ, Dept Physiol, Feinberg Sch Med, 303 E Chicago Ave, Chicago, IL 60611 USA. EM m-martina@northwestern.edu RI Hartmann, Jana/C-1024-2008 FU NIH [NS 09904]; DFG Grant [SFB 870]; Intramural Research Program of the NIH [Z01-ES-101864]; Royal Society, London FX This work was supported by NIH Grant NS 09904 (M.M.), DFG Grant SFB 870 (J.H.), and the Intramural Research Program of the NIH (project Z01-ES-101864, L.B.). E.B.E.B. is the recipient of a Research Fellowship from the Royal Society, London. E.B.E.B. thanks Kay E. Davies for generous support. NR 18 TC 13 Z9 13 U1 0 U2 7 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 DEC 11 PY 2013 VL 33 IS 50 BP 19689 EP 19694 DI 10.1523/JNEUROSCI.2294-13.2013 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 274SP UT WOS:000328626800028 PM 24336732 ER PT J AU Rajendran, A Endo, M Hidaka, K Tran, PLT Mergny, JL Gorelick, RJ Sugiyama, H AF Rajendran, Arivazhagan Endo, Masayuki Hidaka, Kumi Phong Lan Thao Tran Mergny, Jean-Louis Gorelick, Robert J. Sugiyama, Hiroshi TI HIV-1 Nucleocapsid Proteins as Molecular Chaperones for Tetramolecular Antiparallel G-Quadruplex Formation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID TELOMERE-BINDING-PROTEIN; ATOMIC-FORCE MICROSCOPY; ZINC-FINGER STRUCTURES; DNA ORIGAMI; REVERSE TRANSCRIPTION; STRANDED-DNA; G-QUARTETS; IN-VITRO; HELICASE; TYPE-1 AB HIV-1 nucleocapsid proteins (NCps) facilitate remodeling of nucleic acids to fold thermodynamically stable conformations, and thus called nucleic acid chaperones. To date only little is known on the stoichiometry, NCp-NCp interactions, chaperone activity on G-quadruplex formation, and so on. We report here the direct and real-time analysis on such properties of proteolytic intermediate NCp15 and mature NCp7 using DNA origami. The protein particles were found to predominantly exist in monomeric form, while dimeric and multimeric forms were also observed both in free solution and bound to the quadruplex structure. The formation and the dissociation events of the G-quadruplexes were well documented in real-time and the intermediate-like states were also visualized. We anticipate that this pioneering study will strengthen our understanding on the chaperone activity of HIV-1 proteins which in turn will be helpful for the drug design based on G-quadruplex and also for the development of drugs against AIDS. C1 [Rajendran, Arivazhagan; Hidaka, Kumi; Sugiyama, Hiroshi] Kyoto Univ, Dept Chem, Grad Sch Sci, Kyoto 6068502, Japan. [Endo, Masayuki; Sugiyama, Hiroshi] Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Sakyo Ku, Kyoto 6068501, Japan. [Endo, Masayuki; Sugiyama, Hiroshi] Japan Sci & Technol Corp JST, CREST, Chiyoda Ku, Tokyo 1020075, Japan. [Phong Lan Thao Tran; Mergny, Jean-Louis] Univ Bordeaux, INSERM, U869, ARNA Lab, F-33607 Pessac, France. [Gorelick, Robert J.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Endo, M (reprint author), Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Sakyo Ku, Kyoto 6068501, Japan. EM endo@kuchem.kyoto-u.ac.jp; hs@kuchem.kyoto-u.ac.jp RI Sugiyama, Hiroshi/C-7687-2011; Endo, Masayuki/J-5874-2014; Rajendran, Arivazhagan/D-6736-2012; Mergny, Jean-Louis/E-2860-2013 OI Rajendran, Arivazhagan/0000-0002-9319-6107; Mergny, Jean-Louis/0000-0003-3043-8401 FU CREST grant from the Japan Science and Technology Corporation (JST); WPI program (WPI-iCeMS, Kyoto University); JSPS KAKENHI [24310097, 24225005, 24104002]; Mitsubishi Foundation; Asahi Glass Foundation; Japan Society for the Promotion of Science (JSPS); Aquitaine Regional Council; ANR [G4-Toolbox, Quarpdiem, Oligoswitch]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Leidos Biomedical Research, Inc. FX We thank Sebastien Lyonnais and Gilles Mirambeau for their kind assistance with the proteins used in this study. We express our sincere thanks for the CREST grant from the Japan Science and Technology Corporation (JST), grants from the WPI program (WPI-iCeMS, Kyoto University), and JSPS KAKENHI (Grant numbers 24310097, 24225005 and 24104002). Financial supports from The Mitsubishi Foundation and The Asahi Glass Foundation to M.E. are also acknowledged. A.R. expresses sincere thanks to the Japan Society for the Promotion of Science (JSPS) for the Postdoctoral fellowship. P.L.T.T. and J.-L.M. sincerely thank the Aquitaine Regional Council and the ANR program G4-Toolbox, Quarpdiem and Oligoswitch for financial support. For R.J.G., this project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E with Leidos Biomedical Research, Inc. NR 50 TC 17 Z9 17 U1 1 U2 48 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD DEC 11 PY 2013 VL 135 IS 49 BP 18575 EP 18585 DI 10.1021/ja409085j PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 272CU UT WOS:000328438700053 PM 24224650 ER PT J AU Platig, J Ott, E Girvan, M AF Platig, J. Ott, E. Girvan, M. TI Robustness of network measures to link errors SO PHYSICAL REVIEW E LA English DT Article ID COMPLEX NETWORKS; REGULATORY NETWORKS; RECONSTRUCTION; EMERGENCE AB In various applications involving complex networks, network measures are employed to assess the relative importance of network nodes. However, the robustness of such measures in the presence of link inaccuracies has not been well characterized. Here we present two simple stochastic models of false and missing links and study the effect of link errors on three commonly used node centrality measures: degree centrality, betweenness centrality, and dynamical importance. We perform numerical simulations to assess robustness of these three centrality measures. We also develop an analytical theory, which we compare with our simulations, obtaining very good agreement. C1 [Platig, J.; Ott, E.; Girvan, M.] Univ Maryland, Inst Res Elect & Appl Phys, College Pk, MD 20742 USA. [Platig, J.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Platig, J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Platig, J (reprint author), Univ Maryland, Inst Res Elect & Appl Phys, College Pk, MD 20742 USA. EM jplatig@jimmy.harvard.edu RI O, E/F-1630-2015 FU Army Research Office [W911NF-12-1-0101]; University of Maryland/National Cancer Institute (NIH) Partnership for Cancer Technology FX We thank Shane Squires for his helpful input. This work was supported by the Army Research Office under Grant No. W911NF-12-1-0101 and by the University of Maryland/National Cancer Institute (NIH) Partnership for Cancer Technology. NR 23 TC 8 Z9 8 U1 0 U2 15 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 EI 1550-2376 J9 PHYS REV E JI Phys. Rev. E PD DEC 11 PY 2013 VL 88 IS 6 AR 062812 DI 10.1103/PhysRevE.88.062812 PG 8 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 275RM UT WOS:000328695100006 PM 24483516 ER PT J AU Legros, M Xu, CG Morrison, A Scott, TW Lloyd, AL Gould, F AF Legros, Mathieu Xu, Chonggang Morrison, Amy Scott, Thomas W. Lloyd, Alun L. Gould, Fred TI Modeling the Dynamics of a Non- Limited and a Self-Limited Gene Drive System in Structured Aedes aegypti Populations SO PLOS ONE LA English DT Article ID MOSQUITO-BORNE DISEASES; ENGINEERED UNDERDOMINANCE; CULICIDAE PRODUCTION; INSECT POPULATIONS; RNA INTERFERENCE; PEST POPULATIONS; VIRUS-RESISTANCE; MEIOTIC DRIVE; TRANSGENES; DIPTERA AB Recently there have been significant advances in research on genetic strategies to control populations of disease-vectoring insects. Some of these strategies use the gene drive properties of selfish genetic elements to spread physically linked anti-pathogen genes into local vector populations. Because of the potential of these selfish elements to spread through populations, control approaches based on these strategies must be carefully evaluated to ensure a balance between the desirable spread of the refractoriness-conferring genetic cargo and the avoidance of potentially unwanted outcomes such as spread to non-target populations. There is also a need to develop better estimates of the economics of such releases. We present here an evaluation of two such strategies using a biologically realistic mathematical model that simulates the resident Aedes aegypti mosquito population of Iquitos, Peru. One strategy uses the selfish element Medea, a non-limited element that could permanently spread over a large geographic area; the other strategy relies on Killer-Rescue genetic constructs, and has been predicted to have limited spatial and temporal spread. We simulate various operational approaches for deploying these genetic strategies, and quantify the optimal number of released transgenic mosquitoes needed to achieve definitive spread of Medea-linked genes and/or high frequencies of Killer-Rescue-associated elements. We show that for both strategies the most efficient approach for achieving spread of anti-pathogen genes within three years is generally to release adults of both sexes in multiple releases over time. Even though females in these releases should not transmit disease, there could be public concern over such releases, making the less efficient male-only release more practical. This study provides guidelines for operational approaches to population replacement genetic strategies, as well as illustrates the use of detailed spatial models to assist in safe and efficient implementation of such novel genetic strategies. C1 [Legros, Mathieu; Xu, Chonggang; Gould, Fred] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Legros, Mathieu; Morrison, Amy; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Legros, Mathieu] ETH, Inst Integrat Biol, Zurich, Switzerland. [Xu, Chonggang] Los Alamos Natl Lab, Div Earth & Environm Sci, Los Alamos, NM 87545 USA. [Morrison, Amy; Scott, Thomas W.; Lloyd, Alun L.; Gould, Fred] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lloyd, Alun L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Lloyd, Alun L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. RP Legros, M (reprint author), N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. EM legros.mathieu@gmail.com RI Legros, Mathieu/E-6767-2011; OI Legros, Mathieu/0000-0003-3807-8594; Xu, Chonggang/0000-0002-0937-5744 FU National Institutes of Health [R01-AI54954-0IA2]; Regents of the University of California from the Foundation for the National Institutes of Health Grand Challenges in Global Health initiative FX This work was funded by National Institutes of Health grant R01-AI54954-0IA2, and through the Regents of the University of California from the Foundation for the National Institutes of Health Grand Challenges in Global Health initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 5 Z9 5 U1 3 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 DEC 10 PY 2013 VL 8 IS 12 AR UNSP e83354 DI 10.1371/journal.pone.0083354 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 275VW UT WOS:000328707400130 PM 24340097 ER PT J AU Parrow, NL Leshin, JA Levine, M AF Parrow, Nermi L. Leshin, Jonathan A. Levine, Mark TI Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID DOSE VITAMIN-C; RECOMMENDED DIETARY ALLOWANCE; TERMINAL HUMAN CANCER; CELLS IN-VITRO; PHARMACOLOGICAL ASCORBATE; ORTHOMOLECULAR TREATMENT; TUMOR-GROWTH; SUPPLEMENTAL ASCORBATE; MALIGNANT MESOTHELIOMA; SUPPORTIVE TREATMENT AB Significance: Ewan Cameron reported that ascorbate, given orally and intravenously at doses of up to 10g/day, was effective in the treatment of cancer. Double-blind placebo-controlled clinical trials showed no survival advantage when the same doses of ascorbate were given orally, leading the medical and scientific communities to dismiss the use of ascorbate as a potential cancer treatment. However, the route of administration results in major differences in ascorbate bioavailability. Tissue and plasma concentrations are tightly controlled in response to oral administration, but this can be bypassed by intravenous administration. These data provide a plausible scientific rationale for the absence of a response to orally administered ascorbate in the Mayo clinic trials and indicate the need to reassess ascorbate as a cancer therapeutic. Recent Advances: High dose ascorbate is selectively cytotoxic to cancer cell lines through the generation of extracellular hydrogen peroxide (H2O2). Murine xenograft models confirm a growth inhibitory effect of pharmacological concentrations. The safety of intravenous ascorbate has been verified in encouraging pilot clinical studies. Critical Issues: Neither the selective toxicity of pharmacologic ascorbate against cancer cells nor the mechanism of H2O2-mediated cytotoxicity is fully understood. Despite promising preclinical data, the question of clinical efficacy remains. Future Directions: A full delineation of mechanism is of interest because it may indicate susceptible cancer types. Effects of pharmacologic ascorbate used in combination with standard treatments need to be defined. Most importantly, the clinical efficacy of ascorbate needs to be reassessed using proper dosing, route of administration, and controls. Antioxid. Redox Signal. 19, 2141-2156. C1 [Parrow, Nermi L.; Leshin, Jonathan A.; Levine, Mark] NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Levine, M (reprint author), NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bldg 10,Room 4D52,10 Ctr Dr, Bethesda, MD 20892 USA. EM markl@intra.niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH) [ZIA DK053212] FX We are indebted to the patients and healthy volunteers who agreed to participate in the clinical studies reviewed in this article. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH) (ZIA DK053212). The opinions are those of the authors and do not represent official NIH policy. NR 82 TC 21 Z9 23 U1 0 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD DEC 10 PY 2013 VL 19 IS 17 BP 2141 EP 2156 DI 10.1089/ars.2013.5372 PG 16 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 273SQ UT WOS:000328557000012 PM 23621620 ER PT J AU Li, WQ Qureshi, AA Ma, J Goldstein, AM Giovannucci, EL Stampfer, MJ Han, JL AF Li, Wen-Qing Qureshi, Abrar A. Ma, Jing Goldstein, Alisa M. Giovannucci, Edward L. Stampfer, Meir J. Han, Jiali TI Personal History of Prostate Cancer and Increased Risk of Incident Melanoma in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROSPECTIVE COHORT; ANDROGEN RECEPTOR; ASSOCIATION; SUBSEQUENT; TELOMERES; BLOCKADE; HEALTH; CELLS; ACNE; SKIN AB Purpose Steroid hormones, particularly androgens, play a major role in prostatic carcinogenesis. Personal history of severe acne, a surrogate for higher androgen activity, has been associated with an increased risk of prostate cancer (PCa), and one recent study indicated that severe teenage acne was a novel risk factor for melanoma. These findings suggest a possible relationship between PCa and risk of melanoma. We prospectively evaluated this association among US men. Methods A total of 42,372 participants in the Health Professionals' Follow-Up Study (HPFS; 1986 to 2010) were included. Biennially self-reported PCa diagnosis was confirmed using pathology reports. Diagnosis of melanoma and nonmelanoma skin cancer (NMSC) was self-reported biennially, and diagnosis of melanoma was pathologically confirmed. We sought to confirm the association in 18,603 participants from the Physicians' Health Study (PHS; 1982 to 1998). Results We identified 539 melanomas in the HPFS. Personal history of PCa was associated with an increased risk of melanoma (multivariate-adjusted hazard ratio [HR], 1.83; 95% CI, 1.32 to 2.54). Although we also detected a marginally increased risk of NMSC associated with PCa (HR, 1.08; 95% CI, 0.995 to 1.16), the difference in the magnitude of the association between melanoma and NMSC was significant (P for heterogeneity = .002). We did not find an altered risk of melanoma associated with personal history of other cancers. The association between PCa and risk of incident melanoma was confirmed in the PHS (HR, 2.17; 95% CI, 1.12 to 4.21). Conclusion Personal history of PCa is associated with an increased risk of melanoma, which may not be entirely a result of greater medical scrutiny. C1 [Li, Wen-Qing; Goldstein, Alisa M.] NCI, NIH, Rockville, MD USA. [Li, Wen-Qing; Qureshi, Abrar A.; Ma, Jing; Giovannucci, Edward L.; Stampfer, Meir J.; Han, Jiali] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Giovannucci, Edward L.; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Han, Jiali] Indiana Univ, Richard M Fairbanks Sch Publ Hlth, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Han, Jiali] Tianjin Med Univ, Canc Inst & Hosp, Tianjin, Peoples R China. RP Han, JL (reprint author), 181 Longwood Ave, Boston, MA 02115 USA. EM jiali.han@channing.harvard.edu RI Li, Wenqing/N-2293-2014 OI Li, Wenqing/0000-0002-1283-4091 FU National Institutes of Health (NIH) [P01 CA055075]; National Cancer Institute [CA-34944, CA-40360, CA-097193]; National Heart, Lung, and Blood Institute, Bethesda, MD [HL-26490, HL-34595]; Intramural Research Program of the NIH; National Cancer Institute; Division of Cancer Epidemiology and Genetics FX The Health Professionals' Follow-Up Study is partly supported by National Institutes of Health (NIH) Grant No. P01 CA055075. The Physicians' Health Study is supported by Grants No, CA-34944, CA-40360, and CA-097193 from the National Cancer Institute and Grants No. HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute, Bethesda, MD. The current analysis was supported by the Intramural Research Program of the NIH, National Cancer Institute, and the Division of Cancer Epidemiology and Genetics. NR 33 TC 12 Z9 12 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 DEC 10 PY 2013 VL 31 IS 35 BP 4394 EP + DI 10.1200/JCO.2013.51.1915 PG 11 WC Oncology SC Oncology GA 277KJ UT WOS:000328817400004 PM 24190118 ER PT J AU Gao, Y Kuang, Y Du, XW Zhou, J Chandran, P Horkay, F Xu, B AF Gao, Yuan Kuang, Yi Du, Xuewen Zhou, Jie Chandran, Preethi Horkay, Ferenc Xu, Bing TI Imaging Self-Assembly Dependent Spatial Distribution of Small Molecules in a Cellular Environment SO LANGMUIR LA English DT Article ID GREEN FLUORESCENT PROTEIN; SUPRAMOLECULAR HYDROGELS; ENZYMATIC FORMATION; LIVING CELLS; ACTIN CYTOSKELETON; DESIGNED PEPTIDE; NANOFIBERS; NANOSTRUCTURES; DERIVATIVES; INHIBITION AB Self-assembly of small molecules, as a more common phenomenon than one previously thought, can be either beneficial or detrimental to cells. Despite its profound biological implications, how the self-assembly of small molecules behave in a cellular environment is largely unknown and barely explored. This work studies four fluorescent molecules that consist of the same peptidic backbone (e.g., Phe-Phe-Lys) and enzyme trigger (e.g., a phosphotyrosine residue), but bear different fluorophores on the side chain of the lysine residue of the peptidic motif. These molecules, however, exhibit a different ability of self-assembly before and after enzymatic transformation (e.g., dephosphorylation). Fluorescent imaging reveals that self-assembly directly affects the distribution of these