FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Dookeran, KA Dignam, JJ Ferrer, K Sekosan, M Radeke, EK Lad, TE Holloway, N McCaskill-Stevens, WJ Gehlert, SJ AF Dookeran, K. A. Dignam, J. J. Ferrer, K. Sekosan, M. Radeke, E. K. Lad, T. E. Holloway, N. McCaskill-Stevens, W. J. Gehlert, S. J. TI Race and the influence of p53 as a marker of prognosis in women of lower SES with breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Canc Fdn Minor & Underserved Populat, Chicago, IL USA. Univ Chicago, Chicago, IL 60637 USA. Stroger Hosp Cook County, Minor Based Community Clin Program, Chicago, IL USA. NCI, Bethesda, MD USA. Washington Univ, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 10590 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005696 ER PT J AU Dueck, AC Mendoza, TR Reeve, BB Sloan, JA Cleeland, CS Hay, J Li, Y O'Mara, AM Denicoff, A Basch, EM AF Dueck, A. C. Mendoza, T. R. Reeve, B. B. Sloan, J. A. Cleeland, C. S. Hay, J. Li, Y. O'Mara, A. M. Denicoff, A. Basch, E. M. TI Validation study of the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mayo Clin Arizona, Scottsdale, AZ USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. Mayo Clin Rochester, Rochester, MN USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA TPS274 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002274 ER PT J AU Duffy, AG Melillo, G Turkbey, B Allen, D Choyke, PL Chen, C Raffeld, M Doroshow, JH Murgo, A Kummar, S AF Duffy, A. G. Melillo, G. Turkbey, B. Allen, D. Choyke, P. L. Chen, C. Raffeld, M. Doroshow, J. H. Murgo, A. Kummar, S. TI A pilot trial of oral topotecan (TPT) in patients with refractory advanced solid neoplasms expressing HIF-l alpha. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e13518 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852000391 ER PT J AU Egorin, MJ Kummar, S Sarantopoulos, J Shibata, S LoRusso, P Yerk, M Lin, Y Ivy, SP Belani, CP Ramalingam, SS AF Egorin, M. J. Kummar, S. Sarantopoulos, J. Shibata, S. LoRusso, P. Yerk, M. Lin, Y. Ivy, S. P. Belani, C. P. Ramalingam, S. S. TI Phase I study of vorinostat for patients with advanced solid tumors and hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI #8057) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. NCI, Bethesda, MD 20892 USA. Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. City Hope Natl Med Ctr, Duarte, CA USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. NCI, Rockville, MD USA. Penn State Hershey Canc Inst, Hershey, PA USA. Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2545 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003136 ER PT J AU Fisch, M Lee, J Chang, VT Wagner, LI Cella, D Minasian, LM McCaskill-Stevens, WJ Weiss, M Smith, M Cleeland, CS AF Fisch, M. Lee, J. Chang, V. T. Wagner, L. I. Cella, D. Minasian, L. M. McCaskill-Stevens, W. J. Weiss, M. Smith, M. Cleeland, C. S. TI A prospective evaluation of symptom change over 4 weeks for outpatients with common solid tumors: Results from E2Z02 (the SOAPP study) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. VA New Jersey Hlth Care Syst, E Orange, NJ USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Northwestern Univ, Chicago, IL 60611 USA. NCI, Bethesda, MD 20892 USA. Minocqua Ctr, Marshfield Clin, Minocqua, WI USA. Res Advocacy Network, Naperville, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 9120 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005385 ER PT J AU Flaherty, KT Lee, SJ Schuchter, LM Flaherty, LE Wright, JJ Leming, PD Kirkwood, JM AF Flaherty, K. T. Lee, S. J. Schuchter, L. M. Flaherty, L. E. Wright, J. J. Leming, P. D. Kirkwood, J. M. TI Final results of E2603: A double-blind, randomized phase III trial comparing carboplatin (C)/paclitaxel (P) with or without sorafenib (S) in metastatic melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Penn, Philadelphia, PA 19104 USA. Wayne State Univ, Detroit, MI USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Cincinnati Hematol Oncol Inc, Cincinnati, OH USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. NR 0 TC 5 Z9 5 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 8511 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005182 ER PT J AU Fojo, AT Stein, WD Wilkerson, J Bates, SE AF Fojo, A. T. Stein, W. D. Wilkerson, J. Bates, S. E. TI Kinetic analysis of breast cancer tumor decay and growth following ixabepilone plus capecitabine (IXA plus CAP) versus capecitabine alone (CAP) to discern whether the superiorty of the combination is a result of slower growth, enhanced tumor cell kill, or both SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Fojo, A. T.; Stein, W. D.; Wilkerson, J.; Bates, S. E.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 1096 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002611 ER PT J AU Force, J Rajan, A Dombi, E Steinberg, SA Giaccone, A AF Force, J. Rajan, A. Dombi, E. Steinberg, S. A. Giaccone, A. TI Volumetric analysis of advanced thymic malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 7096 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852004639 ER PT J AU Franklin, WA Berg, CD Tze, S Groshong, S Achcar, RD Duan, F Adams, A Marquez, G Seligson, DB Aberle, DR AF Franklin, W. A. Berg, C. D. Tze, S. Groshong, S. Achcar, R. D. Duan, F. Adams, A. Marquez, G. Seligson, D. B. Aberle, D. R. CA Westat ACRIN TI Tissue sampling and digital histologic imaging for the National Lung Screening Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Colorado, Denver, CO 80202 USA. NCI, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Natl Jewish Hlth, Denver, CO USA. Brown Univ, Providence, RI 02912 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e12032 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852000160 ER PT J AU Giaccone, G Rajan, A Kelly, RJ Gutierrez, M Kummar, S Yancey, M Ji, JJ Zhang, Y Parchment, RE Doroshow, JH AF Giaccone, G. Rajan, A. Kelly, R. J. Gutierrez, M. Kummar, S. Yancey, M. Ji, J. J. Zhang, Y. Parchment, R. E. Doroshow, J. H. TI A phase I combination study of olaparib (AZD2281; KU-0059436) and cisplatin (C) plus gemcitabine (G) in adults with solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. SAIC Frederick, Bethesda, MD USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 3027 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003232 ER PT J AU Gogas, H Wang, E Monaco, A Uccellini, L Floudas, CS Metaxas, Y Dafni, U Fountzilas, G Spyropoulou-Vlachou, M Marincola, F AF Gogas, H. Wang, E. Monaco, A. Uccellini, L. Floudas, C. S. Metaxas, Y. Dafni, U. Fountzilas, G. Spyropoulou-Vlachou, M. Marincola, F. TI Evaluation of FOXP3 microsatellite polymorphisms in high-risk melanoma patients receiving adjuvant interferon SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Hellen Cooperat Oncol Grp Data Off, Athens, Greece. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 8538 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005208 ER PT J AU Grignol, VP Olencki, T Taylor, C Kibler, A Kefauver, C Wei, L Walker, MJ Chen, HX Kendra, KL Carson, WE AF Grignol, V. P. Olencki, T. Taylor, C. Kibler, A. Kefauver, C. Wei, L. Walker, M. J. Chen, H. X. Kendra, K. L. Carson, W. E., III TI Phase II trial of bevacizumab and high-dose interferon alpha-2b in metastatic melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Ohio State Univ, Columbus, OH 43210 USA. CTEP Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 8520 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005190 ER PT J AU Gulley, JL Stein, WD Schlom, J Madan, RA Dahut, WL Figg, WD Ming, YM Price, D Bates, SE Fojo, AT AF Gulley, J. L. Stein, W. D. Schlom, J. Madan, R. A. Dahut, W. L. Figg, W. D. Ming, Y. M. Price, D. Bates, S. E. Fojo, A. T. TI A retrospective analysis of intramural NCI prostate cancer trials:Progress made and insights gleaned. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, Bethesda, MD 20892 USA. NCI, US FDA, Silver Spring, MD USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 4657 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852004026 ER PT J AU Haas, NB McWhirter, E Hogg, D Martin, LP Polintan, R Litwin, S Wang, L Alpaugh, RK Zwiebel, JA Oza, AM AF Haas, N. B. McWhirter, E. Hogg, D. Martin, L. P. Polintan, R. Litwin, S. Wang, L. Alpaugh, R. K. Zwiebel, J. A. Oza, A. M. TI Phase II study of vorinostal in patients with advanced melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Juravinski Canc Ctr, Hamilton, ON, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 8530 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005200 ER PT J AU Haluska, P Reinholz, MM Dueck, AC Linden, HM Lingle, WL Bernath, AM Arbushites, MC Youssoufian, H Chen, HX Perez, EA AF Haluska, P. Reinholz, M. M. Dueck, A. C. Linden, H. M. Lingle, W. L. Bernath, A. M. Arbushites, M. C. Youssoufian, H. Chen, H. X. Perez, E. A. TI N0733: Phase II trial of capecitabine and lapatinib plus or minus cixutumumab in HER2-positive breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mayo Clin, Rochester, MN USA. Mayo Clin Arizona, Scottsdale, AZ USA. Univ Washington, Seattle, WA 98195 USA. Geisinger Hlth Syst, Danville, PA USA. GlaxoSmithKline, Collegeville, PA USA. ImClone Syst, Branchburg, NJ USA. NCI, Canc Therapy Evaluat Program, Rockville, MD USA. Mayo Clin Florida, Jacksonville, FL 32224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA TPS129 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002132 ER PT J AU Hassan, R Sharon, E Chen, HX Conlon, K Ling, A Steinberg, SM Pastan, I AF Hassan, R. Sharon, E. Chen, H. X. Conlon, K. Ling, A. Steinberg, S. M. Pastan, I. TI Phase I clinical trial of antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of advanced pleural mesothelioma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NCI, CTEP, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e17518 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852001331 ER PT J AU Hay, J Atkinson, TM Mendoza, TR Reeve, BB Willis, G Gagne, JJ Abernethy, AP Cleeland, CS Schrag, D Basch, EM AF Hay, J. Atkinson, T. M. Mendoza, T. R. Reeve, B. B. Willis, G. Gagne, J. J. Abernethy, A. P. Cleeland, C. S. Schrag, D. Basch, E. M. TI Refinement of the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) via cognitive interviewing. SO JOURNAL OF CLINICAL ONCOLOGY 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. NCI, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. Duke Univ, Med Ctr, Durham, NC USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 9060 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005326 ER PT J AU Jacobs, SA Allegra, CJ Wagman, LD Geller, DA O'Connell, MJ Buyse, ME Wolmark, N AF Jacobs, S. A. Allegra, C. J. Wagman, L. D. Geller, D. A. O'Connell, M. J. Buyse, M. E. Wolmark, N. TI Phase II study to determine surgical conversion rate in patients receiving neoadjuvant mFOLFOX7 plus cetuximab for unresectable wild-type KRAS colorectal cancer with metastases confined to liver SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Univ Florida, Gainesville, FL USA. St Josephs Hosp Orange, Ctr Canc Prevent & Treatment, Orange, CA USA. Univ Pittsburgh, Liver Canc Ctr, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. IDDI, Louvain, Belgium. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA TPS190 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002192 ER PT J AU Janeway, KA Kim, S Lodish, M Nose, V Dahia, P Rustin, P Demetri, GD Fletcher, JA Helman, LJ Stratakis, CA AF Janeway, K. A. Kim, S. Lodish, M. Nose, V. Dahia, P. Rustin, P. Demetri, G. D. Fletcher, J. A. Helman, L. J. Stratakis, C. A. CA Consortium Pediat Wildtype GIST TI Succinate dehydrogenase in KIT/PDGFRA wild-type gastrointestinal stromal tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. Univ Miami, Sch Med, Miami, FL USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Hop Robert Debre, F-75019 Paris, France. Harvard Canc Ctr, Ludwig Ctr, Dana Farber Canc Inst, Boston, MA USA. Sarcoma Ctr, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 10008 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005517 ER PT J AU Ji, JJ Kummar, S Chen, AP Zhang, Y Putvtana, R Kinders, RJ Rubinstein, L Parchment, RE Tomaszewski, JE Doroshow, JH AF Ji, J. J. Kummar, S. Chen, A. P. Zhang, Y. Putvtana, R. Kinders, R. J. Rubinstein, L. Parchment, R. E. Tomaszewski, J. E. Doroshow, J. H. TI Pharmacodynamic response in phase I combination study of ABT-888 and topotecan in adults with refractory solid tumors and lymphomas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 SAIC Frederick, Bethesda, MD USA. NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. SAIC Frederick, Frederick, MD USA. Div Canc Treatment & Diag, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2514 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003106 ER PT J AU Johann, DJ Mukherjee, S Rodriguez-Canales, J Hanson, J Veenstra, TA Emmert-Buck, M Blonder, J AF Johann, D. J. Mukherjee, S. Rodriguez-Canales, J. Hanson, J. Veenstra, T. A. Emmert-Buck, M. Blonder, J. TI Molecular profiling of breast cancer via targeted tissue proteomics SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e21026 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002018 ER PT J AU Kelly, RJ Force, J Rajan, A Keen, C Turkbey, B Cao, L Raffeld, M Steinberg, SM Wright, JJ Giaccone, G AF Kelly, R. J. Force, J. Rajan, A. Keen, C. Turkbey, B. Cao, L. Raffeld, M. Steinberg, S. M. Wright, J. J. Giaccone, G. TI Evaluation of Kras mutations and angiogenic biomarkers in patients with advanced non-small cell lung cancer (NSCLC) receiving single-agent sorafenib (S). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 7626 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005006 ER PT J AU Kim, D Kim-Schulze, S Deraffele, G Schlom, J Kaufman, H AF Kim, D. Kim-Schulze, S. Deraffele, G. Schlom, J. Kaufman, H. TI Evaluation of poxviruses targeting the tumor microenvironment for cancer therapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Rush Univ, Med Ctr, Chicago, IL 60612 USA. Mt Sinai Med Ctr, New York, NY 10029 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2600 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003191 ER PT J AU Kim, G Squires, J Yu, M Walker, A Houston, ND Otten, L Kohn, EC AF Kim, G. Squires, J. Yu, M. Walker, A. Houston, N. D. Otten, L. Kohn, E. C. TI Phase II study of clinical activity of pegaspargase in women with relapsed or refractory epithelial ovarian, fallopian tube, and/or primary peritoneal cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA TPS258 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002258 ER PT J AU Kim, G Annunziata, CM Sarosy, GA Minasian, LM Prindiville, SA Zujewski, J Otten, L Squires, J Houston, ND Kohn, EC AF Kim, G. Annunziata, C. M. Sarosy, G. A. Minasian, L. M. Prindiville, S. A. Zujewski, J. Otten, L. Squires, J. Houston, N. D. Kohn, E. C. TI Phase I study of dasatinib in combination with bevacizumab in advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA TPS163 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002165 ER PT J AU Kim, GP Marsoni, S Monges, G Allegra, CJ Thibodeau, SN Hamilton, SR Kabat, B Yothers, GA Gallinger, S Sargent, DJ AF Kim, G. P. Marsoni, S. Monges, G. Allegra, C. J. Thibodeau, S. N. Hamilton, S. R. Kabat, B. Yothers, G. A. Gallinger, S. Sargent, D. J. TI Analysis of time-dependent patterns of treatment effect and failure to explain the predictive role of deficient mismatch repair (dMMR) in stage II and III colon cancer (CC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. SENDO Fdn, Milan, Italy. Inst J Paoli I Calmettes, F-13009 Marseille, France. Univ Florida, Gainesville, FL USA. Mayo Clin Rochester, Rochester, MN USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Toronto Gen Hosp, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 3518 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003330 ER PT J AU Kim, HK Choi, IJ Kim, CG Green, JE AF Kim, H. K. Choi, I. J. Kim, C. G. Green, J. E. TI Gene set comparison analyses of gene expression signatures for the acquired chemotherapy resistance. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Canc Ctr Korea, Goyang, South Korea. NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 10609 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005715 ER PT J AU Kluetz, PG English, BC Baum, CE Sissung, TA Adelberg, D Dahut, WL Price, DK Figg, WD AF Kluetz, P. G. English, B. C. Baum, C. E. Sissung, T. A. Adelberg, D. Dahut, W. L. Price, D. K. Figg, W. D. TI Evaluation of variants of the rs1934951 locus of CYP2C8 and bisphosphonate-related osteonecrosis of the jaw in castrate-resistant prostate cancer (CRPC) patients. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 9076 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005342 ER PT J AU Kreitman, RJ Tallman, MS Coutre, SE Robak, T Wilson, WH Stetler-Stevenson, M Noei, P FitzGeraid, DJ McDevitt, JT Pastan, I AF Kreitman, R. J. Tallman, M. S. Coutre, S. E. Robak, T. Wilson, W. H. Stetler-Stevenson, M. Noei, P. FitzGeraid, D. J. McDevitt, J. T. Pastan, I. TI Phase I trial of recombinant immunotoxin CAT-8015 (HA22) in multiply relapsed hairy cell leukemia. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. Med Univ Lodz, Lodz, Poland. NCI, Metab Branch, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. MedImmune LLC, Gaithersburg, MD USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 6523 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852004460 ER PT J AU Krishnamurthi, SS Rath, L Bokar, JA Dowlati, A Savvides, P Gibbons, J Cooney, MM Meropol, NJ Ivy, SP Brell, JM AF Krishnamurthi, S. S. Rath, L. Bokar, J. A. Dowlati, A. Savvides, P. Gibbons, J. Cooney, M. M. Meropol, N. J. Ivy, S. P. Brell, J. M. TI A phase I study sunitinib malate (S) and gemcitabine (G) in solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Case Western Reserve Univ, Case Comprehens Canc Ctr, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. NCI, Rockville, MD USA. NCI, Canc Prevent Div, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 3046 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003251 ER PT J AU Kummar, S Chen, AP Ji, JJ Allen, D Egorin, MJ Gandara, DR Lenz, H Morgan, R Newman, EM Doroshow, JH AF Kummar, S. Chen, A. P. Ji, J. J. Allen, D. Egorin, M. J. Gandara, D. R. Lenz, H. Morgan, R. Newman, E. M. Doroshow, J. H. TI A phase I study of ABT-888 (A) in combination with metronomic cyclophosphamide (C) in adults with refractory solid tumors and lymphomas. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. SAIC Frederick, Bethesda, MD USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Univ Calif Davis, Sacramento, CA 95817 USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. City Hope Natl Med Ctr, Duarte, CA USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2605 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003196 ER PT J AU Kunitake, H Zheng, P Yothers, GA Land, SR Petersen, L Fehrenbacher, L Giguere, JK Wickerham, DL Ko, CY Ganz, PA AF Kunitake, H. Zheng, P. Yothers, G. A. Land, S. R. Petersen, L. Fehrenbacher, L. Giguere, J. K. Wickerham, D. L. Ko, C. Y. Ganz, P. A. TI Quality of life and symtoms in long-term survivors (LTS) of colorectal cancer (CRC): Results from NSABP protocol LTS-01 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Natl Surg Adjuvant Breast & Bowel Project, Operat Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Pittsburgh Canc Inst, Pittsburgh, PA 15213 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. Kaiser Permanente Med Ctr, Vallejo, CA USA. Canc Ctr Carolinas, Seneca, SC USA. Allegheny Gen Hosp, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 9035 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005301 ER PT J AU Land, SR Christian, N Cronin, WM Wickerham, D Costantino, JP Ganz, PA AF Land, S. R. Christian, N. Cronin, W. M. Wickerham, D. Costantino, J. P. Ganz, P. A. TI Cigarette smoking, fitness, and obesity as predictors of chemoprevention adherence among women in the National Surgical Adjuvant Breast and Bowel Program (NSABP) Breast Cancer Prevention Trial (BCPT). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project Biostat, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 1524 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002695 ER PT J AU Lee, S Kwon, H Kim, S Oh, S Kwon, K Lee, JH Lee, Y Seo, D Han, J Kim, H AF Lee, S. Kwon, H. Kim, S. Oh, S. Kwon, K. Lee, J. H. Lee, Y. Seo, D. Han, J. Kim, H. TI Identification of genes with different methylation profiles between RAEB and RCMD in myelodysplastic syndrome. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dong A Univ, Med Ctr, Dept Internal Med, Pusan, South Korea. Natl Canc Ctr, Div Convergence Technol, Goyang, South Korea. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Dong A Univ, Med Ctr, Pusan, South Korea. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 6608 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852004544 ER PT J AU Lim, WT Thng, C Toh, CK Chawbay, B Goh, BC Leong, S Ivy, SP Ng, Q Tan, DS Tan, E AF Lim, W. T. Thng, C. Toh, C. K. Chawbay, B. Goh, B. C. Leong, S. Ivy, S. P. Ng, Q. Tan, D. S. Tan, E. TI A phase II study of GW786034 (pazopanib) in Asian patients with recurrent/metastatic undifferentiated nasopharyngeal carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Canc Ctr Singapore, Singapore, Singapore. Natl Univ Hlth Syst, Singapore, Singapore. NCI, Rockville, MD USA. Royal Marsden Hosp NHS Fdn Trust, Sutton, Surrey, England. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 5556 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852004233 ER PT J AU Mackay, H Au, H McWhirter, E Alcindor, T Jarvi, A MacAlpine, K Wang, L Wright, JJ Oza, AM AF Mackay, H. Au, H. McWhirter, E. Alcindor, T. Jarvi, A. MacAlpine, K. Wang, L. Wright, J. J. Oza, A. M. TI A phase II trial of the Src kinase inhibitor AZD0530 in patients with metastatic or locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: A trial of the PMH phase II consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Princess Margaret Hosp, Univ Hlth Network, Toronto, ON M4X 1K9, Canada. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Juravinski Canc Ctr, Hamilton, ON, Canada. McGill Univ, Ctr Hlth, Montreal, PQ, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e14544 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852000674 ER PT J AU Madan, RA Mohebtash, M Arlen, PM Vergati, M Steinberg, SM Tsang, KY Dahut, WL Schlom, J Gulley, JL AF Madan, R. A. Mohebtash, M. Arlen, P. M. Vergati, M. Steinberg, S. M. Tsang, K. Y. Dahut, W. L. Schlom, J. Gulley, J. L. TI Overall survival (OS) analysis of a phase I trial of a vector-based vaccine (PSA-TRICOM) and ipilimumab (lpi) in the treatment of metastatic castration-resistant prostate cancer (mCRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2550 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003141 ER PT J AU Mahalingam, D Beeram, M Rodon, J Sankhala, KK Mita, AC Benjamin, D Michalek, J Tolcher, AW Wright, JJ Sarantopoulos, J AF Mahalingam, D. Beeram, M. Rodon, J. Sankhala, K. K. Mita, A. C. Benjamin, D. Michalek, J. Tolcher, A. W. Wright, J. J. Sarantopoulos, J. TI Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab (B) in combination with sorafenib (S) in patients (pts) with advanced malignant melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. START Ctr Canc Care, San Antonio, TX USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e19008 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852001546 ER PT J AU Mansky, PJ Wallerstedt, DB Sannes, T Stagl, J Johnson, L Blackman, MR Grem, JL Swain, SM Monahan, BP AF Mansky, P. J. Wallerstedt, D. B. Sannes, T. Stagl, J. Johnson, L. Blackman, M. R. Grem, J. L. Swain, S. M. Monahan, B. P. TI NCCAM/NCI phase I study of mistletoe extract and gemcitabine in patients with advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Bellin Hlth, Green Bay, WI USA. NIH, Natl Ctr Complementary & Altenat Med, Bethesda, MD USA. Vet Affairs Med Ctr, Res Serv, Washington, DC 20422 USA. Univ Nebraska Med Ctr, Omaha, NE USA. Washington Hosp Ctr, Washington, DC 20010 USA. US Congress, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2559 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003150 ER PT J AU McCahill, LE Yothers, GA Sharif, S Petrelli, NJ Lopa, S O'Connell, MJ Wolmark, N AF McCahill, L. E. Yothers, G. A. Sharif, S. Petrelli, N. J. Lopa, S. O'Connell, M. J. Wolmark, N. TI A phase II trial of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy plus bevacizumab (bev) for patients (pts) with unresectable stage IV colon cancer and a synchronous asymptomatic primary tumor: Results of NSABP C-10 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Adjuvant Surg Breast & Bowel Project, Grand Rapids, MI USA. Lacks Canc Ctr, Grand Rapids, MI USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Natl Adjuvant Surg Breast & Bowel Project, Pittsburgh, PA 15212 USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Natl Adjuvant Surg Breast & Bowel Project, Newark, DE USA. Helen F Graham Canc Ctr, Newark, DE USA. Natl Adjuvant Surg Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 3527 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003339 ER PT J AU Mcnicol, KA Kreisl, TN Iwamoto, FM Sul, J Fine, HA AF Mcnicol, K. A. Kreisl, T. N. Iwamoto, F. M. Sul, J. Fine, H. A. TI Phase I/II study of vandetanib for patients with recurrent malignant gliomas. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Mcnicol, K. A.; Kreisl, T. N.; Iwamoto, F. M.; Sul, J.; Fine, H. A.] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2083 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003078 ER PT J AU Meeske, KA Ji, L Butturini, A Freyer, DR Gaynon, PS Ruccione, K Sposto, R Seibel, NL Siegel, SE AF Meeske, K. A. Ji, L. Butturini, A. Freyer, D. R. Gaynon, P. S. Ruccione, K. Sposto, R. Seibel, N. L. Siegel, S. E. TI Childhood cancer: Do females experience more acute toxicities than males? A report from the Children's Oncology Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 9515 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005444 ER PT J AU Mendizabal, AM Anderson, WF Garcia-Gonzalez, P Levine, PH AF Mendizabal, A. M. Anderson, W. F. Garcia-Gonzalez, P. Levine, P. H. TI Differing age patterns in chronic myeloid leukemia by racial ethnic group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 George Washington Univ, Dept Epidemiol & Biostat, Washington, DC USA. NCI, Dept Hlth & Human Serv, NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Max Fdn, Edmonds, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 1577 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002744 ER PT J AU Merchant, MS Chou, AJ Price, A Geller, JI Tsokos, M Graham, C Charles, A Meyers, PA Mackall, C AF Merchant, M. S. Chou, A. J. Price, A. Geller, J. I. Tsokos, M. Graham, C. Charles, A. Meyers, P. A. Mackall, C. TI Lexatumumab: Results of phase I trial in pediatric patients with advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 9500 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005431 ER PT J AU Messersmith, WA Nallapareddy, S Arcaroli, J Tan, A Foster, NR Wright, JJ Picus, J Goh, BC Hidalgo, M Erlichman, C AF Messersmith, W. A. Nallapareddy, S. Arcaroli, J. Tan, A. Foster, N. R. Wright, J. J. Picus, J. Goh, B. C. Hidalgo, M. Erlichman, C. TI A phase II trial of saracatinib (AZD0530), and oral Src inhibitor, in previously treated metastatic pancreatic cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Colorado, Ctr Canc, Aurora, CO USA. Univ Colorado Denver, Aurora, CO USA. Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Washington Univ, Sch Med, St Louis, MO USA. Natl Univ Hlth Syst, Singapore, Singapore. Ctr Integral Oncol Clara Campal, Madrid, Spain. Mayo Clin, Rochester, MN USA. RI Tan, Aik Choon/A-3135-2011 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e14515 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852000651 ER PT J AU Milano, MT Li, H Gail, MH Constine, LS Travis, LB AF Milano, M. T. Li, H. Gail, M. H. Constine, L. S. Travis, L. B. TI Long-term survival among 298 Hodgkin lymphoma (HL) patients who develop breast cancer (BC): A population-based study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Rochester, Dept Radiat Oncol, Rochester, NY USA. NCI, Rockville, MD USA. Univ Rochester, Sch Med & Dent, Dept Radiat Oncol, Rochester, NY USA. Univ Rochester, Rochester, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 1502 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002675 ER PT J AU Mitchell, EP Edman, J Bazzan, A Littman, SJ Mahipal, A Kandra, AK Hargrove, H Kennedy, EP Levine, M Monti, D AF Mitchell, E. P. Edman, J. Bazzan, A. Littman, S. J. Mahipal, A. Kandra, A. K. Hargrove, H. Kennedy, E. P. Levine, M. Monti, D. TI Ascorbic acid plus gemcitabine (gem) and erlotinib (erl) in patients with metastatic pancreatic cancer (mPanc): Preliminary safety results SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e14659 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852000778 ER PT J AU Morris, JC Citrin, DE Nottingham, L Rudy, SF Harold, N Cooley-Zgela, T Goldstein, D Wright, JJ Conley, BA Van Waes, C AF Morris, J. C. Citrin, D. E. Nottingham, L. Rudy, S. F. Harold, N. Cooley-Zgela, T. Goldstein, D. Wright, J. J. Conley, B. A. Van Waes, C. TI Phase I study of proteasome inhibitor bortezomib (B) concurrent with re-irradiation therapy (re-RT) for recurrent squamous cell carcinoma of the head and neck (SCCHN). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. NINDS, Bethesda, MD 20892 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Michigan State Univ, E Lansing, MI 48824 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2603 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003194 ER PT J AU Mortazavi, A Deam, D Ling, Y Harper, EJ Phelps, MA Espinoza-Delgodo, IJ Monk, JP Otterson, GA Grever, MR Bekaii-Saab, T AF Mortazavi, A. Deam, D. Ling, Y. Harper, E. J. Phelps, M. A. Espinoza-Delgodo, I. J. Monk, J. P. Otterson, G. A. Grever, M. R. Bekaii-Saab, T. TI A phase I study of prolonged infusion of triapine in combination with a fixed-dose rage of gemcitabine in patients with advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Ohio State Univ, Arthur G James Canc Hosp, Columbus, OH 43210 USA. Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. Ohio State Univ, Columbus, OH 43210 USA. NCI, Bethesda, MD 20892 USA. Arthur G James Canc Hosp, Columbus, OH USA. Solove Res Inst, Columbus, OH USA. RI Bekaii-Saab, Tanios/E-2733-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2602 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003193 ER PT J AU Moustakas, A Iwamoto, FM Kreisl, TN Sul, J Kim, LJ Butman, JA Albert, PS Fine, HA AF Moustakas, A. Iwamoto, F. M. Kreisl, T. N. Sul, J. Kim, L. J. Butman, J. A. Albert, P. S. Fine, H. A. TI Phase II trial of enzastaurin (Enz) with bevacizumab (BV) in adults with recurrent glioblstoma (GBM). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Worcester, MA USA. NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e12511 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852000202 ER PT J AU Naing, A LoRusso, P Gupta, S Benjamin, RS Rohren, E Chen, HX Doyle, L Berry, DA Amin, HM Kurzrock, R AF Naing, A. LoRusso, P. Gupta, S. Benjamin, R. S. Rohren, E. Chen, H. X. Doyle, L. Berry, D. A. Amin, H. M. Kurzrock, R. TI Dual inhibition if IGFR and mTOR pathways SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. NCI, Canc Therapy Evaluat Program, Rockville, MD USA. NCI, Canc Therapy Evaluat Program, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 3007 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003212 ER PT J AU Ning, YM Johnson, JR Farrell, AT Maher, VE Justice, RL Pazdur, R AF Ning, Y. M. Johnson, J. R. Farrell, A. T. Maher, V. E. Justice, R. L. Pazdur, R. TI FDA accelerated approval of anticancer agents SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, US FDA, Silver Spring, MD USA. US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 6065 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852004344 ER PT J AU Niswander, LM Guenther, LM Mendoza, A Khanna, C Christensen, JG Helman, LJ Kim, S AF Niswander, L. M. Guenther, L. M. Mendoza, A. Khanna, C. Christensen, J. G. Helman, L. J. Kim, S. TI Effect of modulation of MET with the small molecule inhibitor PF-04217903 on osteosarcoma metastasis in vivo SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Pfizer Global Res & Dev, Dept Canc Res, La Jolla, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 9567 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005495 ER PT J AU O'Brien, DM Hood, DD Katurakes, NC Harness, JK Bright, MA Chu, K AF O'Brien, D. M. Hood, D. D. Katurakes, N. C. Harness, J. K. Bright, M. A. Chu, K. TI Strategies and benefits to effectively engage minority patients in their cancer care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Community Healthcare Strategies, New York, NY USA. Catholic Hlth Initiat, Denver, CO USA. Christiana Care, Newark, DE USA. St Joseph Orange, Orange, CA USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e19501 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852001576 ER PT J AU O'Connell, MJ Lavery, IC Gray, RG Quirke, P Kerr, DJ Lopatin, M Yothers, GA Lee, M Clark-Langone, K Wolmark, N AF O'Connell, M. J. Lavery, I. C. Gray, R. G. Quirke, P. Kerr, D. J. Lopatin, M. Yothers, G. A. Lee, M. Clark-Langone, K. Wolmark, N. TI Comparison of molecular and pathologic features of stage II and stage III colon cancer in four large studies conducted for development of the 12-gene colon cancer recurrence score SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Birmingham, Birmingham, W Midlands, England. Univ Leeds, Leeds, W Yorkshire, England. Sidra Med & Res Ctr, Doha, Qatar. Genom Hlth, Redwood City, CA USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 3503 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003316 ER PT J AU Pappo, AS Patel, S Crowley, J Reinke, DK Staddon, AP Kuenkele, R Chawla, SP Benjamin, RS Helman, IJ Baker, LH AF Pappo, A. S. Patel, S. Crowley, J. Reinke, D. K. Staddon, A. P. Kuenkele, R. Chawla, S. P. Benjamin, R. S. Helman, I. J. Baker, L. H. CA Sarcoma Alliance Res Collaboration TI Activity of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF1R), in patients (pts) with recurrent or refractory Ewing's sarcoma family of tumors (ESFT): Results of a phase II SARC study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Canc Res & Biostat, Seattle, WA USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Penn, Philadelphia, PA 19104 USA. Hoffmann La Roche, Penzberg, Germany. Sarcoma Oncol Ctr, Santa Monica, CA USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 10000 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005509 ER PT J AU Park, JR Hawkins, DS Ingle, M Borinstein, SC Bender, JLG Yamashiro, D Baruchel, S Chen, AP Adamson, PC Blaney, S AF Park, J. R. Hawkins, D. S. Ingle, M. Borinstein, S. C. Bender, J. L. Glade Yamashiro, D. Baruchel, S. Chen, A. P. Adamson, P. C. Blaney, S. TI A pediatric phase I trial and pharmacokinetic study of aflibercept (VEGF Trap): A Children's Oncology Group Phase I Consortium study. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Seattle Childrens Hosp, Seattle, WA USA. Childrens Oncol Grp, Arcadia, CA USA. Vanderbilt Childrens Hosp, Nashville, TN USA. Columbia Univ, New York, NY USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. NCI, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Texas Childrens Canc Ctr, Houston, TX USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 9530 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005459 ER PT J AU Pogue-Geile, KL Yothers, GA Gavin, P Fumagalli, D Kim, C Colangelo, LH Geyer, CE O'Connell, MJ Wolmark, N Paik, S AF Pogue-Geile, K. L. Yothers, G. A. Gavin, P. Fumagalli, D. Kim, C. Colangelo, L. H. Geyer, C. E. O'Connell, M. J. Wolmark, N. Paik, S. TI Use of a prognostic (prog) gene index and nodal status to identify a subset of state II and III colon cancer patients (pts) who may not need oxaliplatin (ox)-containing adjuvant chemotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 3516 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003328 ER PT J AU Prieto, PA Yang, JC Sherry, RM Hughes, MS Kammula, US White, DE Levy, CL Rosenberg, SA Phan, GQ AF Prieto, P. A. Yang, J. C. Sherry, R. M. Hughes, M. S. Kammula, U. S. White, D. E. Levy, C. L. Rosenberg, S. A. Phan, G. Q. TI Cytotoxic T lymphocyte-associated antigen 4 blockade with ipilimumab: Long-term follow-up of 179 patients with metastatic melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 8544 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005214 ER PT J AU Quinten, C Martinelli, F Vercauteren, J Greimel, E Reeve, BB Taphoorn, MJ Cleeland, CS Weis, J Schmucker-Von Koch, J Bottomley, A AF Quinten, C. Martinelli, F. Vercauteren, J. Greimel, E. Reeve, B. B. Taphoorn, M. J. Cleeland, C. S. Weis, J. Schmucker-Von Koch, J. Bottomley, A. CA EORTC TI Use of health-related quality of life and clinical data as prognostic tools for survival prediction in a subgroup of metastatic cancer patients. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 European Org Res & Treatment Canc Headquarters, Brussels, Belgium. Med Univ Graz, Graz, Austria. NCI, Bethesda, MD 20892 USA. Vrije Univ Amsterdam Med Ctr, Med Ctr Haaglanden, The Hague, Netherlands. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Freiburg, Tumor Biol Ctr, Freiburg, Belgium. Univ Regensburg, Philosoph Fac, Regensbrug, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 9146 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005410 ER PT J AU Rajan, A Berman, AW Kelly, RJ Lopez-Chavez, A Dechowdhury, R Chen, H Giaccone, G AF Rajan, A. Berman, A. W. Kelly, R. J. Lopez-Chavez, A. Dechowdhury, R. Chen, H. Giaccone, G. TI Phase II study of the insulin-like growth factor-1 receptor (IGF-1R) antibody cixutumumab (C) in patients (pts) thymoma (T) and thymic carcinoma (TC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Rajan, A.; Berman, A. W.; Kelly, R. J.; Lopez-Chavez, A.; Dechowdhury, R.; Chen, H.; Giaccone, G.] NCI, Bethesda, MD 20892 USA. NR 0 TC 7 Z9 7 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e17525 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852001338 ER PT J AU Rastogi, P Buyse, ME Tan, AR Jacobs, SA Swain, SM Geyer, CE Wolmark, N AF Rastogi, P. Buyse, M. E. Tan, A. R. Jacobs, S. A. Swain, S. M. Geyer, C. E. Wolmark, N. TI A phase II clinical trail of four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel given concurrently with pazopanib as neoadjuvant therapy followed by postoperative pazopanib for women with locally advanced breast cancer (LABC): A phase II trail of the NSABP Foundation Research Group (FB-6/VEG110264). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. IDDI, Louvain, Belgium. Canc Inst New Jersey, New Brunswick, NJ USA. Washington Hosp Ctr, Washington, DC 20010 USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA TPS107 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002110 ER PT J AU Riordan, SE Hering, MF Hopkins, JR Lambersky, R Marinucci, DM Martier, KE Mooney, MM Nelson, A Rajaram, R Abrams, JS AF Riordan, S. E. Hering, M. F. Hopkins, J. R. Lambersky, R. Marinucci, D. M. Martier, K. E. Mooney, M. M. Nelson, A. Rajaram, R. Abrams, J. S. TI NCI Cancer Trials Support Unit at year 10 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Westat Corp, Rockville, MD USA. Coalit Canc Cooperat Grp, Philadelphia, PA USA. Westat Corp, Durham, NC USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 6077 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852004356 ER PT J AU Salit, RB Fowler, DH Wilson, WH Pavletio, SZ Dunleavy, K Hakim, F Steinberg, SM Odom, J Bryant, K Bishop, MR AF Salit, R. B. Fowler, D. H. Wilson, W. H. Pavletio, S. Z. Dunleavy, K. Hakim, F. Steinberg, S. M. Odom, J. Bryant, K. Bishop, M. R. TI EPOCH-FR: A novel salvage regimen for patients with lymphoid malignancies being considered for reduced-intensity allogeneic hematopoietic stem cell transplantation. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NCI, Metab Branch, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 6536 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852004472 ER PT J AU Sargent, DJ Yothers, GA Green, E Blanke, CD O'Connell, MJ Labianca, R Bleyer, A De Gramont, A Thomas, DM AF Sargent, D. J. Yothers, G. A. Green, E. Blanke, C. D. O'Connell, M. J. Labianca, R. Bleyer, A. De Gramont, A. Thomas, D. M. CA LIVESTRONG Young Adult Alliance ACCENT Collaborative Grp TI Benefits and adverse events (AEs) in younger (Y) (age < 50) versus older patients (pts) receiving adjuvant chemotherapy (AT) for colon cancer (CC): Findings from the 33,574 pt ACCENT dataset SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mayo Clin Rochester, Rochester, MN USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Univ British Columbia, British Columbia Canc Agcy, Vancouver, BC V5Z 1M9, Canada. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Osped Riuniti Bergamo, I-24100 Bergamo, Italy. St Charles Hosp, Bend, OR USA. Hop St Antoine, F-75571 Paris, France. Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 3523 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003335 ER PT J AU Scott, JG Chao, ST Suh, JH Cooper, A Reiner, AS Nayak, L Panageas, K Abrey, LE Iwamoto, FM AF Scott, J. G. Chao, S. T. Suh, J. H. Cooper, A. Reiner, A. S. Nayak, L. Panageas, K. Abrey, L. E. Iwamoto, F. M. TI Prognostic factors for glioblastoma (GBM) in individuals age 70 and older: A study of 446 patients from two tertiary centers. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. Cleveland Clin, Cleveland, OH 44106 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2034 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003029 ER PT J AU Shibata, S Longmate, J Chung, VM Lenz, H Kummar, S Sarantopoulos, J Harrison, ML Synold, TW Ivy, SP Newman, EM AF Shibata, S. Longmate, J. Chung, V. M. Lenz, H. Kummar, S. Sarantopoulos, J. Harrison, M. L. Synold, T. W. Ivy, S. P. Newman, E. M. TI A phase I and pharmacokinetic single agent study of pazopanib (P) in patients (Pts) with advanced malignancies and varying degrees of liver dysfunction (LD) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 City Hope Natl Med Ctr, Duarte, CA USA. Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. NCI, Bethesda, MD 20892 USA. Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. RPA Hosp, Sydney, NSW, Australia. Liverpool Hosp, Sydney, NSW, Australia. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2571 PG 2 WC Oncology SC Oncology GA V30YT UT WOS:000208852003162 ER PT J AU Shonka, NA Gilbert, MR Yung, WA Paio, Y Liu, J Bekele, BN Wen, PY Chen, AP Heymach, J De Groot, JF AF Shonka, N. A. Gilbert, M. R. Yung, W. A. Paio, Y. Liu, J. Bekele, B. N. Wen, P. Y. Chen, A. P. Heymach, J. De Groot, J. F. TI Use of cytokines to predict on-target in patients with recurrent glioblastoma treated with aflibercept SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e12507 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852000199 ER PT J AU Sideras, K Menefee, ME Burton, JK Ivy, SP Erlichman, C Bible, KC AF Sideras, K. Menefee, M. E. Burton, J. K. Ivy, S. P. Erlichman, C. Bible, K. C. TI Effect of pazopanib on hair and skin hypopigmentation: A series of three patients. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mayo Clin, Endocrine Malignancies Dis Oriented Grp, Rochester, MN USA. Mayo Clin, Phase Consortium 2, Rochester, MN USA. Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e13602 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852000458 ER PT J AU Sinicrope, F Foster, NR Sargent, DJ Gallinger, S Benatti, P Marsoni, S Monges, G Labianca, R O'Connell, MJ Allegra, CJ AF Sinicrope, F. Foster, N. R. Sargent, D. J. Gallinger, S. Benatti, P. Marsoni, S. Monges, G. Labianca, R. O'Connell, M. J. Allegra, C. J. TI DNA mismatch repair status and site of tumor recurrence in state II and III colon cancers treated in 5-fluorouracil-based adjuvant therapy trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mayo Clin, Sch Med, Rochester, MN USA. Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. Mayo Clin, Rochester, MN USA. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. Univ Modena & Reggio Emilia, Modena, Italy. SENDO Fdn, Milan, Italy. Inst J Paoli I Calmettes, F-13009 Marseille, France. Osped Riuniti Bergamo, I-24100 Bergamo, Italy. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Florida, Gainesville, FL USA. RI Benatti, Piero/C-1052-2015 OI Benatti, Piero/0000-0002-6826-1480 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 3519 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003331 ER PT J AU Sorbellini, M McNeil, B Simpson, H Giubellino, A Hsieh, T Getzenberg, RH Schoenberg, M Gagani, C Bottaro, DP AF Sorbellini, M. McNeil, B. Simpson, H. Giubellino, A. Hsieh, T. Getzenberg, R. H. Schoenberg, M. Gagani, C. Bottaro, D. P. TI Correlation of Met expression in TCC of the bladder with stage and grade SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. George Washington Univ, Washington, DC USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e15110 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852001117 ER PT J AU Tan, AR Gibbon, D Stein, MN Moss, RA Karantza, V Lin, H Gounder, M Chen, AP Egorin, MJ DiPaola, RS AF Tan, A. R. Gibbon, D. Stein, M. N. Moss, R. A. Karantza, V. Lin, H. Gounder, M. Chen, A. P. Egorin, M. J. DiPaola, R. S. TI Preliminary results of a phase I trial of ABT-888, a poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with cyclophosphamide. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Canc Inst New Jersey, New Brunswick, NJ USA. NCI, Bethesda, MD 20892 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 3000 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003205 ER PT J AU Tang, G Cuzick, J Wale, C Costantino, JP Crager, M Shak, S Wolmark, N Dowsett, M Forbes, JF AF Tang, G. Cuzick, J. Wale, C. Costantino, J. P. Crager, M. Shak, S. Wolmark, N. Dowsett, M. Forbes, J. F. TI Recurrence risk of node-negative and ER-positive early-stage breast cancer patients by combining recurrence score, pathologic, and clinical information: A meta-analysis approach SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ London, London, England. Genom Hlth, Redwood City, CA USA. Natl Surg Adjuvant Breast & Bowel Project & Alleg, Pittsburgh, PA USA. Royal Marsden Hosp, London SW3 6JJ, England. Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 509 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002349 ER PT J AU Van Waes, C Duffy, AG Simone, NL Gibson, MK Arai, Y Rudy, SF Cooley-Zgela, T Nyati, M Wright, JJ Agiris, A AF Van Waes, C. Duffy, A. G. Simone, N. L. Gibson, M. K. Arai, Y. Rudy, S. F. Cooley-Zgela, T. Nyati, M. Wright, J. J. Agiris, A. TI Early disease progression in a phase I study of bortezomb (B), cetuximab (C), and intensity-modulated radiation therapy (IMRT) for squamous cell carcinoma of the head and neck (SCCHN) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NIDCD, Bethesda, MD USA. NCI, Bethesda, MD 20892 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Univ Michigan, Ann Arbor, MI 48109 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 2575 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003166 ER PT J AU Vaughn, LG Li, L Nabell, L Rugo, HS Carey, LA Kimmick, GG Steeg, PS Miller, K AF Vaughn, L. G. Li, L. Nabell, L. Rugo, H. S. Carey, L. A. Kimmick, G. G. Steeg, P. S. Miller, K. TI A phase II study of medroxyprogesterone acetate (MPA) in patients (pts) with hormone receptor-negative (HR-) metastatic breast cancer (MBC): Translational Breast Cancer Research Consortium trial 007 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Indiana Univ, Indianapolis, IN 46204 USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. Univ N Carolina, Chapel Hill, NC USA. Duke Univ, Med Ctr, Durham, NC USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 1074 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002589 ER PT J AU Waxman, AJ Mink, P Devesa, S Anderson, WF Weiss, BM Kristinsson, S McGlynn, K Landgren, O AF Waxman, A. J. Mink, P. Devesa, S. Anderson, W. F. Weiss, B. M. Kristinsson, S. McGlynn, K. Landgren, O. TI Racial disparities in incidence and survival among 37,977 blacks and whites with multiple myeloma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Med Oncol Branch, Bethesda, MD 20892 USA. Emory Univ, Atlanta, GA 30322 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Dept Hlth & Human Serv, NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. Karolinska Univ Hosp & Inst, Stockholm, Sweden. RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 8115 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852005135 ER PT J AU Wells, SA Robinson, BG Gagel, RF Dralle, H Fagin, JA Santoro, M Baudin, E Vasselli, JR Read, J Schlumberger, M AF Wells, S. A. Robinson, B. G. Gagel, R. F. Dralle, H. Fagin, J. A. Santoro, M. Baudin, E. Vasselli, J. R. Read, J. Schlumberger, M. TI Vandetanib (VAN) in locally advance or metastatic medullary thyroid cancer (MTC): A randomized, double-blind phase III trial (ZETA) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Univ Sydney, Sydney, NSW 2006, Australia. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Halle Wittenberg, D-06108 Halle, Germany. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Napoli Frederico II, Naples, Italy. Inst Gustave Roussy, Villejuif, France. AstraZeneca, Wilmington, DE USA. AstraZeneca, Macclesfield, Cheshire, England. NR 0 TC 7 Z9 7 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 5503 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852004182 ER PT J AU Widemann, BC Fisher, MJ Dombi, E Cantor, A Vinks, S Korf, B Schorry, E Gutmann, D Packer, R Weiss, BD AF Widemann, B. C. Fisher, M. J. Dombi, E. Cantor, A. Vinks, S. Korf, B. Schorry, E. Gutmann, D. Packer, R. Weiss, B. D. TI Phase II study of the mTOR inhibitor sirolimus for nonprogressive NF1-associated plexiform neurofibromas: A Neurofibromatosis Consortium study. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Childrens Hosp, Philadelphia, PA 19104 USA. Univ Alabama Birmingham, Birmingham, AL USA. Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. Washington Univ, St Louis, MO USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA e13601 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852000457 ER PT J AU Wilkerson, J Stein, WD Kim, ST Huang, X Motzer, RJ Fojo, AT Bates, SE AF Wilkerson, J. Stein, W. D. Kim, S. T. Huang, X. Motzer, R. J. Fojo, A. T. Bates, S. E. TI Validation of a kinetic analysis of renal mincer regression and growth following treatment with sunitinib and interferon-alfa (IFN-alpha): Analysis of the pivotal randomized trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. Pfizer Inc, La Jolla, CA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 4597 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003720 ER PT J AU Yabroff, K Warren, J Barbera, LC Bremner, K Hoch, J Barrett, M Luo, J Krahn, M AF Yabroff, K. Warren, J. Barbera, L. C. Bremner, K. Hoch, J. Barrett, M. Luo, J. Krahn, M. TI End-of-life care for elderly patients with advanced lung cancer in the United States and Ontario SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Odette Canc Ctr, Toronto, ON, Canada. Toronto Hlth Econ & Technol Assessment Collaborat, Toronto, ON, Canada. Canc Care Ontario, Toronto, ON, Canada. IMS Inc, Silver Spring, MD USA. Inst Clin Evaluat Sci, Toronto, ON, Canada. Univ Toronto, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 6021 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852004300 ER PT J AU Zervoudakis, A Schatzkin, A Strickler, HD Park, Y Hollenbeck, A Gunter, MJ AF Zervoudakis, A. Schatzkin, A. Strickler, H. D. Park, Y. Hollenbeck, A. Gunter, M. J. TI Reproductive history and risk of colorectal cancer in postmenopausal women SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. AARP, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 3618 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852003430 ER PT J AU Zhao, W Duan, W Leon, ME Chen, AP Sofletea, G Thurmond, J Ramaswamy, B O'Malley, D Bekall-Saab, TS Villalona-Calero, MA AF Zhao, W. Duan, W. Leon, M. E. Chen, A. P. Sofletea, G. Thurmond, J. Ramaswamy, B. O'Malley, D. Bekall-Saab, T. S. Villalona-Calero, M. A. TI Targeting fanconi anemia (FA) repair pathway deficiency for treatment with PARP inhibitors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. Arthur G James Canc Hosp, Columbus, OH USA. Solove Res Inst, Columbus, OH USA. NCI, Bethesda, MD 20892 USA. Ohio State Univ, Columbus, OH 43210 USA. RI OMalley, David/E-3789-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA TPS168 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852002170 ER PT J AU Zuckerman, B Corrigan, J AF Zuckerman, B. Corrigan, J. TI The role of NCI-sponsored research in ASCO Clinical Cancer Advances 2005-2008 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Inst Def Anal STPI, Washington, DC USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2010 VL 28 IS 15 SU S MA 6094 PG 1 WC Oncology SC Oncology GA V30YT UT WOS:000208852004373 ER PT J AU Kosmrlj, A Read, EL Qi, Y Allen, TM Altfeld, M Deeks, SG Pereyra, F Carrington, M Walker, BD Chakraborty, AK AF Kosmrlj, Andrej Read, Elizabeth L. Qi, Ying Allen, Todd M. Altfeld, Marcus Deeks, Steven G. Pereyra, Florencia Carrington, Mary Walker, Bruce D. Chakraborty, Arup K. TI Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection SO NATURE LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; RESPONSES; PEPTIDE; BINDING; MOLECULES; ANTIGEN; CD4(+); LYMPHOCYTES; DIVERSITY; EPITOPES AB Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals ('elite controllers') maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8(+) T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies. C1 [Kosmrlj, Andrej; Read, Elizabeth L.; Allen, Todd M.; Altfeld, Marcus; Pereyra, Florencia; Carrington, Mary; Walker, Bruce D.; Chakraborty, Arup K.] Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. [Kosmrlj, Andrej] MIT, Dept Phys, Cambridge, MA 02139 USA. [Read, Elizabeth L.; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Read, Elizabeth L.; Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Qi, Ying; Carrington, Mary] NCI Frederick, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94110 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. RP Chakraborty, AK (reprint author), Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. EM bwalker@partners.org; arupc@mit.edu RI Allen, Todd/F-5473-2011 FU Mark and Lisa Schwartz Foundation; National Institutes of Health (NIH); Philip T and Susan M Ragon Foundation; Jane Coffin Childs Foundation; Bill and Melinda Gates Foundation; NIAID; National Cancer Institute, NIH [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX Financial support was provided by the Mark and Lisa Schwartz Foundation, the National Institutes of Health (NIH) Director's Pioneer award (A. K. C.), Philip T and Susan M Ragon Foundation, Jane Coffin Childs Foundation (E. L. R.), the Bill and Melinda Gates Foundation, and the NIAID (B. D. W., T. M. A. and M. A.). This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 40 TC 139 Z9 141 U1 1 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 20 PY 2010 VL 465 IS 7296 BP 350 EP U107 DI 10.1038/nature08997 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 598IO UT WOS:000277829200041 PM 20445539 ER PT J AU Barnes, AM Raggio, CL Marini, JC AF Barnes, Aileen M. Raggio, Cathleen L. Marini, Joan C. TI Osteogenesis Imperfecta, Normal Collagen Folding, and Lack of Cyclophilin B REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Barnes, Aileen M.; Marini, Joan C.] NIH, Bethesda, MD 20892 USA. [Raggio, Cathleen L.] Hosp Special Surg, New York, NY 10021 USA. RP Barnes, AM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov NR 6 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 20 PY 2010 VL 362 IS 20 BP 1941 EP 1942 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 598EI UT WOS:000277815600028 ER PT J AU Hooten, NN Abdelmohsen, K Gorospe, M Ejiogu, N Zonderman, AB Evans, MK AF Hooten, Nicole Noren Abdelmohsen, Kotb Gorospe, Myriam Ejiogu, Ngozi Zonderman, Alan B. Evans, Michele K. TI microRNA Expression Patterns Reveal Differential Expression of Target Genes with Age SO PLOS ONE LA English DT Article ID CELLULAR SENESCENCE; LIFE-SPAN; REPLICATIVE SENESCENCE; PERIPHERAL-BLOOD; HUMAN CANCER; C. ELEGANS; RECEPTOR; CELLS; PROLIFERATION; TUMORIGENESIS AB Recent evidence supports a role for microRNAs (miRNAs) in regulating the life span of model organisms. However, little is known about how these small RNAs contribute to human aging. Here, we profiled the expression of over 800 miRNAs in peripheral blood mononuclear cells from young and old individuals by real-time RT-PCR analysis. This genome-wide assessment of miRNA expression revealed that the majority of miRNAs studied decreased in abundance with age. We identified nine miRNAs (miR-103, miR-107, miR-128, miR-130a, miR-155, miR-24, miR-221, miR-496, miR-1538) that were significantly lower in older individuals. Among them, five have been implicated in cancer pathogenesis. Predicted targets of several of these miRNAs, including PI3 kinase (PI3K), c-Kit and H2AX, were found to be elevated with advancing age, supporting a possible role for them in the aging process. Furthermore, we found that decreasing the levels of miR-221 was sufficient to cause a corresponding increase in the expression of the predicted target, PI3K. Taken together, these findings demonstrate that changes in miRNA expression occur with human aging and suggest that miRNAs and their predicted targets have the potential to be diagnostic indicators of age or age-related diseases. C1 [Hooten, Nicole Noren; Abdelmohsen, Kotb; Gorospe, Myriam; Evans, Michele K.] NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. [Ejiogu, Ngozi; Evans, Michele K.] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Zonderman, Alan B.] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. RP Hooten, NN (reprint author), NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. EM evansmi@grc.nia.nih.gov OI Noren Hooten, Nicole/0000-0002-1683-3838; abdelmohsen, Kotb/0000-0001-6240-5810; Zonderman, Alan B/0000-0002-6523-4778 FU National Institute of Aging Intramural Research Program at the National Institutes of Health FX This study has been supported in full by National Institute of Aging Intramural Research Program at the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 119 Z9 123 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 20 PY 2010 VL 5 IS 5 AR e10724 DI 10.1371/journal.pone.0010724 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 600VP UT WOS:000278017300004 ER PT J AU Rosenberg, PS Anderson, WF AF Rosenberg, Philip S. Anderson, William F. TI Proportional hazards models and age-period-cohort analysis of cancer ratest SO STATISTICS IN MEDICINE LA English DT Article DE age-period-cohort models; cause-specific hazards; cancer incidence; descriptive epidemiology; racial disparity ID CHRONIC DISEASE RATES; TIME TRENDS; ETIOLOGIC HETEROGENEITY; EUROPEAN COUNTRIES; TEMPORAL VARIATION; TESTICULAR CANCER; MORTALITY-RATES; WHITE WOMEN; VITAL-RATES; CLUES AB Age-period-cohort (APC) analysis is widely used in cancer epidemiology to model trends in cancer rates. We develop methods for comparative APC analysis of two independent cause-specific hazard rates assuming that an APC model holds for each one. We construct linear hypothesis tests to determine whether the two hazards are absolutely proportional or proportional after stratification by cohort, period, or age. When a given proportional hazards model appears adequate, we derive simple expressions for the relative hazards using identifiable APC parameters. To demonstrate the utility of these new methods, we analyze cancer incidence rates in the United States in blacks versus whites for selected cancers, using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The examples illustrate that each type of proportionality may be encountered in practice. Published in 2010 by John Wiley & Sons, Ltd. C1 [Rosenberg, Philip S.; Anderson, William F.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Rosenberg, PS (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Execut Plaza S, Rockville, MD 20852 USA. FU NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics; NCI; National Heart Lung and Blood Institute FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The authors gratefully acknowledge the assistance of Christina McIntosh and Julia Tse for data management and analysis. Julia Tse was supported as a research fellow by the NCI Cancer Research and Training Award (CRTA) Program, and Christina McIntosh was supported as a research fellow by the National Heart Lung and Blood Institute's Biomedical Research Training Program for Underrepresented Groups (BRTPUG). The authors also acknowledge the helpful comments from two reviewers and the associate editor, which led to substantial improvements in the manuscript. NR 27 TC 14 Z9 14 U1 0 U2 8 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAY 20 PY 2010 VL 29 IS 11 BP 1228 EP 1238 DI 10.1002/sim.3865 PG 11 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 600CJ UT WOS:000277960900007 PM 20209480 ER PT J AU Santiago, DJ Curran, JW Bers, DM Lederer, WJ Stern, MD Rios, E Shannon, TR AF Santiago, Demetrio J. Curran, Jerald W. Bers, Donald M. Lederer, W. J. Stern, Michael D. Rios, Eduardo Shannon, Thomas R. TI Ca Sparks Do Not Explain all Ryanodine Receptor-Mediated SR Ca Leak in Mouse Ventricular Myocytes SO BIOPHYSICAL JOURNAL LA English DT Article ID FROG SKELETAL-MUSCLE; PIG CARDIAC MYOCYTES; SARCOPLASMIC-RETICULUM; CALCIUM-RELEASE; RAT-HEART; EVENTS; CELLS; FLUX; CHANNELS; BINDING AB Diastolic Ca leak from the sarcoplasmic reticulum (SR) of ventricular myocytes reduces the SR Ca content, stabilizing the activity of the SR Ca release channel ryanodine receptor for the next beat. SR Ca leak has been visualized globally using whole-cell fluorescence, or locally using confocal microscopy, but never both ways. When using confocal microscopy, leak is imaged as "Ca sparks," which are fluorescent objects generated by the local reaction-diffusion of released Ca and cytosolic indicator. Here, we used confocal microscopy and simultaneously measured the global ryanodine-receptor-mediated leak rate (J(leak)) and Ca spars in intact mouse ventricular myocytes. We found that spark frequency and J(leak) are correlated, as expected if both are manifestations of a common phenomenon. However, we also found that sparks explain approximately half of J(leak). Our strategy unmasks the presence of a subresolution (i.e., nonspark) release of potential physiological relevance. C1 [Santiago, Demetrio J.; Curran, Jerald W.; Rios, Eduardo; Shannon, Thomas R.] Rush Univ, Dept Mol Biophys & Physiol, Chicago, IL 60612 USA. [Bers, Donald M.] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA. [Lederer, W. J.] Univ Maryland, Inst Biotechnol, Baltimore, MD 21201 USA. [Lederer, W. J.] Univ Maryland, Dept Physiol, Baltimore, MD 21201 USA. [Stern, Michael D.] NIA, Baltimore, MD 21224 USA. RP Shannon, TR (reprint author), Rush Univ, Dept Mol Biophys & Physiol, Chicago, IL 60612 USA. EM tshannon@rush.edu RI Curran, Jerry/B-9762-2012; Bers, Donald/C-4507-2012; OI Bers, Donald/0000-0002-2237-9483 FU National Institutes of Health [NIH R01-HL071893]; National Institute on Aging, National Institutes of Health, Bethesda, Maryland FX This research was supported by National Institutes of Health grant No. NIH R01-HL071893 and supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Bethesda, Maryland. NR 35 TC 40 Z9 40 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY 19 PY 2010 VL 98 IS 10 BP 2111 EP 2120 DI 10.1016/j.bpj.2010.01.042 PG 10 WC Biophysics SC Biophysics GA 598SJ UT WOS:000277858400011 PM 20483318 ER PT J AU Han, QA Cai, T Tagle, DA Li, JY AF Han, Qian Cai, Tao Tagle, Danilo A. Li, Jianyong TI Thermal stability, pH dependence and inhibition of four murine kynurenine aminotransferases SO BMC BIOCHEMISTRY LA English DT Article ID MITOCHONDRIAL ASPARTATE-AMINOTRANSFERASE; SPONTANEOUSLY HYPERTENSIVE-RATS; GLUTAMINE TRANSAMINASE-K; EXCITATORY AMINO-ACIDS; CONJUGATE BETA-LYASE; CRYSTAL-STRUCTURE; SUBSTRATE-SPECIFICITY; HUMAN BRAIN; INDOLEAMINE 2,3-DIOXYGENASE; SYNAPTIC-TRANSMISSION AB Background: Kynurenine aminotransferase (KAT) catalyzes the transamination of kynunrenine to kynurenic acid (KYNA). KYNA is a neuroactive compound and functions as an antagonist of alpha7-nicotinic acetylcholine receptors and is the only known endogenous antagonist of N-methyl-D-aspartate receptors. Four KAT enzymes, KAT I/glutamine transaminase K/cysteine conjugate beta-lyase 1, KAT II/aminoadipate aminotransferase, KAT III/cysteine conjugate beta-lyase 2, and KAT IV/glutamic-oxaloacetic transaminase 2/mitochondrial aspartate aminotransferase, have been reported in mammalian brains. Because of the substrate overlap of the four KAT enzymes, it is difficult to assay the specific activity of each KAT in animal brains. Results: This study concerns the functional expression and comparative characterization of KAT I, II, III, and IV from mice. At the applied test conditions, equimolar tryptophan with kynurenine significantly inhibited only mouse KAT I and IV, equimolar methionine inhibited only mouse KAT III and equimolar aspartate inhibited only mouse KAT IV. The activity of mouse KAT II was not significantly inhibited by any proteinogenic amino acids at equimolar concentrations. pH optima, temperature preferences of four KATs were also tested in this study. Midpoint temperatures of the protein melting, half life values at 65 degrees C, and pKa values of mouse KAT I, II, III, and IV were 69.8, 65.9, 64.8 and 66.5 degrees C; 69.7, 27.4, 3.9 and 6.5 min; pH 7.6, 5.7, 8.7 and 6.9, respectively. Conclusion: The characteristics reported here could be used to develop specific assay methods for each of the four murine KATs. These specific assays could be used to identify which KAT is affected in mouse models for research and to develop small molecule drugs for prevention and treatment of KAT-involved human diseases. C1 [Han, Qian; Li, Jianyong] Virginia Tech, Dept Biochem, Blacksburg, VA 24061 USA. [Cai, Tao] NIDCR, OIIB, NIH, Bethesda, MD 20892 USA. [Tagle, Danilo A.] NINDS, Ctr Neurosci, NIH, Bethesda, MD 20892 USA. RP Li, JY (reprint author), Virginia Tech, Dept Biochem, Blacksburg, VA 24061 USA. EM lij@vt.edu RI Han, Qian/J-8696-2014 OI Han, Qian/0000-0001-6245-5252 FU NINDS [NS062836]; NIDCR; NINDS at NIH FX This work was supported by a research grant from NINDS (NS062836) and Intramural Research Programs of NIDCR and NINDS at NIH. We are grateful to Elizabeth Watson (Department of Biochemistry, Virginia Tech) for critically reading this paper, and Randy Saunders for assistance with the mouse experiments. NR 48 TC 13 Z9 14 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2091 J9 BMC BIOCHEM JI BMC Boichem. PD MAY 19 PY 2010 VL 11 AR 19 DI 10.1186/1471-2091-11-19 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 623GG UT WOS:000279726300001 PM 20482848 ER PT J AU Strunnikov, AV AF Strunnikov, Alexander V. TI One-hit wonders of genomic instability SO CELL DIVISION LA English DT Review ID DNA-POLYMERASE-EPSILON; ANAPHASE-PROMOTING COMPLEX/CYCLOSOME; SPINDLE ASSEMBLY CHECKPOINT; S-PHASE CHECKPOINT; CONDENSIN-I; SACCHAROMYCES-CEREVISIAE; CHROMOSOME CONDENSATION; CELL-CYCLE; COLORECTAL CANCERS; SISTER CHROMATIDS AB Recent data show that cells from many cancers exhibit massive chromosome instability. The traditional view is that the gradual accumulation of mutations in genes involved in transcriptional regulation and cell cycle controls results in tumor development. This, however, does not exclude the possibility that some mutations could be more potent than others in destabilizing the genome by targeting both chromosomal integrity and corresponding checkpoint mechanisms simultaneously. Three such examples of "single-hit" lesions potentially leading to heritable genome destabilization are discussed. They include: failure to release sister chromatid cohesion due to the incomplete proteolytic cleavage of cohesin; massive merotelic kinetochore misattachments upon condensin depletion; and chromosome under-replication. In all three cases, cells fail to detect potential chromosomal bridges before anaphase entry, indicating that there is a basic cell cycle requirement to maintain a degree of sister chromatid bridging that is not recognizable as chromosomal damage. C1 NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Strunnikov, AV (reprint author), NIAID, Immunopathol Lab, NIH, 5640 Fishers Lane,Room 1524, Rockville, MD 20852 USA. EM strunnik@mail.nih.gov OI Strunnikov, Alexander/0000-0002-9058-2256 FU NIAID FX This work was supported by the intramural program at NIAID. I would like to thank Dr. Herbert C. Morse III and Dr. Alexei Arnaoutov for critical reading of the manuscript. NR 98 TC 10 Z9 10 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1747-1028 J9 CELL DIV JI Cell Div. PD MAY 19 PY 2010 VL 5 AR 15 DI 10.1186/1747-1028-5-15 PG 12 WC Cell Biology SC Cell Biology GA 675AS UT WOS:000283796400001 PM 20482869 ER PT J AU Cevher, MA Zhang, XK Fernandez, S Kim, S Baquero, J Nilsson, P Lee, S Virtanen, A Kleiman, FE AF Cevher, Murat A. Zhang, Xiaokan Fernandez, Sully Kim, Sergey Baquero, Jorge Nilsson, Per Lee, Sean Virtanen, Anders Kleiman, Frida E. TI Nuclear deadenylation/polyadenylation factors regulate 3 ' processing in response to DNA damage SO EMBO JOURNAL LA English DT Article DE 3 ' RNA processing; deadenylation; DNA damage; polyadenylation ID MESSENGER-RNA DEADENYLATION; B-CELL DIFFERENTIATION; CAP-BINDING COMPLEX; POLYMERASE-II; POLY(A)-SPECIFIC RIBONUCLEASE; POLYADENYLATION FACTOR; POLY(A) POLYMERASE; GENE-EXPRESSION; FAMILY-MEMBERS; FOS FAMILY AB We previously showed that mRNA 3' end cleavage reaction in cell extracts is strongly but transiently inhibited under DNA-damaging conditions. The cleavage stimulation factor-50 (CstF-50) has a role in this response, providing a link between transcription-coupled RNA processing and DNA repair. In this study, we show that CstF-50 interacts with nuclear poly(A)-specific ribonuclease (PARN) using in vitro and in extracts of UV-exposed cells. The CstF-50/PARN complex formation has a role in the inhibition of 3' cleavage and activation of deadenylation upon DNA damage. Extending these results, we found that the tumour suppressor BARD1, which is involved in the UV-induced inhibition of 3' cleavage, strongly activates deadenylation by PARN in the presence of CstF-50, and that CstF-50/BARD1 can revert the cap-binding protein-80 (CBP80)mediated inhibition of PARN activity. We also provide evidence that PARN along with the CstF/BARD1 complex participates in the regulation of endogenous transcripts under DNA-damaging conditions. We speculate that the interplay between polyadenylation, deadenylation and tumour-suppressor factors might prevent the expression of prematurely terminated messengers, contributing to control of gene expression under different cellular conditions. The EMBO Journal (2010) 29, 1674-1687. doi: 10.1038/emboj.2010.59; Published online 8 April 2010 C1 [Cevher, Murat A.; Zhang, Xiaokan; Fernandez, Sully; Kim, Sergey; Baquero, Jorge; Kleiman, Frida E.] CUNY Hunter Coll, Dept Chem, New York, NY 10065 USA. [Nilsson, Per; Virtanen, Anders] Uppsala Univ, Dept Cell & Mol Biol, Uppsala, Sweden. [Lee, Sean] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Kleiman, FE (reprint author), CUNY Hunter Coll, Dept Chem, New York, NY 10065 USA. EM fkleiman@hunter.cuny.edu FU National Institute of General Medical Sciences [SC1GM083806]; Minority Access to Research Careers Program (MARC); Swedish Research Council; Lennanders Foundation at Uppsala University FX We thank Dr JL Manley for the anti-CstF-64 antibodies; Dr M Wormington for the anti-PARN antibodies; Dr I Mattaj for the anti-CBP 80 antibodies and CBP-80-encoding plasmids; Dr Baer for BARD1-encoding plasmids; M Iacovidou and A Takaoka for assistance with qRT-PCR; and Dr JL Manley for advice and discussion. This work is supported by the National Institute of General Medical Sciences grant SC1GM083806 to FEK, by Minority Access to Research Careers Program (MARC) to SF, and by the Swedish Research Council, the Linneus Support from the Swedish Research Council to the Uppsala RNA Research Centre and the Lennanders Foundation at Uppsala University (AV). NR 62 TC 34 Z9 35 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 19 PY 2010 VL 29 IS 10 BP 1674 EP 1687 DI 10.1038/emboj.2010.59 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 598JU UT WOS:000277833100007 PM 20379136 ER PT J AU Insel, TR Wang, PS AF Insel, Thomas R. Wang, Philip S. TI Rethinking Mental Illness SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID EXTINCTION; FEAR C1 [Insel, Thomas R.] NIMH, NIH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, NIH, 6001 Execut Blvd,Room 8235, Bethesda, MD 20892 USA. EM tinsel@mail.nih.gov NR 10 TC 69 Z9 72 U1 1 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 19 PY 2010 VL 303 IS 19 BP 1970 EP 1971 DI 10.1001/jama.2010.555 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 597NJ UT WOS:000277764500024 PM 20483974 ER PT J AU Zink, CF Stein, JL Kempf, L Hakimi, S Meyer-Lindenberg, A AF Zink, Caroline F. Stein, Jason L. Kempf, Lucas Hakimi, Shabnam Meyer-Lindenberg, Andreas TI Vasopressin Modulates Medial Prefrontal Cortex-Amygdala Circuitry during Emotion Processing in Humans SO JOURNAL OF NEUROSCIENCE LA English DT Article ID RECEPTOR KNOCKOUT MICE; FALSE DISCOVERY RATE; AGGRESSIVE-BEHAVIOR; NEURAL MECHANISMS; RHESUS-MONKEY; HUMAN BRAIN; FMRI DATA; OXYTOCIN; ANTAGONIST; CONNECTIVITY AB The neuropeptide vasopressin is a modulator of mammalian social behavior and emotion, particularly fear, aggression, and anxiety. In humans, the neural circuitry underlying behavioral effects of vasopressin is unknown. Using a double-blind crossover administration of 40 IU of vasopressin or placebo and functional MRI during processing of facial emotions in healthy male volunteers, we show that vasopressin specifically reduces differential activation in the subgenual cingulate cortex. Structural equation modeling of a previously evaluated circuit between amygdala, subgenual cingulate, and supragenual cingulate revealed altered effective connectivity between subgenual and supragenual cingulate under vasopressin. Our data demonstrate an impact of vasopressin on activity and connectivity in the cortical component of a medial prefrontal cortex-amygdala circuit implicated in emotional regulation, providing the first data on the neural basis for the effects of vasopressin on social behavior in humans with potential therapeutic significance for mood and anxiety disorders. C1 [Zink, Caroline F.; Stein, Jason L.; Kempf, Lucas; Hakimi, Shabnam; Meyer-Lindenberg, Andreas] NIMH, Genes Cognit & Psychosis Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Meyer-Lindenberg, Andreas] Cent Inst Mental Hlth, D-68159 Mannheim, Germany. [Stein, Jason L.] Univ Calif Los Angeles, Dept Neurol, Lab NeuroImaging, Los Angeles, CA 90095 USA. RP Zink, CF (reprint author), NIMH, NIH, 9000 Rockville Pike,Bldg 10,Room 3C101, Bethesda, MD 20814 USA. EM zinkc@mail.nih.gov; a.meyer-lindenberg@zi-mannheim.de RI Meyer-Lindenberg, Andreas/H-1076-2011; OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123; Stein, Jason/0000-0003-4829-0513; Hakimi, Shabnam/0000-0003-4122-6041 FU National Institute of Mental Health, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. We thank Courtnea A. Rainey, Timothy O. Laumann, and Ian J. Lent for research assistance, Yunxia Tong and Qiang Chen for technical assistance, Gerald Overman and Judith Starling for pharmaceutical management, and Heike Tost for thoughtful discussion. NR 54 TC 64 Z9 66 U1 1 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 19 PY 2010 VL 30 IS 20 BP 7017 EP 7022 DI 10.1523/JNEUROSCI.4899-09.2010 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 598NN UT WOS:000277844700022 PM 20484643 ER PT J AU Lucas, HR DeBeer, S Hong, MS Lee, JC AF Lucas, Heather R. DeBeer, Serena Hong, Myoung-Soon Lee, Jennifer C. TI Evidence for Copper-dioxygen Reactivity during alpha-Synuclein Fibril Formation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID AMYLOID-BETA PEPTIDE; ALZHEIMERS; BINDING; DISEASE; AGGREGATION; MECHANISM; PROTEIN; PRION AB alpha-Synuclein (alpha-syn), a presynaptic protein implicated in Parkinson's disease, binds copper(II) ion (1:1) with submicromolar affinity in vitro. Insights on the molecular details of soluble- and fibrillar-Cu-alpha-syn are gained through X-ray absorption spectroscopy. Our results indicate that the copper coordination environment (3-to-4 N/O ligands, average Cu-ligand distance similar to 1.96 angstrom) exhibits little structural rearrangement upon amyloid formation in spite of the overall polypeptide conformational change from disordered-to-beta-sheet. Interestingly, we find that some population of Cu(II)-alpha-syn reduces to Cu(I)-alpha-syn in the absence of O(2). This autoreduction event appears diminished in the presence of O(2) suggestive of preceding Cu(I)/O(2) chemistry. Evidence for generation of reactive oxygen species is obtained by the observation of new emission features attributed to dityrosine cross-links in fibrillar samples. C1 [Lucas, Heather R.; Hong, Myoung-Soon; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Lucas, Heather R.; Hong, Myoung-Soon; Lee, Jennifer C.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [DeBeer, Serena] Cornell Univ, Baker Lab, Dept Chem & Chem Biol, Ithaca, NY 14853 USA. RP Lee, JC (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov RI DeBeer, Serena/G-6718-2012; Lee, Jennifer/E-9658-2015 OI Lee, Jennifer/0000-0003-0506-8349 FU NIH, NHLBI; Cornell University; DOE; BER; NIH, NCRR FX Supported by the Intramural Research Program at NIH, NHLBI (J.C.L.) and Cornell University (S.D.). XAS was carried out at SSRL, a DOE, BES facility. The SSRL SMB Program is supported by the DOE, BER and NIH, NCRR. We also thank Duck-Yeon Lee (NHLBI Protein Analysis Facility) and Grzegorz Piszczek (NHLBI Biophysical Facility). NR 21 TC 26 Z9 27 U1 0 U2 8 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 MAY 19 PY 2010 VL 132 IS 19 BP 6636 EP + DI 10.1021/ja101756m PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 596YJ UT WOS:000277721500012 PM 20423081 ER PT J AU Gail, MH Mai, PL AF Gail, Mitchell H. Mai, Phuong L. TI Comparing Breast Cancer Risk Assessment Models SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID FAMILY-HISTORY; SCORING SYSTEM; PREDICTION; WOMEN; VALIDATION; BRCA1; MUTATION; PREVENTION; TAMOXIFEN; BOADICEA C1 [Gail, Mitchell H.; Mai, Phuong L.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Rm 8032, Bethesda, MD 20892 USA. EM gailm@mail.nih.gov RI Vinnicombe, Sarah/C-2606-2012 NR 30 TC 46 Z9 46 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 19 PY 2010 VL 102 IS 10 BP 665 EP U10 DI 10.1093/jnci/djq141 PG 4 WC Oncology SC Oncology GA 600MM UT WOS:000277990700001 PM 20427429 ER PT J AU Hocking, WG Hu, P Oken, MM Winslow, SD Kvale, PA Prorok, PC Ragard, LR Commins, J Lynch, DA Andriole, GL Buys, SS Fouad, MN Fuhrman, CR Isaacs, C Yokochi, LA Riley, TL Pinsky, PF Gohagan, JK Berg, CD AF Hocking, William G. Hu, Ping Oken, Martin M. Winslow, Stephen D. Kvale, Paul A. Prorok, Philip C. Ragard, Lawrence R. Commins, John Lynch, David A. Andriole, Gerald L. Buys, Saundra S. Fouad, Mona N. Fuhrman, Carl R. Isaacs, Claudine Yokochi, Lance A. Riley, Thomas L. Pinsky, Paul F. Gohagan, John K. Berg, Christine D. CA PLCO Project Team TI Lung Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID POSITIVE PREDICTIVE-VALUE; FOLLOW-UP; SMOKING; RISK; EPIDEMIOLOGY; STATISTICS; MORTALITY; SURVIVAL; PROGRAM AB Background The 5-year overall survival rate of lung cancer patients is approximately 15%. Most patients are diagnosed with advanced-stage disease and have shorter survival rates than patients with early-stage disease. Although screening for lung cancer has the potential to increase early diagnosis, it has not been shown to reduce lung cancer mortality rates. In 1993, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was initiated specifically to determine whether screening would reduce mortality rates from PLCO cancers. Methods A total of 77 464 participants, aged 55-74 years, were randomly assigned to the intervention arm of the PLCO Cancer Screening Trial between November 8, 1993, and July 2, 2001. Participants received a baseline chest radiograph (CXR), followed by three annual single-view CXRs at the 10 US screening centers. Cancers were classified as screen detected and nonscreen detected (interval or never screened) and according to tumor histology. The positivity rates of screen-detected cancers and positive predictive values (PPVs) were calculated. Because 51.6% of the participants were current or former smokers, logistic regression analysis was performed to control for smoking status. All statistical tests were two-sided. Results Compliance with screening decreased from 86.6% at baseline to 78.9% at the last screening. Overall positivity rates were 8.9% at baseline and 6.6%-7.1% at subsequent screenings; positivity rates increased modestly with smoking risk categories (P(trend) < .001). The PPVs for all participants were 2.0% at baseline and 1.1%, 1.5%, and 2.4% at years 1, 2, and 3, respectively; PPVs in current smokers were 5.9% at baseline and 3.3%, 4.2%, and 5.6% at years 1, 2, and 3, respectively. A total of 564 lung cancers were diagnosed, of which 306 (54%) were screen-detected cancers and 87% were non-small cell lung cancers. Among non-small cell lung cancers, 59.6% of screen-detected cancers and 33.3% of interval cancers were early (I-II) stage. Conclusions The PLCO Cancer Screening Trial demonstrated the ability to recruit, retain, and screen a large population over multiple years at multiple centers. A higher proportion of screen-detected lung cancers were early stage, but a conclusion on the effectiveness of CXR screening must await final PLCO results, which are anticipated at the end of 2015. C1 [Hocking, William G.] Marshfield Clin Fdn Med Res & Educ, Dept Clin Oncol, Marshfield, WI 54449 USA. [Hu, Ping; Prorok, Philip C.; Pinsky, Paul F.; Gohagan, John K.; Berg, Christine D.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Oken, Martin M.] Univ Minnesota, Hubert H Humphrey Canc Ctr, Minneapolis, MN USA. [Winslow, Stephen D.; Commins, John; Riley, Thomas L.] Informat Management Serv Inc, Rockville, MD USA. [Kvale, Paul A.] Henry Ford Hlth Syst, Dept Pulm Dis, Detroit, MI USA. [Ragard, Lawrence R.] Westat Corp, Rockville, MD USA. [Lynch, David A.] Natl Jewish Hlth, Div Radiol, Denver, CO USA. [Andriole, Gerald L.] Washington Univ, Sch Med, Dept Surg Urol Surg, St Louis, MO USA. [Buys, Saundra S.] Univ Utah, Dept Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Fouad, Mona N.] Univ Alabama, Sch Med, Birmingham, AL USA. [Fuhrman, Carl R.] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [Isaacs, Claudine] Georgetown Univ, Dept Hematol Oncol, Washington, DC USA. [Yokochi, Lance A.] Pacific Hlth Res Inst, Honolulu, HI USA. RP Hocking, WG (reprint author), Marshfield Clin Fdn Med Res & Educ, Dept Clin Oncol, 1000 N Oak Ave, Marshfield, WI 54449 USA. EM hocking.william@marshfieldclinic.org OI Hocking, William/0000-0002-0690-3759 FU Division of Cancer Prevention, National Cancer Institute (NCI), National Institutes of Health FX This study was supported by contracts from the Division of Cancer Prevention, National Cancer Institute (NCI), National Institutes of Health to the screening centers, Westat Inc, and Information Management Services. NR 33 TC 40 Z9 43 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 19 PY 2010 VL 102 IS 10 BP 722 EP 731 DI 10.1093/jnci/djq126 PG 10 WC Oncology SC Oncology GA 600MM UT WOS:000277990700012 PM 20442215 ER PT J AU Fu, YP Edvardsen, H Kaushiva, A Arhancet, JP Howe, TM Kohaar, I Porter-Gill, P Shah, A Landmark-Hoyvik, H Fossa, SD Ambs, S Naume, B Borresen-Dale, AL Kristensen, VN Prokunina-Olsson, L AF Fu, Yi-Ping Edvardsen, Hege Kaushiva, Alpana Arhancet, Juan P. Howe, Tiffany M. Kohaar, Indu Porter-Gill, Patricia Shah, Anushi Landmark-Hoyvik, Hege Fossa, Sophie D. Ambs, Stefan Naume, Bjorn Borresen-Dale, Anne-Lise Kristensen, Vessela N. Prokunina-Olsson, Ludmila TI NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations SO MOLECULAR CANCER LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CONFER SUSCEPTIBILITY; COLORECTAL-CANCER; COMMON VARIANTS; P53; RISK; CELL; TISSUE; RESTORATION AB Background: A recent genome-wide association study (GWAS) has identified a single nucleotide polymorphism (SNP) rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger in patients with estrogen receptor (ER)(+) versus ER-cancer. Results: We found association between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of NOTCH2 was found to be lowest in tumors with TP53 mutations and highest in TP53 wild-type/ER(+) tumors (p = 0.0059). In the latter group, the NOTCH2 expression was particularly increased in carriers of the risk genotypes (AG/GG) of rs11249433 when compared to the non-risk AA genotype (p = 0.0062). Similar association between NOTCH2 expression and rs11249433 was observed in 60 samples of purified monocytes from healthy controls (p = 0.015), but not in total blood samples from 302 breast cancer patients and 76 normal breast tissue samples. We also identified the first possible dominant-negative form of NOTCH2, a truncated version of NOTCH2 consisting of only the extracellular domain. Conclusion: This is the first study to show that the expression of NOTCH2 differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433. The NOTCH pathway has key functions in stem cell differentiation of ER(+) luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER(+) luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of NOTCH2 expression by rs11249433 and the role of NOTCH2 splicing forms in breast cancer development. C1 [Fu, Yi-Ping; Kaushiva, Alpana; Arhancet, Juan P.; Kohaar, Indu; Porter-Gill, Patricia; Shah, Anushi; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Edvardsen, Hege; Landmark-Hoyvik, Hege; Borresen-Dale, Anne-Lise; Kristensen, Vessela N.] Oslo Univ Hosp, Dept Genet, Inst Canc Res, Radiumhosp, Oslo, Norway. [Edvardsen, Hege; Fossa, Sophie D.; Borresen-Dale, Anne-Lise; Kristensen, Vessela N.] Univ Oslo, Norwegian Radium Hosp, Fac Div Med, Radiumhosp, Oslo, Norway. [Howe, Tiffany M.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fossa, Sophie D.] Oslo Univ Hosp, Radiumhosp, Dept Clin Canc Res, Canc Clin, Oslo, Norway. [Naume, Bjorn] Oslo Univ Hosp, Radiumhosp, Dept Oncol, Canc Clin, Oslo, Norway. [Kristensen, Vessela N.] Univ Oslo, Inst Clin Epidemiol & Mol Biol EpiGen, Fac Med, Oslo, Norway. RP Prokunina-Olsson, L (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM prokuninal@mail.nih.gov OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU NCI/NIH; Norwegian Research council [155218/V40, 175240/S10]; FUGE-NFR [181600/V11]; Norwegian Cancer Society [D99061, D03067] FX The study was supported by intramural research program of NCI/NIH, the Norwegian Research council grants 155218/V40, 175240/S10 to ALBD, FUGE-NFR 181600/V11 to VNK and a Swizz Bridge Award to ALBD, and the Norwegian Cancer Society grants D99061 to ALBD and D03067 to VNK. NR 52 TC 28 Z9 29 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD MAY 19 PY 2010 VL 9 AR 113 DI 10.1186/1476-4598-9-113 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 617JB UT WOS:000279275800003 PM 20482849 ER PT J AU Hutchinson, MR Lewis, SS Coats, BD Rezvani, N Zhang, Y Wieseler, JL Somogyi, AA Yin, H Maier, SF Rice, KC Watkins, LR AF Hutchinson, M. R. Lewis, S. S. Coats, B. D. Rezvani, N. Zhang, Y. Wieseler, J. L. Somogyi, A. A. Yin, H. Maier, S. F. Rice, K. C. Watkins, L. R. TI POSSIBLE INVOLVEMENT OF TOLL-LIKE RECEPTOR 4/MYELOID DIFFERENTIATION FACTOR-2 ACTIVITY OF OPIOID INACTIVE ISOMERS CAUSES SPINAL PROINFLAMMATION AND RELATED BEHAVIORAL CONSEQUENCES SO NEUROSCIENCE LA English DT Article DE cytokine; chemokine; analgesia; tolerance; microglia ID ACTIVATED PROTEIN-KINASE; DEXTRO-MORPHINE; NEUROPATHIC PAIN; LEVO-MORPHINE; NITRIC-OXIDE; MICROGLIA; ANALGESIA; TOLERANCE; EXPRESSION; MOUSE AB Opioid-induced glial activation and its proinflammatory consequences have been associated with both reduced acute opioid analgesia and the enhanced development of tolerance, hyperalgesia and allodynia following chronic opioid administration. Intriguingly, recent evidence demonstrates that these effects can result independently from the activation of classical, stereoselective opioid receptors. Here, a structurally disparate range of opioids cause activation of signaling by the innate immune receptor toll like receptor 4 (TLR4), resulting in proinflammatory glial activation. In the present series of studies, we demonstrate that the (+)-isomers of methadone and morphine, which bind with negligible affinity to classical opioid receptors, induced upregulation of proinflammatory cytokine and chemokine production in rat isolated dorsal spinal cord. Chronic intrathecal (+)-methadone produced hyperalgesia and allodynia, which were associated with significantly increased spinal glial activation (TLR4 mRNA and protein) and the expression of multiple chemokines and cytokines. Statistical analysis suggests that a cluster of cytokines and chemokines may contribute to these nociceptive behavioral changes. Acute intrathecal (+)-methadone and (+)-morphine were also found to induce microglial, interleukin-1 and TLR4/myeloid differentiation factor-2 (MD-2) dependent enhancement of pain responsivity. In silico docking analysis demonstrated (+)-naloxone sensitive docking of (+)-methadone and (+)-morphine to human MD-2. Collectively, these data provide the first evidence of the pro-nociceptive consequences of small molecule xenobiotic activation of spinal TLR4 signaling independent of classical opioid receptor involvement. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Hutchinson, M. R.; Somogyi, A. A.] Univ Adelaide, Discipline Pharmacol, Sch Med Sci, Adelaide, SA 5005, Australia. [Hutchinson, M. R.; Lewis, S. S.; Coats, B. D.; Rezvani, N.; Zhang, Y.; Wieseler, J. L.; Maier, S. F.; Watkins, L. R.] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Hutchinson, M. R.; Lewis, S. S.; Coats, B. D.; Rezvani, N.; Zhang, Y.; Wieseler, J. L.; Maier, S. F.; Watkins, L. R.] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA. [Yin, H.] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Rice, K. C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Rockville, MD 20892 USA. [Rice, K. C.] NIAAA, Rockville, MD 20892 USA. RP Hutchinson, MR (reprint author), Univ Adelaide, Discipline Pharmacol, Sch Med Sci, Adelaide, SA 5005, Australia. EM mark.hutchinson@adelaide.edu.au RI Hutchinson, Mark/G-4147-2014; YIN, HANG/O-2097-2014 OI Hutchinson, Mark/0000-0003-2154-5950; YIN, HANG/0000-0002-9762-4818 FU International Association for the Study of Pain International Collaborative; American Australian Association; National Health and Medical Research Council [ID 465423]; NIH [DA015642, DA017670, DA024044, DE017782]; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX International Association for the Study of Pain International Collaborative grant, American Australian Association Merck Company Foundation Fellowship, National Health and Medical Research Council CJ Martin Fellowship (ID 465423) and NIH Grants DA015642, DA017670, DA024044 and DE017782. This work was partially supported by the by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. We thank Avigen (Alameda, CA, USA) for the gift of the HEK293-TLR4 cell line. NR 43 TC 51 Z9 53 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD MAY 19 PY 2010 VL 167 IS 3 BP 880 EP 893 DI 10.1016/j.neuroscience.2010.02.011 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 587IY UT WOS:000276985800033 PM 20178837 ER PT J AU Li, J Ribeiro, JMC Yan, GY AF Li, Jun Ribeiro, Jose M. C. Yan, Guiyun TI Allelic Gene Structure Variations in Anopheles gambiae Mosquitoes SO PLOS ONE LA English DT Article ID QUANTITATIVE TRAIT LOCI; GENOME-WIDE SURVEY; MESSENGER-RNA; AB-INITIO; SEQUENCE; PREDICTION; EXON; REFRACTORINESS; IDENTIFICATION; ISOFORMS AB Background: Allelic gene structure variations and alternative splicing are responsible for transcript structure variations. More than 75% of human genes have structural isoforms of transcripts, but to date few studies have been conducted to verify the alternative splicing systematically. Methodology/Principal Findings: The present study used expressed sequence tags (ESTs) and EST tagged SNP patterns to examine the transcript structure variations resulting from allelic gene structure variations in the major human malaria vector, Anopheles gambiae. About 80% of 236,004 available A. gambiae ESTs were successfully aligned to A. gambiae reference genomes. More than 2,340 transcript structure variation events were detected. Because the current A. gambiae annotation is incomplete, we re-annotated the A. gambiae genome with an A. gambiae-specific gene model so that the effect of variations on gene coding could be better evaluated. A total of 15,962 genes were predicted. Among them, 3,873 were novel genes and 12,089 were previously identified genes. The gene completion rate improved from 60% to 84%. Based on EST support, 82.5% of gene structures were predicted correctly. In light of the new annotation, we found that similar to 78% of transcript structure variations were located within the coding sequence (CDS) regions, and >65% of variations in the CDS regions have the same open-reading-frame. The association between transcript structure isoforms and SNPs indicated that more than 28% of transcript structure variation events were contributed by different gene alleles in A. gambiae. Conclusions/Significance: We successfully expanded the A. gambiae genome annotation. We predicted and analyzed transcript structure variations in A. gambiae and found that allelic gene structure variation plays a major role in transcript diversity in this important human malaria vector. C1 [Li, Jun] Univ Minnesota, Dept Microbiol, St Paul, MN 55108 USA. [Ribeiro, Jose M. C.] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Yan, Guiyun] Univ Calif Irvine, Program Publ Hlth, Irvine, CA USA. RP Li, J (reprint author), Univ Minnesota, Dept Microbiol, St Paul, MN 55108 USA. EM junli@umn.edu FU National Institutes of Health [R56AI081829] FX This research is supported by a grant from the National Institutes of Health (R56AI081829 to Jun Li). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 5 Z9 6 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 19 PY 2010 VL 5 IS 5 AR e10699 DI 10.1371/journal.pone.0010699 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 598NT UT WOS:000277845400009 PM 20502664 ER PT J AU Favre, D Mold, J Hunt, PW Kanwar, B Loke, P Seu, L Barbour, JD Lowe, MM Jayawardene, A Aweeka, F Huang, Y Douek, DC Brenchley, JM Martin, JN Hecht, FM Deeks, SG McCune, JM AF Favre, David Mold, Jeff Hunt, Peter W. Kanwar, Bittoo Loke, P'ng Seu, Lillian Barbour, Jason D. Lowe, Margaret M. Jayawardene, Anura Aweeka, Francesca Huang, Yong Douek, Daniel C. Brenchley, Jason M. Martin, Jeffrey N. Hecht, Frederick M. Deeks, Steven G. McCune, Joseph M. TI Tryptophan Catabolism by Indoleamine 2,3-Dioxygenase 1 Alters the Balance of T(H)17 to Regulatory T Cells in HIV Disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; IMMUNE ACTIVATION; INTERFERON-GAMMA; LYMPH-NODES; TH17 CELLS; INFECTION; INDUCTION; DIFFERENTIATION; INFLAMMATION; INHIBITION AB The pathogenesis of human and simian immunodeficiency viruses is characterized by CD4(+) T cell depletion and chronic T cell activation, leading ultimately to AIDS. CD4(+) T helper (T-H) cells provide protective immunity and immune regulation through different immune cell functional subsets, including T(H)1, T(H)2, T regulatory (T-reg),and interleukin-17 (IL-17)-secreting T(H)17 cells. Because IL-17 can enhance host defenses against microbial agents, thus maintaining the integrity of the mucosal barrier, loss of T(H)17 cells may foster microbial translocation and sustained inflammation. Here, we study HIV-seropositive subjects and find that progressive disease is associated with the loss of T(H)17 cells and a reciprocal increase in the fraction of the immunosuppressive T-reg cells both in peripheral blood and in rectosigmoid biopsies. The loss of T(H)17/T-reg balance is associated with induction of indoleamine 2,3-dioxygenase 1 (IDO1) by myeloid antigen-presenting dendritic cells and with increased plasma concentration of microbial products. In vitro, the loss of T(H)17/T-reg balance is mediated directly by the proximal tryptophan catabolite from IDO metabolism, 3-hydroxyanthranilic acid. We postulate that induction of IDO may represent a critical initiating event that results in inversion of the T(H)17/T-reg balance and in the consequent maintenance of a chronic inflammatory state in progressive HIV disease. C1 [Favre, David; Mold, Jeff; Kanwar, Bittoo; Loke, P'ng; Seu, Lillian; Lowe, Margaret M.; McCune, Joseph M.] Univ Calif San Francisco, Dept Med, Div Expt Med, San Francisco, CA 94110 USA. [Hunt, Peter W.; Barbour, Jason D.; Hecht, Frederick M.; Deeks, Steven G.] Univ Calif San Francisco, Dept Med, HIV AIDS Program, San Francisco, CA 94110 USA. [Kanwar, Bittoo] Univ Calif San Francisco, Dept Pediat, Div Gastroenterol, San Francisco, CA 94110 USA. [Jayawardene, Anura; Aweeka, Francesca] Univ Calif San Francisco, Dept Clin Pharm, Drug Res Unit, San Francisco, CA 94143 USA. [Huang, Yong] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP McCune, JM (reprint author), Univ Calif San Francisco, Dept Med, Div Expt Med, San Francisco, CA 94110 USA. EM mike.mccune@ucsf.edu RI seu, lillian/D-1165-2011; OI seu, lillian/0000-0002-8456-019X; Mold, Jeffrey/0000-0003-2195-2978 FU Intramural NIH HHS; NCRR NIH HHS [UL1 RR024131]; NIAID NIH HHS [K01 AI066917, AI069994, K23 AI065244, K24 AI069994, P01 AI071713, P30 AI022763, P30 AI027763, P30 AI27763, R01 AI066917, R01 K23 AI065244, R37 AI040312, R37 AI40312]; NIDDK NIH HHS [K08 DK083334, K08 DK083334-01A1, K24 DK060617, T32 DK007762]; NIH HHS [DP1 OD000329, DPI OD00329]; NIMH NIH HHS [P30 MH59037] NR 62 TC 92 Z9 93 U1 0 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAY 19 PY 2010 VL 2 IS 32 AR 32ra36 DI 10.1126/scitranslmed.3000632 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 598KK UT WOS:000277835400004 PM 20484731 ER PT J AU Nabel, EG AF Nabel, Elizabeth G. TI On Board with the Cures Acceleration Network SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Nabel, Elizabeth G.] Brigham & Womens Hosp, Boston, MA 02116 USA. [Nabel, Elizabeth G.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nabel, Elizabeth G.] NHLBI, NIH, Bethesda, MD 20824 USA. RP Nabel, EG (reprint author), Brigham & Womens Hosp, Boston, MA 02116 USA. EM enabel@partners.org NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAY 19 PY 2010 VL 2 IS 32 AR 32ed2 DI 10.1126/scitranslmed.3001136 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 598KK UT WOS:000277835400001 PM 20484728 ER PT J AU McClenahan, SD Bok, K Sosnovtsev, SV Neill, JD Burek, KA Beckmen, KB Smith, AW Green, KY Romero, CH AF McClenahan, Shasta D. Bok, Karin Sosnovtsev, Stanislav V. Neill, John D. Burek, Kathy A. Beckmen, Kimberlee B. Smith, Alvin W. Green, Kim Y. Romero, Carlos H. TI Expression and self-assembly of virus-like particles from two genotypes of marine vesiviruses and development of an ELISA for the detection of antibodies SO VETERINARY MICROBIOLOGY LA English DT Article DE Caliciviridae; Vesivirus; Virus-like particles; ELISA; Antibodies; Marine mammals ID SEA LION VIRUS; LINKED-IMMUNOSORBENT-ASSAY; CAPSID PROTEIN GENE; FELINE CALICIVIRUS; NUCLEOTIDE-SEQUENCE; VESICULAR EXANTHEMA; EUMETOPIAS-JUBATUS; NEUTRALIZING EPITOPES; SWINE VIRUS; IDENTIFICATION AB Sequences encoding the major and minor capsid proteins (VP1 and VP2) from two marine vesivirus isolates (Steller sea lion viruses V810 and V1415) were engineered for expression of virus-like particles (VLPs) in the baculovirus system. The resulting VLPs were morphologically similar to native vesivirus virions. Purified VLPs were probed in immunoblots with pooled antisera specific for nine San Miguel sea lion virus (SMSV) types, and a predominant protein of approximately 60 kDa was detected. An enzyme linked immunosorbent assay (ELISA) for the detection of antibodies was developed in which the VLPs served as antigen. The VLPs were adsorbed to the wells of a microplate, and the specificity of the ELISA was established with hyperimmune sera raised against 24 serotypes of the genus Vesivirus. The ELISA was used to screen for the presence of vesivirus specific antibodies in the sera of free-ranging Steller sea lions. The ELISA results demonstrated that Steller sea lions that inhabit the Pacific Ocean waters of southeast Alaska are widely exposed to antigenically related marine vesiviruses, while no previous exposure could be demonstrated using VLP antigens in 17 Steller sea lions from the Aleutian Islands. The broad reactivity of these VLPs and their non-infectious nature will facilitate global sero-epidemiological studies aimed at determining the incidence and prevalence of marine vesiviruses in mammals that inhabit the Pacific and Atlantic oceans as well as susceptible terrestrial animals. (C) 2009 Elsevier B.V. All rights reserved. C1 [McClenahan, Shasta D.; Romero, Carlos H.] Univ Florida, Dept Infect Dis & Pathol, Coll Vet Med, Gainesville, FL 32610 USA. [Bok, Karin; Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Neill, John D.] USDA, Natl Anim Dis Ctr, Ames, IA 50010 USA. [Burek, Kathy A.] Alaska Vet Pathol Serv, Eagle River, AK 99577 USA. [Beckmen, Kimberlee B.] Alaska Dept Fish & Game, Div Wildlife Conservat, Fairbanks, AK 99701 USA. [Smith, Alvin W.] Oregon State Univ, Lab Calicivirus Studies, Corvallis, OR 97330 USA. RP Romero, CH (reprint author), 2015 SW 16th Ave,Bldg 1017, Gainesville, FL 32610 USA. EM romeroc@vetmed.ufl.edu FU College of Veterinary Medicine, University of Florida; NIH, NIAID; Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida FX This research was funded by the Marine Mammal Health Program, College of Veterinary Medicine, University of Florida, and in part by the Intramural Research Program of the NIH, NIAID. SDM was funded by the Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida. Sera from marine mammals were obtained under permit numbers 358-1564-03 and 782-1889 from the National Oceanic and Atmospheric administration (NOAA), US Department of Commerce. NR 37 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1135 J9 VET MICROBIOL JI Vet. Microbiol. PD MAY 19 PY 2010 VL 142 IS 3-4 BP 184 EP 192 DI 10.1016/j.vetmic.2009.09.057 PG 9 WC Microbiology; Veterinary Sciences SC Microbiology; Veterinary Sciences GA 609TB UT WOS:000278679000005 PM 19913368 ER PT J AU Subramaniam, AB Lecuyer, S Ramamurthi, KS Losick, R Stone, HA AF Subramaniam, Anand Bala Lecuyer, Sigolene Ramamurthi, Kumaran S. Losick, Richard Stone, Howard A. TI Particle/Fluid Interface Replication as a Means of Producing Topographically Patterned Polydimethylsiloxane Surfaces for Deposition of Lipid Bilayers SO ADVANCED MATERIALS LA English DT Article ID ATOMIC-FORCE MICROSCOPY; GEL TRAPPING TECHNIQUE; PHOSPHOLIPID-BILAYERS; MEMBRANE CURVATURE; WATER INTERFACE; LOCALIZATION; SILICA; MONOLAYERS; ARRAYS; FABRICATION AB A simple method to produce topographically patterned substrates from polydimethylsiloxane (PDMS) is presented. Surfaces with positively or negatively curved features, a combination of positively and negatively curved features or geometrically complex biomimetic features are fabricated. High-quality lipid bilayers that conform to the topography of the substrates can be prepared, a characteristic useful for biophysical studies. C1 [Subramaniam, Anand Bala; Lecuyer, Sigolene; Ramamurthi, Kumaran S.; Losick, Richard; Stone, Howard A.] Princeton Univ, Dept Mech & Aerosp Engn, Princeton, NJ 08544 USA. [Subramaniam, Anand Bala; Lecuyer, Sigolene] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Ramamurthi, Kumaran S.] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. [Losick, Richard] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Stone, HA (reprint author), Princeton Univ, Dept Mech & Aerosp Engn, Princeton, NJ 08544 USA. EM hastone@princeton.edu RI lecuyer, sigolene/E-7626-2012; Ramamurthi, Kumaran/P-3516-2015 FU NIGMS NIH HHS [R01 GM018568-39, R01 GM018568] NR 40 TC 17 Z9 17 U1 2 U2 24 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0935-9648 J9 ADV MATER JI Adv. Mater. PD MAY 18 PY 2010 VL 22 IS 19 BP 2142 EP + DI 10.1002/adma.200903625 PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 608QR UT WOS:000278601400005 PM 20376852 ER PT J AU Kamikubo, Y Zhao, L Wunderlich, M Corpora, T Hyde, RK Paul, TA Kundu, M Garrett, L Compton, S Huang, G Wolff, L Ito, Y Bushweller, J Mulloy, JC Liu, PP AF Kamikubo, Yasuhiko Zhao, Ling Wunderlich, Mark Corpora, Takeshi Hyde, R. Katherine Paul, Thomas A. Kundu, Mondira Garrett, Lisa Compton, Sheila Huang, Gang Wolff, Linda Ito, Yoshiaki Bushweller, John Mulloy, James C. Liu, P. Paul TI Accelerated Leukemogenesis by Truncated CBF beta-SMMHC Defective in High-Affinity Binding with RUNX1 SO CANCER CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; FUSION GENE CBFB-MYH11; TRANSCRIPTION FACTOR; HEMATOPOIESIS; AML1-ETO; PROTEIN; CELLS; AML; PHOSPHORYLATION AB Dominant RUNX1 inhibition has been proposed as a common pathway for CBF leukemia. CBF beta-SMMHC, a fusion protein in human acute myeloid leukemia (AML), dominantly inhibits RUNX1 largely through its RUNX1 high-affinity binding domain (HABD). However, the type I CBF beta-SMMHC fusion in AML patients lacks HABD. Here, we report that the type I CBF beta-SMMHC protein binds RUNX1 inefficiently. Knockin mice expressing CBF beta-SMMHC with a HABD deletion developed leukemia quickly, even though hematopoietic defects associated with Runx1-inhibition were partially rescued. A larger pool of leukemia-initiating cells, increased MN1 expression, and retention of RUNX1 phosphorylation are potential mechanisms for accelerated leukemia development in these mice. Our data suggest that RUNX1 dominant inhibition may not be a critical step for leukemogenesis by CBF beta-SMMHC. C1 [Kamikubo, Yasuhiko; Zhao, Ling; Hyde, R. Katherine; Kundu, Mondira; Compton, Sheila; Liu, P. Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Wunderlich, Mark; Mulloy, James C.] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol, Cincinnati, OH 45226 USA. [Corpora, Takeshi; Wolff, Linda; Bushweller, John] Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA. [Paul, Thomas A.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Huang, Gang; Ito, Yoshiaki] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117456, Singapore. RP Liu, PP (reprint author), NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. EM pliu@mail.nih.gov RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU National Human Genome Research Institute, NIH; NIH [CA118319]; U.S.P.H.S [MO1 RR 08084]; National Center for Research Resources, NIH FX We thank M. Kirby and S. Anderson for FACS analysis, B.A. van der Reijden for the human leukemia sample, C. Wang for statistical analysis of microarray data, A. Elkahloun for microarray hybridization, K. Brewery for the cytokine TPO, and Amgen for FLT3L, SCF, and IL-6. This work was supported by the Intramural Research Programs of National Human Genome Research Institute, NIH, NIH grant CA118319, U.S.P.H.S. Grant Number MO1 RR 08084, and General Clinical Research Centers Program, National Center for Research Resources, NIH. NR 47 TC 15 Z9 15 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD MAY 18 PY 2010 VL 17 IS 5 BP 455 EP 468 DI 10.1016/j.ccr.2010.03.022 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 598UC UT WOS:000277863300008 PM 20478528 ER PT J AU Averbeck, BB AF Averbeck, Bruno B. TI Oxytocin and the salience of social cues SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID HIGH-FUNCTIONING AUTISM; MATERNAL-BEHAVIOR; NEURAL CIRCUITRY; HUMANS; FACES; TRUST; RATS; MIND C1 NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. EM averbeckbb@mail.nih.gov NR 20 TC 28 Z9 29 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 MAY 18 PY 2010 VL 107 IS 20 BP 9033 EP 9034 DI 10.1073/pnas.1004892107 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 598GH UT WOS:000277822600005 PM 20448196 ER PT J AU Pawar, SA Sarkar, TR Balamurugan, K Sharan, S Wang, J Zhang, YH Dowdy, SF Huang, AM Sterneck, E AF Pawar, Snehalata A. Sarkar, Tapasree Roy Balamurugan, Kuppusamy Sharan, Shikha Wang, Jun Zhang, Youhong Dowdy, Steven F. Huang, A-Mei Sterneck, Esta TI C/EBP delta targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE breast cancer; tumor suppressor; cell cycle; anaphase promoting complex; Cdh1/FZR1 ID BINDING-PROTEIN-DELTA; GENE-EXPRESSION; BREAST-CANCER; CELL-CYCLE; GENOMIC STABILITY; TUMOR SUPPRESSION; GROWTH ARREST; DNA-DAMAGE; COMPLEX; TRANSCRIPTION AB The transcription factor CCAAT/enhancer binding protein delta (C/EBP delta, CEBPD, NFIL-6 beta) has tumor suppressor function; however, the molecular mechanism(s) by which C/EBP delta exerts its effect are largely unknown. Here, we report that C/EBP delta induces expression of the Cdc27 (APC3) subunit of the anaphase promoting complex/cyclosome (APC/C), which results in the polyubiquitination and degradation of the prooncogenic cell cycle regulator cyclin D1, and also down-regulates cyclin B1, Skp2, and Plk-1. In C/EBPd knockout mouse embryo fibroblasts (MEF) Cdc27 levels were reduced, whereas cyclin D1 levels were increased even in the presence of activated GSK-3 beta. Silencing of C/EBP delta, Cdc27, or the APC/C coactivator Cdh1 (FZR1) in MCF-10A breast epithelial cells increased cyclin D1 protein expression. Like C/EBP delta, and in contrast to cyclin D1, Cdc27 was down-regulated in several breast cancer cell lines, suggesting that Cdc27 itself may be a tumor suppressor. Cyclin D1 is a known substrate of polyubiquitination complex SKP1/CUL1/F-box (SCF), and our studies show that Cdc27 directs cyclin D1 to alternative degradation by APC/C. These findings shed light on the role and regulation of APC/C, which is critical for most cellular processes. C1 [Pawar, Snehalata A.; Sarkar, Tapasree Roy; Balamurugan, Kuppusamy; Sharan, Shikha; Wang, Jun; Zhang, Youhong; Huang, A-Mei; Sterneck, Esta] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Dowdy, Steven F.] Univ Calif San Diego, Sch Med, Howard Hughes Med Inst, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. RP Sterneck, E (reprint author), NCI, Ctr Canc Res, Frederick, MD 21702 USA. EM sternecg@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX We thank Glenn Summers, Jennifer Beachley, and Linda Miller for outstanding assistance with animal work and Jiro Wada for preparation of the figures. For generously sharing valuable reagents, we thank Drs. Andrew Arnold (University of Connecticut School of Medicine); Ching Shih Chen and James W. DeWille (The Ohio State University); J. Alan Diehl (Abramson Family Cancer Research Institute); Philip Hieter (The University of British Columbia); Peter F. Johnson, Brad St. Croix, Allan M. Weissman, and Kyung S. Lee (CCR, National Cancer Institute); Muthusamy Thangaraju (Medical College of Georgia); and Cynthia Zahnow (The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University). For discussion and constructive comments, we thank Drs. Ira Daar, J. Alan Diehl, Philipp Kaldis, Deborah Morrison, and Allan Weissman. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. BD69319 and 69320 mouse monoclonal antibodies against C/EBP delta were provided by BD Biosciences Pharmingen through an Antibody Co-development Collaboration between the National Cancer Institute and BD Bioscience. NR 42 TC 31 Z9 31 U1 3 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 18 PY 2010 VL 107 IS 20 BP 9210 EP 9215 DI 10.1073/pnas.0913813107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 598GH UT WOS:000277822600036 PM 20439707 ER PT J AU Levy, D Neuhausen, SL Hunt, SC Kimura, M Hwang, SJ Chen, W Bis, JC Fitzpatrick, AL Smith, E Johnson, AD Gardner, JP Srinivasan, SR Schork, N Rotter, JI Herbig, U Psaty, BM Sastrasinh, M Murray, SS Vasan, RS Province, MA Glazer, NL Lu, XB Cao, XJ Kronmal, R Mangino, M Soranzo, N Spector, TD Berenson, GS Aviv, A AF Levy, Daniel Neuhausen, Susan L. Hunt, Steven C. Kimura, Masayuki Hwang, Shih-Jen Chen, Wei Bis, Joshua C. Fitzpatrick, Annette L. Smith, Erin Johnson, Andrew D. Gardner, Jeffrey P. Srinivasan, Sathanur R. Schork, Nicholas Rotter, Jerome I. Herbig, Utz Psaty, Bruce M. Sastrasinh, Malinee Murray, Sarah S. Vasan, Ramachandran S. Province, Michael A. Glazer, Nicole L. Lu, Xiaobin Cao, Xiaojian Kronmal, Richard Mangino, Massimo Soranzo, Nicole Spector, Tim D. Berenson, Gerald S. Aviv, Abraham TI Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genes; aging; CXCR4; TERC ID PATERNAL AGE; CARDIOVASCULAR-DISEASE; PULMONARY-FIBROSIS; PULSE PRESSURE; BONE-MARROW; LENGTH; MUTATIONS; DESIGN; GENE; SNP AB Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging related disorders linked to altered LTL dynamics. C1 [Levy, Daniel; Hwang, Shih-Jen; Johnson, Andrew D.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Levy, Daniel; Hwang, Shih-Jen; Johnson, Andrew D.; Vasan, Ramachandran S.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Levy, Daniel; Hwang, Shih-Jen; Johnson, Andrew D.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Div Cardiol, Boston, MA 02118 USA. [Levy, Daniel; Hwang, Shih-Jen; Johnson, Andrew D.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Div Epidemiol, Boston, MA 02118 USA. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [Hunt, Steven C.] Univ Utah, Sch Med, Cardiovasc Genet Div, Salt Lake City, UT 84112 USA. [Chen, Wei; Srinivasan, Sathanur R.; Berenson, Gerald S.] Tulane Univ, Sch Publ Hlth & Trop Med, Bogalusa Heart Study, New Orleans, LA 70112 USA. [Bis, Joshua C.; Psaty, Bruce M.; Glazer, Nicole L.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98105 USA. [Bis, Joshua C.; Psaty, Bruce M.; Glazer, Nicole L.] Univ Washington, Dept Med, Seattle, WA 98105 USA. [Bis, Joshua C.; Psaty, Bruce M.; Glazer, Nicole L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98105 USA. [Fitzpatrick, Annette L.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98105 USA. [Fitzpatrick, Annette L.] Univ Washington, Dept Global Hlth, Seattle, WA 98105 USA. [Smith, Erin; Schork, Nicholas; Murray, Sarah S.] Scripps Translat Sci Inst, La Jolla, CA 92037 USA. [Smith, Erin; Schork, Nicholas; Murray, Sarah S.] Scripps Res Inst, San Diego, CA 92037 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98105 USA. [Province, Michael A.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63108 USA. [Kronmal, Richard] Univ Washington, Dept Biostat, Seattle, WA 98105 USA. [Mangino, Massimo; Soranzo, Nicole; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Soranzo, Nicole] Wellcome Trust Sanger Inst, Hinxton CB10 1HH, England. [Kimura, Masayuki; Gardner, Jeffrey P.; Herbig, Utz; Sastrasinh, Malinee; Lu, Xiaobin; Cao, Xiaojian; Aviv, Abraham] Univ Med & Dent New Jersey, Ctr Human Dev & Aging, Newark, NJ 07101 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM Levyd@nih.gov; avivab@umdnj.edu RI Smith, Erin/E-5933-2011; Johnson, Andrew/G-6520-2013; mangino, massimo/F-5134-2011; OI mangino, massimo/0000-0002-2167-7470; Soranzo, Nicole/0000-0003-1095-3852; Ramachandran, Vasan/0000-0001-7357-5970 NR 56 TC 121 Z9 123 U1 1 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 18 PY 2010 VL 107 IS 20 BP 9293 EP 9298 DI 10.1073/pnas.0911494107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 598GH UT WOS:000277822600050 PM 20421499 ER PT J AU Poulin, B Butcher, A McWilliams, P Bourgognon, JM Pawlak, R Kong, KC Bottrill, A Mistry, S Wess, J Rosethorne, EM Charlton, SJ Tobin, AB AF Poulin, Benoit Butcher, Adrian McWilliams, Phillip Bourgognon, Julie-Myrtille Pawlak, Robert Kong, Kok Choi Bottrill, Andrew Mistry, Sharad Wess, Juergen Rosethorne, Elizabeth M. Charlton, Steven J. Tobin, Andrew B. TI The M-3-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE fear conditioning; G protein-coupled receptor; hippocampus; ligand bias; Alzheimer's disease ID MUSCARINIC ACETYLCHOLINE-RECEPTOR; PROTEIN-COUPLED RECEPTOR; SH-SY5Y NEUROBLASTOMA-CELLS; 7-TRANSMEMBRANE RECEPTORS; ALZHEIMERS-DISEASE; M1 RECEPTORS; MICE LACKING; MUTANT MICE; HIPPOCAMPUS; FEAR AB Degeneration of the cholinergic system is considered to be the underlying pathology that results in the cognitive deficit in Alzheimer's disease. This pathology is thought to be linked to a loss of signaling through the cholinergic M-1-muscarinic receptor subtype. However, recent studies have cast doubt on whether this is the primary receptor mediating cholinergic-hippocampal learning and memory. The current study offers an alternative mechanism involving the M-3-muscarinic receptor that is expressed in numerous brain regions including the hippocampus. We demonstrate here that M-3-muscarinic receptor knockout mice show a deficit in fear conditioning learning and memory. The mechanism used by the M-3-muscarinic receptor in this process involves receptor phosphorylation because a knockin mouse strain expressing a phosphorylation-deficient receptor mutant also shows a deficit in fear conditioning. Consistent with a role for receptor phosphorylation, we demonstrate that the M-3-muscarinic receptor is phosphorylated in the hippocampus following agonist treatment and following fear conditioning training. Importantly, the phosphorylation-deficient M-3-muscarinic receptor was coupled normally to G(q/11)-signaling but was uncoupled from phosphorylation-dependent processes such as receptor internalization and arrestin recruitment. It can, therefore, be concluded that M-3-muscarinic receptor-dependent learning and memory depends, at least in part, on receptor phosphorylation/arrestin signaling. This study opens the potential for biased M-3-muscarinic receptor ligands that direct phosphorylation/arrestin-dependent (non-G protein) signaling as being beneficial in cognitive disorders. C1 [Poulin, Benoit; Butcher, Adrian; McWilliams, Phillip; Bourgognon, Julie-Myrtille; Pawlak, Robert; Kong, Kok Choi; Tobin, Andrew B.] Univ Leicester, Dept Cell Physiol & Pharmacol, Leicester LE1 9HN, Leics, England. [Bottrill, Andrew; Mistry, Sharad] Univ Leicester, Prot & Nucle Acid Chem Lab, Leicester LE1 9HN, Leics, England. [Wess, Juergen] NIDDK, Mol Signaling Sect, NIH, Bethesda, MD 20892 USA. RP Tobin, AB (reprint author), Univ Leicester, Dept Cell Physiol & Pharmacol, Leicester LE1 9HN, Leics, England. EM tba@leicester.ac.uk RI Bottrill, Andrew/C-6367-2013; OI Bottrill, Andrew/0000-0002-5182-3643; Rosethorne, Elizabeth/0000-0001-6877-2320 FU Wellcome Trust [047600]; European Commission [MEXT-CT-2006-042265] FX We thank Prof. Ian Forsythe and Martin Haustein for help and support. A. B. T. is supported by the Wellcome Trust (047600). R. P. is supported by Marie Curie Excellence Grant MEXT-CT-2006-042265 from the European Commission. NR 30 TC 56 Z9 57 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 MAY 18 PY 2010 VL 107 IS 20 BP 9440 EP 9445 DI 10.1073/pnas.0914801107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 598GH UT WOS:000277822600075 PM 20439723 ER PT J AU Greten, TF Forner, A Korangy, F N'Kontchou, G Barget, N Ayuso, C Ormandy, LA Manns, MP Beaugrand, M Bruix, J AF Greten, Tim F. Forner, Alejandro Korangy, Firouzeh N'Kontchou, Gisele Barget, Nathalie Ayuso, Carmen Ormandy, Lars A. Manns, Michael P. Beaugrand, Michel Bruix, Jordi TI A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma SO BMC CANCER LA English DT Article ID T-CELL RESPONSES; METASTATIC PROSTATE-CANCER; LOW-DOSE CYCLOPHOSPHAMIDE; DENDRITIC CELLS; PANCREATIC-CANCER; IMMUNE-RESPONSE; TUMOR-IMMUNITY; IMMUNOTHERAPY; I/II; SORAFENIB AB Background: The sole effective option for patients with advanced HCC is sorafenib and there is an urgent need to develop new therapeutic approaches. Immunotherapy is a promising option that deserves major investigation. In this open label, single arm clinical trial, we analyzed the effect of a low dose cyclophosphamide treatment in combination with a telomerase peptide (GV1001) vaccination in patients with advanced HCC. Methods: 40 patients with advanced HCC were treated with 300 mg/m(2) cyclophosphamide on day -3 followed by GM-CSF + GV1001 vaccinations on days 1, 3, 5, 8, 15, 22, 36 followed by 4-weekly injections. Primary endpoint of this phase II trial was tumor response; secondary endpoints evaluated were TTP, TTSP, PFS, OS, safety and immune responses. Results: None of the patients had a complete or partial response to treatment, 17 patients (45.9%) demonstrated a stable disease six months after initiation of treatment. The median TTP was 57.0 days; the median TTSP was estimated to be 358.0 days. Cyclophosphamide, GV1001 and GM-CSF treatment were well tolerated and most adverse events, which were of grade 1 or 2, were generally related to the injection procedure and injection site reactions. GV1001 treatment resulted in a decrease in CD4(+)CD25(+)Foxp3(+) regulatory T cells; however, no GV1001 specific immune responses were detected after vaccination. Conclusions: Low dose cyclophosphamide treatment followed by GV1001 vaccinations did not show antitumor efficacy as per tumor response and time to progression. Further studies are needed to analyze the effect of a combined chemo-immunotherapy to treat patients with HCC. Trial registration: NCT00444782 C1 [Greten, Tim F.; Korangy, Firouzeh; Ormandy, Lars A.; Manns, Michael P.] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-30625 Hannover, Germany. [Greten, Tim F.; Korangy, Firouzeh] Twincore Ctr Expt & Clin Infect Res, D-30625 Hannover, Germany. [N'Kontchou, Gisele; Barget, Nathalie; Beaugrand, Michel] Univ Paris 13, Hop Jean Verdier, AP HP, Serv Hepatogastroenterol, F-93143 Bondy, France. [Forner, Alejandro; Ayuso, Carmen; Bruix, Jordi] Univ Barcelona, BCLC Grp, Liver Unit, Hosp Clin,IDIBAPS,CIBEREHD, E-08036 Barcelona, Spain. [Ormandy, Lars A.] Univ Med Ctr Gottingen, Dept Legal Med, D-37075 Gottingen, Germany. [Greten, Tim F.; Korangy, Firouzeh] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM tim.greten@nih.gov; jbruix@clinic.ub.es RI Greten, Tim/B-3127-2015; Forner, Alejandro/C-8884-2016; OI Greten, Tim/0000-0002-0806-2535; Forner, Alejandro/0000-0002-9014-4950; Ayuso, Carmen/0000-0002-9606-6957; Bruix, Jordi/0000-0002-9826-0753 FU Pharmexa A/S Biosciences FX This study was supported by Pharmexa A/S Biosciences to TFG, MB and JB. NR 27 TC 62 Z9 63 U1 1 U2 9 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 MAY 17 PY 2010 VL 10 AR 209 DI 10.1186/1471-2407-10-209 PG 7 WC Oncology SC Oncology GA 623ZQ UT WOS:000279786300002 PM 20478057 ER PT J AU Mirabello, L Savage, SA Korde, L Gadalla, SM Greene, MH AF Mirabello, Lisa Savage, Sharon A. Korde, Larissa Gadalla, Shahinaz M. Greene, Mark H. TI LINE-1 methylation is inherited in familial testicular cancer kindreds SO BMC MEDICAL GENETICS LA English DT Article ID GERM-CELL TUMORS; GLOBAL DNA HYPOMETHYLATION; EPIGENETIC INHERITANCE; COLORECTAL-CANCER; ASSOCIATION; SUSCEPTIBILITY; EPIMUTATION; BLOOD; RISK; LOCI AB Background: Testicular germ cell tumors (TGCT) are the most frequent cancers among young men. There is a clear familial component to TGCT etiology, but no high-penetrance susceptibility gene has been identified. Epigenetic aberrations of the genome represent an alternative mechanism for cancer susceptibility; and, studies suggest that epigenetic changes that influence cancer risk can be inherited through the germline. Global DNA hypomethylation has been associated with the risk of cancers of the bladder and head/neck. Methods: We performed a pilot study of global methylation at long interspersed nuclear elements-1 (LINE-1) in peripheral blood DNA isolated from 466 family members of 101 multiple-case testicular cancer families. Results: Investigating the correlation of LINE-1 methylation levels among parent-child pairs independent of affection status (n = 355) revealed a strong positive association only between mother-daughter (r = 0.48, P = <0.001) and father-daughter pairs (r = 0.31, P = 0.02), suggesting gender-specific inheritance of methylation. Incorporating cancer status, we observed a strong correlation in LINE-1 methylation levels only among affected father-affected son pairs (r = 0.49, P = 0.03). There was a marginally significant inverse association between lower LINE-1 methylation levels and increased TGCT risk, compared with healthy male relatives (P = 0.049). Conclusions: Our data suggest that heritability of LINE-1 methylation may be gender-specific. Further, the strong correlation between LINE-1 methylation levels among affected father-affected son pairs suggests that transgenerational inheritance of an epigenetic event may be associated with disease risk. Larger studies are needed to clarify these preliminary observations. C1 [Mirabello, Lisa; Savage, Sharon A.; Korde, Larissa; Gadalla, Shahinaz M.