small molecules in a cellular environment. Moreover, cell viability tests suggest that the states and the locations of the molecular assemblies in the cellular environment control the phenotypes of the cells. For example, the molecular nanofibers of one of the small molecules apparently stabilize actin filaments and alleviate the insult of an F-actin toxin (e.g., latrunculin A). Combining fluorescent imaging and enzyme-instructed self-assembly of small peptidic molecules, this work demonstrates self-assembly as a key factor for dictating the spatial distribution of small molecules in a cellular environment. In addition, it illustrates a useful approach, based on enzyme-instructed self-assembly of small molecules, to modulate spatiotemporal profiles of small molecules in a cellular environment, which allows the use of the emergent properties of small molecules to control the fate of cells. C1 [Gao, Yuan; Kuang, Yi; Du, Xuewen; Zhou, Jie; Xu, Bing] Brandeis Univ, Dept Chem, Waltham, MA 02454 USA. [Gao, Yuan; Horkay, Ferenc] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Chandran, Preethi] Howard Univ, Dept Chem Engn, Washington, DC 20059 USA. RP Xu, B (reprint author), Brandeis Univ, Dept Chem, 415 South St, Waltham, MA 02454 USA. EM bxu@brandeis.edu RI Gao, Yuan/D-7441-2012; XU, Bing/A-7828-2008 OI Gao, Yuan/0000-0001-9509-4924; XU, Bing/0000-0002-4639-387X FU National Institutes of Health (NIH) [R01CA142746]; Human Frontiers Science Program (HFSP); MRSEC; National Research Council Research Associateship Award at NICHD; Intramural Research Program of the NICHD/NIH; Brandeis FX The authors acknowledge the National Institutes of Health (NIH R01CA142746), Human Frontiers Science Program (HFSP), MRSEC, start-up fund of Brandeis for funding to B.X. and National Research Council Research Associateship Award to Y.G. at NICHD. Y.G., P.C., and F.H. acknowledge the support of the Intramural Research Program of the NICHD/NIH. NR 48 TC 12 Z9 12 U1 2 U2 32 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD DEC 10 PY 2013 VL 29 IS 49 BP 15191 EP 15200 DI 10.1021/la403457c PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 272CD UT WOS:000328437000008 PM 24266765 ER PT J AU Liu, T Ren, D Zhu, XP Yin, Z Jin, GX Zhao, Z Robinson, D Li, XP Wong, K Cui, KM Zhao, H Wong, STC AF Liu, Timothy Ren, Ding Zhu, Xiaoping Yin, Zheng Jin, Guangxu Zhao, Zhen Robinson, Daniel Li, Xuping Wong, Kelvin Cui, Kemi Zhao, Hong Wong, Stephen T. C. TI Transcriptional signaling pathways inversely regulated in Alzheimer's disease and glioblastoma multiform SO SCIENTIFIC REPORTS LA English DT Article ID CELL-CYCLE PROGRESSION; IN-VIVO; PARKINSONS-DISEASE; BREAST-CANCER; PIN1; TAU; PROTEIN; KINASE; ACTIVATION; DIAGNOSIS AB Convincing epidemiological data suggest an inverse association between cancer and neurodegeneration, including Alzheimer's disease (AD). Since both AD and cancer are characterized by abnormal, but opposing cellular behavior, i.e., increased cell death in AD while excessive cell growth occurs in cancer, this motivates us to initiate the study into unraveling the shared genes and cell signaling pathways linking AD and glioblastoma multiform (GBM). In this study, a comprehensive bioinformatics analysis on clinical microarray datasets of 1,091 GBM and 524 AD cohorts was performed. Significant genes and pathways were identified from the bioinformatics analyses - in particular ERK/MAPK signaling, up-regulated in GBM and Angiopoietin Signaling pathway, reciprocally up-regulated in AD - connecting GBM and AD (P < 0.001), were investigated in details for their roles in GBM growth in an AD environment. Our results showed that suppression of GBM growth in an AD background was mediated by the ERK-AKT-p21-cell cycle pathway and anti-angiogenesis pathway. C1 [Liu, Timothy; Ren, Ding; Zhu, Xiaoping; Yin, Zheng; Jin, Guangxu; Zhao, Zhen; Robinson, Daniel; Li, Xuping; Wong, Kelvin; Cui, Kemi; Zhao, Hong; Wong, Stephen T. C.] Weill Cornell Med Coll, Houston Methodist Res Inst, Dept Syst Med & Bioengn, Houston, TX 77030 USA. [Jin, Guangxu; Zhao, Hong; Wong, Stephen T. C.] NCI, Ctr Modeling Canc Dev, Houston Methodist Res Inst, Houston, TX 77030 USA. [Yin, Zheng; Zhao, Zhen; Li, Xuping; Wong, Kelvin; Wong, Stephen T. C.] Houston Methodist Res Inst, Dept Syst Med & Bioengn, TT & WF Chao Ctr BRAIN, Houston, TX 77030 USA. [Ren, Ding] PLA 85 Hosp, Dept Oncol, Shanghai 200030, Peoples R China. RP Zhao, H (reprint author), Weill Cornell Med Coll, Houston Methodist Res Inst, Dept Syst Med & Bioengn, Houston, TX 77030 USA. EM hzhao@tmhs.org; stwong@tmhs.org RI Yin, Zheng/J-9307-2015 OI Yin, Zheng/0000-0002-3547-0606 FU NIH [U54 CA149196, R01 CA121225]; TT & WF Chao Foundation; John S. Dunn Research Foundation; Texas Advanced Computing Center (TACC) [TG-MCB110130] FX This research is funded by NIH U54 CA149196, NIH R01 CA121225, TT & WF Chao Foundation grant and John S. Dunn Research Foundation grant to STCW. We thank Dr. Neal Copeland for providing comments on the manuscript, and Drs. James Mancuso and Rebecca Danforth for proofreading, Drs. Dennis Selkoe (Harvard Medical School) and Santosh Kesari (UC San Diego School of Medicine) for providing the 7PA2, U87VIII, and GL261 cell lines. All the microscopic imaging and ImageStream analysis were performed at Houston Methodist Research Institute's Advanced Cellular and Tissue Microscope Core Facility. We also acknowledge the computational time funding support from the Texas Advanced Computing Center (TACC; Project ID: TG-MCB110130) at the University of Texas in Austin and BlueBioU (IBM POWER 7 Bioscience Computing Core at Rice University) to access super-computing resources. NR 53 TC 6 Z9 6 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 10 PY 2013 VL 3 AR 3467 DI 10.1038/srep03467 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267VF UT WOS:000328125700006 PM 24322672 ER PT J AU Pickl-Herk, A Luque, D Vives-Adrian, L Querol-Audi, J Garriga, D Trus, BL Verdaguer, N Blaas, D Caston, JR AF Pickl-Herk, Angela Luque, Daniel Vives-Adrian, Laia Querol-Audi, Jordi Garriga, Damia Trus, Benes L. Verdaguer, Nuria Blaas, Dieter Caston, Jose R. TI Uncoating of common cold virus is preceded by RNA switching as determined by X-ray and cryo-EM analyses of the subviral A-particle SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genome uncoating; X-ray analysis; 3D cryo-EM; picornavirus ID RECEPTOR-MEMBRANE COMPLEX; HUMAN RHINOVIRUS; ELECTRON-MICROSCOPY; POLIOVIRUS-RECEPTOR; MATURATION CLEAVAGE; DISEASE VIRUS; CELL ENTRY; RESOLUTION; MECHANISM; INTERMEDIATE AB During infection, viruses undergo conformational changes that lead to delivery of their genome into host cytosol. In human rhinovirus A2, this conversion is triggered by exposure to acid pH in the endosome. The first subviral intermediate, the A-particle, is expanded and has lost the internal viral protein 4 (VP4), but retains its RNA genome. The nucleic acid is subsequently released, presumably through one of the large pores that open at the icosahedral twofold axes, and is transferred along a conduit in the endosomal membrane; the remaining empty capsids, termed B-particles, are shuttled to lysosomes for degradation. Previous structural analyses revealed important differences between the native protein shell and the empty capsid. Nonetheless, little is known of A-particle architecture or conformation of the RNA core. Using 3D cryo-electron microscopy and X-ray crystallography, we found notable changes in RNA-protein contacts during conversion of native virus into the A-particle uncoating intermediate. In the native virion, we confirmed interaction of nucleotide(s) with Trp(38) of VP2 and identified additional contacts with the VP1 N terminus. Study of A-particle structure showed that the VP2 contact is maintained, that VP1 interactions are lost after exit of the VP1 N-terminal extension, and that the RNA also interacts with residues of the VP3 N terminus at the fivefold axis. These associations lead to formation of a well-ordered RNA layer beneath the protein shell, suggesting that these interactions guide ordered RNA egress. C1 [Pickl-Herk, Angela; Blaas, Dieter] Med Univ Vienna, Dept Med Biochem, Max F Perutz Labs, A-1030 Vienna, Austria. [Luque, Daniel; Caston, Jose R.] CSIC, Ctr Nacl Biotecnol, Dept Struct Macromol, E-28049 Madrid, Spain. [Luque, Daniel; Caston, Jose R.] CSIC, Ctr Nacl Biotecnol, Dept Mol & Cellular Biol, E-28049 Madrid, Spain. [Luque, Daniel] Inst Salud Carlos III, Ctr Nacl Microbiol, Madrid 28220, Spain. [Vives-Adrian, Laia; Querol-Audi, Jordi; Verdaguer, Nuria] CSIC, Inst Biol Mol Barcelona, E-08028 Barcelona, Spain. [Trus, Benes L.] NIH, Imaging Sci Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Caston, JR (reprint author), CSIC, Ctr Nacl Biotecnol, Dept Struct Macromol, Plaza Murillo 2, E-28049 Madrid, Spain. EM nvmcri@ibmb.csic.es; dieter.blaas@medunivie.ac.at; jrcaston@cnb.csic.es RI Caston, Jose/L-5896-2014; Luque, Daniel/I-6467-2015; OI Caston, Jose/0000-0003-2350-9048; Luque, Daniel/0000-0002-0151-6020; Garriga, Damia/0000-0003-0410-538X FU Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR); Spanish Ministry of Economy and Competitivity [BIO2011-24333, BFU2011-25902]; National Institutes of Health Intramural Research Program; Center for Information Technology; Austrian Science Foundation [18693-B09]; Austrian Exchange Service [Ostereichischer Austauschdienst (OEAD)] [ES 03/2010, AT2009-0041]; [70172]; [2669] FX We thank I. Gosler for preparing the virus, T. Marlovits for advice, G. Resch for help with the Polara microscope, H. Kowalski for critical reading of the manuscript and helpful comments, and C. Mark for editorial assistance. D.B. and A.P.-H. are particularly thankful to S. Hafenstein and R. S. Sinkovic for help and advice in the early phase of the project, and K. Djinovic-Carugo in the initial crystallization trials. Part of the data processing was performed on the Vienna Scientific Cluster (Project 70172 to D.B.), and X-ray data were obtained at the SLS (beamline PX1) Villigen, Switzerland (BioStruct Project 2669). L.V.-A. is the recipient of a Formacio de Investigadors (FI) fellowship from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR). This work was supported by grants from the Spanish Ministry of Economy and Competitivity (BIO2011-24333 to N.V. and BFU2011-25902 to J.R.C.), the National Institutes of Health Intramural Research Program and the Center for Information Technology (to B.L.T.), and the Austrian Science Foundation Project 18693-B09. Short stays in Madrid were made possible by funding through "Acciones Integradas" (ES 03/2010 to D.B. and AT2009-0041 to N.V.) awarded by the Austrian Exchange Service [Ostereichischer Austauschdienst (OEAD)]. NR 43 TC 18 Z9 18 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 10 PY 2013 VL 110 IS 50 BP 20063 EP 20068 DI 10.1073/pnas.1312128110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266YY UT WOS:000328061700036 PM 24277846 ER PT J AU Furuta, K Walseng, E Roche, PA AF Furuta, Kazuyuki Walseng, Even Roche, Paul A. TI Internalizing MHC class II-peptide complexes are ubiquitinated in early endosomes and targeted for lysosomal degradation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INVARIANT CHAIN CONTAINS; DENDRITIC CELLS; RAPID INTERNALIZATION; SURFACE EXPRESSION; CYTOPLASMIC TAIL; DOWN-REGULATION; CLATHRIN; COMPARTMENTS; MOLECULES; PATHWAY AB As sentinels of the immune system, dendritic cells (DCs) continuously generate and turnover antigenic peptide-MHC class II complexes (pMHC-II). pMHC-II generation is a complex process that involves many well-characterized MHC-II biosynthetic intermediates; however, the mechanisms leading to MHC-II turnover/degradation are poorly understood. We now show that pMHC-II complexes undergoing clathrin-independent endocytosis from the DC surface are efficiently ubiquitinated by the E3 ubiquitin ligase March-I in early endosomes, whereas biosynthetically immature MHC-II-Invariant chain (Ii) complexes are not. The inability of MHC-II-Ii to serve as a March-I substrate is a consequence of Ii sorting motifs that divert the MHC-II-Ii complex away from March-I+ early endosomes. When these sorting motifs are mutated, or when clathrin-mediated endocytosis is inhibited, MHC-II-Ii complexes internalize by using a clathrin-independent endocytosis pathway and are now ubiquitinated as efficiently as pMHC-II complexes. These data show that the selective ubiquitination of internalizing surface pMHC-II in March-I+ early endosomes promotes degradation of "old" pMHC-II and spares forms of MHC-II that have not yet loaded antigenic peptides or have not yet reached the DC surface. C1 [Furuta, Kazuyuki; Walseng, Even; Roche, Paul A.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Furuta, Kazuyuki] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Deptartment Immunobiol, Okayama 7008530, Japan. [Walseng, Even] Scripps Florida, Scripps Res Inst, Dept Canc Biol, Jupiter, FL 33458 USA. RP Roche, PA (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM paul.roche@nih.gov FU Japan Society for the Promotion of Science; National Institutes of Health FX We thank Peter Cresswell, Satoshi Ishido, and Juan Bonifacino for the gift of reagents used in this study; Mike Kruhlak and the Experimental Immunology Branch microscopy facility for expert technical advice; and Richard Hodes for critical reading of this manuscript. This work was supported by the Japan Society for the Promotion of Science (K. F.) and the Intramural Research Program of the National Institutes of Health (P.A.R.). NR 34 TC 9 Z9 9 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 10 PY 2013 VL 110 IS 50 BP 20188 EP 20193 DI 10.1073/pnas.1312994110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266YY UT WOS:000328061700057 PM 24277838 ER PT J AU Chen, ZC Fischer, ER Kouiavskaia, D Hansen, BT Ludtke, SJ Bidzhieva, B Makiya, M Agulto, L Purcell, RH Chumakov, K AF Chen, Zhaochun Fischer, Elizabeth R. Kouiavskaia, Diana Hansen, Bryan T. Ludtke, Steven J. Bidzhieva, Bella Makiya, Michelle Agulto, Liane Purcell, Robert H. Chumakov, Konstantin TI Cross-neutralizing human anti-poliovirus antibodies bind the recognition site for cellular receptor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE phage display; passive immunization; antiviral therapy; broadly reactive antibodies ID ELECTRON-MICROSCOPY; ANTIGENIC STRUCTURE; MONOCLONAL-ANTIBODIES; COMPLEXES; ERADICATION; MUTANTS; VIRUS; CD155; RNA AB Most structural information about poliovirus interaction with neutralizing antibodies was obtained in the 1980s in studies of mouse monoclonal antibodies. Recently we have isolated a number of human/chimpanzee anti-poliovirus antibodies and demonstrated that one of them, MAb A12, could neutralize polioviruses of both serotypes 1 and 2. This communication presents data on isolation of an additional cross-neutralizing antibody (F12) and identification of a previously unknown epitope on the surface of poliovirus virions. Epitope mapping was performed by sequencing of antibody-resistant mutants and by cryo-EM of complexes of virions with Fab fragments. The results have demonstrated that both cross-neutralizing antibodies bind the site located at the bottom of the canyon surrounding the fivefold axis of symmetry that was previously shown to interact with cellular poliovirus receptor CD155. However, the same antibody binds to serotypes 1 and 2 through different specific interactions. It was also shown to interact with type 3 poliovirus, albeit with about 10-fold lower affinity, insufficient for effective neutralization. Antibody interaction with the binding site of the cellular receptor may explain its broad reactivity and suggest that further screening or antibody engineering could lead to a universal antibody capable of neutralizing all three serotypes of poliovirus. C1 [Chen, Zhaochun; Makiya, Michelle; Agulto, Liane; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Fischer, Elizabeth R.; Hansen, Bryan T.] NIAID, Electron Microscopy Unit, Res Technol Branch, Rocky Mt Labs, Hamilton, MT 59840 USA. [Kouiavskaia, Diana; Bidzhieva, Bella; Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Ludtke, Steven J.] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Natl Ctr Macromol Imaging, Houston, TX 77030 USA. RP Purcell, RH (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM robert.purcell@nih.gov; konstantin.chumakov@fda.hhs.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; Food and Drug Administration Center for Biologics Evaluation and Research; NIH [R01-GM080139] FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, the Food and Drug Administration Center for Biologics Evaluation and Research, and NIH Grant R01-GM080139 (to S.L.). NR 31 TC 16 Z9 16 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 10 PY 2013 VL 110 IS 50 BP 20242 EP 20247 DI 10.1073/pnas.1320041110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266YY UT WOS:000328061700066 PM 24277851 ER PT J AU Kim, TS Park, JE Shukla, A Choi, S Murugan, RN Lee, JH Ahn, M Rhee, K Bang, JK Kim, BY Loncarek, J Erikson, RL Lee, KS AF Kim, Tae-Sung Park, Jung-Eun Shukla, Anil Choi, Sunho Murugan, Ravichandran N. Lee, Jin H. Ahn, Mija Rhee, Kunsoo Bang, Jeong K. Kim, Bo Y. Loncarek, Jadranka Erikson, Raymond L. Lee, Kyung S. TI Hierarchical recruitment of Plk4 and regulation of centriole biogenesis by two centrosomal scaffolds, Cep192 and Cep152 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DUPLICATION; ELEGANS; PROTEIN; REVEALS; CELLS; SAS-6; INTERACTS; SUGGEST; KINASE; ZYG-1 AB Centrosomes play an important role in various cellular processes, including spindle formation and chromosome segregation. They are composed of two orthogonally arranged centrioles, whose duplication occurs only once per cell cycle. Accurate control of centriole numbers is essential for the maintenance of genomic integrity. Although it is well appreciated that polo-like kinase 4 (Plk4) plays a central role in centriole biogenesis, how it is recruited to centrosomes and whether this step is necessary for centriole biogenesis remain largely elusive. Here we showed that Plk4 localizes to distinct subcentrosomal regions in a temporally and spatially regulated manner, and that Cep192 and Cep152 serve as two distinct scaffolds that recruit Plk4 to centrosomes in a hierarchical order. Interestingly, Cep192 and Cep152 competitively interacted with the cryptic polo box of Plk4 through their homologous N-terminal sequences containing acidic-alpha-helix and N/Q-rich motifs. Consistent with these observations, the expression of either one of these N-terminal fragments was sufficient to delocalize Plk4 from centrosomes. Furthermore, loss of the Cep192- or Cep152-dependent interaction with Plk4 resulted in impaired centriole duplication that led to delayed cell proliferation. Thus, the spatiotemporal regulation of Plk4 localization by two hierarchical scaffolds, Cep192 and Cep152, is critical for centriole biogenesis. C1 [Kim, Tae-Sung; Park, Jung-Eun; Choi, Sunho; Lee, Jin H.; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Shukla, Anil; Loncarek, Jadranka] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Choi, Sunho] Dong A ST, Res Labs, Yongin 449905, Gyeonggi Do, South Korea. [Murugan, Ravichandran N.; Ahn, Mija; Bang, Jeong K.] Korean Basic Sci Inst, Div Magnet Resonance, Ochang 363883, Chungbuk Do, South Korea. [Rhee, Kunsoo] Seoul Natl Univ, Dept Biol Sci, Seoul 151742, South Korea. [Kim, Bo Y.] Korea Res Inst Biosci & Biotechnol, World Class Inst, Ochang 363883, Chungbuk Do, South Korea. [Erikson, Raymond L.] Harvard Univ, Biol Labs, Cambridge, MA 02138 USA. RP Erikson, RL (reprint author), Harvard Univ, Biol Labs, Cambridge, MA 02138 USA. EM erikson@mcb.harvard.edu; kyunglee@mail.nih.gov OI Shukla, Anil/0000-0001-7797-7299 FU National Cancer Institute; Korea Basic Science Institute Research Grant [T33418]; World Class Institute Program [WCI 2009002]; Ministry of Science, ICT, and Future Planning of Korea FX This work was supported in part by National Cancer Institute Intramural Grants (to K. S. L. and J.L.), Korea Basic Science Institute Research Grant T33418 (to J.K.B.), and the World Class Institute (WCI 2009002) Program funded by Ministry of Science, ICT, and Future Planning of Korea (to B.Y.K.). NR 34 TC 39 Z9 39 U1 3 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 10 PY 2013 VL 110 IS 50 BP E4849 EP E4857 DI 10.1073/pnas.1319656110 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266YY UT WOS:000328061700007 PM 24277814 ER PT J AU Vargesson, N Mahony, C Erskine, L Niven, J Greig, NH Figg, WD AF Vargesson, Neil Mahony, Chris Erskine, Lynda Niven, Jennifer Greig, Nigel H. Figg, William Douglas TI Reply to D'Amato et al. and Zeldis et al.: Screening of thalidomide derivatives in chicken and zebrafish embryos SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID INHIBITS ANGIOGENESIS C1 [Vargesson, Neil; Mahony, Chris; Erskine, Lynda] Univ Aberdeen, Sch Med Sci, Aberdeen AB25 2ZD, Scotland. [Niven, Jennifer] Univ Aberdeen, Sch Med, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. [Figg, William Douglas] NCI, Mol Pharmacol Sect, Genitourinary Malignancies Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Vargesson, N (reprint author), Univ Aberdeen, Sch Med Sci, Aberdeen AB25 2ZD, Scotland. EM n.vargesson@abdn.ac.uk RI Figg Sr, William/M-2411-2016; OI Vargesson, Neil/0000-0001-8027-114X NR 7 TC 1 Z9 1 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 10 PY 2013 VL 110 IS 50 BP E4820 EP E4820 DI 10.1073/pnas.1318475110 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266YY UT WOS:000328061700003 PM 24471177 ER PT J AU Dobrovolskaia, MA McNeil, SE AF Dobrovolskaia, Marina A. McNeil, Scott E. TI Understanding the correlation between in vitro and in vivo immunotoxicity tests for nanomedicines SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Nanoparticles; Thrombosis; Disseminated intravascular coagulation; Procoagulant activity; Coagulopathy; Hemolysis; Complement activation; Cytokines; Anaphylaxis; Phagocytosis ID CFU-GM ASSAY; HUMAN WHOLE-BLOOD; COMPLEMENT ACTIVATION; IMMUNE-SYSTEM; PROCOAGULANT ACTIVITY; RISK-ASSESSMENT; EXTENDED HISTOPATHOLOGY; PLATELET-AGGREGATION; SCAVENGER RECEPTOR; THROMBUS FORMATION AB Preclinical characterization of novel nanotechnology-based formulations is often challenged by physicochemical characteristics, sterility/sterilization issues, safety and efficacy. Such challenges are not unique to nanomedicine, as they are common in the development of small and macromolecular drugs. However, due to the lack of a general consensus on critical characterization parameters, a shortage of harmonized protocols to support testing, and the vast variety of engineered nanomaterials, the translation of nanomedicines into clinic is particularly complex. Understanding the immune compatibility of nanoformulations has been identified as one of the important factors in (pre) clinical development and requires reliable in vitro and in vivo immunotoxicity tests. The generally low sensitivity of standard in vivo toxicity tests to immunotoxicities, inter-species variability in the structure and function of the immune system, high costs and relatively low throughput of in vivo tests, and ethical concerns about animal use underscore the need for trustworthy in vitro assays. Here, we consider the correlation (or lack thereof) between in vitro and in vivo immunotoxicity tests as a mean to identify useful in vitro assays. We review literature examples and case studies from the experience of the NCI Nanotechnology Characterization Lab, and highlight assays where predictability has been demonstrated for a variety of nanomaterials and assays with high potential for predictability in vivo. (C) 2013 Elsevier B.V. All rights reserved. C1 [Dobrovolskaia, Marina A.; McNeil, Scott E.] NCI, Nanotechnol Characterizat Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP McNeil, SE (reprint author), NCI, Nanotechnol Characterizat Lab, SAIC Frederick Inc, 1050 Boyles St,Bldg 469, Frederick, MD 21702 USA. EM ncl@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract 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. We are grateful to Allen Kane for the help with preparation of illustrations, to the NCL technical staff Barry Neun, Timothy Potter, Christopher McLeland, Jamie Rodrigues and Sarah Skoczen for generating the data using various in vitro immunoassays and to the NCL's toxicologist Dr. Stephan Stern for sharing his expertise and help with establishing in vitro-in vivo correlation for immunoassays. NR 114 TC 40 Z9 40 U1 4 U2 53 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD DEC 10 PY 2013 VL 172 IS 2 BP 456 EP 466 DI 10.1016/j.jconrel.2013.05.025 PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 260NN UT WOS:000327601700009 PM 23742883 ER PT J AU Stern, ST Zou, P Skoczen, S Xie, SW Liboiron, B Harasym, T Tardi, P Mayer, LD McNeil, SE AF Stern, Stephan T. Zou, Peng Skoczen, Sarah Xie, Sherwin Liboiron, Barry Harasym, Troy Tardi, Paul Mayer, Lawrence D. McNeil, Scott E. TI Prediction of nanoparticle prodrug metabolism by pharmacokinetic modeling of biliary excretion SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Biliary clearance; Pharmacokinetic modeling and simulation; Nanomicellar prodrug ID IN-VIVO; UNBOUND PACLITAXEL; CANCER-PATIENTS; PHASE-I; DOCETAXEL; RATS; FORMULATION; EFFICACY; PLASMA AB Pharmacokinetic modeling and simulation is a powerful tool for the prediction of drug concentrations in the absence of analytical techniques that allow for direct quantification. The present study applied this modeling approach to determine active drug release from a nanoparticle prodrug formulation. A comparative pharmacokinetic study of a nanoscale micellar docetaxel (DTX) prodrug, Procet 8, and commercial DTX formulation, Taxotere, was conducted in bile duct cannulated rats. The nanoscale (similar to 40 nm) size of the Procet 8 formulation resulted in confinement within the plasma space and high prodrug plasma concentrations. Ex vivo prodrug hydrolysis during plasma sample preparation resulted in unacceptable error that precluded direct measurement of DTX concentrations. Pharmacokinetic modeling of Taxotere and Procet 8 plasma concentrations, and their associated biliary metabolites, allowed for prediction of the DTX concentration profile and DTX bioavailability, and thereby evaluation of Procet 8 metabolism. Procet 8 plasma decay and in vitro plasma hydrolytic rates were identical, suggesting that systemic clearance of the prodrug was primarily metabolic. The Procet 8 and Taxotere plasma profiles, and associated docetaxel hydroxy-tert-butyl carbamate (HDTX) metabolite biliary excretion, were best fit by a two compartment model, with both linear and non-linear DTX clearance, and first order Procet 8 hydrolysis. The model estimated HDTX clearance rate agreed with in vitro literature values, supporting the predictability of the proposed model. Model simulation at the 10 mg DTX equivalent/kg dose level predicted DTX formation rate-limited kinetics and a peak plasma DTX concentration of 39 ng/mL at 4 h for Procet 8, in comparison to 2826 ng/mL for Taxotere. As a result of non-linear DTX clearance, the DTX AUCinf for the Procet 8 formulation was predicted to be 2.6 times lower than Taxotere (775 vs. 2017 h x ng/mL, respectively), resulting in an absolute bioavailability estimate of 38%. As DTX clearance in man is considered linear, this low bioavailability is likely species-dependent. These data support the use of pharmacokinetic modeling and simulation in cases of complex formulations, where analytical methods for direct measurement of free (released) drug concentrations are unavailable. Uses of such models may include interpretation of preclinical toxicology studies, selection of first in man dosing regimens, and PK/PD model development. (C) 2013 Elsevier B.V. All rights reserved. C1 [Stern, Stephan T.; Zou, Peng; Skoczen, Sarah; McNeil, Scott E.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Adv Technol Program, Nanotechnol Characterizat Lab, Frederick, MD 21702 USA. [Xie, Sherwin; Liboiron, Barry; Harasym, Troy; Tardi, Paul; Mayer, Lawrence D.] Celator Pharmaceut Corp, Vancouver, BC V6P 6P2, Canada. RP Stern, ST (reprint author), SAIC Frederick Inc, Frederick Natl Lab Canc Res, Adv Technol Program, Nanotechnol Characterizat Lab, Frederick, MD 21702 USA. EM sternstephan@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012; Zou, Peng/J-9300-2015 FU National Cancer Institute, the National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, the National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors thank Drs. Rachael M. Crist and Jennifer Hall Grossman for assistance with the preparation of the manuscript. NR 26 TC 3 Z9 3 U1 2 U2 38 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD DEC 10 PY 2013 VL 172 IS 2 BP 558 EP 567 DI 10.1016/j.jconrel.2013.04.025 PG 10 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 260NN UT WOS:000327601700019 PM 23664969 ER PT J AU Kovalchik, SA Varadhan, R Weiss, CO AF Kovalchik, Stephanie A. Varadhan, Ravi Weiss, Carlos O. TI Assessing heterogeneity of treatment effect in a clinical trial with the proportional interactions model SO STATISTICS IN MEDICINE LA English DT Article DE effect modification; heterogeneity of treatment effect; interaction; risk stratification; subgroup analysis ID GENERALIZED LINEAR-MODELS; SAMPLE-SIZE CALCULATIONS; SUBGROUP ANALYSES; TESTS; POWER AB Understanding how individuals vary in their response to treatment is an important task of clinical research. For standard regression models, a proportional interactions model first described by Follmann and Proschan (1999) offers a powerful approach for identifying effect modification in a randomized clinical trial when multiple variables influence treatment response. In this paper, we present a framework for using the proportional interactions model in the context of a parallel-arm clinical trial with multiple prespecified candidate effect modifiers. To protect against model misspecification, we propose a selection strategy that considers all possible proportional interactions models. We develop a modified Bonferroni correction for multiple testing that accounts for the positive correlation among candidate models. We describe methods for constructing a confidence interval for the proportionality parameter. In simulation studies, we show that our modified Bonferroni adjustment controls familywise error and has greater power to detect proportional interactions compared with multiplcity-corrected subgroup analyses. We demonstrate our methodology by using the Studies of Left Ventricular Dysfunction Treatment trial, a placebo-controlled randomized clinical trial of the efficacy of enalapril to reduce the risk of death or hospitalization in chronic heart failure patients. An R package called anoint is available for implementing the proportional interactions methodology. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Kovalchik, Stephanie A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Varadhan, Ravi] Johns Hopkins Univ, Ctr Aging & Hlth, Baltimore, MD 21205 USA. [Varadhan, Ravi] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Weiss, Carlos O.] Johns Hopkins Univ, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. RP Varadhan, R (reprint author), Johns Hopkins Univ, Ctr Aging & Hlth, 2024 E Monument St,Suite 2-700, Baltimore, MD 21205 USA. EM rvaradhan@jhmi.edu FU Food and Drug Administration, Department of Health and Human Services [HHSF2232010000072C]; RSR [08-48]; Center for Drug Evaluation and Research, U.S. Food and Drug Administration; National Cancer Institute FX We are grateful to Dr. Nilanjan Chatterjee, Dr. Hormuzd Katki, Dr. Sue-Jane Wang, and Dr. Estelle Russek-Cohen for the useful comments they provided to us during the writing of this manuscript. Our study used research materials from the SOLVD-T obtained from the National Heart Lung and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center and does not necessarily reflect the opinions or views of the SOLVD-T or the National Heart Lung and Blood Institute. The analyses upon which this publication is based were performed under contract number HHSF2232010000072C, entitled, "Partnership in Applied Comparative Effectiveness Science", sponsored by the Food and Drug Administration, Department of Health and Human Services. This research was also supported by the RSR grant no.08-48 and awarded by the Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Dr. Kovalchik's work was supported by the intramural research program of the National Cancer Institute. Dr. Varadhan is a Brookdale Leadership in Aging Fellow at the Johns Hopkins University. NR 17 TC 4 Z9 4 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD DEC 10 PY 2013 VL 32 IS 28 BP 4906 EP 4923 DI 10.1002/sim.5881 PG 18 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 248UH UT WOS:000326729100004 PM 23788362 ER PT J AU Puetz, TW Morley, CA Herring, MP AF Puetz, Timothy W. Morley, Christopher A. Herring, Matthew P. TI The Challenge of Definition and Moving Creative Arts Therapy Research Forward SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Puetz, Timothy W.] NIH, Off Director, Bethesda, MD 20802 USA. [Morley, Christopher A.] ArtReach Fdn Inc, Atlanta, GA USA. [Herring, Matthew P.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. RP Puetz, TW (reprint author), NIH, Off Director, 9000 Rockville Pike, Bethesda, MD 20802 USA. EM timothy.puetz@nih.gov RI Herring, Matthew/O-2265-2014 OI Herring, Matthew/0000-0002-6835-5321 NR 5 TC 0 Z9 0 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD DEC 9 PY 2013 VL 173 IS 22 BP 2094 EP 2095 DI 10.1001/jamainternmed.2013.10494 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AA2WL UT WOS:000330954800027 PM 24322467 ER PT J AU Jacobs, AC Calkins, MJ Jadhav, A Dorjsuren, D Maloney, D Simeonov, A Jaruga, P Dizdaroglu, M McCullough, AK Lloyd, RS AF Jacobs, Aaron C. Calkins, Marcus J. Jadhav, Ajit Dorjsuren, Dorjbal Maloney, David Simeonov, Anton Jaruga, Pawel Dizdaroglu, Miral McCullough, Amanda K. Lloyd, R. Stephen TI Inhibition of DNA Glycosylases via Small Molecule Purine Analogs SO PLOS ONE LA English DT Article ID OXIDATIVELY DAMAGED DNA; T4 ENDONUCLEASE-V; REPAIR ENZYME; NEIL1 DNA; THYMIDYLATE SYNTHASE; PARP INHIBITORS; EXCISION-REPAIR; MODIFIED BASES; IN-VITRO; PROTEIN AB Following the formation of oxidatively-induced DNA damage, several DNA glycosylases are required to initiate repair of the base lesions that are formed. Recently, NEIL1 and other DNA glycosylases, including OGG1 and NTH1 were identified as potential targets in combination chemotherapeutic strategies. The potential therapeutic benefit for the inhibition of DNA glycosylases was validated by demonstrating synthetic lethality with drugs that are commonly used to limit DNA replication through dNTP pool depletion via inhibition of thymidylate synthetase and dihydrofolate reductase. Additionally, NEIL1-associated synthetic lethality has been achieved in combination with Fanconi anemia, group G. As a prelude to the development of strategies to exploit the potential benefits of DNA glycosylase inhibition, it was necessary to develop a reliable high-throughput screening protocol for this class of enzymes. Using NEIL1 as the proof-of-principle glycosylase, a fluorescence-based assay was developed that utilizes incision of site-specifically modified oligodeoxynucleotides to detect enzymatic activity. This assay was miniaturized to a 1536-well format and used to screen small molecule libraries for inhibitors of the combined glycosylase/AP lyase activities. Among the top hits of these screens were several purine analogs, whose postulated presence in the active site of NEIL1 was consistent with the paradigm of NEIL1 recognition and excision of damaged purines. Although a subset of these small molecules could inhibit other DNA glycosylases that excise oxidatively-induced DNA adducts, they could not inhibit a pyrimidine dimer-specific glycosylase. C1 [Jacobs, Aaron C.; Calkins, Marcus J.; McCullough, Amanda K.; Lloyd, R. Stephen] Oregon Hlth & Sci Univ, Ctr Res Occupat & Environm Toxicol, Portland, OR 97201 USA. [Jadhav, Ajit; Dorjsuren, Dorjbal; Maloney, David; Simeonov, Anton] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Jaruga, Pawel; Dizdaroglu, Miral] NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. [McCullough, Amanda K.; Lloyd, R. Stephen] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. RP Lloyd, RS (reprint author), Oregon Hlth & Sci Univ, Ctr Res Occupat & Environm Toxicol, Portland, OR 97201 USA. EM lloydst@ohsu.edu RI Jaruga, Pawel/M-4378-2015 FU National Institutes of Health [R01 DK75974, P01 CA160032, T32 ES007060]; National Cancer Institute of the National Institutes of Health [T32CA106195]; National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [U54MH084681] FX This work was supported in part by National Institutes of Health (R01 DK75974, P01 CA160032) to RSL. ACJ was supported by National Institutes of Health (T32 ES007060). Research reported in this publication was also partially supported by the National Cancer Institute of the National Institutes of Health under award number T32CA106195 for MC. Support by the intramural research program of the National Center for Advancing Translational Sciences and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research (U54MH084681) is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 10 Z9 10 U1 1 U2 12 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 DEC 9 PY 2013 VL 8 IS 12 AR e81667 DI 10.1371/journal.pone.0081667 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 275VD UT WOS:000328705200041 PM 24349107 