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gadalla, Shahinaz M.] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. RP Greene, MH (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM greenem@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Intramural Research Program of the NIH; National Cancer Institute; Division of Cancer Epidemiology and Genetics; Westat Inc [NO2-CP-11019-50, NO2-CP-65504-50] FX We thank Drs Marston Linehan and Jennifer Loud, Susan Pfeiffer, and June Peters for their contributions to the CGB Familial Testicular Cancer study. We thank Dr. Nicolas Wentzensen for helpful manuscript comments. We are grateful to the patients and families who participated in this study. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and by support services contracts NO2-CP-11019-50 and NO2-CP-65504-50 with Westat Inc. NR 48 TC 29 Z9 29 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD MAY 17 PY 2010 VL 11 AR 77 DI 10.1186/1471-2350-11-77 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 605YK UT WOS:000278385100002 PM 20478068 ER PT J AU Taylor, TJ Vaisman, II AF Taylor, Todd J. Vaisman, Iosif I. TI Discrimination of thermophilic and mesophilic proteins SO BMC STRUCTURAL BIOLOGY LA English DT Article; Proceedings Paper CT 3rd Computational Structural Bioinformatics Workshop CY NOV 01, 2009 CL Washington, DC ID COMPUTATIONAL GEOMETRY APPROACH; AMINO-ACID-RESIDUES; STRUCTURE ALIGNMENT; CRYSTAL-STRUCTURE; DELAUNAY TESSELLATION; PYROCOCCUS-FURIOSUS; ANGSTROM RESOLUTION; THERMAL-STABILITY; CITRATE SYNTHASE; SALT BRIDGES AB Background: There is a considerable literature on the source of the thermostability of proteins from thermophilic organisms. Understanding the mechanisms for this thermostability would provide insights into proteins generally and permit the design of synthetic hyperstable biocatalysts. Results: We have systematically tested a large number of sequence and structure derived quantities for their ability to discriminate thermostable proteins from their non-thermostable orthologs using sets of mesophile-thermophile ortholog pairs. Most of the quantities tested correspond to properties previously reported to be associated with thermostability. Many of the structure related properties were derived from the Delaunay tessellation of protein structures. Conclusions: Carefully selected sequence based indices discriminate better than purely structure based indices. Combined sequence and structure based indices improve performance somewhat further. Based on our analysis, the strongest contributors to thermostability are an increase in ion pairs on the protein surface and a more strongly hydrophobic interior. C1 [Taylor, Todd J.] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. [Vaisman, Iosif I.] George Mason Univ, Dept Bioinformat & Computat Biol, Manassas, VA 20110 USA. RP Taylor, TJ (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,MS 4264, Bethesda, MD 20892 USA. EM todd.taylor@nih.gov RI Vaisman, Iosif/K-5268-2012 OI Vaisman, Iosif/0000-0001-6858-1516 NR 71 TC 34 Z9 34 U1 1 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2237 J9 BMC STRUCT BIOL JI BMC Struct. Biol. PD MAY 17 PY 2010 VL 10 SU 1 AR S5 DI 10.1186/1472-6807-10-S1-S5 PG 10 WC Biophysics SC Biophysics GA 602JN UT WOS:000278135500006 PM 20487512 ER PT J AU de Manzano, O Cervenka, S Karabanov, A Farde, L Ullen, F AF de Manzano, Orjan Cervenka, Simon Karabanov, Anke Farde, Lars Ullen, Fredrik TI Thinking Outside a Less Intact Box: Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Individuals SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; HUMAN BRAIN; PREFRONTAL CORTEX; VERBAL CREATIVITY; LATENT INHIBITION; WORKING-MEMORY; IN-VIVO; SCHIZOPHRENIA; BINDING; PET AB Several lines of evidence support that dopaminergic neurotransmission plays a role in creative thought and behavior. Here, we investigated the relationship between creative ability and dopamine D2 receptor expression in healthy individuals, with a focus on regions where aberrations in dopaminergic function have previously been associated with psychotic symptoms and a genetic liability to schizophrenia. Scores on divergent thinking tests (Inventiveness battery, Berliner Intelligenz Struktur Test) were correlated with regional D2 receptor densities, as measured by Positron Emission Tomography, and the radioligands [(11)C] raclopride and [(11)C]FLB 457. The results show a negative correlation between divergent thinking scores and D2 density in the thalamus, also when controlling for age and general cognitive ability. Hence, the results demonstrate that the D2 receptor system, and specifically thalamic function, is important for creative performance, and may be one crucial link between creativity and psychopathology. We suggest that decreased D2 receptor densities in the thalamus lower thalamic gating thresholds, thus increasing thalamocortical information flow. In healthy individuals, who do not suffer from the detrimental effects of psychiatric disease, this may increase performance on divergent thinking tests. In combination with the cognitive functions of higher order cortical networks, this could constitute a basis for the generative and selective processes that underlie real life creativity. C1 [de Manzano, Orjan; Karabanov, Anke; Ullen, Fredrik] Karolinska Inst, Neuropediat Res Unit, Dept Womens & Childrens Hlth, Stockholm, Sweden. [de Manzano, Orjan; Cervenka, Simon; Karabanov, Anke; Farde, Lars; Ullen, Fredrik] Karolinska Inst, Stockholm Brain Inst, Stockholm, Sweden. [Cervenka, Simon; Farde, Lars] Karolinska Inst, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden. [Karabanov, Anke] NINDS, Human Motor Control Unit, NIH, Bethesda, MD 20892 USA. RP de Manzano, O (reprint author), Karolinska Inst, Neuropediat Res Unit, Dept Womens & Childrens Hlth, Stockholm, Sweden. EM orjan.demanzano@ki.se OI de Manzano, Orjan/0000-0002-4632-1112; Karabanov, Anke Ninija/0000-0003-1874-393X; Cervenka, Simon/0000-0001-8103-6977 FU Swedish Research Council [2006-4733] FX Funding was provided by the Swedish Research Council 2006-4733. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 36 Z9 36 U1 2 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 17 PY 2010 VL 5 IS 5 AR e10670 DI 10.1371/journal.pone.0010670 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 597QK UT WOS:000277773700013 PM 20498850 ER PT J AU Amarnath, S Flomerfelt, FA Costanzo, CM Foley, JE Mariotti, J Konecki, DM Gangopadhyay, A Eckhaus, M Wong, S Levine, BL June, CH Fowler, DH AF Amarnath, Shoba Flomerfelt, Francis A. Costanzo, Carliann M. Foley, Jason E. Mariotti, Jacopo Konecki, Daniel M. Gangopadhyay, Anu Eckhaus, Michael Wong, Susan Levine, Bruce L. June, Carl H. Fowler, Daniel H. TI Rapamycin generates anti-apoptotic human Th1/Tc1 cells via autophagy for induction of xenogeneic GVHD SO AUTOPHAGY LA English DT Article DE Th1/Tc1; rapamycin; autophagy; apoptosis resistance; xenogeneic GVHD ID VERSUS-HOST-DISEASE; CD4(+) T-CELLS; ISOLATED RAT HEPATOCYTES; DONOR TH2 CELLS; EX-VIVO; ADOPTIVE TRANSFER; CD28 COSTIMULATION; BCL-2 PROTEIN; CD8+T CELLS; IFN-ALPHA AB Murine T cells exposed to rapamycin maintain flexibility towards Th1/Tc1 differentiation, thereby indicating that rapamycin promotion of regulatory T cells (Tregs) is conditional. The degree to which rapamycin might inhibit human Th1/Tc1 differentiation has not been evaluated. In the presence of rapamycin, T cell costimulation and polarization with IL-12 or IFN alpha permitted human CD4(+) and CD8(+) T cell differentiation towards a Th1/Tc1 phenotype; activation of STAT1 and STAT4 pathways essential for Th1/Tc1 polarity was preserved during mTOR blockade but instead abrogated by PI3 kinase inhibition. Such rapamycin-resistant human Th1/Tc1 cells: (1) were generated through autophagy (increased LC3BII expression; phenotype reversion by autophagy inhibition via 3-MA or siRNA for Beclin 1); (2) expressed anti-apoptotic bcl-2 family members (reduced Bax, Bak; increased phospho-Bad); (3) maintained mitochondrial membrane potentials; and (4) displayed reduced apoptosis. In vivo, type I polarized and rapamycin-resistant human T cells caused increased xenogeneic graft-versus-host disease (x-GVHD). Murine recipients of rapamycin-resistant human Th1/Tc1 cells had: (1) persistent T cell engraftment; (2) increased T cell cytokine and cytolytic effector function; and (3) T cell infiltration of skin, gut and liver. Rapamycin therefore does not impair human T cell capacity for type I differentiation. Rather, rapamycin yields an anti-apoptotic Th1/Tc1 effector phenotype by promoting autophagy. C1 [Amarnath, Shoba; Flomerfelt, Francis A.; Costanzo, Carliann M.; Foley, Jason E.; Mariotti, Jacopo; Konecki, Daniel M.; Gangopadhyay, Anu; Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Eckhaus, Michael] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. [Wong, Susan] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Levine, Bruce L.; June, Carl H.] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. RP Amarnath, S (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. EM samarnath@mail.nih.gov RI Levine, Bruce/D-1688-2009 FU Center for Cancer Research; National Cancer Institute; Intramural Research Program FX This work was supported by the Center for Cancer Research, National Cancer Institute, Intramural Research Program. NR 58 TC 19 Z9 23 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD MAY 16 PY 2010 VL 6 IS 4 BP 523 EP 541 PG 19 WC Cell Biology SC Cell Biology GA 619KM UT WOS:000279429100010 PM 20404486 ER PT J AU Boyd, K Dunn, DT Castro, H Gibb, DM Duong, T Aboulker, JP Bulterys, M Cortina-Borja, M Gabiano, C Galli, L Giaquinto, C Harris, DR Hughes, M McKinney, R Mofenson, L Moye, J Newell, ML Pahwa, S Palumbo, P Rudin, C Sharland, M Shearer, W Thompson, B Tookey, P AF Boyd, K. Dunn, D. T. Castro, H. Gibb, D. M. Duong, T. Aboulker, J. P. Bulterys, M. Cortina-Borja, M. Gabiano, C. Galli, L. Giaquinto, C. Harris, D. R. Hughes, M. McKinney, R. Mofenson, L. Moye, J. Newell, M. L. Pahwa, S. Palumbo, P. Rudin, C. Sharland, M. Shearer, W. Thompson, B. Tookey, P. CA HIV Paediat Prognostic Markers Col TI Discordance between CD4 cell count and CD4 cell percentage: implications for when to start antiretroviral therapy in HIV-1 infected children HIV Paediatric Prognostic Markers Collaborative Study SO AIDS LA English DT Article DE CD4; epidemiology; natural history; paediatrics; prognosis ID SHORT-TERM RISK; DISEASE PROGRESSION; LYMPHOCYTE COUNT; INFECTED CHILDREN; METAANALYSIS; MORTALITY AB Objective: Antiretroviral therapy (ART) guidelines for HIV-1-infected children specify both absolute CD4 cell count and CD4 percentage thresholds at which consideration should be given to initiating ART. This leads to clinical dilemma when one marker is below the threshold, whereas the other is above. Design: Data were obtained on a large group of children followed longitudinally in trials and cohort studies in Europe and the USA. Follow-up was censored 6 months after the start of any antiretroviral drug other than zidovudine monotherapy. Methods: Discordance between CD4 cell count and percentage was defined in relation to ART initiation thresholds in World Health Organization (WHO) and European paediatric treatment guidelines. The relative prognostic value of CD4 cell count and percentage for progression to AIDS/death was investigated using time-updated Cox proportional hazards models, stratified by age. Results: Among 3345 children, with a total of 21 815 pairs of CD4 measurements analysed, 980 developed AIDS and/or died after a median follow-up of 1.7 years. Over one-half of children had discordant values of CD4 cell markers at the first visit when one or both treatment thresholds were crossed and approximately one-third had the same pattern of discordance at a subsequent measurement. Models suggested that CD4 percentage had little or no prognostic value over and above that contained in CD4 cell count, irrespective of age. Conclusions: More emphasis should be placed on CD4 cell count than on CD4 percentage in deciding when to start ART in HIV-1-infected children. (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Boyd, K.; Dunn, D. T.; Castro, H.; Gibb, D. M.; Duong, T.] MRC, Clin Trials Unit, London NW1 2DA, England. [Aboulker, J. P.] INSERM SC10, Villejuif, France. [Bulterys, M.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Cortina-Borja, M.] UCL, Inst Child Hlth, London WC1E 6BT, England. [Gabiano, C.] Univ Turin, Dept Pediat, Turin, Italy. [Galli, L.] Univ Florence, Dept Pediat, Florence, Italy. [Giaquinto, C.] Univ Padua, Dept Pediat, Padua, Italy. [Harris, D. R.] Westat Corp, Rockville, MD USA. [Hughes, M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [McKinney, R.] Duke Univ, Med Ctr, Durham, NC USA. [Mofenson, L.] NICHHD, NIH, Rockville, MD USA. [Newell, M. L.; Tookey, P.] UCL, Inst Child Hlth, London WC1E 6BT, England. [Pahwa, S.] N Shore LIJ Res Inst, Manhasset, NY USA. [Palumbo, P.] UMDNJ Med Sch, Newark, NJ USA. [Rudin, C.] Univ Childrens Hosp, Basel, Switzerland. [Sharland, M.] St George Hosp, Sch Med, London, England. [Shearer, W.] Baylor Coll Med, Houston, TX 77030 USA. [Thompson, B.] Clin Trials & Surveys Corp, Baltimore, MD USA. RP Dunn, DT (reprint author), MRC, Clin Trials Unit, 222 Euston Rd, London NW1 2DA, England. RI Tookey, Pat /G-2732-2010; Cortina Borja, Mario/A-3847-2009; SHCS, all/G-4072-2011; SHCS, int. coll. A/G-4083-2011 OI Tookey, Pat /0000-0001-6258-0387; NR 18 TC 13 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 15 PY 2010 VL 24 IS 8 BP 1213 EP 1217 DI 10.1097/QAD.0b013e3283389f41 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 588NV UT WOS:000277079400015 ER PT J AU Hagstromer, M Troiano, RP Sjostrom, M Berrigan, D AF Hagstromer, Maria Troiano, Richard P. Sjostrom, Michael Berrigan, David TI Levels and Patterns of Objectively Assessed Physical Activity-A Comparison Between Sweden and the United States SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Europe; exercise; internationality; motor activity; nutrition surveys; sedentary lifestyle ID INTERNATIONAL PREVALENCE; ACCELEROMETER OUTPUT; ADULTS; TIME; QUESTIONNAIRE; SPORTS AB This study compares levels and patterns of objectively assessed physical activity in Sweden and the United States by using identical accelerometer metrics. Data of adult respondents with >= 4 days with >= 10 hours per day of accelerometer wear from Sweden (2001-2002, n = 1,172) and the United States (2003-2004, n = 2,925) were compared. Outcomes reported by age and body mass index within sex include accelerometer counts per minute and amounts and bouts of activity at different intensities, that is, sedentary, low, lifestyle, and moderate or higher intensity physical activity. The mean counts per minute were 375 (95% confidence interval (CI): 360, 390) and 377 (95% CI: 363, 391) for Swedish and US males, respectively, and 363 (95% CI: 347, 379) and 298 (95% CI: 289, 307) for Swedish and US females. Older respondents and those with higher body mass index had lower activity levels. Swedish and US males spent 36 (95% CI: 34, 38) and 33 (95% CI: 31, 36) minutes per day, and Swedish and US females spent 32 (95% CI: 29, 34) and 19 (95% CI: 17, 21) minutes per day in moderate or higher intensity physical activity. Older Swedes were more active in moderate or higher intensity activities than were older US respondents. However, younger Swedish males had more sedentary behavior time than did younger US males. These results provide a framework for international comparisons of physical activity levels and patterns, and they represent strong evidence for the importance of investment in objective measurement of physical activity. C1 [Hagstromer, Maria; Sjostrom, Michael] Karolinska Inst, Dept Biosci & Nutr, Unit Prevent Nutr, Stockholm, Sweden. [Hagstromer, Maria] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Physiotherapy, Stockholm, Sweden. [Troiano, Richard P.; Berrigan, David] NCI, NIH, Bethesda, MD 20892 USA. RP Hagstromer, M (reprint author), Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Physiotherapy, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden. EM maria.hagstromer@ki.se OI Hagstromer, Maria/0000-0002-4607-8677; Troiano, Richard/0000-0002-6807-989X FU Stockholm County Council; European Union [2006120]; Swedish Foundation for International Cooperation in Research and Higher Education [KU2003-4539]; Swedish Council for Working Life and Social Research [2008-1655] FX This work was supported by a grant from the Stockholm County Council; the project ALPHA, which received funding from the European Union in the framework of the Public Health Programme (agreement 2006120 to M. S.); the Swedish Foundation for International Cooperation in Research and Higher Education (grant KU2003-4539 to M. H.); and the Swedish Council for Working Life and Social Research (grant 2008-1655 to M. H.). NR 30 TC 110 Z9 111 U1 1 U2 23 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 15 PY 2010 VL 171 IS 10 BP 1055 EP 1064 DI 10.1093/aje/kwq069 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 597AU UT WOS:000277728400001 PM 20406758 ER PT J AU Murray, ET Roux, AVD Carnethon, M Lutsey, PL Ni, HY O'Meara, ES AF Murray, Emily T. Roux, Ana V. Diez Carnethon, Mercedes Lutsey, Pamela L. Ni, Hanyu O'Meara, Ellen S. TI Trajectories of Neighborhood Poverty and Associations With Subclinical Atherosclerosis and Associated Risk Factors SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body mass index; carotid artery; internal; diabetes mellitus; hypertension; models; statistical; residential mobility; retrospective studies; smoking ID CORONARY-HEART-DISEASE; INTIMA-MEDIA THICKNESS; CARDIOVASCULAR-DISEASE; LIFE-COURSE; DEVELOPMENTAL TRAJECTORIES; MYOCARDIAL-INFARCTION; MULTILEVEL ANALYSIS; SOCIAL-CLASS; DEPRIVATION; HEALTH AB The authors used data from the Multi-Ethnic Study of Atherosclerosis and latent trajectory class modeling to determine patterns of neighborhood poverty over 20 years (1980-2000 residential history questionnaires were geocoded and linked to US Census data). Using these patterns, the authors examined 1) whether trajectories of neighborhood poverty were associated with differences in the amount of subclinical atherosclerosis (common carotid intimal-media thickness) and 2) associated risk factors (body mass index, hypertension, diabetes, current smoking) at baseline (January 2000-August 2002). The authors found evidence of 5 stable trajectory groups with differing levels of neighborhood poverty (similar to 6%, 12%, 20%, 30%, and 45%) and 1 group with 29% poverty in 1980 and approximately 11% in 2000. Mostly for women, higher cumulative neighborhood poverty was generally significantly associated with worse cardiovascular outcomes. Trends generally persisted after adjustment for adulthood socioeconomic position and race/ethnicity, although they were no longer statistically significant. Among women who had moved during the 20 years, the long-term measure had stronger associations with outcomes (except smoking) than a single, contemporaneous measure. Results indicate that cumulative 20-year exposure to neighborhood poverty is associated with greater cardiovascular risk for women. In residentially mobile populations, single-point-in-time measures underestimate long-term effects. C1 [Murray, Emily T.; Roux, Ana V. Diez] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Carnethon, Mercedes] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Lutsey, Pamela L.] Univ Minnesota, Dept Epidemiol & Community Hlth, Minneapolis, MN USA. [Ni, Hanyu] NHLBI, Epidemiol Branch, Div Prevent & Populat Serv, NIH, Bethesda, MD 20892 USA. [O'Meara, Ellen S.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Murray, ET (reprint author), Lab Epidemiol Demog & Biometry, Gateway Bldg,3C309,7201 Wisconsin Ave, Bethesda, MD 20814 USA. EM emily.lemelin@nih.gov FU National Heart, Lung, and Blood Institute [2R01-HL071759, N01-HC-95159, N01-HC-95165, N01-HC-95169] FX This study was supported by grant 2R01-HL071759 from the National Heart, Lung, and Blood Institute (A. D. R., Principal Investigator). The Multi-Ethnic Study of Atherosclerosis is supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute. NR 28 TC 23 Z9 23 U1 2 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 15 PY 2010 VL 171 IS 10 BP 1099 EP 1108 DI 10.1093/aje/kwq044 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 597AU UT WOS:000277728400006 PM 20423931 ER PT J AU Fang, F Kwee, LC Allen, KD Umbach, DM Ye, WM Watson, M Keller, J Oddone, EZ Sandler, DP Schmidt, S Kamel, F AF Fang, Fang Kwee, Lydia C. Allen, Kelli D. Umbach, David M. Ye, Weimin Watson, Mary Keller, Jean Oddone, Eugene Z. Sandler, Dale P. Schmidt, Silke Kamel, Freya TI Association Between Blood Lead and the Risk of Amyotrophic Lateral Sclerosis SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE amyotrophic lateral sclerosis; bone and bones; bone resorption; lead; odds ratio; osteogenesis ID AMINOLEVULINIC-ACID DEHYDRATASE; MOTOR-NEURON-DISEASE; GULF-WAR VETERANS; CIGARETTE-SMOKING; GENETIC SUSCEPTIBILITY; OCCUPATIONAL EXPOSURES; ANTECEDENT EVENTS; MEN; QUALITY; COHORT AB The authors conducted a 2003-2007 case-control study including 184 cases and 194 controls to examine the association between blood lead and the risk of amyotrophic lateral sclerosis (ALS) among US veterans and to explore the influence on this association of bone turnover and genetic factors related to lead toxicokinetics. Blood lead, plasma biomarkers of bone formation (procollagen type 1 amino-terminal peptide (PINP)) and resorption (C-terminal telopeptides of type 1 collagen (CTX)), and the K59N polymorphism in the delta-aminolevulinic acid dehydratase gene, ALAD, were measured. Odds ratios and 95% confidence intervals for the association of blood lead with ALS were estimated with unconditional logistic regression after adjustment for age and bone turnover. Blood lead levels were higher among cases compared with controls (P < 0.0001, age adjusted). A doubling of blood lead was associated with a 1.9-fold increased risk of ALS (95% confidence interval: 1.3, 2.7) after adjustment for age and CTX. Additional adjustment for PINP did not alter the results. Significant lead-ALS associations were observed in substrata of PINP and CTX levels. The K59N polymorphism in the ALAD gene did not modify the lead-ALS association (P = 0.32). These results extend earlier findings by accounting for bone turnover in confirming the association between elevated blood lead level and higher risk of ALS. C1 [Fang, Fang; Sandler, Dale P.; Kamel, Freya] NIEHS, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Fang, Fang; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Kwee, Lydia C.; Schmidt, Silke] Duke Univ, Med Ctr, Dept Med, Ctr Human Genet, Durham, NC 27710 USA. [Kwee, Lydia C.; Allen, Kelli D.; Oddone, Eugene Z.; Schmidt, Silke] Durham VA Med Ctr, Epidemiol Res & Informat Ctr, Durham, NC USA. [Kwee, Lydia C.; Allen, Kelli D.; Oddone, Eugene Z.; Schmidt, Silke] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Watson, Mary] Social & Sci Syst Inc, Durham, NC USA. [Keller, Jean] Westat Corp, Durham, NC USA. RP Kamel, F (reprint author), NIEHS, Epidemiol Branch, NIH, US Dept HHS, POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM kamel@niehs.nih.gov OI Fang, Fang/0000-0002-3310-6456; Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES49005-15]; National Institute of Environmental Health Sciences/ National Institutes of Health [R01 ES 013244]; ALS Association [ALSA 1230]; Office of Research and Development, Cooperative Studies Program, Department of Veterans Affairs [500A, 478] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01-ES49005-15) and by grants from the National Institute of Environmental Health Sciences/ National Institutes of Health (R01 ES 013244) and the ALS Association (ALSA 1230). The work of the National Registry of Veterans with ALS and its DNA bank was supported by the Office of Research and Development, Cooperative Studies Program, Department of Veterans Affairs (CSP #500A, CSP #478). NR 34 TC 38 Z9 39 U1 0 U2 4 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 MAY 15 PY 2010 VL 171 IS 10 BP 1126 EP 1133 DI 10.1093/aje/kwq063 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 597AU UT WOS:000277728400009 PM 20406759 ER PT J AU Kiley, J Noel, P Weinmann, G AF Kiley, James Noel, Patricia Weinmann, Gail TI Addressing the Gaps in Translational Pulmonary Research A Division of Lung Diseases Perspective SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material C1 [Kiley, James; Noel, Patricia; Weinmann, Gail] NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. RP Kiley, J (reprint author), NHLBI, Div Lung Dis, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 15 PY 2010 VL 181 IS 10 BP 1015 EP 1016 DI 10.1164/rccm.201004-0529ED PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 596ME UT WOS:000277688400001 PM 20460543 ER PT J AU Dweik, RA Sorkness, RL Wenzel, S Hammel, J Curran-Everett, D Comhair, SAA Bleecker, E Busse, W Calhoun, WJ Castro, M Chung, KF Israel, E Jarjour, N Moore, W Peters, S Teague, G Gaston, B Erzurum, SC AF Dweik, Raed A. Sorkness, Ronald L. Wenzel, Sally Hammel, Jeffrey Curran-Everett, Douglas Comhair, Suzy A. A. Bleecker, Eugene Busse, William Calhoun, William J. Castro, Mario Chung, Kian Fan Israel, Elliot Jarjour, Nizar Moore, Wendy Peters, Stephen Teague, Gerald Gaston, Benjamin Erzurum, Serpil C. CA Natl Heart Lung Blood Inst Severe TI Use of Exhaled Nitric Oxide Measurement to Identify a Reactive, at-Risk Phenotype among Patients with Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE nitric oxide; severe asthma; phenotype; airway reactivity; exhaled breath ID EOSINOPHILIC AIRWAY INFLAMMATION; TOTAL LUNG CAPACITY; ALLERGEN CHALLENGE; CHILDHOOD ASTHMA; REFERENCE VALUES; NO SYNTHESIS; MILD ASTHMA; EXACERBATIONS; THERAPY; FLOW AB Rationale: Exhaled nitric oxide (FE(NO)) is a biomarker of airway inflammation in mild to moderate asthma. However, whether FE(NO) levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classification of severe asthma based on airway inflammation as defined by FEN levels would identify a more reactive, at-risk asthma phenotype. Methods: FEN and major features of asthma, including airway inflammation, airflow limitation, hyperinflation, hyperresponsiveness, and atopy, were determined in 446 individuals with various degrees of asthma severity (175 severe, 271 nonsevere) and 49 healthy subjects enrolled in the Severe Asthma Research Program. Measurements and Main Results: FE(NO) levels were similar among patients with severe and nonsevere asthma. The proportion of individuals with high FE(NO) levels (>35 ppb) was the same (40%) among groups despite greater corticosteroid therapy in severe asthma. All patients with asthma and high FE(NO) had more airway reactivity (maximal reversal in response to bronchodilator administration and by methacholine challenge), more evidence of allergic airway inflammation (sputum eosinophils), more evidence of atopy (positive skin tests, higher serum IgE and blood eosinophils), and more hyperinflation, but decreased awareness of their symptoms. High FEN identified those patients with severe asthma characterized by the greatest airflow obstruction and hyperinflation and most frequent use of emergency care. Conclusions: Grouping of asthma by FE(NO) provides an independent classification of asthma severity, and among patients with severe asthma identifies the most reactive and worrisome asthma phenotype. C1 [Dweik, Raed A.; Erzurum, Serpil C.] Cleveland Clin, Dept Pulm Allergy & Crit Care Med, Resp Inst, Cleveland, OH 44195 USA. [Dweik, Raed A.; Hammel, Jeffrey; Comhair, Suzy A. A.; Erzurum, Serpil C.] Cleveland Clin, Dept Pathobiol, Lerner Res Inst, Cleveland, OH 44195 USA. [Dweik, Raed A.; Sorkness, Ronald L.; Wenzel, Sally; Curran-Everett, Douglas; Comhair, Suzy A. A.; Bleecker, Eugene; Busse, William; Calhoun, William J.; Castro, Mario; Chung, Kian Fan; Israel, Elliot; Jarjour, Nizar; Moore, Wendy; Peters, Stephen; Teague, Gerald; Gaston, Benjamin; Erzurum, Serpil C.] NHLBI, Severe Asthma Res Program, Bethesda, MD 20892 USA. RP Dweik, RA (reprint author), Cleveland Clin, Dept Pulm Allergy & Crit Care Med, Resp Inst, Desk A-90,9500 Euclid Ave, Cleveland, OH 44195 USA. EM dweikr@ccf.org OI Chung, Kian Fan/0000-0001-7101-1426 FU Ohio Department of Development [AI70649, HL04265, HL68863, HL69116, HL69174, HL69167, HL069155, HL69130, HL69149, HL69170, HL069349, ACRN U10HL74225, P01/U01HL67663, TECH09-003]; National Center for Research Resources [M01 RR018390] FX Supported by HL69170, AI70649, HL04265, HL68863, HL69116, HL69174, HL69167, HL069155, HL69130, HL69149, HL69170, HL069349, ACRN U10HL74225, P01/U01HL67663, and P01/U01 HL67663; by a Third Frontier grant (TECH09-003) from the Ohio Department of Development; and by M01 RR018390 from the National Center for Research Resources. NR 63 TC 117 Z9 121 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 15 PY 2010 VL 181 IS 10 BP 1033 EP 1041 DI 10.1164/rccm.200905-0695OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 596ME UT WOS:000277688400006 PM 20133930 ER PT J AU Spragg, RG Bernard, GR Checkley, W Curtis, JR Gajic, O Guyatt, G Hall, J Israel, E Jain, M Needham, DM Randolph, AG Rubenfeld, GD Schoenfeld, D Thompson, BT Ware, LB Young, D Harabin, AL AF Spragg, Roger G. Bernard, Gordon R. Checkley, William Curtis, J. Randall Gajic, Ognjen Guyatt, Gordon Hall, Jesse Israel, Elliott Jain, Manu Needham, Dale M. Randolph, Adrienne G. Rubenfeld, Gordon D. Schoenfeld, David Thompson, B. Taylor Ware, Lorraine B. Young, Duncan Harabin, Andrea L. TI Beyond Mortality Future Clinical Research in Acute Lung Injury SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE clinical trials; acute respiratory distress syndrome; pulmonary diseases; edema; inflammation ID RESPIRATORY-DISTRESS-SYNDROME; RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; PULMONARY-ARTERY; MECHANICAL VENTILATION; OUTCOMES; ARDS; SURVIVORS; RISK; INFLAMMATION AB Mortality in National Heart, Lung and Blood Institute sponsored clinical trials of treatments for acute lung injury (ALI) has decreased dramatically during the past two decades. As a consequence, design of such trials based on a mortality outcome requires ever-increasing numbers of patients. Recognizing that advances in clinical trial design might be applicable to these trials and might allow trials with fewer patients, the National Heart, Lung and Blood Institute convened a workshop of extramural experts from several disciplines. The workshop assessed the current state of clinical research addressing ALI, identified research needs, and recommended: (1) continued performance of trials evaluating treatments of patients with ALI; (2) development of strategies to perform ALI prevention trials; (3) observational studies of patients without ALI undergoing prolonged mechanical ventilation; and (4) development of a standardized format for reporting methods, endpoints, and results of ALI trials. C1 [Harabin, Andrea L.] NHLBI, Div Lung Dis, NIH, Bethesda, MD 20892 USA. [Spragg, Roger G.