ER PT J AU Cooper, A Garcia, M Petrovas, C Yamamoto, T Koup, RA Nabel, GJ AF Cooper, Arik Garcia, Mayra Petrovas, Constantinos Yamamoto, Takuya Koup, Richard A. Nabel, Gary J. TI HIV integration and T cell death: additional commentary SO RETROVIROLOGY LA English DT Editorial Material ID DEPENDENT PROTEIN-KINASE; VIRUS TYPE-1 INFECTION; SIV INFECTION; GASTROINTESTINAL-TRACT; LYMPHOID-TISSUE; IN-VIVO; DEPLETION; LYMPHOCYTES; APOPTOSIS; REPLICATION AB Estaquier et al. provide commentary on our paper that elucidated the mechanism by which HIV-1 causes cell death in activated CD4 T lymphocytes. We showed that proviral DNA integration triggers DNA-PK dependent death signaling, leading to p53 phosphorylation and cell demise (Cooper A et al. Nature 498:376-379, 2013). They have raised several hypothetical points that we further clarify here. C1 [Cooper, Arik; Garcia, Mayra; Nabel, Gary J.] NIAID, Virol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Petrovas, Constantinos; Yamamoto, Takuya; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), Sanofi, 640 Mem Dr, Cambridge, MA 02139 USA. EM Gary.Nabel@sanofi.com RI Yamamoto, Takuya/L-2642-2013 OI Yamamoto, Takuya/0000-0003-3753-1211 NR 27 TC 2 Z9 2 U1 0 U2 2 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 DEC 9 PY 2013 VL 10 AR 150 DI 10.1186/1742-4690-10-150 PG 3 WC Virology SC Virology GA 280RZ UT WOS:000329049800002 PM 24321564 ER PT J AU Anchoori, RK Karanam, B Peng, SW Wang, JW Jiang, R Tanno, T Orlowski, RZ Matsui, W Zhao, M Rudek, MA Hung, CF Chen, X Walters, KJ Roden, RBS AF Anchoori, Ravi K. Karanam, Balasubramanyam Peng, Shiwen Wang, Joshua W. Jiang, Rosie Tanno, Toshihiko Orlowski, Robert Z. Matsui, William Zhao, Ming Rudek, Michelle A. Hung, Chien-fu Chen, Xiang Walters, Kylie J. Roden, Richard B. S. TI A bis-Benzylidine Piperidone Targeting Proteasome Ubiquitin Receptor RPN13/ADRM1 as a Therapy for Cancer SO CANCER CELL LA English DT Article ID OVERCOME BORTEZOMIB RESISTANCE; DEUBIQUITINATING ENZYME; MULTIPLE-MYELOMA; OVARIAN-CANCER; PROTEIN INTERACTOME; 26S PROTEASOME; SYSTEM; SUBUNIT; CELLS; INHIBITOR AB The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of ubiquitin receptor RPN13 in the 19S regulatory particle and inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins. Multiple myeloma (MM) lines, even those resistant to bortezomib, were sensitive to RA190 via endoplasmic reticulum stress-related apoptosis. RA190 stabilized targets of human papillonnavirus (HPV) E6 oncoprotein, and preferentially killed HPV-transformed cells. After oral or intraperitoneal dosing of mice, RA190 distributed to plasma and major organs except the brain and inhibited proteasome function in skin and muscle. RA190 administration profoundly reduced growth of MM and ovarian cancer xenografts, and oral RA190 treatment retarded HPV16(+) syngeneic mouse tumor growth, without affecting spontaneous HPV-specific CD8(+) T cell responses, suggesting its therapeutic potential. C1 [Anchoori, Ravi K.; Tanno, Toshihiko; Matsui, William; Zhao, Ming; Rudek, Michelle A.; Roden, Richard B. S.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21231 USA. [Karanam, Balasubramanyam; Peng, Shiwen; Wang, Joshua W.; Jiang, Rosie; Hung, Chien-fu; Roden, Richard B. S.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21231 USA. [Roden, Richard B. S.] Johns Hopkins Univ, Dept Gynecol & Obstet, Baltimore, MD 21231 USA. [Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Div Canc Med, Houston, TX 77030 USA. [Chen, Xiang; Walters, Kylie J.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Chen, Xiang; Walters, Kylie J.] NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Roden, RBS (reprint author), Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21231 USA. EM roden@jhmi.edu OI Matsui, William/0000-0002-3088-0964 FU National Institutes of Health ATIP Program [P50 CA098252, CA136472]; M.D. Anderson Cancer Center Specialized Program of Research Excellence in Multiple Myeloma [P50 CA142509]; Sidney Kimmel Comprehensive Cancer Center Analytical Pharmacology Core at Johns Hopkins [P30 CA006973, UL1 RR 025005]; HERA Foundation; Ephraim and Wilma Shaw Roseman Foundation FX We thank B. Vogelstein (Johns Hopkins University) for the HCT116 lines and D. Piwnica-Worms (Washington University, St. Louis, MO) for the 4UbFL and FL plasmids. Grant support was provided by National Institutes of Health ATIP Program grants P50 CA098252 and CA136472 and the M.D. Anderson Cancer Center Specialized Program of Research Excellence in Multiple Myeloma (P50 CA142509). The project was supported in part by the Sidney Kimmel Comprehensive Cancer Center Analytical Pharmacology Core at Johns Hopkins (P30 CA006973 and UL1 RR 025005). We also thank the HERA Foundation and the Ephraim and Wilma Shaw Roseman Foundation for support. NMR data were acquired in the NMR facility at the University of Minnesota, and data processing and depiction occurred in the Minnesota Supercomputing Institute Basic Sciences Computing Lab. We also thank P. Villalta (University of Minnesota) for his help with the LC-MS and E. Arriaga (University of Minnesota) for allowing us to use his spectrofluorometer. NR 38 TC 34 Z9 34 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD DEC 9 PY 2013 VL 24 IS 6 BP 791 EP 805 DI 10.1016/j.ccr.2013.11.001 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 272EN UT WOS:000328443200012 PM 24332045 ER PT J AU Yasuda, K Zhang, HY Loiselle, D Haystead, T Macara, IG Mili, S AF Yasuda, Kyota Zhang, Huaye Loiselle, David Haystead, Timothy Macara, Ian G. Mili, Stavroula TI The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules SO JOURNAL OF CELL BIOLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; POLYPOSIS-COLI PROTEIN; STRESS GRANULES; SACCHAROMYCES-CEREVISIAE; CELL-MIGRATION; P BODIES; IN-VIVO; POLARITY; TDP-43; ROLES AB RNA localization pathways direct numerous mRNAs to distinct subcellular regions and affect many physiological processes. In one such pathway the tumor-suppressor protein adenomatous polyposis coli (APC) targets RNAs to cell protrusions, forming APC-containing ribonucleoprotein complexes (APC-RNPs). Here, we show that APC-RNPs associate with the RNA-binding protein Fus/TLS (fused in sarcoma/translocated in liposarcoma). Fus is not required for APC-RNP localization but is required for efficient translation of associated transcripts. Labeling of newly synthesized proteins revealed that Fus promotes translation preferentially within protrusions. Mutations in Fus cause amyotrophic lateral sclerosis (ALS) and the mutant protein forms inclusions that appear to correspond to stress granules. We show that overexpression or mutation of Fus results in formation of granules, which preferentially recruit APC-RNPs. Remarkably, these granules are not translationally silent. Instead, APC-RNP transcripts are translated within cytoplasmic Fus granules. These results unexpectedly show that translation can occur within stress-like granules. Importantly, they identify a new local function for cytoplasmic Fus with implications for ALS pathology. C1 [Yasuda, Kyota; Mili, Stavroula] NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Zhang, Huaye] Rutgers State Univ, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA. [Loiselle, David; Haystead, Timothy] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Macara, Ian G.] Vanderbilt Univ, Med Ctr, Dept Cell & Dev Biol, Nashville, TN 37232 USA. RP Mili, S (reprint author), NCI, Cellular & Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM voula.mili@nih.gov FU NIH [CA138905]; Human Frontier Science Program [HFSP-RGP0031] FX This work was supported by grant CA138905 from the NIH to S. Mill and grant HFSP-RGP0031 from the Human Frontier Science Program to I.G. Macara. NR 39 TC 32 Z9 32 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 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD DEC 9 PY 2013 VL 203 IS 5 BP 737 EP 746 DI 10.1083/jcb.201306058 PG 10 WC Cell Biology SC Cell Biology GA 270HQ UT WOS:000328309900005 PM 24297750 ER PT J AU Bouvier, A Deleaval, F Doyley, MM Yazdani, SK Finet, G Le Floc'h, S Cloutier, G Pettigrew, RI Ohayon, J AF Bouvier, Adeline Deleaval, Flavien Doyley, Marvin M. Yazdani, Saami K. Finet, Gerard Le Floc'h, Simon Cloutier, Guy Pettigrew, Roderic I. Ohayon, Jacques TI A direct vulnerable atherosclerotic plaque elasticity reconstruction method based on an original material-finite element formulation: theoretical framework SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID INTRAVASCULAR ULTRASOUND; IN-VIVO; CORONARY-ARTERY; CIRCUMFERENTIAL STRESS; RADIOFREQUENCY DATA; CAP THICKNESS; WORKING GROUP; ELASTOGRAPHY; MODEL; RUPTURE AB The peak cap stress (PCS) amplitude is recognized as a biomechanical predictor of vulnerable plaque (VP) rupture. However, quantifying PCS in vivo remains a challenge since the stress depends on the plaque mechanical properties. In response, an iterative material finite element (FE) elasticity reconstruction method using strain measurements has been implemented for the solution of these inverse problems. Although this approach could resolve the mechanical characterization of VPs, it suffers from major limitations since (i) it is not adapted to characterize VPs exhibiting high material discontinuities between inclusions, and (ii) does not permit real time elasticity reconstruction for clinical use. The present theoretical study was therefore designed to develop a direct material-FE algorithm for elasticity reconstruction problems which accounts for material heterogeneities. We originally modified and adapted the extended FE method (Xfem), used mainly in crack analysis, to model material heterogeneities. This new algorithm was successfully applied to six coronary lesions of patients imaged in vivo with intravascular ultrasound. The results demonstrated that the mean relative absolute errors of the reconstructed Young's moduli obtained for the arterial wall, fibrosis, necrotic core, and calcified regions of the VPs decreased from 95.3 +/- 15.56%, 98.85 +/- 72.42%, 103.29 +/- 111.86% and 95.3 +/- 10.49%, respectively, to values smaller than 2.6 x 10(-8)+/- 5.7 x 10(-8)% (i.e. close to the exact solutions) when including modified-Xfem method into our direct elasticity reconstruction method. C1 [Bouvier, Adeline; Deleaval, Flavien; Ohayon, Jacques] UJF, CNRS, Lab TIMC IMAG DyCTiM, UMR 5525,In3S, Grenoble, France. [Doyley, Marvin M.] Univ Rochester, Dept Elect & Comp Engn, Rochester, NY USA. [Yazdani, Saami K.] Univ S Alabama, Dept Mech Engn, Mobile, AL 36688 USA. [Finet, Gerard] Hosp Civils Lyon, Dept Hemodynam & Intervent Cardiol, Lyon, France. [Finet, Gerard] Univ Lyon 1, INSERM, U886, F-69365 Lyon, France. [Le Floc'h, Simon] Univ Montpellier 2, CNRS, UMR 5508, Lab LMGC, Montpellier, France. [Cloutier, Guy] Univ Montreal Hosp Res Ctr CRCHUM, Lab Biorheol & Med Ultrason, Montreal, PQ, Canada. [Pettigrew, Roderic I.] NIDDK, Lab Integrat Cardiovasc Imaging Sci, NIH, Bethesda, MD 20892 USA. [Ohayon, Jacques] Univ Savoie, Polytech Annecy Chambery, Le Bourget Du Lac, France. RP Pettigrew, RI (reprint author), NIDDK, Lab Integrat Cardiovasc Imaging Sci, NIH, Bethesda, MD 20892 USA. EM jacques.ohayon@imag.fr RI Doyley, Marvin/N-3765-2013; Ohayon, Jacques/M-6576-2014 FU ANR (MELANII) [09-BLANC-0423]; NSERC [STPGP-381136-09]; la Region Rhone-Alpes, France; French Ministry for Higher Education and Research (MENRT) FX This research was supported by a joint international program of the ANR (MELANII project # 09-BLANC-0423) and NSERC strategic grant #STPGP-381136-09. Flavien Deleaval held a doctoral fellowship from la Region Rhone-Alpes, France (2010-13). Adeline Bouvier held a doctoral fellowship from the French Ministry for Higher Education and Research (MENRT 2010-13). NR 55 TC 4 Z9 4 U1 1 U2 14 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD DEC 7 PY 2013 VL 58 IS 23 BP 8457 EP 8476 DI 10.1088/0031-9155/58/23/8457 PG 20 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 266SA UT WOS:000328042800012 PM 24240392 ER PT J AU Kang'ethe, W Bernstein, HD AF Kang'ethe, Wanyoike Bernstein, Harris D. TI Stepwise Folding of an Autotransporter Passenger Domain Is Not Essential for Its Secretion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Escherichia coli; Membrane Proteins; Protein Folding; Protein Translocation; Virulence Factors; Autotransporter ID OUTER-MEMBRANE TRANSLOCATION; PARALLEL BETA-HELIX; ESCHERICHIA-COLI; BACTERIAL AUTOTRANSPORTER; CRYSTAL-STRUCTURE; RECOMBINANT PROTEINS; VIRULENCE FACTOR; SERINE-PROTEASE; P22 TAILSPIKE; BIOGENESIS AB Background: It has been proposed that stepwise folding of the extracellular (passenger) domains of bacterial autotransporter proteins drives their secretion. Results: Mutations in N-terminal or medial segments of a passenger domain that severely impair folding only moderately reduce secretion efficiency. Conclusion: Stepwise folding only partially accounts for the energetics of autotransporter secretion. Significance: Autotransporter secretion may involve the use of a novel energy source. Autotransporters are a superfamily of virulence proteins produced by Gram-negative bacteria. They consist of an N-terminal -helical domain (passenger domain) that is secreted into the extracellular space and a C-terminal -barrel domain (-domain) that anchors the protein to the outer membrane. Because the periplasm lacks ATP, vectorial folding of the passenger domain in a C-to-N-terminal direction has been proposed to drive the secretion reaction. Consistent with this hypothesis, mutations that disrupt the folding of the C terminus of the passenger domain of the Escherichia coli O157:H7 autotransporter EspP have been shown to cause strong secretion defects. Here, we show that point mutations introduced at specific locations near the middle or N terminus of the EspP -helix that perturb folding also impair secretion, but to a lesser degree. Surprisingly, we found that even multiple mutations that potentially abolish the stability of several consecutive rungs of the -helix only moderately reduce secretion efficiency. Although these results provide evidence that the free energy derived from passenger domain folding contributes to secretion efficiency, they also suggest that a significant fraction of the energy required for secretion is derived from another source. C1 [Kang'ethe, Wanyoike; Bernstein, Harris D.] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDK, Genet & Biochem Branch, Bldg 5,Rm 201, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov FU NIDDK Intramural Research Program of the National Institutes of Health FX This work was supported, in whole or in part, by the NIDDK Intramural Research Program of the National Institutes of Health. NR 44 TC 10 Z9 10 U1 4 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 6 PY 2013 VL 288 IS 49 BP 35028 EP 35038 DI 10.1074/jbc.M113.515635 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 291YA UT WOS:000329867600005 PM 24165126 ER PT J AU Mulligan, C Mindell, JA AF Mulligan, Christopher Mindell, Joseph A. TI Mechanism of Transport Modulation by an Extracellular Loop in an Archaeal Excitatory Amino Acid Transporter (EAAT) Homolog SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Amino Acid Transport; Chemical Modification; Glutamate; Membrane Transport; Reconstitution of Membrane Transporters; Transporters; Protein Cross-linking ID DEPENDENT ASPARTATE TRANSPORTER; GLUTAMATE TRANSPORTER; PYROCOCCUS-HORIKOSHII; CRYSTAL-STRUCTURE; TRANSLOCATION; BINDING; SODIUM; STOICHIOMETRY; SUBSTRATE; EXCHANGE AB Background: The extracellular loop, 3L4, plays an important, unknown role in the transport cycle of the glutamate transporter homolog, Glt(Ph). Results: Cleaving 3L4 differentially affects transport cycle steps. Conclusion: 3L4 discriminates between substrate-loaded and empty states of the transporter. Significance: Empty and loaded forms of the transport domain have structurally distinguishable forms, reflecting essential features of the transport mechanism. Secondary transporters in the excitatory amino acid transporter family terminate glutamatergic synaptic transmission by catalyzing Na+-dependent removal of glutamate from the synaptic cleft. Recent structural studies of the aspartate-specific archaeal homolog, Glt(Ph), suggest that transport is achieved by a rigid body, piston-like movement of the transport domain, which houses the substrate-binding site, between the extracellular and cytoplasmic sides of the membrane. This transport domain is connected to an immobile scaffold by three loops, one of which, the 3-4 loop (3L4), undergoes substrate-sensitive conformational change. Proteolytic cleavage of the 3L4 was found to abolish transport activity indicating an essential function for this loop in the transport mechanism. Here, we demonstrate that despite the presence of fully cleaved 3L4, Glt(Ph) is still able to sample conformations relevant for transport. Optimized reconstitution conditions reveal that fully cleaved Glt(Ph) retains some transport activity. Analysis of the kinetics and temperature dependence of transport accompanied by direct measurements of substrate binding reveal that this decreased transport activity is not due to alteration of the substrate binding characteristics but is caused by the significantly reduced turnover rate. By measuring solute counterflow activity and cross-link formation rates, we demonstrate that cleaving 3L4 severely and specifically compromises one or more steps contributing to the movement of the substrate-loaded transport domain between the outward- and inward-facing conformational states, sparing the equivalent step(s) during the movement of the empty transport domain. These results reveal a hitherto unknown role for the 3L4 in modulating an essential step in the transport process. C1 [Mulligan, Christopher; Mindell, Joseph A.] NINDS, Membrane Transport Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Mindell, JA (reprint author), NINDS, Membrane Transport Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM mindellj@ninds.nih.gov OI Mindell, Joseph/0000-0002-6952-8247 FU Intramural Research Program of the National Institutes of Health, NINDS FX This work was supported by the Intramural Research Program of the National Institutes of Health, NINDS. NR 27 TC 9 Z9 9 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 6 PY 2013 VL 288 IS 49 BP 35266 EP 35276 DI 10.1074/jbc.M113.508408 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 291YA UT WOS:000329867600025 PM 24155238 ER PT J AU Lam, MPY Lau, E Liem, DA Ping, PP AF Lam, Maggie P. Y. Lau, Edward Liem, David A. Ping, Peipei TI Cyclophilin D and Acetylation A New Link in Cardiac Signaling SO CIRCULATION RESEARCH LA English DT Editorial Material DE Editorials; acetylation; cyclophilin D; metabolism; mitochondria; proteomics ID MITOCHONDRIAL PROTEIN-PHOSPHORYLATION; PERMEABILITY TRANSITION; HEART-FAILURE; DEACETYLATION; PROTECTION; SIRTUIN-3; BIOLOGY C1 [Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, NHLBI, Dept Physiol,Prote Ctr, Los Angeles, CA 90095 USA. [Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, NHLBI, Dept Med,Prote Ctr, Los Angeles, CA 90095 USA. RP Ping, PP (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, NHLBI, Dept Physiol,Prote Ctr, Los Angeles, CA 90095 USA. EM pping@mednet.ucla.edu OI Lau, Edward/0000-0001-9083-5922; Ping, Peipei/0000-0003-3583-3881 FU NHLBI NIH HHS [R37 HL063901, HL-R37-63901]; PHS HHS [HHSN268201000035C] NR 16 TC 3 Z9 3 U1 1 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD DEC 6 PY 2013 VL 113 IS 12 BP 1268 EP 1269 DI 10.1161/CIRCRESAHA.113.302687 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 298VY UT WOS:000330353800037 PM 24311610 ER PT J AU Nguyen, TTM Wong, R Menazza, S Sun, JH Chen, Y Wang, GH Gucek, M Steenbergen, C Sack, MN Murphy, E AF Nguyen, Tiffany Tuyen M. Wong, Renee Menazza, Sara Sun, Junhui Chen, Yong Wang, Guanghui Gucek, Marjan Steenbergen, Charles Sack, Michael N. Murphy, Elizabeth TI Cyclophilin D Modulates Mitochondrial Acetylome SO CIRCULATION RESEARCH LA English DT Article DE acetylation; cyclophilin D; mitochondria; proteomics; sirtuin 3 ID PERMEABILITY TRANSITION PORE; LYSINE ACETYLATION; CELL-DEATH; EMERGING CHARACTERIZATION; CALORIE RESTRICTION; S-NITROSYLATION; HEART-FAILURE; SIRT3; DEACETYLATION; PROTEINS AB Rationale: Mice lacking cyclophilin D (CypD(-/-)), a mitochondrial chaperone protein, have altered cardiac metabolism. As acetylation has been shown to regulate metabolism, we tested whether changes in protein acetylation might play a role in these metabolic changes in CypD(-/-) hearts. Objective: Our aim was to test the hypothesis that loss of CypD alters the cardiac mitochondrial acetylome. Methods and Results: To identify changes in lysine-acetylated proteins and to map acetylation sites after ablation of CypD, we subjected tryptic digests of isolated cardiac mitochondria from wild-type and CypD(-/-) mice to immunoprecipitation using agarose beads coupled to antiacetyl lysine antibodies followed by mass spectrometry. We used label-free analysis for the relative quantification of the 875 common peptides that were acetylated in wildtype and CypD(-/-) samples and found 11 peptides (10 proteins) decreased and 96 peptides (48 proteins) increased in CypD(-/-) samples. We found increased acetylation of proteins in fatty acid oxidation and branched-chain amino acid metabolism. To evaluate whether this increase in acetylation might play a role in the inhibition of fatty acid oxidation that was previously reported in CypD(-/-) hearts, we measured the activity of L-3-hydroxyacyl-CoA dehydrogenase, which was acetylated in the CypD(-/-) hearts. Consistent with the hypothesis, L-3-hydroxyacyl-CoA dehydrogenase activity was inhibited by approximate to 50% compared with the wild-type mitochondria. Conclusions: These results implicate a role for CypD in modulating protein acetylation. Taken together, these results suggest that ablation of CypD leads to changes in the mitochondrial acetylome, which may contribute to altered mitochondrial metabolism in CypD(-/-) mice. C1 [Nguyen, Tiffany Tuyen M.; Menazza, Sara; Sun, Junhui; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Wong, Renee] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Chen, Yong; Wang, Guanghui; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Sack, Michael N.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Steenbergen, Charles] Johns Hopkins Med Ctr, Dept Pathol, Baltimore, MD USA. RP Murphy, E (reprint author), NHLBI, NIH, Bldg 10,Rm 8N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov RI chen, yong/E-2432-2011 FU National Institutes of Health's National Heart, Lung, and Blood Institute intramural program FX This work was supported by the National Institutes of Health's National Heart, Lung, and Blood Institute intramural program. NR 38 TC 22 Z9 23 U1 4 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD DEC 6 PY 2013 VL 113 IS 12 BP 1308 EP + DI 10.1161/CIRCRESAHA.113.301867 PG 19 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 298VY UT WOS:000330353800047 PM 24062335 ER PT J AU Pollitt, LC Mackinnon, MJ Mideo, N Read, AF AF Pollitt, Laura C. Mackinnon, Margaret J. Mideo, Nicole Read, Andrew F. TI Mosquito transmission, growth phenotypes and the virulence of malaria parasites SO MALARIA JOURNAL LA English DT Article DE Malaria; Transmission; Virulence; Mosquitoes; Within-host dynamics; Plasmodium chabaudi ID RODENT MALARIA; EVOLUTION AB Background: A series of elegant experiments was recently published which demonstrated that transmission of malaria parasites through mosquitoes elicited an attenuated growth phenotype, whereby infections grew more slowly and reached peak parasitaemia at least five-fold lower than parasites which had not been mosquito transmitted. To assess the implications of these results it is essential to understand whether the attenuated infection phenotype is a general phenomenon across parasites genotypes and conditions. Methods: Using previously published data, the impact of mosquito transmission on parasite growth rates and virulence of six Plasmodium chabaudi lines was analysed. Results: The effect of mosquito transmission varied among strains, but did not lead to pronounced or consistent reductions in parasite growth rate. Conclusions: Mosquito-induced attenuated growth phenotype is sensitive to experimental conditions. C1 [Pollitt, Laura C.; Read, Andrew F.] Penn State Univ, Ctr Infect Dis Dynam, State Coll, PA 16801 USA. [Mackinnon, Margaret J.] Kenya Govt Med Res Ctr, Wellcome Trust Res Programme, Kilifi, Kenya. [Mackinnon, Margaret J.] Univ Oxford, Nuffield Dept Med, Oxford, England. [Mideo, Nicole] Univ Toronto, Dept Ecol & Evolut Biol, Toronto, ON, Canada. [Read, Andrew F.] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Pollitt, LC (reprint author), Penn State Univ, Ctr Infect Dis Dynam, Millennium Sci Complex, State Coll, PA 16801 USA. EM laura.pollitt@googlemail.com RI Mackinnon, Margaret/L-3155-2013 OI Mackinnon, Margaret/0000-0003-1279-9625 FU National Institutes of Health [R01 GM089932, R01AI089819]; NSERC; Leverhulme Trust FX Authors are funded by the National Institutes of Health (LCP and AFR; R01 GM089932 and R01AI089819), and an NSERC Discovery Grant (NM). The original experiments were funded by The Leverhulme Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank members of the Read-Thomas lab group, the Center for Infectious Disease Dynamics, and the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center for discussion. NR 8 TC 5 Z9 5 U1 1 U2 16 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 DEC 6 PY 2013 VL 12 AR 440 DI 10.1186/1475-2875-12-440 PG 4 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 281OD UT WOS:000329110000001 PM 24314024 ER PT J AU Griffin, AJ Crane, DD Wehrly, TD Scott, DP Bosio, CM AF Griffin, Amanda J. Crane, Deborah D. Wehrly, Tara D. Scott, Dana P. Bosio, Catharine M. TI Alternative Activation of Macrophages and Induction of Arginase Are Not Components of Pathogenesis Mediated by Francisella Species SO PLOS ONE LA English DT Article ID EARLY IL-4 PRODUCTION; TULARENSIS SCHU S4; SCHISTOSOMA-MANSONI; IMMUNE-RESPONSE; TULAREMIA; INFECTION; PULMONARY; VACCINE; CELLS; REPLICATION AB Virulent Francisella tularensis ssp tularensis is an intracellular, Gram negative bacterium that causes acute lethal disease following inhalation of fewer than 15 organisms. Pathogenicity of Francisella infections is tied to its unique ability to evade and suppress inflammatory responses in host cells. It has been proposed that induction of alternative activation of infected macrophages is a mechanism by which attenuated Francisella species modulate host responses. In this report we reveal that neither attenuated F. tularensis Live Vaccine Strain (LVS) nor virulent F. tularensis strain SchuS4 induce alternative activation of macrophages in vitro or in vivo. LVS, but not SchuS4, provoked production of arginase1 independent of alternative activation in vitro and in vivo. However, absence of arginase1 did not significantly impact intracellular replication of LVS or SchuS4. Together our data establish that neither induction of alternative activation nor expression of arginase1 are critical features of disease mediated by attenuated or virulent Francisella species. C1 [Griffin, Amanda J.; Crane, Deborah D.; Wehrly, Tara D.; Bosio, Catharine M.] NIAID, Immun Pulm Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Vet Branch,Rocky Mt Labs,NIH, Hamilton, MT USA. [Scott, Dana P.] NIAID, Vet Pathol Sect, Rocky Mt Vet Branch, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Bosio, CM (reprint author), NIAID, Immun Pulm Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Vet Branch,Rocky Mt Labs,NIH, Hamilton, MT USA. EM bosioc@niaid.nih.gov RI Bosio, Catharine/D-7456-2015 NR 33 TC 5 Z9 5 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 DEC 6 PY 2013 VL 8 IS 12 AR e82096 DI 10.1371/journal.pone.0082096 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273WJ UT WOS:000328566700058 PM 24324751 ER PT J AU Roll-Mecak, A AF Roll-Mecak, Antonina TI Shining Light at Microtubule Crossroads SO SCIENCE LA English DT Editorial Material ID KATANIN; ARRAYS; ORGANIZATION; SITES C1 NIH, Cell Biol & Biophys Unit, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Roll-Mecak, A (reprint author), NIH, Cell Biol & Biophys Unit, Porter Neurosci Res Ctr, 35 Convent Dr,MSC 3700, Bethesda, MD 20892 USA. EM antonina@mail.nih.gov FU Intramural NIH HHS NR 13 TC 0 Z9 0 U1 0 U2 12 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 DEC 6 PY 2013 VL 342 IS 6163 BP 1180 EP 1181 DI 10.1126/science.1248235 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 264DT UT WOS:000327857900027 PM 24311672 ER PT J AU de la Roche, M Ritter, AT Angus, KL Dinsmore, C Earnshaw, CH Reiter, JF Griffiths, GM AF de la Roche, Maike Ritter, Alex T. Angus, Karen L. Dinsmore, Colin Earnshaw, Charles H. Reiter, Jeremy F. Griffiths, Gillian M. TI Hedgehog Signaling Controls T Cell Killing at the Immunological Synapse SO SCIENCE LA English DT Article ID PRIMARY CILIUM; INDIAN HEDGEHOG; ACTIVATION; DIFFERENTIATION; POLARIZATION; INHIBITION; TRANSPORT AB The centrosome is essential for cytotoxic T lymphocyte (CTL) function, contacting the plasma membrane and directing cytotoxic granules for secretion at the immunological synapse. Centrosome docking at the plasma membrane also occurs during cilia formation. The primary cilium, formed in nonhematopoietic cells, is essential for vertebrate Hedgehog (Hh) signaling. Lymphocytes do not form primary cilia, but we found and describe here that Hh signaling played an important role in CTL killing. T cell receptor activation, which "prearms" CTLs with cytotoxic granules, also initiated Hh signaling. Hh pathway activation occurred intracellularly and triggered Rac1 synthesis. These events "prearmed" CTLs for action by promoting the actin remodeling required for centrosome polarization and granule release. Thus, Hh signaling plays a role in CTL function, and the immunological synapse may represent a modified cilium. C1 [de la Roche, Maike; Ritter, Alex T.; Angus, Karen L.; Earnshaw, Charles H.; Griffiths, Gillian M.] Univ Cambridge, Cambridge Inst Med Res, Cambridge CB2 0XY, England. [Dinsmore, Colin; Reiter, Jeremy F.] Univ Calif San Francisco, Cardiovasc Res Inst, Dept Biochem & Biophys, San Francisco, CA 94158 USA. [Ritter, Alex T.] NICHD, NIH, Bethesda, MD 20892 USA. RP Griffiths, GM (reprint author), Univ Cambridge, Cambridge Inst Med Res, Hills Rd, Cambridge CB2 0XY, England. EM gg305@cam.ac.uk OI Earnshaw, Charles/0000-0002-7926-8506; Griffiths, Gillian/0000-0003-0434-5842 FU Wellcome Trust [075880]; Wellcome Trust Strategic Award for core facilities at the CIMR [100140]; NIH [R01AR05439, R01GM095941]; Burroughs Wellcome Fund; David and Lucile F. Packard Foundation; Sandler Family Supporting Foundation FX We thank R. Rohatgi for the MSCV-Ptch1-EYFP construct and the Smo antibodies; S. Munro (Cambridge) for PACT (pericentrin)-RFP; M. Davidson (University of Florida) for Farnesyl-5-TagBFP2; R. Zamoyska for Lck-depleted spleens; D. Fearon, T. Crompton, J. Kaufman, M. A. de la Roche, and A. Schuldt for helpful discussions and critical reading of the manuscript; and R. Rohatgi and J. Stinchcombe for helpful discussions. We also thank the flow cytometry core facility at the Cambridge Institute for Medical Research (CIMR) for cell sorting and assistance with the calcium assay. This work was supported by a Wellcome Trust Principal Research Fellowship to G. M. G. (075880), a Wellcome Trust Strategic Award for core facilities at the CIMR (100140), NIH (R01AR05439 and R01GM095941), the Burroughs Wellcome Fund, the David and Lucile F. Packard Foundation, and the Sandler Family Supporting Foundation to J. R. The data presented in this paper are provided in the main paper and supplementary materials. NR 30 TC 40 Z9 40 U1 3 U2 19 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 DEC 6 PY 2013 VL 342 IS 6163 BP 1247 EP 1250 DI 10.1126/science.1244689 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 264DT UT WOS:000327857900051 PM 24311692 ER PT J AU Behl, M Elmore, SA Malarkey, DE Hejtmancik, MR Gerken, DK Chhabra, RS AF Behl, Mamta Elmore, Susan A. Malarkey, David E. Hejtmancik, Milton R. Gerken, Diane K. Chhabra, Rajendra S. TI Perinatal toxicity and carcinogenicity studies of styrene-acrylonitrile trimer, a ground water contaminant SO TOXICOLOGY LA English DT Article DE Styrene acrylonitrile trimer; Cancer; Toxicity; Rats; Developmental AB Styrene acrylonitrile (SAN) trimer is a by-product in the production of acrylonitrile styrene plastics. Following a report of a childhood cancer cluster in the Toms River section of Dover Township, New Jersey, SAN Trimer was identified as one of the groundwater contaminants at Reich Farm Superfund site in the township. The contaminants from the Reich Farm site's ground water plume impacted two wells at the Parkway well field. The National Toxicology Program (NTP) studied the toxicity and carcinogenicity of SAN Trimer in rats exposed during their perinatal developmental period and adulthood. The chronic toxicity and carcinogenicity studies in F344/N rats were preceded by 7- and 18-week perinatal toxicity studies to determine the exposure concentrations for the 2-year studies. Subsequently, Fisher 344 pregnant dams were exposed to SAN Trimer containing diet at 400, 800, or 1600 ppm concentrations during gestation, nursing and weaning periods of offspring followed by two year of adult exposures to both male and female pups. There was no statistically significant evidence of carcinogenic activity following SAN-Trimer exposure; however, rare neoplasms in the brain and spinal cord were observed in males and to lesser extent in female rats. These incidences were considered within the range of historical background in the animal model used in the current studies. Therefore, the presence of a few rarely occurring CNS tumors in the treated groups were not judged to be associated with the SAN Trimer exposure. The major finding was a dose-related peripheral neuropathy associated with the sciatic nerves in females and spinal nerve roots in males and females thereby suggesting that SAN Trimer is potentially a nervous system toxicant. Published by Elsevier Ireland Ltd. C1 [Behl, Mamta] Kelly Govt Solut, Res Triangle Pk, NC USA. [Behl, Mamta; Elmore, Susan A.; Malarkey, David E.; Chhabra, Rajendra S.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Hejtmancik, Milton R.; Gerken, Diane K.] Battelle Mem Inst, Columbus, OH 43201 USA. RP Behl, M (reprint author), NIEHS, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM behlmv@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 21 TC 0 Z9 1 U1 1 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD DEC 6 PY 2013 VL 314 IS 1 BP 84 EP 94 DI 10.1016/j.cox.2013.09.006 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA V39SC UT WOS:000209429700010 PM 24060431 ER PT J AU Thakur, SA Flake, GP Travlos, GS Dill, JA Grumbein, SL Harbo, SJ Hooth, MJ AF Thakur, Sheetal A. Flake, Gordon P. Travlos, Greg S. Dill, Jeffrey A. Grumbein, Sondra L. Harbo, Sam J. Hooth, Michelle J. TI Evaluation of propargyl alcohol toxicity and carcinogenicity in F344/N rats and B6C3F1/N mice following whole-body inhalation exposure SO TOXICOLOGY LA English DT Article DE Propargyl alcohol; Toxicity; Carcinogenicity; Chronic; Occupational; Respiratory AB Propargyl alcohol (PA) is a high production volume chemical used in synthesis of many industrial chemicals and agricultural products. Despite the potential for prolonged or accidental exposure to PA in industrial settings, the toxicity potential of PA was not well characterized. To address the knowledge gaps relevant to the toxicity profile of PA, the National Toxicology Program (NTP) conducted 2-week, 14-week and 2-year studies in male and female F344/N rats and B6C3F1/N mice. For the 2-week inhalation study, the rats and mice were exposed to 0, 31.3, 62.5, 125, 250 or 500 ppm. Significant mortality was observed in both rats and mice exposed to >= 125 ppm of PA. The major target organ of toxicity in both mice and rats was the liver with exposure-related histopathological changes (250 and 500 ppm). Based on the decreased survival in the 2-week study, the rats and mice were exposed to 0, 4, 8, 16, 32 or 64 ppm of PA in the 14-week study. No treatment-related mortality was observed. Mean body weights of male (>= 8 ppm) and female mice (32 and 64 ppm) were significantly decreased (7-16%). Histopathological changes were noted in the nasal cavity, and included suppurative inflammation, squamous metaplasia, hyaline droplet accumulation, olfactory epithelium atrophy, and necrosis. In the 2-year inhalation studies, the rats were exposed to 0, 16, 32 and 64 ppm of PA and the mice were exposed to 0, 8, 16 and 32 ppm of PA. Survival of male rats was significantly reduced (32 and 64 ppm). Mean body weights of 64 ppm male rats were significantly decreased relative to the controls. Both mice and rats showed a spectrum of non-neoplastic changes in the nose. Increased neoplastic incidences of nasal respiratory/transitional epithelial adenoma were observed in both rats and mice. The incidence of mononuclear cell leukemia was significantly increased in male rats and was considered to be treatment-related. In conclusion, the key findings from this study indicated that the nose was the primary target organ of toxicity for PA. Long term inhalation exposure to PA led to nonneoplastic changes in the nose, and increased incidences of respiratory/transitional epithelial adenomas in both mice and rats. Increased incidences of harderian gland adenoma may also have been related to exposure