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Bernard, Gordon R.; Ware, Lorraine B.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Checkley, William; Needham, Dale M.] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD USA. [Curtis, J. Randall] Univ Washington, Harborview Med Ctr, Dept Med, Div Pulm & Crit Care Med, Seattle, WA 98104 USA. [Gajic, Ognjen] Mayo Clin, Div Pulm & Crit Care, Rochester, MN USA. [Guyatt, Gordon] McMaster Univ, Dept Epidemiol & Biostat, Hamilton, ON, Canada. [Guyatt, Gordon] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Hall, Jesse] Univ Chicago, Med Ctr, Pulm & Crit Care Med Sect, Chicago, IL 60637 USA. [Israel, Elliott] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Jain, Manu] Northwestern Univ, Div Pulm & Crit Care Med, Chicago, IL 60611 USA. [Randolph, Adrienne G.] Childrens Hosp Boston, Boston, MA USA. [Rubenfeld, Gordon D.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Schoenfeld, David] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Young, Duncan] John Radcliffe Hosp, Oxford OX3 9DU, England. RP Harabin, AL (reprint author), NHLBI, Div Lung Dis, NIH, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM Harabin@nih.gov OI Randolph, Adrienne/0000-0002-3084-3071 FU National Heart, Lung and Blood Institute, National Institutes of Health FX Supported by National Heart, Lung and Blood Institute, National Institutes of Health. NR 53 TC 122 Z9 126 U1 1 U2 8 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 15 PY 2010 VL 181 IS 10 BP 1121 EP 1127 DI 10.1164/rccm.201001-0024WS PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 596ME UT WOS:000277688400016 PM 20224063 ER PT J AU Masood, MA Yuan, CQ Acharya, JK Veenstra, TD Blonder, J AF Masood, M. Athar Yuan, Changqing Acharya, Jairaj K. Veenstra, Timothy D. Blonder, Josip TI Quantitation of ceramide phosphorylethanolamines containing saturated and unsaturated sphingoid base cores SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Drosophila; Liquid chromatography; Single ion monitoring-neutral loss scans; Selected reaction monitoring; Quantitation; Ceramide phosphorylethanolamines; Sphingoid bases ID TANDEM MASS-SPECTROMETRY; ELECTROSPRAY-IONIZATION; DROSOPHILA-MELANOGASTER; SIGNAL-TRANSDUCTION; BIOLOGICAL SAMPLES; MEMBRANE-LIPIDS; SPHINGOLIPIDS; CHROMATOGRAPHY; 1-PHOSPHATE; IDENTIFICATION AB Sphingomyelin (SM) and ceramide-phosphoethanolamines (cer-PEs) are related lipids present in mammals and insects, respectively. Owing to the critical roles that cer-PEs play in eukaryotic cellular function, there is a need to develop methods that provide accurate quantitation of these compounds. Results obtained in this study demonstrate that Drosophila contains cer-PEs with unsaturated sphingoid base cores as well as low levels of cer-PEs that possess saturated sphingoid base cores. Specifically, the method developed in this study enabled the quantitation of picogram amounts of cer-PE containing both unsaturated d14:1(Delta 4) and d16:1(Delta 4) and saturated d14:0 sphingoid base cores. Using this method, cer-PE compounds with both saturated and unsaturated sphingoid base cores were initially identified by neutral loss scanning, followed by quantitation using selected reaction monitoring (SRM) scans. The SRM scans measured a product ion originating from the sphingoid base backbone, rather than from the head group, increasing the specificity and sensitivity of the quantitation measurement. (C) 2010 Elsevier Inc. All rights reserved. C1 [Masood, M. Athar; Veenstra, Timothy D.; Blonder, Josip] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick, Frederick, MD 21702 USA. [Yuan, Changqing; Acharya, Jairaj K.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Masood, MA (reprint author), NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick, Frederick, MD 21702 USA. EM masoodaa@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 47 TC 5 Z9 5 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 15 PY 2010 VL 400 IS 2 BP 259 EP 269 DI 10.1016/j.ab.2010.01.033 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 578CW UT WOS:000276272000015 PM 20122889 ER PT J AU Mohanty, JG Bhamidipaty, S Evans, MK Rifkind, JM AF Mohanty, Joy G. Bhamidipaty, Surya Evans, Michele K. Rifkind, Joseph M. TI A fluorimetric semi-microplate format assay of protein carbonyls in blood plasma SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Protein carbonyl; Fluorescence; Fluorimetric; Assay; Human plasma; Fluorescein thiosemicarbazide; Microplate format ID OXIDATIVE STRESS; ELISA METHOD; DISEASE; MALONDIALDEHYDE; FLUORESCEIN; DAMAGE AB Oxidative stress, originating from reactive oxygen species (ROS), has been implicated in aging and various human diseases. The ROS generated can oxidize proteins producing protein carbonyl derivatives. The level of protein carbonyls in blood plasma has been used as a measure of overall oxidative stress in the body. Classically, protein carbonyls have been quantitated spectrophotometrically by directly reacting them with 2,4-dinitrophenylhydrazine (DNPH). However, the applicability of this method to biological samples is limited by its low inherent sensitivity. This limitation has been overcome by the development of sensitive enzyme-linked immunosorbent assay (ELISA) methods to measure protein carbonyls. As part of the Healthy Aging in Neighborhoods of Diversity across the Lifespan (HANDL) study, oxidative stress in humans was quantified by measuring blood plasma protein carbonyls using the two commercially available ELISA kits and the spectrophotometric DNPH assay. Surprisingly, two ELISA methods gave very different values for protein carbonyls, both of which were different from the value of the spectrophotometric method. We have developed a fluorescent semi-microplate format assay of protein carbonyls involving direct reaction of protein carbonyls with fluorescein thiosemicarbazide that correlates (R = 0.992) with the direct spectrophotometric method. It has a coefficient of variation of 4.99% and is at least 100 times more sensitive than the spectrophotometric method. Published by Elsevier Inc. C1 [Mohanty, Joy G.; Bhamidipaty, Surya; Rifkind, Joseph M.] NIA, Mol Dynam Sect, Baltimore, MD 21224 USA. [Evans, Michele K.] NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. RP Mohanty, JG (reprint author), NIA, Mol Dynam Sect, Baltimore, MD 21224 USA. EM mohantyj@mail.nih.gov FU National Institutes of Health, National Institute on Aging FX This research was supported entirely by the Intramural Research program of the National Institutes of Health, National Institute on Aging. NR 25 TC 17 Z9 17 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 15 PY 2010 VL 400 IS 2 BP 289 EP 294 DI 10.1016/j.ab.2010.01.032 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 578CW UT WOS:000276272000018 PM 20122892 ER PT J AU Johnson, AD AF Johnson, Andrew D. TI An extended IUPAC nomenclature code for polymorphic nucleic acids SO BIOINFORMATICS LA English DT Article ID GENOME; SEQUENCE; ASSOCIATION; IMPUTATION AB The International Union of Pure and Applied Chemistry (IUPAC) code specified nearly 25 years ago provides a nomenclature for incompletely specified nucleic acids. However, no system currently exists that allows for the informatics representation of the relative abundance at polymorphic nucleic acids (e. g. single nucleotide polymorphisms) in a single specified character, or a string of characters. Here, I propose such an information code as a natural extension to the IUPAC nomenclature code, and present some potential uses and limitations to such a code. The primary anticipated use of this extended nomenclature code is to assist in the representation of the rapidly growing space of information in human genetic variation. C1 NHLBI, Framingham Heart Study, Ctr Populat Studies, Framingham, MA 01702 USA. RP Johnson, AD (reprint author), NHLBI, Framingham Heart Study, Ctr Populat Studies, Framingham, MA 01702 USA. EM johnsonad2@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013 FU American Heart Association [AHA0515157B]; NIH/NHLBI FX American Heart Association Pre-doctoral Fellowship (AHA0515157B to A.D.J.) and an NIH/NHLBI Post-doctoral IRTA Fellowship (to A.D.J.). NR 14 TC 2 Z9 2 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAY 15 PY 2010 VL 26 IS 10 BP 1386 EP 1389 DI 10.1093/bioinformatics/btq098 PG 4 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 593IP UT WOS:000277447500022 PM 20202974 ER PT J AU Weickert, TW Goldberg, TE Egan, MF Apud, JA Meeter, M Myers, CE Gluck, MA Weinberger, DR AF Weickert, Thomas W. Goldberg, Terry E. Egan, Michael F. Apud, Jose A. Meeter, Martijn Myers, Catherine E. Gluck, Mark A. Weinberger, Daniel R. TI Relative Risk of Probabilistic Category Learning Deficits in Patients with Schizophrenia and Their Siblings SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Antipsychotics; caudate nucleus; cognition; probability learning; relative risk; schizophrenia ID EMISSION COMPUTERIZED-TOMOGRAPHY; CARD SORTING TEST; COGNITIVE SKILL; HUMAN-BRAIN; DOPAMINE-RECEPTORS; WORKING-MEMORY; BASAL GANGLIA; NONDECLARATIVE MEMORY; HUNTINGTONS-DISEASE; PARKINSONS-DISEASE AB Background: Although patients with schizophrenia display an overall probabilistic category learning performance deficit, the extent to which this deficit occurs in unaffected siblings of patients with schizophrenia is unknown. There are also discrepant findings regarding probabilistic category learning acquisition rate and performance in patients with schizophrenia. Methods: A probabilistic category learning test was administered to 108 patients with schizophrenia, 82 unaffected siblings, and 121 healthy participants. Results: Patients with schizophrenia displayed significant differences from their unaffected siblings and healthy participants with respect to probabilistic category learning acquisition rates. Although siblings on the whole failed to differ from healthy participants on strategy and quantitative indexes of overall performance and learning acquisition, application of a revised learning criterion enabling classification into good and poor learners on the basis of individual learning curves revealed significant differences between percentages of sibling and healthy poor learners: healthy (13.2%), siblings (34.1%), patients (48.1%), yielding a moderate relative risk. Conclusions: These results clarify previous discrepant findings pertaining to probabilistic category learning acquisition rate in schizophrenia and provide the first evidence for the relative risk of probabilistic category learning abnormalities in unaffected siblings of patients with schizophrenia, supporting genetic underpinnings of probabilistic category learning deficits in schizophrenia. These findings also raise questions regarding the contribution of antipsychotic medication to the probabilistic category learning deficit in schizophrenia. The distinction between good and poor learning might be used to inform genetic studies designed to detect schizophrenia risk alleles. C1 [Weickert, Thomas W.; Goldberg, Terry E.; Egan, Michael F.; Apud, Jose A.; Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Weickert, Thomas W.] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Weickert, Thomas W.] Prince Wales Med Res Inst, Randwick, NSW 2031, Australia. [Goldberg, Terry E.] Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY USA. [Meeter, Martijn] Vrije Univ Amsterdam, Dept Cognit Psychol, Amsterdam, Netherlands. [Myers, Catherine E.] Rutgers State Univ, Dept Psychol, Newark, NJ 07102 USA. [Myers, Catherine E.] New Jersey Hlth Care Syst, Vet Affairs Med Ctr, E Orange, NJ USA. [Gluck, Mark A.] Rutgers State Univ, Ctr Mol & Behav Neurosci, Newark, NJ 07102 USA. RP Weickert, TW (reprint author), Prince Wales Med Res Inst, Randwick, NSW 2031, Australia. EM t.weickert@unsw.edu.au RI Meeter, Martijn/A-2926-2009; OI Meeter, Martijn/0000-0002-5112-6717; Myers, Catherine/0000-0002-2776-4823 FU National Institutes of Health-National Institute of Mental Health FX This research was supported by the Intramural Research Program of the National Institutes of Health-National Institute of Mental Health. NR 70 TC 22 Z9 23 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2010 VL 67 IS 10 BP 948 EP 955 DI 10.1016/j.biopsych.2009.12.027 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 595RK UT WOS:000277629900008 PM 20172502 ER PT J AU Anderson, WF Tucker, MA Rosenberg, PS AF Anderson, William F. Tucker, Margaret A. Rosenberg, Philip S. TI Divergent Cancer Pathways for Early Onset and Late Onset Cutaneous Malignant Melanoma A Role for Sex-Site Interaction Reply SO CANCER LA English DT Letter C1 [Anderson, William F.; Tucker, Margaret A.; Rosenberg, Philip S.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Anderson, WF (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015 NR 4 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD MAY 15 PY 2010 VL 116 IS 10 BP 2500 EP 2500 DI 10.1002/cncr.24992 PG 1 WC Oncology SC Oncology GA 588ZC UT WOS:000277112300029 ER PT J AU Hernandez, L Hsu, SC Davidson, B Birrer, MJ Kohn, EC Annunziata, CM AF Hernandez, Lidia Hsu, Sarah C. Davidson, Ben Birrer, Michael J. Kohn, Elise C. Annunziata, Christina M. TI Activation of NF-KB Signaling by Inhibitor of NF-KB Kinase beta Increases Aggressiveness of Ovarian Cancer SO CANCER RESEARCH LA English DT Article ID KAPPA-B; IKK-BETA; CARCINOMA; GROWTH; MANAGEMENT; ONCOGENE; INVASION; SYSTEM AB The NF-kappa B family of transcription factors has been implicated in the propagation of ovarian cancer, but the significance of constitutive NF-kappa B signaling in ovarian cancer is unknown. We hypothesized that constitutive NF-kappa B signaling defines a subset of ovarian cancer susceptible to therapeutic targeting of this pathway. We investigated the biological relevance of NF-kappa B in ovarian cancer using a small-molecule inhibitor of inhibitor of NF-kappa B kinase beta (IKK beta) and confirmed with RNA interference toward IKK beta. We developed a gene expression signature of IKK beta signaling in ovarian cancer using both pharmacologic and genetic manipulation of IKK beta. The expression of IKK beta protein itself and the nine-gene ovarian cancer-specific IKK beta signature were related to poor outcome in independently collected sets of primary ovarian cancers (P = 0.02). IKK beta signaling in ovarian cancer regulated the transcription of genes involved in a wide range of cellular effects known to increase the aggressive nature of the cells. We functionally validated the effect of IKK beta signaling on proliferation, invasion, and adhesion. Downregulating IKK beta activity, either by a small-molecule kinase inhibitor or by short hairpin RNA depletion of IKK beta, blocked all of these cellular functions, reflecting the negative regulation of the target genes identified. The diversity of functions controlled by IKK beta in ovarian cancer suggests that therapeutic blockade of this pathway could be efficacious if specific IKK beta inhibitor therapy is focused to patients whose tumors express a molecular profile suggestive of dependence on IKK beta activity. Cancer Res; 70(10); 4005-14. (C) 2010 AACR. C1 [Hernandez, Lidia; Hsu, Sarah C.; Kohn, Elise C.; Annunziata, Christina M.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Davidson, Ben] Univ Oslo, Fac Med, Oslo Univ Hosp, Fac Div,Radiumhosp,Norwegian Radium Hosp,Div Path, Oslo, Norway. [Birrer, Michael J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Annunziata, CM (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, 10 Ctr Dr,Room 12N226, Bethesda, MD 20892 USA. EM annunzic@mail.nih.gov RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 FU Center for Cancer Research, NCI; Marsha Rivkin Foundation for Ovarian Cancer Research; Norwegian Cancer Society and Health Region of South-Eastern Norway FX Grant Support; Intramural Program of the Center for Cancer Research, NCI (C. M. Annunziata and E. C. Kohn); Marsha Rivkin Foundation for Ovarian Cancer Research (C. M. Annunziata); and Norwegian Cancer Society and Health Region of South-Eastern Norway (B. Davidson). NR 26 TC 60 Z9 62 U1 2 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2010 VL 70 IS 10 BP 4005 EP 4014 DI 10.1158/0008-5472.CAN-09-3912 PG 10 WC Oncology SC Oncology GA 607GE UT WOS:000278486300018 PM 20424119 ER PT J AU Aryee, DNT Niedan, S Kauer, M Schwentner, R Bennani-Baiti, IM Ban, J Muehlbacher, K Kreppel, M Walker, RL Meltzer, P Poremba, C Kofler, R Kovar, H AF Aryee, Dave N. T. Niedan, Stephan Kauer, Maximilian Schwentner, Raphaela Bennani-Baiti, Idriss M. Ban, Jozef Muehlbacher, Karin Kreppel, Michael Walker, Robert L. Meltzer, Paul Poremba, Christopher Kofler, Reinhard Kovar, Heinrich TI Hypoxia Modulates EWS-FLI1 Transcriptional Signature and Enhances the Malignant Properties of Ewing's Sarcoma Cells In vitro SO CANCER RESEARCH LA English DT Article ID INDUCIBLE FACTOR 1-ALPHA; GENE SET ENRICHMENT; PROSTATE-CANCER; FAMILY TUMORS; EXPRESSION; GROWTH; HIF-1; MODEL; METABOLISM; APOPTOSIS AB Hypoxia is an important condition in the tumor cell microenvironment and approximately 1% to 1.5% of the genome is transcriptionally responsive to hypoxia with hypoxia-inducible factor-1 (HIF-1) as a major mediator of transcriptional activation. Tumor hypoxia is associated with a more aggressive phenotype of many cancers in adults, but data on pediatric tumors are scarce. Because, by immunohistochemistry, HIF-1 alpha expression was readily detectable in 18 of 28 primary Ewing's sarcoma family tumors (ESFT), a group of highly malignant bone-associated tumors in children and young adults, we studied the effect of hypoxia on ESFT cell lines in vitro. Intriguingly, we found that EWS-FLI1 protein expression, which characterizes ESFT, is upregulated by hypoxia in a HIF-1 alpha-dependent manner. Hypoxia modulated the EWS-FLI1 transcriptional signature relative to normoxic conditions. Both synergistic as well as antagonistic transcriptional effects of EWS-FLI1 and of hypoxia were observed. Consistent with alterations in the expression of metastasis-related genes, hypoxia stimulated the invasiveness and soft agar colony formation of ESFT cells in vitro. Our data represent the first transcriptome analysis of hypoxic ESFT cells and identify hypoxia as an important microenvironmental factor modulating EWS-FLI1 expression and target gene activity with far-reaching consequences for the malignant properties of ESFT. Cancer Res; 70(10); 4015-23. (C) 2010 AACR. C1 [Aryee, Dave N. T.; Niedan, Stephan; Kauer, Maximilian; Schwentner, Raphaela; Bennani-Baiti, Idriss M.; Ban, Jozef; Muehlbacher, Karin; Kreppel, Michael; Kovar, Heinrich] St Anna Kinderkrebsforsch, Childrens Canc Res Inst, A-1090 Vienna, Austria. [Walker, Robert L.; Meltzer, Paul] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Poremba, Christopher] Ctr Histopathol Cytol & Mol Diagnost, Trier, Germany. [Kofler, Reinhard] Med Univ Innsbruck, Div Mol Pathophysiol, Bioctr, Innsbruck, Austria. RP Aryee, DNT (reprint author), St Anna Kinderkrebsforsch, Childrens Canc Res Inst, Zimmermannpl 10, A-1090 Vienna, Austria. EM dave.aryee@ccri.at OI Kovar, Heinrich/0000-0001-6873-9109 FU Austrian National Bank Jubilaeumsfonds [12675]; EU [037260]; COMET center Oncotyrol FX Grant Support; Grants 12675 of the Austrian National Bank Jubilaeumsfonds (D.N.T. Aryee), EU-FP7 grant 037260 (EET-Pipeline), and the COMET center Oncotyrol (R. Kofler). NR 48 TC 27 Z9 31 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 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2010 VL 70 IS 10 BP 4015 EP 4023 DI 10.1158/0008-5472.CAN-09-4333 PG 9 WC Oncology SC Oncology GA 607GE UT WOS:000278486300019 PM 20442286 ER PT J AU Cha, H Lowe, JM Li, HH Lee, JS Belova, GI Bulavin, DV Fornace, AJ AF Cha, Hyukjin Lowe, Julie M. Li, Henghong Lee, Ji-Seon Belova, Galina I. Bulavin, Dmitry V. Fornace, Albert J., Jr. TI Wip1 Directly Dephosphorylates (Y)-H2AX and Attenuates the DNA Damage Response SO CANCER RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; HISTONE H2AX; PROTEIN PHOSPHATASE; GENOMIC INSTABILITY; IONIZING-RADIATION; SIGNALING PATHWAYS; TUMOR-SUPPRESSOR; GAMMA-H2AX FOCI; UV-IRRADIATION; PPM1D AB The integrity of DNA is constantly challenged throughout the life of a cell by both endogenous and exogenous stresses. A well-organized rapid damage response and proficient DNA repair, therefore, become critically important for maintaining genomic stability and cell survival. When DNA is damaged, the DNA damage response (DDR) can be initiated by alterations in chromosomal structure and histone modifications, such as the phosphorylation of the histone H2AX ( the phosphorylated form is referred to as gamma-H2AX). gamma-H2AX plays a crucial role in recruiting DDR factors to damage sites for accurate DNA repair. On repair completion, gamma-H2AX must then be reverted to H2AX by dephosphorylation for attenuation of the DDR. Here, we report that the wild-type p53-induced phosphatase 1 (Wip1) phosphatase, which is often overexpressed in a variety of tumors, effectively dephosphorylates gamma-H2AX in vitro and in vivo. Ectopic expression of Wip1 significantly reduces the level of gamma-H2AX after ionizing as well as UV radiation. Forced premature dephosphorylation of gamma-H2AX by Wip1 disrupts recruitment of important DNA repair factors to damaged sites and delays DNA damage repair. Additionally, deletion of Wip1 enhances gamma-H2AX levels in cells undergoing constitutive oncogenic stress. Taken together, our studies show that Wip1 is an important mammalian phosphatase for gamma-H2AX and shows an additional mechanism for Wip1 in the tumor surveillance network. Cancer Res; 70(10); 4112-22. (C) 2010 AACR. C1 [Fornace, Albert J., Jr.] Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Washington, DC 20057 USA. [Cha, Hyukjin; Lowe, Julie M.; Li, Henghong; Fornace, Albert J., Jr.] Georgetown Univ, Dept Oncol, Washington, DC 20057 USA. [Cha, Hyukjin; Lee, Ji-Seon] CHA Univ, Dept Biomed Sci, Cha Stem Cell Inst, Seoul 135081, South Korea. [Belova, Galina I.] NCI, Neurooncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Bulavin, Dmitry V.] Natl Univ Singapore, Inst Mol & Cell Biol, Singapore 117548, Singapore. [Cha, Hyukjin; Li, Henghong; Fornace, Albert J., Jr.] Harvard Univ, Sch Publ Hlth, John B Little Ctr Radiat Sci & Environm Hlth, Boston, MA 02115 USA. RP Fornace, AJ (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Res Bldg,Room E504,3970 Reservoir Rd NW, Washington, DC 20057 USA. EM hjcha@cha.ac.kr; af294@georgetown.edu RI ASTAR, IMCB/E-2320-2012 FU National Institute of Allergy and Infectious Diseases [1 U19 AI067773]; Korea Science and Engineering Foundation (KOSEF) [M20806000049-08B0600-04910]; Ministry of Education, Science and Technology [R31-10069] FX National Institute of Allergy and Infectious Diseases grant 1 U19 AI067773; grant M20806000049-08B0600-04910 the Korea Science and Engineering Foundation (KOSEF); and grant R31-10069 (WCU program) through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology. NR 55 TC 74 Z9 77 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2010 VL 70 IS 10 BP 4112 EP 4122 DI 10.1158/0008-5472.CAN-09-4244 PG 11 WC Oncology SC Oncology GA 607GE UT WOS:000278486300029 PM 20460517 ER PT J AU Takeshita, K Kawaguchi, K Fujii-Aikawa, K Ueno, M Okazaki, S Ono, M Krishna, MC Kuppusamy, P Ozawa, T Ikota, N AF Takeshita, Keizo Kawaguchi, Kumiko Fujii-Aikawa, Kaori Ueno, Megumi Okazaki, Shoko Ono, Mitsuhiro Krishna, Murali C. Kuppusamy, Periannan Ozawa, Toshihiko Ikota, Nobuo TI Heterogeneity of Regional Redox Status and Relation of the Redox Status to Oxygenation in a Tumor Model, Evaluated Using Electron Paramagnetic Resonance Imaging SO CANCER RESEARCH LA English DT Article ID NITROXIDE SPIN LABELS; BUTHIONINE SULFOXIMINE; LITHIUM PHTHALOCYANINE; MEDIATED REDUCTION; LIVER-MICROSOMES; ESR SPECTROSCOPY; FREE-RADICALS; EPR OXIMETRY; WHOLE MICE; RAT-LIVER AB It is widely accepted that redox status, along with the partial pressure of oxygen (pO(2)), determines the efficacy of some therapeutic methods applied to treat tumors, including radiation. Redox status, evaluated by the reduction of a nitroxyl probe, was reportedly heterogeneous in a mouse tumor model. However, neither variation of heterogeneity of the redox status among mice nor the relation of the redox status to pO(2) in tumors has been characterized sufficiently. In this study, the regional reduction status in a mouse radiation-induced fibrosarcoma tumor model was evaluated using sequential three-dimensional electron paramagnetic resonance (EPR) imaging after i.v. injection of a tissue-permeable nitroxyl probe, HM-PROXYL. The regional decay of HM-PROXYL signal obeyed first-order kinetics, and the amplitude of the reduction rate and extent of its heterogeneity in a tumor varied among six mice. The tissue pO(2) was measured using EPR oximetry with lithium phthalocyanine (LiPc) microcrystals implanted within the tumor. The location of LiPc was determined with EPR imaging. A sequential image was obtained following the injection of HM-PROXYL, even after LiPc implantation, by choosing an HM-PROXYL signal peak which does not overlap with the signal of LiPc. The relationship between pO(2) and the reduction rate at the region of pO(2) measurement was found to be low (r - 0.357) in 13 tumor-bearing mice, indicating that the extent of oxygenation does not necessarily affect the redox status under air-breathing conditions. The results strongly indicate the necessity of measurements of both redox status and oxygenation in every tumor to characterize tumor physiology. Cancer Res; 70(10); 4133-40. (C)2010 AACR. C1 [Takeshita, Keizo] Sojo Univ, Analyt Chem Lab, Fac Pharmaceut Sci, Kumamoto 8600082, Japan. [Takeshita, Keizo; Kawaguchi, Kumiko; Fujii-Aikawa, Kaori; Ueno, Megumi; Ozawa, Toshihiko; Ikota, Nobuo] Natl Inst Radiol Sci, Chiba 260, Japan. [Ono, Mitsuhiro] Yamagata Univ, Yamagata 990, Japan. [Krishna, Murali C.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Kuppusamy, Periannan] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Kuppusamy, Periannan] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Ozawa, Toshihiko] Yokohama Coll Pharm, Totsuka Ku, Yokohama, Kanagawa, Japan. [Ikota, Nobuo] Shujitsu Univ, Sch Pharm, Naka Ku, Okayama, Japan. RP Takeshita, K (reprint author), Sojo Univ, Analyt Chem Lab, Fac Pharmaceut Sci, 4-22-1 Ikeda, Kumamoto 8600082, Japan. EM keizo@ph.sojo-u.ac.jp RI dong, guofa/D-5248-2011 FU Japan Society for the Promotion of Science [19590050] FX Grants-in-Aid for Scientific Research (no. 19590050) from Japan Society for the Promotion of Science (K. Takeshita). NR 40 TC 14 Z9 14 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2010 VL 70 IS 10 BP 4133 EP 4140 DI 10.1158/0008-5472.CAN-09-4369 PG 8 WC Oncology SC Oncology GA 607GE UT WOS:000278486300031 PM 20442282 ER PT J AU Mofenson, LM AF Mofenson, Lynne M. TI Prevention in Neglected Subpopulations: Prevention of Mother-to-Child Transmission of HIV Infection SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID SINGLE-DOSE NEVIRAPINE; DAR-ES-SALAAM; 1ST 6 MONTHS; ANTIRETROVIRAL THERAPY; PREGNANT-WOMEN; RESISTANCE MUTATIONS; VERTICAL TRANSMISSION; SUBTYPE-C; RANDOMIZED-TRIAL; COTE-DIVOIRE AB Worldwide, > 1000 children are newly infected with human immunodeficiency virus (HIV) each day; the majority of these children are in sub-Saharan Africa. The primary mode of HIV acquisition is through mother-to-child transmission (MTCT) during pregnancy, childbirth, or breastfeeding. In well-resourced health care systems, like those in the United States, universal HIV testing for pregnant women, provision of antiretroviral therapy (when needed for maternal health) or prophylaxis, elective cesarean delivery, and avoidance of breastfeeding has reduced MTCT of HIV infection to 1%-2%. However, in resource-limited countries, the perinatal epidemic continues generally unabated. Clinical trials have identified simple, less expensive, effective antiretroviral prophylaxis regimens that can be implemented in resource-limited settings. However, implementation has been slow, and postnatal transmission of HIV through breastfeeding remains a significant challenge. This article will review the research on prevention of MTCT of HIV infection in resource-limited countries and the challenges to expansion of the benefits of preventive interventions for MTCT throughout the world. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD 20852 USA. RP Mofenson, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, 6100 Execut Blvd,Rm 4B11, Rockville, MD 20852 USA. EM LM65D@nih.gov OI Mofenson, Lynne/0000-0002-2818-9808 FU Center for Global Health Policy; Infectious Diseases Society of America; HIV Medicine Association, through the Bill & Melinda Gates Foundation FX This article is part of a supplement entitled "Synergistic Pandemics: Confronting the Global HIV and Tuberculosis Epidemics," which was sponsored by the Center for Global Health Policy, a project of the Infectious Diseases Society of America and the HIV Medicine Association, through a grant from the Bill & Melinda Gates Foundation. NR 107 TC 68 Z9 68 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2010 VL 50 SU 3 BP S130 EP S148 DI 10.1086/651484 PG 19 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 584PV UT WOS:000276765600010 PM 20397941 ER PT J AU Reynolds, SJ Quinn, TC AF Reynolds, Steven J. Quinn, Thomas C. TI Setting the Stage: Current State of Affairs and Major Challenges SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RESOURCE-LIMITED SETTINGS; ANTIRETROVIRAL THERAPY; HIV TRANSMISSION; VIRAL LOAD; MALE CIRCUMCISION; CONTROLLED-TRIAL; RURAL UGANDA; MEN; AFRICA AB The global human immunodeficiency virus (HIV) pandemic reached staggering proportions over the past 2 decades, particularly in areas of sub-Saharan Africa and other developing countries. Tremendous increases in donor resources over the past decade have allowed for a rapid scale-up of antiretroviral treatment and greater access to basic care and prevention programs in countries worst affected by HIV infection and AIDS. These programs have had a tremendous impact on the lives of millions of individuals and have also created optimism and hope where previously there was despair. Major challenges remain in combating the current HIV pandemic with regard to access to treatment; efficiency, quality, and sustainability of current programs; and the scale-up of evidence-based, effective prevention strategies. The global health community and political leaders will need to overcome these challenges if a long-term effective response to the HIV pandemic is to be achieved. C1 [Reynolds, Steven J.; Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Reynolds, Steven J.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. RP Reynolds, SJ (reprint author), 2190 Kampala Pl, Washington, DC 20521 USA. EM sjr@jhmi.edu FU Center for Global Health Policy; Infectious Diseases Society of America; HIV Medicine Association, through the Bill & Melinda Gates Foundation FX This article is part of a supplement entitled "Synergistic Pandemics: Confronting the Global HIV and Tuberculosis Epidemics," which was sponsored by the Center for Global Health Policy, a project of the Infectious Diseases Society of America and the HIV Medicine Association, through a grant from the Bill & Melinda Gates Foundation. NR 40 TC 5 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2010 VL 50 SU 3 BP S71 EP S76 DI 10.1086/651476 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 584PV UT WOS:000276765600002 PM 20397959 ER PT J AU Dupont, C Segars, J DeCherney, A Bavister, BD Armant, DR Brenner, CA AF Dupont, Catherine Segars, James DeCherney, Alan Bavister, Barry D. Armant, D. Randall Brenner, Carol A. TI Incidence of chromosomal mosaicism in morphologically normal nonhuman primate preimplantation embryos SO FERTILITY AND STERILITY LA English DT Article DE Mosaicism; embryos; monkey; nonhuman primate; aneuploidy; FISH ID COMPARATIVE GENOMIC HYBRIDIZATION; IN-SITU HYBRIDIZATION; PREGNANCY FOLLOW-UP; CLEAVAGE-STAGE EMBRYOS; MACAQUE MACACA-MULATTA; PGD CONSORTIUM; GENETIC DIAGNOSIS; RHESUS-MONKEY; BLASTOCYST STAGE; RECURRENT MISCARRIAGE AB Objective: To establish the exact rates of chromosomal mosaicism in morphologically normal rhesus macaque embryos by determining the chromosomal complement of all blastomeres. Design: Retrospective rhesus monkey IVF study. Setting: Academic laboratory and primate research center. Patient(s): Young fertile rhesus macaque females. Intervention(s): Morphologically normal in vitro-produced rhesus macaque embryos were dissociated and cytogenetically assessed using a five-color fluorescent in situ hybridization assay developed for rhesus macaque chromosomes homologous to human chromosomes 13, 16, 18, X, and Y. Main Outcome Measure(s): The incidence and extent of chromosomal mosaicism in rhesus macaque preimplantation embryos. Result(s): Seventy-seven preimplantation embryos, displaying normal morphology and development, from 17 young rhesus macaque females were analyzed. Overall, 39 embryos (50.6%) were normal, 14 embryos (18.2%) were completely abnormal, and 24 embryos (31.2%) were mosaic. Of the 226 blastomeres analyzed in the mosaic group, 110 blastomeres (48.7%) were normal. Conclusion(s): The observed rate of mosaicism in good-quality rhesus embryos resembles previously documented frequencies in poor-quality human preimplantation embryos. A high incidence of mosaicism may limit the diagnostic accuracy of preimplantation genetic diagnosis. (Fertil Steril (R) 2010; 93: 2545-50. (C) 2010 by American Society for Reproductive Medicine.) C1 [Brenner, Carol A.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, CS Mott Ctr Human Growth & Dev, Detroit, MI 48201 USA. [Dupont, Catherine; Brenner, Carol A.] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA. [Armant, D. Randall] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Segars, James; DeCherney, Alan; Armant, D. Randall] NICHHD, Program Reprod & Adult Endocrinol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bavister, Barry D.] Caribbean Primate Res Ctr, Sabana Seca, PR USA. RP Brenner, CA (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, CS Mott Ctr Human Growth & Dev, 275 Hancock St, Detroit, MI 48201 USA. EM cbrenner@med.wayne.edu OI Armant, D. Randall/0000-0001-5904-9325 FU National Institutes of Health [1R01HD045966-01A2, 5R24RR015395-04, R03HD046553-01A1, 1R21RR021881-01, RR03640] FX Supported by the National Institutes of Health (1R01HD045966-01A2 and 5R24RR015395-04 awarded to B. D. Bavister, 1R03HD046553-01A1 and 1R21RR021881-01 awarded to C. A. Brenner, and RR03640 awarded to the Caribbean Primate Research Center and the Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development). NR 51 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD MAY 15 PY 2010 VL 93 IS 8 BP 2545 EP 2550 DI 10.1016/j.fertnstert.2009.06.040 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 595KH UT WOS:000277608700011 PM 19732891 ER PT J AU Peddi, P Loftin, CW Dickey, JS Hair, JM Burns, KJ Aziz, K Francisco, DC Panayiotidis, MI Sedelnikova, OA Bonner, WM Winters, TA Georgakilas, AG AF Peddi, Prakash Loftin, Charles W. Dickey, Jennifer S. Hair, Jessica M. Burns, Kara J. Aziz, Khaled Francisco, Dave C. Panayiotidis, Mihalis I. Sedelnikova, Olga A. Bonner, William M. Winters, Thomas A. Georgakilas, Alexandros G. TI DNA-PKcs deficiency leads to persistence of oxidatively induced clustered DNA lesions in human tumor cells SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Oxidative clustered DNA lesions; DNA-PKcs; Cancer; DNA damage; gamma-H2AX; Free radicals ID DEPENDENT PROTEIN-KINASE; DOUBLE-STRAND BREAKS; BASE-EXCISION-REPAIR; CATALYTIC SUBUNIT; MAMMALIAN-CELLS; CANCER-CELLS; NALM-6 CELLS; DAMAGE; END; RADIATION AB DNA-dependent protein kinase (DNA-PM) is a key non-homologous-end-joining (NHEJ) nuclear serine/threonine protein kinase involved in various DNA metabolic and damage signaling pathways contributing to the maintenance of genomic stability and prevention of cancer. To examine the role of DNA-PM in processing of non-DSB clustered DNA damage, we have used three models of DNA-PM deficiency, i.e., chemical inactivation of its kinase activity by the novel inhibitors IC86621 and NU7026, knockdown and complete absence of the protein in human breast cancer (MCF-7) and glioblastoma cell lines (MO59-J/K). A compromised DNA-PM repair pathway led to the accumulation of clustered DNA lesions induced by gamma-rays. Tumor cells lacking protein expression or with inhibited kinase activity showed a marked decrease in their ability to process oxidatively induced non-DSB clustered DNA lesions measured using a modified version of pulsed-field gel electrophoresis or single-cell gel electrophoresis (comet assay). In all cases, DNA-PM inactivation led to a higher level of lesion persistence even after 24-72 h of repair. We suggest a model in which DNA-PM deficiency affects the processing of these clusters first by compromising base excision repair and second by the presence of catalytically inactive DNA-PM inhibiting the efficient processing of these lesions owing to the failure of DNA-PM to disassociate from the DNA ends. The information rendered will be important for understanding not only cancer etiology in the presence of an NHEJ deficiency but also cancer treatments based on the induction of oxidative stress and inhibition of cluster repair. (C) 2010 Elsevier Inc. All rights reserved. C1 [Peddi, Prakash; Loftin, Charles W.; Hair, Jessica M.; Burns, Kara J.; Aziz, Khaled; Francisco, Dave C.; Georgakilas, Alexandros G.] E Carolina Univ, Thomas Harriot Coll Arts & Sci, Dept Biol, Greenville, NC 27858 USA. [Dickey, Jennifer S.; Sedelnikova, Olga A.; Bonner, William M.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20895 USA. [Panayiotidis, Mihalis I.] Univ Ioannina, Sch Med, Dept Pathol, GR-45110 Ioannina, Greece. [Winters, Thomas A.] NIH, Dept Nucl Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Georgakilas, AG (reprint author), E Carolina Univ, Thomas Harriot Coll Arts & Sci, Dept Biol, Greenville, NC 27858 USA. EM georgakilasa@ecu.edu OI Panagiotidis, Mihalis/0000-0002-1130-5972 FU East Carolina University; National Cancer Institute, NIH FX The authors thank Dr. Jac Nickoloff for helpful discussions. We also thank Angela Cecil, Peter Kalogerinis, and Chris Richardson for their help on the data analysis. This work was supported by funds provided to Dr. Georgakilas by a 2009/2010 Research/Creative Activity Grant from East Carolina University and partly by the Intramural Research Program of the National Cancer Institute, NIH (J.S.D., W.M.B., and O.A.S.). NR 62 TC 35 Z9 35 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD MAY 15 PY 2010 VL 48 IS 10 BP 1435 EP 1443 DI 10.1016/j.freeradbiomed.2010.02.033 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 592AT UT WOS:000277347700018 PM 20193758 ER PT J AU Sen, R Grosschedl, R AF Sen, Ranjan Grosschedl, Rudolf TI Memories of lost enhancers SO GENES & DEVELOPMENT LA English DT Article DE Epigenetics; transcription; chromatin; gene regulation; CD4; T-cell development ID LOCUS-CONTROL REGION; BETA-GLOBIN LOCUS; OPEN CHROMATIN-STRUCTURE; HEAVY-CHAIN GENE; EPIGENETIC MEMORY; TRANSCRIPTION FACTORIES; NUCLEAR-ENVELOPE; CELL DEVELOPMENT; ERYTHROID-CELLS; EXPRESSION AB Transcriptional enhancers are key determinants of developmentally regulated gene expression. Models of enhancer function must distinguish between analog or digital control of transcription, as well as their requirement to initiate or maintain transcriptional activity of a gene. In light of a recent study by Chong and colleagues (pp. 659-669) providing evidence of a transient requirement of an enhancer associated with the CD4 gene, we discuss possible mechanisms by which transcriptional memory can be propagated in the absence of enhancers. C1 [Sen, Ranjan] NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. [Grosschedl, Rudolf] Max Planck Inst Immunobiol, D-79108 Freiburg, Germany. RP Sen, R (reprint author), NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. EM rs465z@nih.gov; grosschedl@immunbio.mpg.de FU Intramural Research Program of the National Institute on Aging (Baltimore, MD); Max Planck Society and German Research Foundation FX Work in our laboratories is supported by the Intramural Research Program of the National Institute on Aging (Baltimore, MD) (R. S.) and the Max Planck Society and German Research Foundation (R. G.). NR 45 TC 14 Z9 15 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAY 15 PY 2010 VL 24 IS 10 BP 973 EP 979 DI 10.1101/gad.1930610 PG 7 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 596ZR UT WOS:000277725300001 PM 20478992 ER PT J AU Fogarty, MP Xiao, R Prokunina-Olsson, L Scott, LJ Mohlke, KL AF Fogarty, Marie P. Xiao, Rui Prokunina-Olsson, Ludmila Scott, Laura J. Mohlke, Karen L. TI Allelic expression imbalance at high-density lipoprotein cholesterol locus MMAB-MVK SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENE-EXPRESSION; METABOLISM; VARIANTS; ACIDURIA; DISEASE; GENOME AB Genome-wide association studies (GWAS) have identified numerous loci associated with various complex traits for which the underlying susceptibility gene(s) remain unknown. In a GWAS for high-density lipoprotein-cholesterol (HDL-C) level, one strongly associated locus contains at least two biologically compelling candidates, methylmalonic aciduria cblB type (MMAB) and mevalonate kinase (MVK). To detect evidence of cis-acting regulation at this locus, we measured relative allelic expression of transcribed SNPs in five genes using human hepatocyte samples heterozygous for the transcribed SNP. If an HDL-C-associated SNP allele differentially regulates mRNA level in cis, samples heterozygous both for a transcribed SNP and an HDL-C-associated SNP should display allelic expression imbalance (AEI) of the transcribed SNP. We designed statistical tests to detect AEI in a comprehensive set of linkage disequilibrium (LD) scenarios between the transcribed SNP and an HDL-C-associated SNP (rs7298565) in phase unknown samples. We observed significant AEI of 22% in MMAB (P = 1.4 x 10(-13), transcribed SNP rs11067231), and the allele associated with lower HDL-C level was associated with greater MMAB transcript level. The same rs7298565 allele was also associated with higher MMAB mRNA level (P = 0.0081) and higher MMAB protein level (P = 0.0020). In contrast, MVK, UBE3B, KCTD10 and ACACB did not show significant AEI (P >= 0.05). These data suggest MMAB is the most likely gene influencing HDL-C levels at this locus and demonstrate that measuring AEI at loci containing more than one candidate gene can prioritize genes for functional studies. C1 [Fogarty, Marie P.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Xiao, Rui; Scott, Laura J.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Xiao, Rui; Scott, Laura J.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Prokunina-Olsson, Ludmila] NCI, Div Canc Epidemiol & Genet, Lab Translat Genom, NIH, Gaithersburg, MD 20892 USA. RP Mohlke, KL (reprint author), 5096 Genet Med Bldg,120 Mason Farm Rd, Chapel Hill, NC 27599 USA. EM mohlke@med.unc.edu OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU National Institutes of Health [DK072193, DK062370] FX This research was funded by the National Institutes of Health (DK072193, DK062370). NR 23 TC 19 Z9 20 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2010 VL 19 IS 10 BP 1921 EP 1929 DI 10.1093/hmg/ddq067 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 590PD UT WOS:000277238200005 PM 20159775 ER PT J AU Shebl, FM Bhatia, K Engels, EA AF Shebl, Fatma M. Bhatia, Kishor Engels, Eric A. TI Salivary gland and nasopharyngeal cancers in individuals with acquired immunodeficiency syndrome in United States SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE epidemiology; HIV/AIDS; salivary gland cancer; nasopharyngeal cancer; lymphoepithelial carcinoma; EBV-related malignancies ID EPSTEIN-BARR-VIRUS; IN-SITU HYBRIDIZATION; MALIGNANT LYMPHOEPITHELIAL LESIONS; UNDIFFERENTIATED CARCINOMA; HUMAN-PAPILLOMAVIRUS; PAROTID-GLAND; STRONG ASSOCIATION; NECK CANCERS; INFECTION; RISK AB Individuals with acquired immunodeficiency syndrome (AIDS) manifest an increased risk of cancer, particularly cancers caused by oncogenic viruses. Because some salivary gland and nasopharyngeal cancers are associated with Epstein Barr virus, the impact of AIDS on these cancers needs further evaluation. We used linked U.S. AIDS and cancer registry data (N = 519,934 people with AIDS) to derive standardized incidence ratios (SIRs) comparing risk of salivary gland and nasopharyngeal cancers to the general population. For salivary gland cancers (N = 43 cases), individuals with AIDS had strongly elevated risks for lymphoepithelial carcinoma (SIR 39, 95% Cl 16-81) and squamous cell carcinoma (SIR 4.9, 95% Cl 2.5-8.6). Among nasopharyngeal cancers (N = 39 cases), risks were elevated for both keratinizing and nonkeratinizing carcinomas (SIR 2.4, 95% Cl 1.5-3.7 and SIR 2.4, 95% Cl 1.2-4.4, respectively). The elevated risks of salivary gland and nasopharyngeal cancers among people with AIDS suggest that immunosuppression and oncogenic viral infections are etiologically important. C1 [Shebl, Fatma M.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Rockville, MD 20852 USA. RP Shebl, FM (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, 6120 Execut Blvd,EPS 7074, Rockville, MD 20852 USA. EM sheblf@mail.nih.gov FU National Cancer Institute FX Grant sponsor: Intramural Research Program of the National Cancer Institute NR 61 TC 7 Z9 7 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 15 PY 2010 VL 126 IS 10 BP 2503 EP 2508 DI 10.1002/ijc.24930 PG 6 WC Oncology SC Oncology GA 586RF UT WOS:000276928700024 PM 19810095 ER PT J AU McCann, CP Kriebel, PW Parent, CA Losert, W AF McCann, Colin P. Kriebel, Paul W. Parent, Carole A. Losert, Wolfgang TI Cell speed, persistence and information transmission during signal relay and collective migration SO JOURNAL OF CELL SCIENCE LA English DT Article DE Chemotaxis; Dictyostelium discoideum; Collective migration ID DICTYOSTELIUM-DISCOIDEUM; DICYOSTELIUM-DISCOIDEUM; DIFFUSION-COEFFICIENT; MOLECULAR-GENETICS; WAVE-PROPAGATION; SLIME-MOLDS; CHEMOTAXIS; MODEL; MOVEMENT; DENSITY AB Collective migration is a key feature of the social amoebae Dictyostelium discoideum, where the binding of chemoattractants leads to the production and secretion of additional chemoattractant and the relay of the signal to neighboring cells. This then guides cells to migrate collectively in a head-to-tail fashion. We used mutants that were defective in signal relay to elucidate which quantitative metrics of cell migration are most strongly affected by signal relay and collective motion. We show that neither signal relay nor collective motion markedly impact the speed of cell migration. Cells maintained a preferred overall direction of motion for several minutes with similar persistence, regardless of whether or not they were attracted to moving neighbors, moving collectively in contact with their neighbors, or simply following a fixed exogenous signal. We quantitatively establish that signal relay not only increases the number of cells that respond to a chemotactic signal, but most remarkably, also transmits information about the location of the source accurately over large distances, independently of the strength of the exogenous signal. We envision that signal relay has a similar key role in the migration of a variety of chemotaxing mammalian cells that can relay chemoattractant signals. C1 [McCann, Colin P.; Kriebel, Paul W.; Parent, Carole A.; Losert, Wolfgang] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [McCann, Colin P.; Losert, Wolfgang] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. RP Parent, CA (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM parentc@mail.nih.gov FU NIST Center for computational Materials Science; NSF [PHY0750371]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX The authors would like to thank Alan Kimmel for the use of his microscope for self-aggregation experiments as well as the Dictyostelium Stock Center for providing cells lacking CMF. We also like to thank the Parent and Losert lab members for excellent discussions and in particular Meghan Driscoll for insightful suggestions. W.L. and C.M. acknowledge support from the NIST Center for computational Materials Science and from NSF grant PHY0750371. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Deposited in PMC for release after 12 months. NR 50 TC 36 Z9 36 U1 5 U2 21 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAY 15 PY 2010 VL 123 IS 10 BP 1724 EP 1731 DI 10.1242/jcs.060137 PG 8 WC Cell Biology SC Cell Biology GA 592EB UT WOS:000277357400013 PM 20427323 ER PT J AU Wang, CW Kang, SG HogenEsch, H Love, PE Kim, CH AF Wang, Chuanwu Kang, Seung G. HogenEsch, Harm Love, Paul E. Kim, Chang H. TI Retinoic Acid Determines the Precise Tissue Tropism of Inflammatory Th17 Cells in the Intestine SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; THYMUS-EXPRESSED CHEMOKINE; ACTIVE CROHNS-DISEASE; DENDRITIC CELLS; BOWEL-DISEASE; RECEPTOR CCR9; IMMUNE-RESPONSES; HELPER-CELLS; DIFFERENTIATION; LYMPHOCYTES AB Th17 cells are major effector T cells in the intestine, but the regulation of their tissue tropism within the gut is poorly understood. We investigated the roles of vitamin A and retinoic acid in generation of inflammatory Th17 cells with distinct tissue tropisms within the intestine. We found that Th17 cells with distinct tissue tropisms and pathogenic activities are generated depending on the available concentration of retinoic acid (RA). In contrast to the widespread perception that RA would suppress the generation of Th17 cells, we provide evidence that RA is actually required for generation of Th17 cells with specific tissue tropisms within the gut. Th17 cells induced at suboptimal serum concentrations of RA migrated and induced moderate inflammation mainly in the large intestine, whereas the Th17 cells induced with optimal levels of exogenous RA (similar to 10 nM) migrated to the small intestine and induced more severe inflammation. The Th17 cells, induced in the presence or absence of RA, differentially expressed the trafficking receptors CCR9 and alpha 4 beta 7. CCR9 is required for Th17 cell migration to the small intestine, whereas alpha 4 beta 7 is required for the migration of Th17 cells throughout the whole intestine. Our results identified RA as a major signal that regulates the generation of gut Th17 cells with distinct capacities in migration and inflammatory activities. The results indicate also that specific gut tropism of Th17 cells is determined by the combination of trafficking receptors regulated by the RA signal. The Journal of Immunology, 2010,184: 5519-5526. C1 [Wang, Chuanwu; Kang, Seung G.; HogenEsch, Harm; Kim, Chang H.] Purdue Univ, Dept Comparat Pathobiol, Lab Immunol & Hematopoiesis, Purdue Canc Ctr, W Lafayette, IN 47907 USA. [Love, Paul E.] NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. [Love, Paul E.] NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Kim, CH (reprint author), Purdue Univ, Dept Comparat Pathobiol, Lab Immunol & Hematopoiesis, Purdue Canc Ctr, 725 Harrison St, W Lafayette, IN 47907 USA. EM chkim@purdue.edu RI Wang, Chuanwu/E-9117-2012; Wang, Chuanwu/N-3186-2013; OI HogenEsch, Harm/0000-0002-2738-9189 FU National Institutes of Health [1R01AI074745, 1R56A1080769, 1R01DK076616]; Crohn's and Colitis Foundation of America FX This work was supported by National Institutes of Health Grants 1R01AI074745, 1R56A1080769, and 1R01DK076616 and the Crohn's and Colitis Foundation of America (to C.H.K.). NR 49 TC 47 Z9 49 U1 2 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2010 VL 184 IS 10 BP 5519 EP 5526 DI 10.4049/jimmunol.0903942 PG 8 WC Immunology SC Immunology GA 594IO UT WOS:000277530700012 PM 20400707 ER PT J AU Su, XZ AF Su, Xin-zhuan TI Human Malaria Parasites: Are We Ready for a New Species? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID PLASMODIUM-OVALE; RIBOSOMAL-RNA; TARGET; VIVAX C1 NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,MSC 8132,Twinbrook 3,Room 3E, Bethesda, MD 20892 USA. EM xsu@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 FU Intramural NIH HHS [ZIA AI000892-09] NR 15 TC 4 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2010 VL 201 IS 10 BP 1453 EP 1454 DI 10.1086/652238 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 584QO UT WOS:000276767600003 PM 20380563 ER PT J AU Gray, RH Serwadda, D Kong, XR Makumbi, F Kigozi, G Gravitt, PE Watya, S Nalugoda, F Ssempijja, V Tobian, AAR Kiwanuka, N Moulton, LH Sewankambo, NK Reynolds, SJ Quinn, TC Iga, B Laeyendecker, O Oliver, AE Wawer, MJ AF Gray, Ronald H. Serwadda, David Kong, Xiangrong Makumbi, Frederick Kigozi, Godfrey Gravitt, Patti E. Watya, Stephen Nalugoda, Fred Ssempijja, Victor Tobian, Aaron A. R. Kiwanuka, Noah Moulton, Lawrence H. Sewankambo, Nelson K. Reynolds, Steven J. Quinn, Thomas C. Iga, Boaz Laeyendecker, Oliver Oliver, Amy E. Wawer, Maria J. TI Male Circumcision Decreases Acquisition and Increases Clearance of High-Risk Human Papillomavirus in HIV-Negative Men: A Randomized Trial in Rakai, Uganda SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CERVICAL-CANCER; YOUNG MEN; INFECTION; PREVALENCE; PREVENTION; SITES AB Methods. Uncircumcised human immunodeficiency virus (HIV)-negative men aged 15-49 years were randomized to immediate circumcision (intervention arm, 441 subjects) or delayed circumcision (control arm, 399 subjects). Human papillomavirus (HPV) was detected by Roche HPV Linear Array at enrollment, and at 6, 12, and 24 months. Incident high-risk HPV (HR-HPV) was estimated in men who acquired a new HR-HPV genotype. HR-HPV clearance was determined in men with prior genotype-specific HR-HPV infections. Rate ratios (RRs) and 95% confidence intervals (CIs) of HR-HPV acquisition were estimated by Poisson multiple regression. Results. Enrollment characteristics were comparable between study groups. HR-HPV incidence was 19.7 cases per 100 person-years (PYs) in the intervention arm (70 cases per 355.8 PYs) and 29.4 cases per 100 PYs (125 cases per 424.8 PYs) in the control arm (RR, 0.67; 95% CI, 0.51-0.89; P = .006). The incidence of multiple HR-HPV infections was 6.7 cases per 100 PYs in the intervention arm and 14.8 cases per 100 PYs in the control arm (RR, 0.45; 95% CI, 0.28-0.73), but there was no significant effect on single infections (RR, 0.89; 95% CI, 0.60-1.30). HR-HPV incidence was lower in the intervention arm for all genotypes and demographic/behavioral subgroups. The clearance of preexisting HR-HPV infections was 215.8 cases per 100 PYs (205 cases per 95 PYs) in the intervention arm and 159.1 cases per 100 PYs (255 cases per 160.25 PYs) in the control arm (adjusted RR, 1.39; 95% CI, 1.17-1.64). Conclusions. Male circumcision reduces the incidence of multiple HR-HPV infections and increases clearance of HR-HPV infections in HIV-uninfected men. C1 [Gray, Ronald H.; Kong, Xiangrong; Wawer, Maria J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD 21205 USA. [Gravitt, Patti E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Moulton, Lawrence H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. [Tobian, Aaron A. R.; Iga, Boaz] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Reynolds, Steven J.; Quinn, Thomas C.; Laeyendecker, Oliver; Oliver, Amy E.] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Reynolds, Steven J.; Quinn, Thomas C.; Laeyendecker, Oliver] NIAID, NIH, Bethesda, MD 20892 USA. [Gray, Ronald H.; Serwadda, David; Makumbi, Frederick; Kigozi, Godfrey; Nalugoda, Fred; Ssempijja, Victor; Kiwanuka, Noah; Sewankambo, Nelson K.; Iga, Boaz; Wawer, Maria J.] Rakai Hlth Sci Program, Kalisizo, Uganda. [Serwadda, David; Makumbi, Frederick; Kiwanuka, Noah] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Watya, Stephen] Makerere Univ, Urol Unit, Dept Surg, Mulago Hosp, Kampala, Uganda. [Sewankambo, Nelson K.] Makerere Univ, Fac Med, Coll Hlth Sci, Kampala, Uganda. RP Gray, RH (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, 615 N Wolfe St,Ste E4132, Baltimore, MD 21205 USA. EM rgray@jhsph.edu RI Laeyendecker, Oliver/B-9331-2009; Kong, Xiangrong/B-5098-2010; OI Sewankambo, Nelson/0000-0001-9362-053X; Laeyendecker, Oliver/0000-0002-6429-4760; Moulton, Lawrence/0000-0001-7041-7387 FU National Institutes of Allergy and Infectious Disease (NIAID), Division of AIDS, National Institutes of Health (NIH) [U01 AI11171-01-02]; Division of Intramural Research, NIAID, NIH; Fogarty International Center/USNIH [2D43 TW000010-19-AITRP] FX The study was primarily supported by the National Institutes of Allergy and Infectious Disease (NIAID), Division of AIDS, National Institutes of Health (NIH) (grant U01 AI11171-01-02) and in part by the Division of Intramural Research, NIAID, NIH. This publication was supported in part by a fellowship from the Fogarty International Center/USNIH (grant 2D43 TW000010-19-AITRP). NR 18 TC 80 Z9 81 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2010 VL 201 IS 10 BP 1455 EP 1462 DI 10.1086/652184 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 584QO UT WOS:000276767600004 PM 20370483 ER PT J AU Serwadda, D Wawer, MJ Makumbi, F Kong, XR Kigozi, G Gravitt, P Watya, S Nalugoda, F Ssempijja, V Tobian, AAR Kiwanuka, N Moulton, LH Sewankambo, NK Reynolds, SJ Quinn, TC Oliver, AE Iga, B Laeyendecker, O Gray, RH AF Serwadda, David Wawer, Maria J. Makumbi, Frederick Kong, Xiangrong Kigozi, Godfrey Gravitt, Patti Watya, Stephen Nalugoda, Fred Ssempijja, Victor Tobian, Aaron A. R. Kiwanuka, Noah Moulton, Lawrence H. Sewankambo, Nelson K. Reynolds, Steven J. Quinn, Thomas C. Oliver, Amy E. Iga, Boaz Laeyendecker, Oliver Gray, Ronald H. TI Circumcision of HIV-Infected Men: Effects on High-Risk Human Papillomavirus Infections in a Randomized Trial in Rakai, Uganda SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID YOUNG MEN; FEMALE PARTNERS; CERVICAL-CANCER; RURAL RAKAI; PREVALENCE; PREVENTION; CLEARANCE; SITES; KENYA AB In Rakai, Uganda, human immunodeficiency virus (HIV)-positive men were randomized to undergo either immediate circumcision (intervention arm) or delayed circumcision (control arm). Penile swab samples were assayed for high-risk human papillomavirus (HR-HPV) by Roche HPV Linear Array at enrollment and at 24 months (intervention arm, 103 subjects; control arm, 107 subjects). Rate ratios (RRs) of HR-HPV were estimated by Poisson regression. At 24 months, HR-HPV prevalence was found in 57 (55.3%) of 103 subjects in the intervention arm and in 77 (71.7%) of 107 subjects in the control arm (RR, 0.77; 95% confidence interval [CI], 0.62-0.97). Multiple HR-HPV infections were found in 19 (22.4%) of 85 subjects in the intervention arm and in 45 (42.5%) of 106 subjects in the control arm (RR, 0.53; 95% CI, 0.33-0.83). New HR-HPV genotypes were acquired by 34 (42.0%) of 81 subjects in the intervention arm and by 53 (57.0%) 85 subjects in the control arm (RR, 0.74; 95% CI, 0.54-1.01; P = .06). Multiple new HR-HPV genotypes were acquired by 8 (9.9%) of 81 subjects in the intervention arm and by 23 (24.7%) of 93 subjects in the control arm (RR, 0.40; 95% CI, 0.19-0.84; P = .01). Circumcision did not affect the acquisition of single HR-HPV infections (RR, 1.00; 95% CI 0.65-1.53) or clearance of HR-HPV infections (RR, 1.09; 95% CI 0.94-1.27). Circumcision of HIV-positive men reduced the prevalence and incidence of multiple HR-HPV infections. C1 [Wawer, Maria J.; Kong, Xiangrong; Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD 21205 USA. [Gravitt, Patti] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Moulton, Lawrence H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. [Watya, Stephen] Makerere Univ, Urol Unit, Dept Surg, Mulago Hosp, Kampala, Uganda. [Sewankambo, Nelson K.] Makerere Univ, Fac Med, Coll Hlth Sci, Kampala, Uganda. [Serwadda, David; Makumbi, Frederick; Kiwanuka, Noah] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Serwadda, David; Wawer, Maria J.; Makumbi, Frederick; Kigozi, Godfrey; Nalugoda, Fred; Ssempijja, Victor; Kiwanuka, Noah; Iga, Boaz; Gray, Ronald H.] Rakai Hlth Sci Program, Kalisizo, Uganda. [Tobian, Aaron A. R.