to PA in male mice. (C) 2013 Published by Elsevier Ireland Ltd. C1 [Thakur, Sheetal A.; Flake, Gordon P.; Travlos, Greg S.; Hooth, Michelle J.] NIEHS, Div Natl Toxicol Program, NIH, NTP, Res Triangle Pk, NC 27709 USA. [Dill, Jeffrey A.; Grumbein, Sondra L.; Harbo, Sam J.] Battelle Toxicol Northwest, Richland, WA 99352 USA. RP Hooth, MJ (reprint author), NIEHS, Div Natl Toxicol Program, NIH, NTP, 111 TW Alexander Dr,POB 12233,MD K2-07, Res Triangle Pk, NC 27709 USA. EM thakursa@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX This research was supported by the NIH, National Institute of Environmental Health Sciences. We thank Dr. Mathew Stout (DNTP/NIEHS) and Dr. Deepa Rao (Contractor, DNTP/NIEHS) for their helpful review of the manuscript. NR 42 TC 1 Z9 2 U1 1 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD DEC 6 PY 2013 VL 314 IS 1 BP 100 EP 111 DI 10.1016/j.tox.2013.09.002 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA V39SC UT WOS:000209429700012 PM 24035744 ER PT J AU Wang, HY Dittmer, TA Richards, EJ AF Wang, Haiyi Dittmer, Travis A. Richards, Eric J. TI Arabidopsis CROWDED NUCLEI (CRWN) proteins are required for nuclear size control and heterochromatin organization SO BMC PLANT BIOLOGY LA English DT Article DE Nuclear organization; Nuclear morphology; Nuclear DNA density; Heterochromatin ID SUN-KASH BRIDGES; INTERPHASE NUCLEI; PORE COMPLEX; CELL-SIZE; THALIANA; ENVELOPE; MORPHOLOGY; PLANTS; CHROMATIN; DOMAIN AB Background: Plant nuclei superficially resemble animal and fungal nuclei, but the machinery and processes that underlie nuclear organization in these eukaryotic lineages appear to be evolutionarily distinct. Among the candidates for nuclear architectural elements in plants are coiled-coil proteins in the NMCP (Nuclear Matrix Constituent Protein) family. Using genetic and cytological approaches, we dissect the function of the four NMCP family proteins in Arabidopsis encoded by the CRWN genes, which were originally named LINC (LITTLE NUCLEI). Results: CRWN proteins are essential for viability as evidenced by the inability to recover mutants that have disruptions in all four CRWN genes. Mutants deficient in different combinations of the four CRWN paralogs exhibit altered nuclear organization, including reduced nuclear size, aberrant nuclear shape and abnormal spatial organization of constitutive heterochromatin. Our results demonstrate functional diversification among CRWN paralogs; CRWN1 plays the predominant role in control of nuclear size and shape followed by CRWN4. Proper chromocenter organization is most sensitive to the deficiency of CRWN4. The reduction in nuclear volume in crwn mutants in the absence of a commensurate reduction in endoreduplication levels leads to an increase in average nuclear DNA density. Conclusions: Our findings indicate that CRWN proteins are important architectural components of plant nuclei that play diverse roles in both heterochromatin organization and the control of nuclear morphology. C1 [Wang, Haiyi; Richards, Eric J.] Cornell Univ, Boyce Thompson Inst Plant Res, Ithaca, NY 14853 USA. [Dittmer, Travis A.] NCI, NIH, Bethesda, MD 20892 USA. RP Richards, EJ (reprint author), Cornell Univ, Boyce Thompson Inst Plant Res, 533 Tower Rd, Ithaca, NY 14853 USA. EM ejr77@cornell.edu RI Richards, Eric/E-6866-2012 FU National Science Foundation [MCB-0956820]; Boyce Thompson Institute FX We are grateful for the guidance and facilities provided by Wojtek Pawlowski, Choon-lin Tiang, Mamta Srivastava and Boyce Thompson Institute's Plant Cell Imaging Center. We thank Natalie Henkhaus, Erika Hughes, and Molly Shook for helpful comments and discussion. The T-DNA mutant lines used in this study were obtained from the Arabidopsis Biological Resource Center at The Ohio State University. This work was supported by a grant from the National Science Foundation to EJR (MCB-0956820) and from funds provided by the Boyce Thompson Institute. NR 38 TC 21 Z9 22 U1 4 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2229 J9 BMC PLANT BIOL JI BMC Plant Biol. PD DEC 5 PY 2013 VL 13 AR UNSP 200 DI 10.1186/1471-2229-13-200 PG 13 WC Plant Sciences SC Plant Sciences GA AC1GC UT WOS:000332241200001 PM 24308514 ER PT J AU Berglund, LJ Avery, DT Ma, CS Moens, L Deenick, EK Bustamante, J Boisson-Dupuis, S Wong, M Adelstein, S Arkwright, PD Bacchetta, R Bezrodnik, L Dadi, H Roifman, CM Fulcher, DA Ziegler, JB Smart, JM Kobayashi, M Picard, C Durandy, A Cook, MC Casanova, JL Uzel, G Tangye, SG AF Berglund, Lucinda J. Avery, Danielle T. Ma, Cindy S. Moens, Leen Deenick, Elissa K. Bustamante, Jacinta Boisson-Dupuis, Stephanie Wong, Melanie Adelstein, Stephen Arkwright, Peter D. Bacchetta, Rosa Bezrodnik, Liliana Dadi, Harjit Roifman, Chaim M. Fulcher, David A. Ziegler, John B. Smart, Joanne M. Kobayashi, Masao Picard, Capucine Durandy, Anne Cook, Matthew C. Casanova, Jean-Laurent Uzel, Gulbu Tangye, Stuart G. TI IL-21 signalling via STAT3 primes human naive B cells to respond to IL-2 to enhance their differentiation into plasmablasts SO BLOOD LA English DT Article ID HYPER-IGE SYNDROME; FOLLICULAR-HELPER-CELLS; ANTIBODY-RESPONSES; T-CELLS; TERMINAL DIFFERENTIATION; HYPERIMMUNOGLOBULIN-E; IMMUNE-RESPONSES; IMMUNOGLOBULIN-A; SECRETING CELLS; EXPRESSION AB B-cell responses are guided by the integration of signals through the B-cell receptor (BCR), CD40, and cytokine receptors. The common gamma chain (gamma c)-binding cytokine interleukin (IL)-21 drives humoral immune responses via STAT3-dependent induction of transcription factors required for plasma cell generation. We investigated additional mechanisms by which IL-21/STAT3 signaling modulates human B-cell responses by studying patients with STAT3 mutations. IL-21 strongly induced CD25 (IL-2R alpha) in normal, but not STAT3-deficient, CD40L-stimulated naive B cells. Chromatin immunoprecipitation confirmed IL2RA as a direct target of STAT3. IL-21-induced CD25 expression was also impaired on B cells from patients with IL2RG or IL21R mutations, confirming a requirement for intact IL-21R signaling in this process. IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25-deficient, naive B cells stimulated with CD40L/IL-21. IL-2 and IL-21 were produced by T follicular helper cells, and neutralizing both cytokines abolished the B-cell helper capacity of these cells. Our results demonstrate that IL-21, via STAT3, sensitizes B cells to the stimulatory effects of IL-2. Thus, IL-2 may play an adjunctive role in IL-21-induced B-cell differentiation. Lack of this secondary effect of IL-21 may amplify the humoral immunodeficiency in patients with mutations in STAT3, IL2RG, or IL21R due to impaired responsiveness to IL-21. (Blood. 2013;122(24):3940-3950) C1 [Berglund, Lucinda J.; Avery, Danielle T.; Ma, Cindy S.; Moens, Leen; Deenick, Elissa K.; Tangye, Stuart G.] St Vincents Hosp, Garvan Inst Med Res, Immunol Res Program, Darlinghurst, NSW 2010, Australia. [Berglund, Lucinda J.; Ma, Cindy S.; Deenick, Elissa K.; Tangye, Stuart G.] Univ New S Wales, St Vincents Clin Sch, Sydney, NSW 2052, Australia. [Berglund, Lucinda J.; Fulcher, David A.] Westmead Hosp, Dept Immunol, Inst Clin Pathol & Med Res, Westmead, NSW 2145, Australia. [Bustamante, Jacinta; Boisson-Dupuis, Stephanie; Picard, Capucine; Casanova, Jean-Laurent] Univ Paris 05, Necker Med Sch, Lab Human Genet Infect Dis, Necker Branch,INSERM,U980, Paris, France. [Bustamante, Jacinta; Picard, Capucine; Durandy, Anne] Hop Necker Enfants Malad, AP HP, Study Ctr Primary Immunodeficiencies, Paris, France. [Bustamante, Jacinta; Picard, Capucine; Durandy, Anne; Casanova, Jean-Laurent] Univ Paris 05, Inst Imagine, Paris, France. [Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent] Rockefeller Univ, Rockefeller Branch, Lab Human Genet Infect Dis, New York, NY 10021 USA. [Wong, Melanie] Childrens Hosp Westmead, Dept Immunol, Westmead, NSW, Australia. [Adelstein, Stephen] Royal Prince Alfred Hosp, Sydney, NSW, Australia. [Arkwright, Peter D.] Univ Manchester, Royal Manchester Childrens Hosp, Manchester, Lancs, England. [Bacchetta, Rosa] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy HSR TIGET, I-20132 Milan, Italy. [Bezrodnik, Liliana] Ricardo Gutierrez Children Hosp, Immunol Unit, Buenos Aires, DF, Argentina. [Dadi, Harjit; Roifman, Chaim M.] Hosp Sick Children, Canadian Ctr Primary Immunodeficiency, Toronto, ON M5G 1X8, Canada. [Dadi, Harjit; Roifman, Chaim M.] Univ Toronto, Toronto, ON, Canada. [Ziegler, John B.] Sydney Childrens Hosp, Dept Immunol, Randwick, NSW, Australia. [Ziegler, John B.] Univ NSW, Sch Womens & Childrens Hlth, Randwick, NSW, Australia. [Smart, Joanne M.] Royal Childrens Hosp Melbourne, Dept Allergy & Immunol, Melbourne, Vic, Australia. [Kobayashi, Masao] Hiroshima Univ, Dept Pediat, Grad Sch Biomed Sci, Hiroshima, Japan. [Durandy, Anne] Hop Necker Enfants Malad, INSERM, U768, Paris, France. [Cook, Matthew C.] Australian Natl Univ, Sch Med, Canberra, ACT, Australia. [Cook, Matthew C.] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 2601, Australia. [Cook, Matthew C.] Canberra Hosp, Dept Immunol, Canberra, ACT, Australia. [Uzel, Gulbu] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Tangye, SG (reprint author), Garvan Inst Med Res, 384 Victoria St, Darlinghurst, NSW 2010, Australia. EM s.tangye@garvan.org.au RI Tangye, Stuart/H-4023-2014; Adelstein, Stephen/I-7936-2016; OI Adelstein, Stephen/0000-0001-7221-6298; Deenick, Elissa/0000-0002-9271-0004; Picard, Capucine/0000-0001-8788-5056; Arkwright, Peter/0000-0002-7411-5375 FU National Health and Medical Research Council of Australia; Research Foundation-Flanders (FWO), Belgium FX This work was supported by research grants and fellowships awarded by the National Health and Medical Research Council of Australia (L.J.B., C. S. M., E. K. D., M. C. C., S. G. T.) and a Postdoctoral Fellowship from Research Foundation-Flanders (FWO), Belgium (L.M). NR 50 TC 28 Z9 29 U1 1 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 5 PY 2013 VL 122 IS 24 BP 3940 EP 3950 DI 10.1182/blood-2013-06-506865 PG 11 WC Hematology SC Hematology GA 290EV UT WOS:000329737600018 PM 24159173 ER PT J AU Wang, L Miao, YL Zheng, XF Lackford, B Zhou, BY Han, L Yao, CG Ward, JM Burkholder, A Lipchina, I Fargo, DC Hochedlinger, K Shi, YS Williams, CJ Hu, G AF Wang, Li Miao, Yi-Liang Zheng, Xiaofeng Lackford, Brad Zhou, Bingying Han, Leng Yao, Chengguo Ward, James M. Burkholder, Adam Lipchina, Inna Fargo, David C. Hochedlinger, Konrad Shi, Yongsheng Williams, Carmen J. Hu, Guang TI The THO Complex Regulates Pluripotency Gene mRNA Export and Controls Embryonic Stem Cell Self-Renewal and Somatic Cell Reprogramming SO CELL STEM CELL LA English DT Article ID GENOME-WIDE ANALYSIS; HUMAN TREX COMPLEX; TRANSCRIPTIONAL NETWORK; MRNP BIOGENESIS; MOUSE; DIFFERENTIATION; EXPRESSION; CIRCUITRY; PROTEIN; NANOG AB Embryonic stem cell (ESC) self-renewal and differentiation are governed by a broad-ranging regulatory network. Although the transcriptional regulatory mechanisms involved have been investigated extensively, posttranscriptional regulation is still poorly understood. Here we describe a critical role of the THO complex in ESC self-renewal and differentiation. We show that THO preferentially interacts with pluripotency gene transcripts through Thoc5 and is required for self-renewal at least in part by regulating their export and expression. During differentiation, THO loses its interaction with those transcripts due to reduced Thoc5 expression, leading to decreased expression of pluripotency proteins that facilitates exit from self-renewal. THO is also important for the establishment of pluripotency, because its depletion inhibits somatic cell reprogramming and blastocyst development. Together, our data indicate that THO regulates pluripotency gene mRNA export to control ESC self-renewal and differentiation, and therefore uncover a role for this aspect of posttranscriptional regulation in stem cell fate specification. C1 [Wang, Li; Zheng, Xiaofeng; Lackford, Brad; Hu, Guang] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Miao, Yi-Liang; Williams, Carmen J.] NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Zhou, Bingying] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Zhou, Bingying] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Han, Leng] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Yao, Chengguo; Shi, Yongsheng] Univ Calif Irvine, Dept Microbiol & Mol Genet, Sch Med, Irvine, CA 92697 USA. [Ward, James M.; Burkholder, Adam; Fargo, David C.] NIEHS, Res Triangle Pk, NC 27709 USA. [Lipchina, Inna; Hochedlinger, Konrad] Massachusetts Gen Hosp, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Boston, MA 02114 USA. RP Hu, G (reprint author), NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM hug4@niehs.nih.gov RI Williams, Carmen/E-2170-2013; Hu, Guang/E-7474-2016 OI Williams, Carmen/0000-0001-6440-7086; Hu, Guang/0000-0003-0437-4723 FU NIH, National Institute of Environmental Health Sciences [1ZIAES102745, 1ZIAES102985]; NIH [R01GM090056, R01HD058013]; American Cancer Society [RSG-12-186] FX We thank Drs. Karen Adelman, Perry Blackshear, Traci Hall, Raja Jothi, and Paul Wade for critically reading the manuscript. This study was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences 1ZIAES102745 (to L. W., X.Z., B. L., and G. H.) and 1ZIAES102985 (to Y.M. and C. W.), NIH R01GM090056 and American Cancer Society Grant RSG-12-186 (to C.Y. and Y.S.), and NIH R01HD058013 (to I. L. and K.H.). NR 68 TC 23 Z9 24 U1 2 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD DEC 5 PY 2013 VL 13 IS 6 BP 676 EP 690 DI 10.1016/j.stem.2013.10.008 PG 15 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 287VZ UT WOS:000329571700011 PM 24315442 ER PT J AU Meyer, KB O'Reilly, M Michailidou, K Carlebur, S Edwards, SL French, JD Prathalingham, R Dennis, J Bolla, MK Wang, Q de Santiago, I Hopper, JL Tsimiklis, H Apicella, C Southey, MC Schmidt, MK Broeks, A Van't Veer, LJ Hogervorst, FB Muir, K Lophatananon, A Stewart-Brown, S Siriwanarangsan, P Fasching, PA Lux, MP Ekici, AB Beckmann, MW Peto, J Silva, ID Fletcher, O Johnson, N Sawyer, EJ Tomlinson, I Kerin, MJ Miller, N Marme, F Schneeweiss, A Sohn, C Burwinkel, B Guenel, P Truong, T Laurent-Puig, P Menegaux, F Bojesen, SE Nordestgaard, BG Nielsen, SF Flyger, H Milne, RL Zamora, MP Arias, JI Benitez, J Neuhausen, S Anton-Culver, H Ziogas, A Dur, CC Brenner, H Muller, H Arndt, V Stegmaier, C Meindl, A Schmutzler, RK Engel, C Ditsch, N Brauch, H Bruning, T Ko, YD Nevanlinna, H Muranen, TA Aittomaki, K Blomqvist, C Matsuo, K Ito, H Iwata, H Yatabe, Y Dork, T Helbig, S Bogdanova, NV Lindblom, A Margolin, S Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Chenevix-Trench, G Wu, AH Tseng, CC Van Den Berg, D Stram, DO Lambrechts, D Thienpont, B Christiaens, MR Smeets, A Chang-Claude, J Rudolph, A Seibold, P Flesch-Janys, D Radice, P Peterlongo, P Bonanni, B Bernard, L Couch, FJ Olson, JE Wang, XS Purrington, K Giles, GG Severi, G Baglietto, L McLean, C Haiman, CA Henderson, BE Schumacher, F Le Marchand, L Simard, J Goldberg, MS Labreche, F Dumont, M Teo, SH Yip, CH Phuah, SY Kristensen, V Alnaes, GG Borresen-Dale, AL Zheng, W Deming-Halverson, S Shrubsole, M Long, JR Winqvist, R Pylkas, K Jukkola-Vuorinen, A Kauppila, S Andrulis, IL Knight, JA Glendon, G Tchatchou, S Devilee, P Tollenaar, RAEM Seynaeve, CM Garcia-Closas, M Figueroa, J Chanock, SJ Lissowska, J Czene, K Darabi, H Eriksson, K Hooning, MJ Martens, JWM van den Ouweland, AMW van Deurzen, CHM Hall, P Li, JM Liu, JJ Humphreys, K Shu, XO Lu, W Gao, YT Cai, H Cox, A Reed, MWR Blot, W Signorello, LB Cai, QY Pharoah, PDP Ghoussaini, M Harrington, P Tyrer, J Kang, D Choi, JY Park, SK Noh, DY Hartman, M Hui, M Lim, WY Buhari, SA Hamann, U Forsti, A Rudiger, T Ulmer, HU Jakubowska, A Lubinski, J Jaworska, K Durda, K Sangrajrang, S Gaborieau, V Brennan, P Mckay, J Vachon, C Slager, S Fostira, F Pilarski, R Shen, CY Hsiung, CN Wu, PE Hou, MF Swerdlow, A Ashworth, A Orr, N Schoemaker, MJ Ponder, BAJ Dunning, AM Easton, DF AF Meyer, Kerstin B. O'Reilly, Martin Michailidou, Kyriaki Carlebur, Saskia Edwards, Stacey L. French, Juliet D. Prathalingham, Radhika Dennis, Joe Bolla, Manjeet K. Wang, Qin de Santiago, Ines Hopper, John L. Tsimiklis, Helen Apicella, Carmel Southey, Melissa C. Schmidt, Marjanka K. Broeks, Annegien Van't Veer, Laura J. Hogervorst, Frans B. Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Fasching, Peter A. Lux, Michael P. Ekici, Arif B. Beckmann, Matthias W. Peto, Julian Silva, Isabel dos Santos Fletcher, Olivia Johnson, Nichola Sawyer, Elinor J. Tomlinson, Ian Kerin, Michael J. Miller, Nicola Marme, Federick Schneeweiss, Andreas Sohn, Christof Burwinkel, Barbara Guenel, Pascal Truong, Therese Laurent-Puig, Pierre Menegaux, Florence Bojesen, Stig E. Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Milne, Roger L. Pilar Zamora, M. Arias, Jose I. Benitez, Javier Neuhausen, Susan Anton-Culver, Hoda Ziogas, Argyrios Dur, Christina C. Brenner, Hermann Mueller, Heiko Arndt, Volker Stegmaier, Christa Meindl, Alfons Schmutzler, Rita K. Engel, Christoph Ditsch, Nina Brauch, Hiltrud Bruening, Thomas Ko, Yon-Dschun Nevanlinna, Heli Muranen, Taru A. Aittomaeki, Kristiina Blomqvist, Carl Matsuo, Keitaro Ito, Hidemi Iwata, Hiroji Yatabe, Yasushi Doerk, Thilo Helbig, Sonja Bogdanova, Natalia V. Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Chenevix-Trench, Georgia Wu, Anna H. Tseng, Chiu-chen Van Den Berg, David Stram, Daniel O. Lambrechts, Diether Thienpont, Bernard Christiaens, Marie-Rose Smeets, Ann Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Radice, Paolo Peterlongo, Paolo Bonanni, Bernardo Bernard, Loris Couch, Fergus J. Olson, Janet E. Wang, Xianshu Purrington, Kristen Giles, Graham G. Severi, Gianluca Baglietto, Laura McLean, Catriona Haiman, Christopher A. Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Simard, Jacques Goldberg, Mark S. Labreche, France Dumont, Martine Teo, Soo-Hwang Yip, Cheng-Har Phuah, Sze-Yee Kristensen, Vessela Alnaes, Grethe Grenaker Borresen-Dale, Anne-Lise Zheng, Wei Deming-Halverson, Sandra Shrubsole, Martha Long, Jirong Winqvist, Robert Pylkaes, Katri Jukkola-Vuorinen, Arja Kauppila, Saila Andrulis, Irene L. Knight, Julia A. Glendon, Gord Tchatchou, Sandrine Devilee, Peter Tollenaar, Robert A. E. M. Seynaeve, Caroline M. Garcia-Closas, Montserrat Figueroa, Jonine Chanock, Stephen J. Lissowska, Jolanta Czene, Kamila Darabi, Hartef Eriksson, Kimael Hooning, Maartje J. Martens, John W. M. van den Ouweland, Ans M. W. van Deurzen, Carolien H. M. Hall, Per Li, Jingmei Liu, Jianjun Humphreys, Keith Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Cai, Hui Cox, Angela Reed, Malcolm W. R. Blot, William Signorello, Lisa B. Cai, Qiuyin Pharoah, Paul D. P. Ghoussaini, Maya Harrington, Patricia Tyrer, Jonathan Kang, Daehee Choi, Ji-Yeob Park, Sue K. Noh, Dong-Young Hartman, Mikael Hui, Miao Lim, Wei-Yen Buhari, Shaik A. Hamann, Ute Foersti, Asta Ruediger, Thomas Ulmer, Hans-Ulrich Jakubowska, Anna Lubinski, Jan Jaworska, Katarzyna Durda, Katarzyna Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul Mckay, James Vachon, Celine Slager, Susan Fostira, Florentia Pilarski, Robert Shen, Chen-Yang Hsiung, Chia-Ni Wu, Pei-Ei Hou, Ming-Feng Swerdlow, Anthony Ashworth, Alan Orr, Nick Schoemaker, Minouk J. Ponder, Bruce A. J. Dunning, Alison M. Easton, Douglas F. CA Network, G Investigators, K Group, AOCS TI Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus: Putative Functional Variants Differentially Bind FOXA1 and E2F1 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; ESTROGEN-RECEPTOR BINDING; SUSCEPTIBILITY LOCI; AFRICAN-AMERICAN; EXPRESSION; TRANSCRIPTION; DETERMINANT; CHROMATIN; REVEALS; WOMEN AB The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ER alpha to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease. C1 [Meyer, Kerstin B.; O'Reilly, Martin; Carlebur, Saskia; Prathalingham, Radhika; de Santiago, Ines; Ponder, Bruce A. J.] Univ Cambridge, CRUK Cambridge Inst, Li Ka Shing Ctr, Cambridge CB2 0RE, England. [Meyer, Kerstin B.; O'Reilly, Martin; Carlebur, Saskia; Prathalingham, Radhika; de Santiago, Ines; Ponder, Bruce A. J.] Univ Cambridge, Dept Oncol, Li Ka Shing Ctr, Cambridge CB2 0RE, England. [Michailidou, Kyriaki; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Pharoah, Paul D. P.; Ghoussaini, Maya; Harrington, Patricia; Tyrer, Jonathan; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Michailidou, Kyriaki; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Pharoah, Paul D. P.; Ghoussaini, Maya; Harrington, Patricia; Tyrer, Jonathan; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge CB1 8RN, England. [Edwards, Stacey L.; French, Juliet D.; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld 4029, Australia. [Edwards, Stacey L.; French, Juliet D.] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia. [Hopper, John L.; Apicella, Carmel; Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3010, Australia. [Tsimiklis, Helen; Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, Laura J.; Hogervorst, Frans B.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands. [Muir, Kenneth] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester M13 9PL, Lancs, England. [Lophatananon, Artitaya; Stewart-Brown, Sarah] Univ Warwick, Div Hlth Sci, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Siriwanarangsan, Pornthep] Minist Publ Hlth, Bangkok 10400, Thailand. [Fasching, Peter A.; Lux, Michael P.] Univ Erlangen Nurnberg, Univ Breast Ctr Franconia, Dept Gynecol & Obstet, Univ Hosp Erlangen, D-91054 Erlangen, Germany. [Fasching, Peter A.; Ekici, Arif B.; Beckmann, Matthias W.] Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Peto, Julian; Silva, Isabel dos Santos] Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England. [Fletcher, Olivia; Johnson, Nichola; Garcia-Closas, Montserrat; Ashworth, Alan; Orr, Nick] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Sawyer, Elinor J.] Guys & St Thomas NHS Fdn Trust, Div Canc Studies, NIHR Comprehensive Biomed Res Ctr, London SE1 9RT, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England. [Kerin, Michael J.; Miller, Nicola] Univ Coll Hosp Galway, Inst Clin Sci, Galway, Ireland. [Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany. [Marme, Federick; Schneeweiss, Andreas] Heidelberg Univ, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, D-69120 Heidelberg, Germany. [Guenel, Pascal; Truong, Therese; Menegaux, Florence] INSERM, CESP, UMRS 1018, F-94807 Villejuif, France. [Guenel, Pascal; Truong, Therese; Menegaux, Florence] Univ Paris Sud, INSERM, UMRS 1018, F-94807 Villejuif, France. [Laurent-Puig, Pierre] Univ Paris Sorbonne Cite, UMR S775 Inserm, F-75270 Paris, France. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Univ Copenhagen, Herlev Hosp, Copenhagen Univ Hosp, Copenhagen Gen Populat Stud, DK-2730 Herlev, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Univ Copenhagen, Herlev Hosp, Copenhagen Univ Hosp, Dept Clin Biochem, DK-2730 Herlev, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Dept Breast Surg, Herlev Hosp, DK-2730 Herlev, Denmark. [Milne, Roger L.] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Human Canc Genet Program, Madrid 28029, Spain. [Pilar Zamora, M.] Hosp Univ Paz, Serv Oncol Med, Madrid 28046, Spain. [Arias, Jose I.] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo 33012, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Genet Grp, Human Canc Genet Program, Madrid 28029, Spain. [Benitez, Javier] CIBERER, Valencia 46010, Spain. [Neuhausen, Susan] Beckman Res Inst, Duarte, CA 91010 USA. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA. [Dur, Christina C.] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [Brenner, Hermann; Mueller, Heiko; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, D-66024 Saarbrucken, Germany. [Meindl, Alfons] Tech Univ Munich, Div Obstet & Gynecol, D-81675 Munich, Germany. [Schmutzler, Rita K.] Univ Cologne, Div Mol Gynecooncol, Dept Obstet & Gynaecol, D-50931 Cologne, Germany. [Engel, Christoph] Univ Leipzig, Inst Med Informat Statist & Epidemiol, D-04107 Leipzig, Germany. [Ditsch, Nina] Univ Munich, Dept Obstet & Gynaecol, D-80539 Munich, Germany. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, D-72074 Tubingen, Germany. [Bruening, Thomas] Ruhr Univ Bochum, Inst Prevent & Occupat Med German Social Accident, D-44789 Bochum, Germany. [Ko, Yon-Dschun] Evangel Klin Bonn gGmbH, Dept Internal Med, D-53113 Bonn, Germany. [Nevanlinna, Heli; Muranen, Taru A.] Univ Helsinki, Dept Obstet & Gynaecol, Helsinki 00029, Finland. [Nevanlinna, Heli; Muranen, Taru A.] Helsinki Univ Cent Hosp, Helsinki 00029, Finland. [Aittomaeki, Kristiina] Helsinki Univ Cent Hosp, Dept Clin Genet, Helsinki 00029, Finland. [Blomqvist, Carl] Helsinki Univ Cent Hosp, Dept Oncol, Helsinki 00029, Finland. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka 8128582, Japan. [Ito, Hidemi] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 4648681, Japan. [Iwata, Hiroji] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi 4648681, Japan. [Yatabe, Yasushi] Aichi Canc Ctr Hosp, Dept Pathol & Mol Diagnost, Nagoya, Aichi 4648681, Japan. [Doerk, Thilo; Helbig, Sonja] Hannover Med Sch, Dept Obstet & Gynaecol, D-30625 Hannover, Germany. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, D-30625 Hannover, Germany. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Sch Med, Inst Clin Med Pathol & Forens Med, Dept Clin Pathol, Kuopio 70211, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Sch Med, Canc Ctr Eastern Finland, Dept Clin Pathol, Kuopio 70211, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Sch Med, Univ Eastern Finland, Dept Clin Pathol, Kuopio 70211, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Sch Med, Imaging Ctr, Dept Clin Pathol, Kuopio 70211, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Sch Med, Inst Clin Med Oncol, Univ Eastern Finland, Kuopio 70211, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Sch Med, Inst Clin Med Oncol, Canc Ctr, Kuopio 70211, Finland. [Wu, Anna H.; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O.; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Lambrechts, Diether; Thienpont, Bernard] VRC, VIB, B-3000 Louvain, Belgium. [Lambrechts, Diether; Thienpont, Bernard] Univ Leuven, B-3000 Louvain, Belgium. [Christiaens, Marie-Rose] Univ Hosp Gasthuisberg, Dept Oncol, B-3000 Louvain, Belgium. [Smeets, Ann] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Dept Canc Epidemiol, Clin Canc Registry, D-20246 Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Dept Canc Epidemiol, Inst Med Biometr & Epidemiol, D-20246 Hamburg, Germany. [Radice, Paolo] INT, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent Predict Med, Fdn IRCCS, I-20133 Milan, Italy. [Peterlongo, Paolo] IFOM, Fdn Ist FIRC Oncol Mol, I-20139 Milan, Italy. [Bonanni, Bernardo] IEO, Div Canc Prevent & Genet, I-20141 Milan, Italy. [Bernard, Loris] IEO, Dept Expt Oncol, I-20141 Milan, Italy. [Bernard, Loris] Cogentech Canc Genet Test Lab, I-20139 Milan, Italy. [Couch, Fergus J.; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Olson, Janet E.; Vachon, Celine; Slager, Susan] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Purrington, Kristen] Karmanos Canc Ctr, Detroit, MI 48201 USA. [Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Canc Epidemiol Ctr, Canc Council Victoria, Melbourne, Vic 3053, Australia. [McLean, Catriona] Alfred Hosp, Melbourne, Vic 3181, Australia. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Epidemiol Program, Honolulu, HI 96813 USA. [Simard, Jacques; Dumont, Martine] Univ Quebec, Canc Genom Lab, Ctr Hosp, Quebec City, PQ QCG1V4G2, Canada. [Simard, Jacques; Dumont, Martine] Univ Laval, Canc Genom Lab, Quebec City, PQ QCG1V4G2, Canada. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ H3A 1A1, Canada. [Goldberg, Mark S.] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Hlth Ctr, Montreal, PQ H3A 1A1, Canada. [Labreche, France] Univ Montreal, Dept Social & Prevent Med, Dept Sante Environm & Sante Travail, Montreal, PQ H3A 3C2, Canada. [Teo, Soo-Hwang; Phuah, Sze-Yee] Canc Res Initiat Fdn, Sime Darby Med Ctr, Selangor 47500, Malaysia. [Teo, Soo-Hwang; Yip, Cheng-Har; Phuah, Sze-Yee] Univ Malaya, Med Ctr, Breast Canc Res Unit, Univ Malaya Canc Res Inst, Kuala Lumpur 50603, Malaysia. [Kristensen, Vessela; Alnaes, Grethe Grenaker; Borresen-Dale, Anne-Lise] Oslo Univ Hosp, Dept Genet, Inst Canc Res, N-0310 Oslo, Norway. [Kristensen, Vessela; Borresen-Dale, Anne-Lise] Univ Oslo, Fac Med Fac Div Ahus, N-0318 Oslo, Norway. [Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Shu, Xiao-Ou; Cai, Hui; Blot, William; Signorello, Lisa B.; Cai, Qiuyin] Vanderbilt Univ, Sch Med,Vanderbilt Ingram Canc Ctr, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr,, Nashville, TN 37203 USA. [Winqvist, Robert; Pylkaes, Katri] Univ Oulu, Lab Canc Genet & Tumor Biol, Dept Clin Chem, Oulu Univ Hosp, Oulu 90014, Finland. [Winqvist, Robert; Pylkaes, Katri] Univ Oulu, Lab Canc Genet & Tumor Biol, Bioctr Oulu, Oulu Univ Hosp, Oulu 90014, Finland. [Jukkola-Vuorinen, Arja; Kauppila, Saila] Univ Oulu, Dept Oncol, Oulu Univ Hosp, Oulu 90014, Finland. [Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G IX5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S IA8, Canada. [Knight, Julia A.] Univ Toronto, Div Epidemiol, Dalla Lana Sch Publ Hlth, Toronto, ON M5S 1A8, Canada. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, NL-2300 RC Leiden, Netherlands. [Tollenaar, Robert A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2300 RC Leiden, Netherlands. [Seynaeve, Caroline M.; Hooning, Maartje J.; Martens, John W. M.] Erasmus MC Canc Inst, Dept Med Oncol, NL-3075 EA Rotterdam, Netherlands. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Surrey SM2 5NG, England. [Figueroa, Jonine; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Lissowska, Jolanta; Swerdlow, Anthony; Schoemaker, Minouk J.] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Lissowska, Jolanta; Swerdlow, Anthony; Schoemaker, Minouk J.] Inst Oncol, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Czene, Kamila; Darabi, Hartef; Eriksson, Kimael; Hall, Per; Humphreys, Keith] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [van den Ouweland, Ans M. W.] Erasmus Univ, Med Ctr, Dept Clin Genet, NL-3008 AE Rotterdam, Netherlands. [van Deurzen, Carolien H. M.] Erasmus Univ, Med Ctr, Dept Pathol, NL-3008 AE Rotterdam, Netherlands. [Li, Jingmei; Liu, Jianjun] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore. [Lu, Wei] Shanghai Ctr Dis Control & Prevent, Shanghai 200336, Peoples R China. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai 200032, Peoples R China. [Cox, Angela; Reed, Malcolm W. R.; Blot, William] Univ Sheffield, CRUK, YCR Sheffield Canc Res Ctr, Sheffield S10 2RX, S Yorkshire, England. [Signorello, Lisa B.] Int Epidemiol Inst, Rockville, MD 20850 USA. [Kang, Daehee; Park, Sue K.] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. [Kang, Daehee; Choi, Ji-Yeob] Seoul Natl Univ, Dept Biomed Sci, Grad Sch, Seoul 110799, South Korea. [Noh, Dong-Young] Seoul Natl Univ, Coll Med, Dept Surg, Seoul 110799, South Korea. [Hartman, Mikael; Hui, Miao; Lim, Wei-Yen] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. [Hartman, Mikael; Hui, Miao; Lim, Wei-Yen] Natl Univ Hlth Syst, Singapore 119228, Singapore. [Buhari, Shaik A.] Natl Univ Hlth Syst, Div Gen Surg, Singapore 119228, Singapore. [Hamann, Ute] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Foersti, Asta] Skanes Univ Sjukhus, Ctr Primary Hlth Care Res, Clin Res Ctr, S-20502 Malmo, Sweden. [Ruediger, Thomas] Stadt Klin Karlsruhe, Inst Pathol, D-76133 Karlsruhe, Germany. [Ulmer, Hans-Ulrich] Frauenklin Stadtklin Baden Baden, D-76532 Baden Baden, Germany. [Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna] Pomeranian Med Univ, Dept Genet & Pathol, PL-70115 Szczecin, Poland. [Jaworska, Katarzyna] Med Univ Warsaw, Postgrad Sch Mol Med, PL-02091 Warsaw, Poland. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok 10400, Thailand. [Gaborieau, Valerie; Brennan, Paul; Mckay, James] Int Agcy Res Canc, F-69372 Lyon, France. [Fostira, Florentia] NSCR Demokritos, INRASTES, Mol Diagnost Lab, Athens 15310, Greece. [Pilarski, Robert] Ohio State Univ, Dept Internal Med, James Comprehens Canc Ctr, Columbus, OH 43210 USA. [Shen, Chen-Yang; Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. [Shen, Chen-Yang; Wu, Pei-Ei] China Med Univ, Coll Publ Hlth, Taichung 40402, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Taiwan Biobank, Kaohsiung, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Ctr Canc, Kaohsiung, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Dept Surg, Kaohsiung, Taiwan. [Swerdlow, Anthony; Ashworth, Alan; Orr, Nick] Inst Canc Res, Div Breast Canc Res, Surrey SM2 5NG, England. RP Meyer, KB (reprint author), Univ Cambridge, CRUK Cambridge Inst, Li Ka Shing Ctr, Robinson Way, Cambridge CB2 0RE, England. RI Jakubowska, Anna/O-8050-2014; Yip, Cheng-Har/B-1909-2010; Hartikainen, Jaana/E-6256-2015; Garcia-Closas, Montserrat /F-3871-2015; French, Juliet/A-4982-2011; Radice, Paolo/O-3119-2013; Li, Jingmei/I-2904-2012; Andrulis, Irene/E-7267-2013; Ditsch, Nina/F-6267-2014; Teo, Soo-hwang/H-2353-2014; Hartman, Mikael/B-4324-2011; Noh, Dong-Young/G-5531-2011; Bernard, Loris/K-5953-2014; Knight, Julia/A-6843-2012; Pilarski, Robert/E-3871-2011; Shrubsole, Martha/K-5052-2015; Dork, Thilo/J-8620-2012; U-ID, Kyushu/C-5291-2016; laurent-puig, pierre/B-2226-2013; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Edwards, Stacey/A-4980-2011; Brenner, Hermann/B-4627-2017; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Li, Jingmei/0000-0001-8587-7511; Lux, Michael Patrick/0000-0002-2781-2178; Czene, Kamila/0000-0002-3233-5695; Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; Muranen, Taru/0000-0002-5895-1808; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; Thienpont, Bernard/0000-0002-8772-6845; Giles, Graham/0000-0003-4946-9099; Matsuo, Keitaro/0000-0003-1761-6314; Arndt, Volker/0000-0001-9320-8684; Shrubsole, Martha/0000-0002-5591-7575; laurent-puig, pierre/0000-0001-8475-5459; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; Devilee, Peter/0000-0002-8023-2009; Schoemaker, Minouk/0000-0001-8403-2234 FU Cancer Research UK [10124, 10118, 10119]; NCI NIH HHS [P30 CA015083, R01 CA077398, R01 CA092447]; Wellcome Trust [090532] NR 35 TC 39 Z9 39 U1 2 U2 40 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC 5 PY 2013 VL 93 IS 6 BP 1046 EP 1060 DI 10.1016/j.ajhg.2013.10.026 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 273FS UT WOS:000328521300005 PM 24290378 ER PT J AU Lin, SW Abnet, CC Freedman, ND Murphy, G Risques, R Prunkard, D Rabinovitch, P Pan, QJ Roth, MJ Wang, GQ Wei, WQ Lu, N Taylor, PR Qiao, YL Dawsey, SM AF Lin, Shih-Wen Abnet, Christian C. Freedman, Neal D. Murphy, Gwen Risques, Rosana Prunkard, Donna Rabinovitch, Peter Pan, Qin-Jing Roth, Mark J. Wang, Guo-Qing Wei, Wen-Qiang Lu, Ning Taylor, Philip R. Qiao, You-Lin Dawsey, Sanford M. TI Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma SO BMC CANCER LA English DT Article DE Esophageal squamous cell carcinoma; Esophageal squamous dysplasia; Early detection; Screening; Balloon cytology; Telomeres ID GENERAL-POPULATION TRIAL; COLORECTAL-CANCER; ASYMPTOMATIC ADULTS; CYTOLOGIC DETECTION; BARRETTS-ESOPHAGUS; CHINA; LINXIAN; RISK; INSTABILITY; DYSPLASIA AB Background: Esophageal cancer is the sixth leading cause of cancer death worldwide; current early detection screening tests are inadequate. Esophageal balloon cytology successfully retrieves exfoliated and scraped superficial esophageal epithelial cells, but cytologic reading of these cells has poor sensitivity and specificity for detecting esophageal squamous dysplasia (ESD), the precursor lesion of esophageal squamous cell carcinoma (ESCC). Measuring telomere length, a marker for chromosomal instability, may improve the utility of balloon cytology for detecting ESD and early ESCC. Methods: We examined balloon cytology specimens from 89 asymptomatic cases of ESD (37 low-grade and 52 high-grade) and 92 age-and sex-matched normal controls from an esophageal cancer early detection screening study. All subjects also underwent endoscopy and biopsy, and ESD was diagnosed histopathologically. DNA was extracted from the balloon cytology cells, and telomere length was measured by quantitative PCR. A receiver operating characteristic (ROC) curve was plotted for telomere length as a diagnostic marker for high-grade dysplasia. Results: Telomere lengths were comparable among the low-and high-grade dysplasia cases and controls, with means of 0.96, 0.96, and 0.92, respectively. The area under the ROC curve was 0.55 for telomere length as a diagnostic marker for high-grade dysplasia. Further adjustment for subject characteristics, including sex, age, smoking, drinking, hypertension, and body mass index did not improve the use of telomere length as a marker for ESD. Conclusions: Telomere length of esophageal balloon cytology cells was not associated with ESCC precursor lesions. Therefore, telomere length shows little promise as an early detection marker for ESCC in esophageal balloon samples. C1 [Lin, Shih-Wen; Abnet, Christian C.; Freedman, Neal D.; Murphy, Gwen; Taylor, Philip R.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Risques, Rosana; Prunkard, Donna; Rabinovitch, Peter] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Pan, Qin-Jing; Wang, Guo-Qing; Wei, Wen-Qiang; Lu, Ning; Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. [Roth, Mark J.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Lin, SW (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM lins4@mail.nih.gov; qiaoy@public.bta.net.cn RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015; Murphy, Gwen/G-7443-2015; Freedman, Neal/B-9741-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU National Cancer Institute [N01-SC-91019]; Cancer Institute of the Chinese Academy of Medical Sciences; Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH FX This study was supported by National Cancer Institute contract N01-SC-91019 with the Cancer Institute of the Chinese Academy of Medical Sciences and by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH. NR 40 TC 6 Z9 6 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD DEC 5 PY 2013 VL 13 AR 578 DI 10.1186/1471-2407-13-578 PG 8 WC Oncology SC Oncology GA 280MN UT WOS:000329034600002 PM 24308314 ER PT J AU Trost, B Kindrachuk, J Scruten, E Griebel, P Kusalik, A Napper, S AF Trost, Brett Kindrachuk, Jason Scruten, Erin Griebel, Philip Kusalik, Anthony Napper, Scott TI Kinotypes: stable species- and individual-specific profiles of cellular kinase activity SO BMC GENOMICS LA English DT Article ID PERSONALIZED MEDICINE; PROTEIN-KINASES; CANCER; BIOMARKERS; KINOME; PHOSPHOPROTEOME; RESPONSES; TARGETS; ANTIGEN; MODELS AB Background: Recently, questions have been raised regarding the ability of animal models to recapitulate human disease at the molecular level. It has also been demonstrated that cellular kinases, individually or as a collective unit (the kinome), play critical roles in regulating complex biology. Despite the intimate relationship between kinases and health, little is known about the variability, consistency and stability of kinome profiles across species and individuals. Results: As a preliminary investigation of the existence of species-and individual-specific kinotypes (kinome signatures), peptide arrays were employed for the analysis of peripheral blood mononuclear cells collected weekly from human and porcine subjects (n = 6) over a one month period. The data revealed strong evidence for species-specific signalling profiles. Both humans and pigs also exhibited evidence for individual-specific kinome profiles that were independent of natural changes in blood cell populations. Conclusions: Species-specific kinotypes could have applications in disease research by facilitating the selection of appropriate animal models or by revealing a baseline kinomic signature to which treatment-induced profiles could be compared. Similarly, individual-specific kinotypes could have implications in personalized medicine, where the identification of molecular patterns or signatures within the kinome may depend on both the levels of kinome diversity and temporal stability across individuals. C1 [Trost, Brett; Kusalik, Anthony] Univ Saskatchewan, Dept Comp Sci, Saskatoon, SK S7N 0W0, Canada. [Kindrachuk, Jason] NIAID, NIH, Emerging Viral Pathogens Sect, Frederick, MD USA. [Scruten, Erin; Griebel, Philip; Napper, Scott] Univ Saskatchewan, Vaccine & Infect Dis Org, Saskatoon, SK, Canada. [Griebel, Philip] Univ Saskatchewan, Sch Publ Hlth, Saskatoon, SK, Canada. [Napper, Scott] Univ Saskatchewan, Dept Biochem, Saskatoon, SK S7N 0W0, Canada. RP Napper, S (reprint author), Univ Saskatchewan, Vaccine & Infect Dis Org, Saskatoon, SK, Canada. EM scott.napper@usask.ca RI Trost, Brett/K-4127-2016; OI Trost, Brett/0000-0003-4863-7273; Kindrachuk, Jason/0000-0002-3305-7084 FU Genome Canada; Natural Sciences and Engineering Research Council of Canada (NSERC); Intramural Research Program of the NIH/NIAID FX This work was supported in part by Genome Canada, the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Intramural Research Program of the NIH/NIAID. NR 35 TC 5 Z9 5 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 5 PY 2013 VL 14 AR 854 DI 10.1186/1471-2164-14-854 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 275AP UT WOS:000328647700001 PM 24314169 ER PT J AU Grinholc, M Nakonieczna, J Negri, A Rapacka-Zdonczyk, A Motyka, A Fila, G Kurlenda, J Leibner-Ciszak, J Otto, M Bielawski, KP AF Grinholc, Mariusz Nakonieczna, Joanna Negri, Alessandro Rapacka-Zdonczyk, Aleksandra Motyka, Agata Fila, Grzegorz Kurlenda, Julianna Leibner-Ciszak, Justyna Otto, Michael Bielawski, Krzysztof P. TI The agr function and polymorphism: Impact on Staphylococcus aureus susceptibility to photoinactivation SO JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY LA English DT Article DE Accessory gene regulator; Gene polymorphism; Photoinactivation; Staphylococcus aureus ID METHICILLIN-RESISTANT; PHOTODYNAMIC INACTIVATION; GROWTH-PHASE; VIRULENCE; THERAPY; EXPRESSION; BACTERIA; ALLELES; LOCUS; TIME AB Staphylococcus aureus is an important human pathogen that causes healthcare-associated and community-acquired infections. Moreover, the growing prevalence of multiresistant strains requires the development of alternative methods to antibiotic therapy. One effective therapeutic option may be antimicrobial photodynamic inactivation (aPDI). Recently, S. aureus strain-dependent response to PDI was demonstrated, although the mechanism underlying this phenomenon remains unexplained. The aim of the current study was to investigate statistically relevant correlations between the functionality and polymorphisms of agr gene determined for 750 methicillin-susceptible and methicillin-resistant S. aureus strains and their responses to photodynamic inactivation using protoporphyrin IX. An AluI and RsaI digestion of the agr gene PCR product revealed existing correlations between the determined digestion profiles (designations used for the first time) and the PDI response. Moreover, the functionality of the agr system affected S. aureus susceptibility to PDI. Based on our results, we conclude that the agr gene may be a genetic factor affecting the strain dependent response to PDI. (C) 2013 Elsevier B.V. All rights reserved. C1 [Grinholc, Mariusz; Nakonieczna, Joanna; Negri, Alessandro; Rapacka-Zdonczyk, Aleksandra; Motyka, Agata; Fila, Grzegorz; Bielawski, Krzysztof P.] Univ Gdansk, Intercoll Fac Biotechnol, Dept Biotechnol, Lab Mol Diagnost, PL-80822 Gdansk, Poland. [Grinholc, Mariusz; Nakonieczna, Joanna; Negri, Alessandro; Rapacka-Zdonczyk, Aleksandra; Motyka, Agata; Fila, Grzegorz; Bielawski, Krzysztof P.] Med Univ Gdansk, PL-80822 Gdansk, Poland. [Kurlenda, Julianna] State Higher Vocat Sch Koszalin, PL-75582 Koszalin, Poland. [Leibner-Ciszak, Justyna] BLIRT SA BioLab Innovat Res Technol, PL-80172 Gdansk, Poland. [Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. RP Grinholc, M (reprint author), Univ Gdansk, Intercoll Fac Biotechnol, Dept Biotechnol, Lab Mol Diagnost, Kladki 24, PL-80822 Gdansk, Poland. EM grinholc@biotech.ug.edu.pl RI Motyka, Agata/D-2450-2017; Grinholc, Mariusz/F-5962-2011; Bielawski, Krzysztof/D-8711-2011 OI Motyka, Agata/0000-0001-7717-8251; Otto, Michael/0000-0002-2222-4115; FU NIAID/NIH [HHSN27220 0700055C]; National Science Centre (NCN) [1651/B/P01/2010/39]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) FX Isogenic pairs of agr mutants were obtained through the Network of Antimicrobial Resistance in Staphylococcus aureus (NARSA) program supported under NIAID/NIH Contract#HHSN27220 0700055C. MALDI-TOF MS analysis were performed at LM Bruss Laboratory in Poland. This work was supported by the Grant No. 1651/B/P01/2010/39 from the National Science Centre (NCN). M.O. was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH). NR 36 TC 1 Z9 1 U1 0 U2 6 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1011-1344 J9 J PHOTOCH PHOTOBIO B JI J. Photochem. Photobiol. B-Biol. PD DEC 5 PY 2013 VL 129 BP 100 EP 107 DI 10.1016/j.jphotobiol.2013.10.006 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 275WS UT WOS:000328710500012 PM 24211295 ER PT J AU Barupal, DK Lee, SJ Karoly, ED Adhya, S AF Barupal, Dinesh Kumar Lee, Sang Jun Karoly, Edward D. Adhya, Sankar TI Inactivation of Metabolic Genes Causes Short- and Long-Range dys-Regulation in Escherichia coli Metabolic Network SO PLOS ONE LA English DT Article ID TRANSCRIPTIONAL REGULATION; EVOLUTION; GLUCOSE; STRESS; FLUX; EXPRESSION; MODULARITY; CONVERSION; PATHWAYS; BACTERIA AB The metabolic network in E. coli can be severely affected by the inactivation of metabolic genes that are required to catabolize a nutrient (D-galactose). We hypothesized that the resulting accumulation of small molecules can yield local as well as systemic effects on the metabolic network. Analysis of metabolomics data in wild-type and D-galactose non-utilizing mutants, galT, galU and galE, reveal the large metabolic differences between the wild-type and the mutants when the strains were grown in D-galactose. Network mapping suggested that the enzymatic defects affected the metabolic modules located both at short-and long-ranges from the D-galactose metabolic module. These modules suggested alterations in glutathione, energy, nucleotide and lipid metabolism and disturbed carbon to nitrogen ratio in mutant strains. The altered modules are required for normal cell growth for the wild-type strain, explaining why the cell growth is inhibited in the mutants in the presence of D-galactose. Identification of these distance-based dys-regulations would enhance the systems level understanding of metabolic networks of microorganisms having importance in biomedical and biotechnological research. C1 [Barupal, Dinesh Kumar] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. [Lee, Sang Jun] KRIBB, Infect & Immun Res Ctr, Taejon, South Korea. [Lee, Sang Jun] Univ Sci & Technol, Taejon, South Korea. [Lee, Sang Jun; Adhya, Sankar] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Karoly, Edward D.] Metabolon Inc, Durham, NC USA. RP Adhya, S (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM sadhya@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 2 Z9 2 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 DEC 5 PY 2013 VL 8 IS 12 AR e78360 DI 10.1371/journal.pone.0078360 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273WD UT WOS:000328566100003 PM 24363806 ER PT J AU Chufan, EE Kapoor, K Sim, HM Singh, S Talele, TT Durell, SR Ambudkar, SV AF Chufan, Eduardo E. Kapoor, Khyati Sim, Hong-May Singh, Satyakam Talele, Tanaji T. Durell, Stewart R. Ambudkar, Suresh V. TI Multiple Transport-Active Binding Sites Are Available for a Single Substrate on Human P-Glycoprotein (ABCB1) SO PLOS ONE LA English DT Article ID DRUG-BINDING; MULTIDRUG-RESISTANCE; CATALYTIC CYCLE; ATP HYDROLYSIS; FUNCTIONAL-CHARACTERIZATION; EXPRESSION SYSTEM; MAMMALIAN-CELLS; MOLECULAR-BASIS; RESIDUES; REVEALS AB P-glycoprotein (Pgp, ABCB1) is an ATP-Binding Cassette (ABC) transporter that is associated with the development of multidrug resistance in cancer cells. Pgp transports a variety of chemically dissimilar amphipathic compounds using the energy from ATP hydrolysis. In the present study, to elucidate the binding sites on Pgp for substrates and modulators, we employed site-directed mutagenesis, cell-and membrane-based assays, molecular modeling and docking. We generated single, double and triple mutants with substitutions of the Y307, F343, Q725, F728, F978 and V982 residues at the proposed drug-binding site with cys in a cysless Pgp, and expressed them in insect and mammalian cells using a baculovirus expression system. All the mutant proteins were expressed at the cell surface to the same extent as the cysless wild-type Pgp. With substitution of three residues of the pocket (Y307, Q725 and V982) with cysteine in a cysless Pgp, QZ59S-SSS, cyclosporine A, tariquidar, valinomycin and FSBA lose the ability to inhibit the labeling of Pgp with a transport substrate, [I-125]-Iodoarylazidoprazosin, indicating these drugs cannot bind at their primary binding sites. However, the drugs can modulate the ATP hydrolysis of the mutant Pgps, demonstrating that they bind at secondary sites. In addition, the transport of six fluorescent substrates in HeLa cells expressing triple mutant (Y307C/Q725C/V982C) Pgp is also not significantly altered, showing that substrates bound at secondary sites are still transported. The homology modeling of human Pgp and substrate and modulator docking studies support the biochemical and transport data. In aggregate, our results demonstrate that a large flexible pocket in the Pgp transmembrane domains is able to bind chemically diverse compounds. When residues of the primary drug-binding site are mutated, substrates and modulators bind to secondary sites on the transporter and more than one transport-active binding site is available for each substrate. C1 [Chufan, Eduardo E.; Kapoor, Khyati; Sim, Hong-May; Durell, Stewart R.; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Singh, Satyakam; Talele, Tanaji T.] St Johns Univ, Dept Pharmaceut Sci, Coll Pharm & Hlth Sci, Queens, NY USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 21 Z9 21 U1 1 U2 21 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 DEC 5 PY 2013 VL 8 IS 12 AR e82463 DI 10.1371/journal.pone.0082463 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273WD UT WOS:000328566100113 PM 24349290 ER PT J AU Baz, M Luke, CJ Cheng, X Jin, H Subbarao, K AF Baz, Mariana Luke, Catherine J. Cheng, Xing Jin, Hong Subbarao, Kanta TI H5N1 vaccines in humans SO VIRUS RESEARCH LA English DT Article DE H5N1; Vaccine strategies; Pandemic; Adjuvants; Clinical trials ID INFLUENZA-A H5N1; VIRUS-LIKE PARTICLES; PROTECTIVE IMMUNE-RESPONSES; INACTIVATED WHOLE VIRUS; CROSS-REACTIVE IMMUNITY; MEMORY B-CELLS; TO-PERSON TRANSMISSION; CHILDREN AGED 3; AVIAN-INFLUENZA; PANDEMIC INFLUENZA AB The spread of highly pathogenic avian H5N1 influenza viruses since 1997 and their virulence for poultry and humans has raised concerns about their potential to cause an influenza pandemic. Vaccines offer the most viable means to combat a pandemic threat. However, it will be a challenge to produce, distribute and implement a new vaccine if a pandemic spreads rapidly. Therefore, efforts are being undertaken to develop pandemic vaccines that use less antigen and induce cross-protective and long-lasting responses, that can be administered as soon as a pandemic is declared or possibly even before, in order to prime the population and allow for a rapid and protective antibody response. In the last few years, several vaccine manufacturers have developed candidate pandemic and pre-pandemic vaccines, based on reverse genetics and have improved the immunogenicity by formulating these vaccines with different adjuvants. Some of the important and consistent observations from clinical studies with H5N1 vaccines are as follows: two doses of inactivated vaccine are generally necessary to elicit the level of immunity required to meet licensure criteria, less antigen can be used if an oil-in-water adjuvant is included, in general antibody titers decline rapidly but can be boosted with additional doses of vaccine and if high titers of antibody are elicited, cross-reactivity against other clades is observed. Prime-boost strategies elicit a more robust immune response. In this review, we discuss data from clinical trials with a variety of H5N1 influenza vaccines. We also describe studies conducted in animal models to explore the possibility of reassortment between pandemic live attenuated vaccine candidates and seasonal influenza viruses, since this is an important consideration for the use of live vaccines in a pandemic setting. Published by Elsevier B.V. C1 [Baz, Mariana; Luke, Catherine J.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Cheng, Xing; Jin, Hong] MedImmune, Mountain View, CA USA. RP Subbarao, K (reprint author), NIAID, Emerging Resp Viruses Sect, Infect Dis Lab, NIH, Bldg 33,Room 3E13C-1,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU Intramural Research Program of the NIAID, NIH FX We thank Jadon Jackson and the staff of the Comparative Medicine Branch, NIAID, for excellent technical support and animal care. All animal experiments were done at the NIH Bethesda, MD, in compliance with the guidelines of the NIAID/NIH Institutional Animal Care and Use Committee. Histopathological analysis was conducted by Lily Cheng and Fernando Torres-Velez from the Comparative Medicine Branch, NIAID. We thank Leatrice Vogel, Weijia Wang and Winnie Chan for excellent technical assistance. We thank George Kemble for helpful discussions on the reassortant studies. This research was supported by the Intramural Research Program of the NIAID, NIH, and was performed as part of a Cooperative Research and Development Agreement (CRADA No. AI-0155) between the Laboratory of Infectious Diseases, NIAID and MedImmune. NR 195 TC 33 Z9 35 U1 0 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD DEC 5 PY 2013 VL 178 IS 1 BP 78 EP 98 DI 10.1016/j.virusres.2013.05.006 PG 21 WC Virology SC Virology GA 273GA UT WOS:000328522100010 PM 23726847 ER PT J AU Kost, RG Lee, LM Yessis, J Wesley, RA Henderson, DK Coller, BS AF Kost, Rhonda G. Lee, Laura M. Yessis, Jennifer Wesley, Robert A. Henderson, David K. Coller, Barry S. TI Assessing Participant-Centered Outcomes to Improve Clinical Research SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PERCEPTION C1 [Kost, Rhonda G.; Coller, Barry S.] Rockefeller Univ, New York, NY 10021 USA. [Lee, Laura M.; Wesley, Robert A.; Henderson, David K.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Yessis, Jennifer] Univ Waterloo, Propel Ctr Populat Hlth Impact, Waterloo, ON N2L 3G1, Canada. RP Kost, RG (reprint author), Rockefeller Univ, 1230 York Ave, New York, NY 10021 USA. FU NCATS NIH HHS [UL1 TR000043]; NCRR NIH HHS [UL1 RR024143] NR 5 TC 12 Z9 12 U1 1 U2 4 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 DEC 5 PY 2013 VL 369 IS 23 BP 2179 EP 2181 DI 10.1056/NEJMp1311461 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 263II UT WOS:000327801100004 PM 24304050 ER PT J AU Parsa, A Kao, WHL Xie, DW Astor, BC Li, M Hsu, CY Feldman, HI Parekh, RS Kusek, JW Greene, TH Fink, JC Anderson, AH Choi, MJ Wright, JT Lash, JP Freedman, BI Ojo, A Winkler, CA Raj, DS Kopp, JB He, J Jensvold, NG Tao, KX Lipkowitz, MS Appel, LJ AF Parsa, Afshin Kao, W. H. Linda Xie, Dawei Astor, Brad C. Li, Man Hsu, Chi-yuan Feldman, Harold I. Parekh, Rulan S. Kusek, John W. Greene, Tom H. Fink, Jeffrey C. Anderson, Amanda H. Choi, Michael J. Wright, Jackson T., Jr. Lash, James P. Freedman, Barry I. Ojo, Akinlolu Winkler, Cheryl A. Raj, Dominic S. Kopp, Jeffrey B. He, Jiang Jensvold, Nancy G. Tao, Kaixiang Lipkowitz, Michael S. Appel, Lawrence J. CA AASK Study Investigators CRIC Study Investigators TI APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID STAGE RENAL-DISEASE; BASE-LINE CHARACTERISTICS; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; AFRICAN-AMERICANS; RACIAL-DIFFERENCES; INSUFFICIENCY COHORT; FUNCTION DECLINE; GENE; MYH9; CKD AB BackgroundAmong patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. MethodsIn two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. ResultsIn the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white pat