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Reynolds, Steven J.; Quinn, Thomas C.; Oliver, Amy E.; Laeyendecker, Oliver] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Reynolds, Steven J.; Quinn, Thomas C.; Laeyendecker, Oliver] NIAID, NIH, Bethesda, MD 20892 USA. RP Gray, RH (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, 615 N Wolfe St,Ste E4132, Baltimore, MD 21205 USA. EM rgray@jhsph.edu RI Laeyendecker, Oliver/B-9331-2009; Kong, Xiangrong/B-5098-2010; OI Sewankambo, Nelson/0000-0001-9362-053X; Laeyendecker, Oliver/0000-0002-6429-4760; Moulton, Lawrence/0000-0001-7041-7387 FU Bill and Melinda Gates Foundation [22006]; Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health; Fogarty International Center [5D43TW001508, D43TW00015]; National Cancer Institute [BRC 55502-23] FX This study was funded by The Bill and Melinda Gates Foundation (grant 22006). Additional support for laboratory analyses and training were provided, respectively, by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, and the Fogarty International Center (grants 5D43TW001508 and D43TW00015). Support for HPV assays was provided by Dr Charles Rabkin under subcontract BRC 55502-23 from the National Cancer Institute. NR 20 TC 40 Z9 40 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2010 VL 201 IS 10 BP 1463 EP 1469 DI 10.1086/652185 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 584QO UT WOS:000276767600005 PM 20370481 ER PT J AU Lu, SY Chun, JH Pike, VW AF Lu, Shuiyu Chun, Joong-Hyun Pike, Victor W. TI FLUORINE-18 CHEMISTRY IN MICRO-REACTORS SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract CT 10th International Symposium on Synthesis and Application of Isotopes and Isotopically Labelled Compounds CY JUN 14-18, 2009 CL Chicago, IL SP Int Isotope Soc, Soc Whole Body Autoradiog DE micro-reactor; microfluidics; fluorine-18; fluorination; PET ID DIARYLIODONIUM-SALTS; MICROFLUIDIC REACTOR; PET; RADIOFLUORINATION; ION; RADIOLIGAND; DIFLUORIDE; FLUORIDE; BRAIN C1 [Lu, Shuiyu; Chun, Joong-Hyun; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Lu, SY (reprint author), NIMH, Mol Imaging Branch, NIH, 10 Ctr Dr,Room B3 C346, Bethesda, MD 20892 USA. OI Lu, Shuiyu/0000-0003-0310-4318 FU Intramural NIH HHS [Z01 MH002793-07]; NIMH NIH HHS [Z01 MH002793] NR 27 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2010 VL 53 IS 5-6 SI SI BP 234 EP 238 PG 5 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 618UM UT WOS:000279381200004 PM 20936095 ER PT J AU Han, JC Lawlor, DA Kimm, SYS AF Han, Joan C. Lawlor, Debbie A. Kimm, Sue Y. S. TI Childhood obesity SO LANCET LA English DT Article ID BODY-MASS INDEX; EARLY-ONSET OBESITY; RANDOMIZED CONTROLLED-TRIAL; PRADER-WILLI-SYNDROME; LOW-CARBOHYDRATE DIET; WEIGHT-LOSS; PHYSICAL-ACTIVITY; RISK-FACTORS; LEPTIN RECEPTOR; PROOPIOMELANOCORTIN POMC AB Worldwide prevalence of childhood obesity has increased greatly during the past three decades. The increasing occurrence in children of disorders such as type 2 diabetes is believed to be a consequence of this obesity epidemic. Much progress has been made in understanding of the genetics and physiology of appetite control and from these advances, elucidation of the causes of some rare obesity syndromes. However, these rare disorders have so far taught us few lessons about prevention or reversal of obesity in most children. Calorie intake and activity recommendations need reassessment and improved quantification at a population level because of sedentary lifestyles of children nowadays. For individual treatment, currently recommended calorie prescriptions might be too conservative in view of evolving insight into the so-called energy gap. Although quality of research into both prevention and treatment has improved, high-quality multicentre trials with long-term follow-up are needed. Meanwhile, prevention and treatment approaches to increase energy expenditure and decrease intake should continue. Recent data suggest that the spiralling increase in childhood obesity prevalence might be abating; increased efforts should be made on all fronts to continue this potentially exciting trend. C1 [Kimm, Sue Y. S.] Univ New Mexico, Hlth Sci Ctr, Dept Internal Med Epidemiol, Sch Med, Albuquerque, NM 87131 USA. [Han, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD USA. [Lawlor, Debbie A.] Univ Bristol, MRC, Ctr Causal Analyses Translat Epidemiol, Dept Social Med, Bristol, Avon, England. RP Kimm, SYS (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Internal Med Epidemiol, Sch Med, MSC 10 5550, Albuquerque, NM 87131 USA. EM kimm@pitt.edu RI Fruyt, Sofie/F-6843-2011 OI Lawlor, Debbie A/0000-0002-6793-2262; FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; US National Institutes of Health [R01 DK077659]; UK Medical Research Council [G0600705, G0801456]; National Institute for Health Research [RP-PG-0407-10044] FX JCH receives research support from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and is a commissioned officer in the US Public Health Service, Department of Health and Human Services. The funding source had no direct role in writing of this Seminar. DAL receives funding from the US National Institutes of Health (R01 DK077659), UK Medical Research Council (G0600705 and G0801456), and National Institute for Health Research (RP-PG-0407-10044) for her work in the area of childhood obesity and determining causality from observational research. The opinions and assertions expressed in this report are those of the authors and are not to be construed as reflecting the views of the US Public Health Service or any other funding body. NR 141 TC 495 Z9 521 U1 26 U2 174 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD MAY 15 PY 2010 VL 375 IS 9727 BP 1737 EP 1748 DI 10.1016/S0140-6736(10)60171-7 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 599DK UT WOS:000277890200035 PM 20451244 ER PT J AU Im, E Motiejunaite, R Aranda, J Park, EY Federico, L Kim, TI Clair, T Stracke, ML Smyth, S Kazlauskas, A AF Im, Eunok Motiejunaite, Ruta Aranda, Jorge Park, Eun Young Federico, Lorenzo Kim, Tae-im Clair, Timothy Stracke, Mary L. Smyth, Susan Kazlauskas, Andrius TI Phospholipase C gamma Activation Drives Increased Production of Autotaxin in Endothelial Cells and Lysophosphatidic Acid-Dependent Regression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GROWTH-FACTOR; MACULAR DEGENERATION; LYSOPHOSPHOLIPASE-D; BLOOD-VESSELS; ANGIOGENESIS; MOUSE; DEATH; VASCULOGENESIS; VASCULATURE; MACROPHAGES AB We previously reported that vascular endothelial growth factor (VEGF)-dependent activation of phospholipase C gamma 1 (PLC gamma) regulated tube stability by competing with phosphoinositide 3-kinase (PI3K) for their common substrate. Here we describe an additional mechanism by which PLC gamma promoted regression of tubes and blood vessels. Namely, it increased the level of autotaxin (ATX), which is a secreted form of lysophospholipase D that produces lysophosphatidic acid (LPA). LPA promoted motility of endothelial cells, leading to disorganization/regression of tubes in vitro. Furthermore, mice that under-or overexpressed members of this intrinsic destabilization pathway showed either delayed or accelerated, respectively, regression of blood vessels. We conclude that endothelial cells can be instructed to engage a PLC gamma-dependent intrinsic destabilization pathway that results in the production of soluble regression factors such as ATX and LPA. These findings are likely to potentiate ongoing efforts to prevent, manage, and eradicate numerous angiogenesis-based diseases such as proliferative diabetic retinopathy and solid tumors. C1 [Im, Eunok; Motiejunaite, Ruta; Aranda, Jorge; Park, Eun Young; Kazlauskas, Andrius] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. [Federico, Lorenzo; Smyth, Susan] Univ Kentucky, Dept Pharmacol, Lexington, KY 40536 USA. [Kim, Tae-im] Yonsei Univ, Coll Med, Dept Ophthalmol, Corneal Dystrophy Res Inst, Seoul, South Korea. [Motiejunaite, Ruta] Vilnius Univ, Dept Biochem & Biophys, Vilnius, Lithuania. [Clair, Timothy; Stracke, Mary L.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kazlauskas, A (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM ak@eri.harvard.edu FU Flight Attendant Medical Research Institute; NIH/NIDDK [1KO1 DK083336, EY016385]; Pew Latin American Fellows Program in the Biomedical Sciences; American Diabetes Association Mentor-Based Minority Postdoctoral Fellowship [7-09-MI-04] FX This study was supported by a Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (to E. I.), NIH/NIDDK grant 1KO1 DK083336 (to E. I.), NIH grant EY016385 (to A. K.), and Pew Latin American Fellows Program in the Biomedical Sciences and American Diabetes Association Mentor-Based Minority Postdoctoral Fellowship 7-09-MI-04 (to J. A.). This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research (to T. C. and M. S.). NR 49 TC 24 Z9 24 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY 15 PY 2010 VL 30 IS 10 BP 2401 EP 2410 DI 10.1128/MCB.01275-09 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 588BK UT WOS:000277040900009 PM 20231358 ER PT J AU Fu, D Brophy, JAN Chan, CTY Atmore, KA Begley, U Paules, RS Dedon, PC Begley, TJ Samson, LD AF Fu, Dragony Brophy, Jennifer A. N. Chan, Clement T. Y. Atmore, Kyle A. Begley, Ulrike Paules, Richard S. Dedon, Peter C. Begley, Thomas J. Samson, Leona D. TI Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ESCHERICHIA-COLI; OXIDATIVE DEMETHYLATION; MODIFIER URM1; PROTEIN; REPAIR; YEAST; TRANSLATION; IDENTIFICATION; LOCALIZATION; METHYLATION AB tRNA nucleosides are extensively modified to ensure their proper function in translation. However, many of the enzymes responsible for tRNA modifications in mammals await identification. Here, we show that human AlkB homolog 8 (ABH8) catalyzes tRNA methylation to generate 5-methylcarboxymethyl uridine (mcm(5)U) at the wobble position of certain tRNAs, a critical anticodon loop modification linked to DNA damage survival. We find that ABH8 interacts specifically with tRNAs containing mcm(5)U and that purified ABH8 complexes methylate RNA in vitro. Significantly, ABH8 depletion in human cells reduces endogenous levels of mcm(5)U in RNA and increases cellular sensitivity to DNA-damaging agents. Moreover, DNA-damaging agents induce ABH8 expression in an ATM-dependent manner. These results expand the role of mammalian AlkB proteins beyond that of direct DNA repair and support a regulatory mechanism in the DNA damage response pathway involving modulation of tRNA modification. C1 [Fu, Dragony; Brophy, Jennifer A. N.; Chan, Clement T. Y.; Atmore, Kyle A.; Dedon, Peter C.; Samson, Leona D.] MIT, Dept Biol Engn, Cambridge, MA 02138 USA. [Fu, Dragony; Samson, Leona D.] MIT, Dept Biol, Cambridge, MA 02138 USA. [Chan, Clement T. Y.; Dedon, Peter C.] MIT, Dept Chem, Cambridge, MA 02138 USA. [Fu, Dragony; Brophy, Jennifer A. N.; Chan, Clement T. Y.; Atmore, Kyle A.; Dedon, Peter C.; Samson, Leona D.] MIT, Ctr Environm Hlth Sci, Cambridge, MA 02138 USA. [Fu, Dragony; Samson, Leona D.] MIT, Koch Inst Canc Res, Cambridge, MA 02138 USA. [Begley, Ulrike; Begley, Thomas J.] SUNY Albany, GeNYsis Ctr Excellence Canc Genom, Dept Biomed Sci, Rensselaer, NY 12144 USA. [Paules, Richard S.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Samson, LD (reprint author), 77 Massachusetts Ave 56-230, Cambridge, MA 02139 USA. EM lsamson@mit.edu RI Fu, Dragony/A-2146-2013; OI Dedon, Peter/0000-0003-0011-3067; Chan, Tsz Yan Clement/0000-0001-7940-3459; Fu, Dragony/0000-0002-8725-8658 FU NIH [CA055042, ES002109, ES01701]; MIT Westaway Fund; NCRR [S10- RR023783]; American Cancer Society TJX Postdoctoral Fellowship; American Cancer Society Research FX This work was supported by NIH grants CA055042 and ES002109 to L.D.S.and ES01701 to T.J.B., by the Intramural Research Program of the NIH (R.S.P.), and by the MIT Westaway Fund and NCRR grant S10- RR023783 to P.C.D.D.F.is supported by an American Cancer Society TJX Postdoctoral Fellowship, and L.D.S.is an American Cancer Society Research Professor. NR 46 TC 72 Z9 74 U1 2 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY 15 PY 2010 VL 30 IS 10 BP 2449 EP 2459 DI 10.1128/MCB.01604-09 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 588BK UT WOS:000277040900013 PM 20308323 ER PT J AU Islam, MN Fox, D Guo, R Enomoto, T Wang, WD AF Islam, M. Nurul Fox, David, III Guo, Rong Enomoto, Takemi Wang, Weidong TI RecQL5 Promotes Genome Stabilization through Two Parallel Mechanisms-Interacting with RNA Polymerase II and Acting as a Helicase SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; KIX DOMAIN; REPLICATION FORK; DNA HELICASE; HOMOLOGOUS RECOMBINATION; TRANSACTIVATION DOMAIN; TOPOISOMERASE-III; HUMAN RECQ5-BETA; FANCONI-ANEMIA; BLOOM-SYNDROME AB The RecQL5 helicase is essential for maintaining genome stability and reducing cancer risk. To elucidate its mechanism of action, we purified a RecQL5-associated complex and identified its major component as RNA polymerase II (Pol II). Bioinformatics and structural modeling-guided mutagenesis revealed two conserved regions in RecQL5 as KIX and SRI domains, already known in transcriptional regulators for Pol II. The RecQL5-KIX domain binds both initiation (Pol IIa) and elongation (Pol IIo) forms of the polymerase, whereas the RecQL5-SRI domain interacts only with the elongation form. Fully functional RecQL5 requires both helicase activity and associations with the initiation polymerase, because mutants lacking either activity are partially defective in the suppression of sister chromatid exchange and resistance to camptothecin-induced DNA damage, and mutants lacking both activities are completely defective. We propose that RecQL5 promotes genome stabilization through two parallel mechanisms: by participation in homologous recombination-dependent DNA repair as a RecQ helicase and by regulating the initiation of Pol II to reduce transcription-associated replication impairment and recombination. C1 [Islam, M. Nurul; Fox, David, III; Guo, Rong; Wang, Weidong] NIA, Genet Lab, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. [Enomoto, Takemi] Tohoku Univ, Grad Sch Pharmaceut Sci, Mol Cell Biol Lab, Sendai, Miyagi 9808578, Japan. RP Wang, WD (reprint author), NIA, Genet Lab, NIH, NIH Biomed Res Ctr, Room 10B113,251 Bayview Blvd, Baltimore, MD 21224 USA. EM wangw@grc.nia.nih.gov FU National Institute on Aging [Z01: AG000657-09]; National Institutes of Health; Fanconi Anemia Research Fund FX This work was supported in part by the Intramural Research Program of the National Institute on Aging (Z01: AG000657-09), National Institutes of Health. The work of the group of W. W. has also been supported by a grant from the Fanconi Anemia Research Fund. NR 48 TC 35 Z9 39 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY 15 PY 2010 VL 30 IS 10 BP 2460 EP 2472 DI 10.1128/MCB.01583-09 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 588BK UT WOS:000277040900014 PM 20231364 ER PT J AU Suzuki, T Kosaka-Suzuki, N Pack, S Shin, DM Yoon, J Abdullaev, Z Pugacheva, E Morse, HC Loukinov, D Lobanenkov, V AF Suzuki, Teruhiko Kosaka-Suzuki, Natsuki Pack, Svetlana Shin, Dong-Mi Yoon, Jeongheon Abdullaev, Ziedulla Pugacheva, Elena Morse, Herbert C., III Loukinov, Dmitri Lobanenkov, Victor TI Expression of a Testis-Specific Form of Gal3st1 (CST), a Gene Essential for Spermatogenesis, Is Regulated by the CTCF Paralogous Gene BORIS SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID C-MYC GENE; ENHANCER-BLOCKING; PROTEIN CTCF; TRANSCRIPTION FACTOR; CONTROL REGION; LUNG-CANCER; PROMOTER; BINDING; INSULATOR; CHROMATIN AB Previously, it was shown that the CTCF paralogous gene, BORIS (brother of the regulator of imprinted sites) is expressed in male germ cells, but its function in spermatogenesis has not been defined. To develop an understanding of the functional activities of BORIS, we generated BORIS knockout (KO) mice. Mice homozygous for the null allele had a defect in spermatogenesis that resulted in small testes associated with increased cell death. The defect was evident as early as postnatal day 21 and was manifested by delayed production of haploid cells. By gene expression profiling, we found that transcript levels for Gal3st1 (also known as cerebroside sulfotransferase [CST]), known to play a crucial role in meiosis, were dramatically reduced in BORIS KO testes. We found that CST is expressed in testis as a novel testis-specific isoform, CST form F(TS), that has a short exon 1f. We showed that BORIS bound to and activated the promoter of CST form F(TS). Mutation of the BORIS binding site in the promoter reduced the ability of BORIS to activate the promoter. These findings define transcriptional regulation of CST expression as a critical role for BORIS in spermatogenesis. C1 [Lobanenkov, Victor] NIAID, Mol Pathol Sect, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Lobanenkov, V (reprint author), NIAID, Mol Pathol Sect, Immunopathol Lab, NIH, Twinbrook 1,Room 1417,MSC-8152,5640 Fishers Lane, Rockville, MD 20852 USA. EM spack@mail.nih.gov; vlobanenkov@niaid.nih.gov RI Pack, Svetlana/C-2020-2014; OI Lobanenkov, Victor/0000-0001-6665-3635; Morse, Herbert/0000-0002-9331-3705 FU NIAID, NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. NR 61 TC 23 Z9 23 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY 15 PY 2010 VL 30 IS 10 BP 2473 EP 2484 DI 10.1128/MCB.01093-09 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 588BK UT WOS:000277040900015 PM 20231363 ER PT J AU Liu, ZM Fukunaga, M de Zwart, JA Duyn, JH AF Liu, Zhongming Fukunaga, Masaki de Zwart, Jacco A. Duyn, Jeff H. TI Large-scale spontaneous fluctuations and correlations in brain electrical activity observed with magnetoencephalography SO NEUROIMAGE LA English DT Article DE Functional connectivity; Resting state; Magnetoencephalography; Band-limited power; Correlation; Coherence ID PRIMARY VISUAL-CORTEX; FUNCTIONAL CONNECTIVITY; TEMPORAL CORRELATIONS; NEURONAL-ACTIVITY; SENSORY STIMULATION; PHASE SYNCHRONY; GLOBAL SIGNAL; OSCILLATIONS; FMRI; NETWORKS AB Knowledge about the intrinsic functional architecture of the human brain has been greatly expanded by the extensive use of resting-state functional magnetic resonance imaging (fMRI). However, the neurophysiological correlates and origins of spontaneous fMRI signal changes remain poorly understood. In the present study, we characterized the power modulations of spontaneous magnetoencephalography (MEG) rhythms recorded from human subjects during wakeful rest (with eyes open and eyes closed) and light sleep. Through spectral, correlation and coherence analyses, we found that resting-state MEG rhythms demonstrated ultraslow (<0.1 Hz) spontaneous power modulations that synchronized over a large spatial distance, especially between bilaterally homologous regions in opposite hemispheres. These observations are in line with the known spatio-temporal properties of spontaneous fMRI signals, and further suggest that the coherent power modulation of spontaneous rhythmic activity reflects the electrophysiological signature of the large-scale functional networks previously observed with fMRI in the resting brain. Published by Elsevier Inc. C1 [Liu, Zhongming] NINDS, Adv MRI Sect, LEMI, NIH, Bethesda, MD 20982 USA. RP Liu, ZM (reprint author), NINDS, Adv MRI Sect, LEMI, NIH, Bldg 10,Room B1D-723,9000 Rockville Pike MSC 1065, Bethesda, MD 20982 USA. EM liuz5@mail.nih.gov RI Duyn, Jozef/F-2483-2010; Fukunaga, Masaki/F-6441-2013 OI Fukunaga, Masaki/0000-0003-1010-2644 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health FX The authors thank Tom Holroyd, Fred Carver and Judy Mitchell-Francis from NIMH MEG Core Facility for helpful suggestions and assistance with the MEG acquisition. This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 48 TC 70 Z9 70 U1 1 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAY 15 PY 2010 VL 51 IS 1 BP 102 EP 111 DI 10.1016/j.neuroimage.2010.01.092 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 580WC UT WOS:000276480200012 PM 20123024 ER PT J AU Christensen, GB Baffoe-Bonnie, AB George, A Powell, I Bailey-Wilson, JE Carpten, JD Giles, GG Hopper, JL Seven, G English, DR Foulkes, WD Maehle, L Moller, P Eeles, R Easton, D Badzioch, MD Whittemore, AS Oakley-Girvan, I Hsieh, CL Dimitrov, L Xu, JF Stanford, JL Johanneson, B Deutsch, K McIntosh, L Ostrander, EA Wiley, KE Isaacs, SD Walsh, PC Isaacs, WB Thibodeau, SN McDonnell, SK Hebbring, S Schaid, DJ Lange, EM Cooney, KA Tammela, TLJ Schleutker, J Paiss, T Maier, C Gronberg, H Wiklund, F Emanuelsson, M Farnham, JM Cannon-Albright, LA Camp, NJ AF Christensen, G. Bryce Baffoe-Bonnie, Agnes B. George, Asha Powell, Isaac Bailey-Wilson, Joan E. Carpten, John D. Giles, Graham G. Hopper, John L. Seven, Gianluca English, Dallas R. Foulkes, William D. Maehle, Lovise Moller, Pal Eeles, Ros Easton, Douglas Badzioch, Michael D. Whittemore, Alice S. Oakley-Girvan, Ingrid Hsieh, Chih-Lin Dimitrov, Latchezar Xu, Jianfeng Stanford, Janet L. Johanneson, Bo Deutsch, Kerry McIntosh, Laura Ostrander, Elaine A. Wiley, Kathleen E. Isaacs, Sarah D. Walsh, Patrick C. Isaacs, William B. Thibodeau, Stephen N. McDonnell, Shannon K. Hebbring, Scott Schaid, Daniel J. Lange, Ethan M. Cooney, Kathleen A. Tammela, Teuvo L. J. Schleutker, Johanna Paiss, Thomas Maier, Christiane Gronberg, Henrik Wiklund, Fredrik Emanuelsson, Monica Farnham, James M. Cannon-Albright, Lisa A. Camp, Nicola J. CA Int Consortium Prostate Canc Genet TI Genome-Wide Linkage Analysis of 1,233 Prostate Cancer Pedigrees From the International Consortium for Prostate Cancer Genetics Using Novel sum LINK and sum LOD Analyses SO PROSTATE LA English DT Article DE genetic epidemiology; meta analysis; susceptibility; predisposition; cancer ID SUSCEPTIBILITY; FAMILIES; LOCI; AGGRESSIVENESS; GENES; SCAN; ASSOCIATION; 22Q12.3; RISK AB BACKGROUND. Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS. We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS. Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. CONCLUSIONS. Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate 70: 735-744, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Christensen, G. Bryce; Farnham, James M.; Cannon-Albright, Lisa A.; Camp, Nicola J.] Univ Utah, Sch Med, Div Genet Epidemiol, Salt Lake City, UT 84108 USA. [Christensen, G. Bryce; Farnham, James M.; Cannon-Albright, Lisa A.; Camp, Nicola J.] Univ Utah, ICPCG Grp, Salt Lake City, UT 84108 USA. [Baffoe-Bonnie, Agnes B.; George, Asha] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Baffoe-Bonnie, Agnes B.; Bailey-Wilson, Joan E.] NHGRI, NIH, Bethesda, MD 20892 USA. [Powell, Isaac] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Carpten, John D.] Translat Genom Res Inst, Genet Basis Human Dis Res Div, Phoenix, AZ USA. [Giles, Graham G.; Seven, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Hopper, John L.; English, Dallas R.] Univ Melbourne, Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Foulkes, William D.] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Maehle, Lovise; Moller, Pal] Norwegian Radium Hosp, Oslo, Norway. [Eeles, Ros] Royal Marsden NHS Fdn Trust, Inst Canc Res, Surrey, England. [Easton, Douglas] Canc Res UK Genet Epidemiol Unit, Cambridge, England. [Badzioch, Michael D.] Univ Washington, Med Ctr, Div Med Genet, Seattle, WA 98195 USA. [Whittemore, Alice S.] Stanford Sch Med, Dept Hlth Res & Policy, Stanford, CA USA. [Whittemore, Alice S.; Oakley-Girvan, Ingrid] Stanford Sch Med, Stanford Comprehens Canc Ctr, Stanford, CA USA. [Hsieh, Chih-Lin] Univ So Calif, Dept Urol, Los Angeles, CA USA. [Hsieh, Chih-Lin] Univ So Calif, Dept Biochem & Mol Biol, Los Angeles, CA USA. [Dimitrov, Latchezar; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Data Coordinating Ctr ICPCG, Winston Salem, NC USA. [Dimitrov, Latchezar; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. [Stanford, Janet L.; McIntosh, Laura] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Johanneson, Bo; Ostrander, Elaine A.] NIH, Canc Genet Branch, Bethesda, MD 20892 USA. [Deutsch, Kerry] Inst Syst Biol, Seattle, WA USA. [Wiley, Kathleen E.; Isaacs, Sarah D.; Walsh, Patrick C.; Isaacs, William B.] Johns Hopkins Univ, ICPCG Grp, Baltimore, MD USA. [Wiley, Kathleen E.; Isaacs, Sarah D.; Walsh, Patrick C.; Isaacs, William B.] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. [Thibodeau, Stephen N.; McDonnell, Shannon K.; Hebbring, Scott; Schaid, Daniel J.] Mayo Clin, ICPCG Grp, Rochester, MN USA. [Lange, Ethan M.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Lange, Ethan M.; Cooney, Kathleen A.] Univ Michigan, ICPCG Grp, Ann Arbor, MI 48109 USA. [Tammela, Teuvo L. J.; Schleutker, Johanna] Univ Tampere, ICPCG Grp, FIN-33101 Tampere, Finland. [Tammela, Teuvo L. J.; Schleutker, Johanna] Tampere Univ Hosp, Tampere, Finland. [Paiss, Thomas; Maier, Christiane] Univ Ulm, ICPCG Grp, Ulm, Germany. [Paiss, Thomas] Univ Ulm, Dept Urol, Ulm, Germany. [Maier, Christiane] Univ Ulm, Inst Human Genet, Ulm, Germany. [Gronberg, Henrik; Wiklund, Fredrik; Emanuelsson, Monica] Umea Univ, ICPCG Grp, Umea, Sweden. [Gronberg, Henrik; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Emanuelsson, Monica] Umea Univ, Ctr Oncol, Umea, Sweden. RP Christensen, GB (reprint author), Univ Utah, Sch Med, Div Genet Epidemiol, 391 Chipeta Way,Suite D, Salt Lake City, UT 84108 USA. EM bryce.christensen@utah.eclu OI Bailey-Wilson, Joan/0000-0002-9153-2920; Eeles, Rosalind/0000-0002-3698-6241; Farnham, James/0000-0002-8213-949X; albright, lisa/0000-0003-2602-3668; foulkes, william/0000-0001-7427-4651; Giles, Graham/0000-0003-4946-9099; English, Dallas/0000-0001-7828-8188; Ostrander, Elaine/0000-0001-6075-9738 FU National Institutes of Health [U01 CA89600]; National Library of Medicine [T15 LM07124]; USPHS [CA98364, CA-06927, CA67044, CA80122, CA78836, CA72818, CA079596, CA90752, CA106523, CA95052]; National Human Genome Research Institute (NHGRI); NIH Center for Minority and Health Disparities [1-HG-75418]; NIH (NHGRI); National Center for Research Institute [RR03048]; National Center for Research Resources [RR03048, M01-RR00064]; Cancer Research UK (CR-UK); The Prostate Cancer Research Foundation; The Times Christmas Appeal; Institute of Cancer Research; BREAKTHROUGH Breast Cancer-Charity [328323]; The Cancer Council Victoria; The National Health and Medical Research Council [940934, 251533, 209057, 126402, 396407]; Tattersall's; The Whitten Foundation; NCI [R25]; Pirkanmaa Hospital District; Reino Lahtikari Foundation; Finnish Cancer Organisations; Sigrid Juselius Foundation; Academy of Finland [211123]; Deutsche Krebshilfe [70-3111-V03]; Umea University Hospital, Umea, Sweden; National Cancer Institute [N01-PC-35141]; Utah State Department of Heath; University of Utah; University of Utah Huntsman Cancer Institute; Center for Inherited Disease Research [N01-HG-65403]; Department of Defense [PC051264] FX We would like to express our gratitude to the many families who participated in the many studies involved in the International Consortium for Prostate Cancer Genetics (ICPCG). The ICPCG, including the consortium's Data Coordinating Center (DCC), is made possible by a grant from the National Institutes of Health U01 CA89600 (to W.B.I.). G.B.C. was supported by National Library of Medicine training grant NLM T15 LM07124. N.J.C. was supported in part by USPHS CA98364 (to N.J.C.). Additional support to participating groups, or members within groups, is as follows: AAHPC Group: The authors would like to express their gratitude to the African-American Hereditary Prostate Cancer Study (AAHPC) families and study participants for their continued involvement in this research. We specifically name, C. Ahaghotu, J. Bennett, W. Boykin, G. Hoke, T. Mason, C. Pettaway, S. Vijayakumar, S. Weinrich, M. Franklin, P. Roberson, J. Frost, E. Johnson, L. Faison-Smith, C. Meegan, M. Johnson, L. Kososki, C. Jones, and R. Mejia. We would also like to thank members of the National Human Genome Center (NHGC) at Howard University namely R. Kitties, G.M. Dunston, P. Furbert-Harris, and C. Royal. We would also like to acknowledge the contribution of the National Human Genome Research Institute (NHGRI) and TGen genotyping staff including E. Gillanders and C. Robbins. The AAHPC study would not have been possible without F. Collins (Director of NHGRI) and J. Trent (Director of TGen). This research was funded primarily through the NIH Center for Minority and Health Disparities (1-HG-75418). A.B.B.-B. and A.G. also received support from USPHS CA-06927 and an appropriation from the Commonwealth of Pennsylvania. This research was also supported in part by the Intramural Research Program of the NIH (NHGRI) and USPHS RR03048 from the National Center for Research Institute and USPHS RR03048 from the National Center for Research Resources. ACTANE Group: Genotyping and statistical analysis for this study, and recruitment of UK families, was supported by Cancer Research UK (CR-UK). Additional support was provided by The Prostate Cancer Research Foundation, The Times Christmas Appeal and the Institute of Cancer Research. Genotyping was conducted in the "Jean Rook Gene Cloning Laboratory" which is supported by BREAKTHROUGH Breast Cancer-Charity No. 328323. The funds for the ABI 377 used in this study were generously provided by the legacy of the late Marion Silcock. We thank S. Seal and A. Hall for kindly storing and logging the samples that were provided. D.F.E. is a Principal Research Fellow of CR-UK. Funding in Australia was obtained from The Cancer Council Victoria, The National Health and Medical Research Council (grants 940934, 251533, 209057, 126402, 396407), Tattersall's and The Whitten Foundation. We would like to acknowledge the work of the study coordinator M. Staples and the Research Team B. McCudden, J. Connal, R. Thorowgood, C. Costa, M. Kevan, and S. Palmer, and to J. Karpowicz for DNA extractions. The Texas study of familial prostate cancer was initiated by the Department of Epidemiology, M.D. Anderson Cancer Center. M.B. was supported by an NCI Post-doctoral Fellowship in Cancer Prevention (R25). We would also like to specifically thank the following members of ACTANE: S. Edwards, M. Guy, Q. Hope, S. Bullock, S. Bryant, S. Mulholland, S. Jugurnauth, N. Garcia, A. Ardern-Jones, A. Hall, L. O'Brien, B. Gehr-Swain, R. Wilkinson, D.; Dearnaley, The UKGPCS Collaborators, British Association of tiro logical Surgeons' Section of Oncology (UK Sutton); Chris Evans (UK Camridge); M. Southey (Australia); N. Hamel, S. Narod, J. Simard (Canada); C. Amos (USA Texas); N. Wessel, T. Andersen (Norway); D.T. Bishop (EU Biomed). BC/CA/HI Group: USPHS CA67044. FHCRC Group: USPHS CA80122 (to J.L.S.) which supports the family collection; USPHS CA78836 (to E.A.O.). E.A.O. was supported in part by the NHGRI. JHU Group: Genotyping for the JHU, University of Michigan, University of Tampere, and University of Umea Groups' pedigrees was provided by NHGRI and TGen genotyping staff including E. Gillanders, M.P. Jones, D. Gildea, E. Riedesel, J. Albertus, D. Freas-Lutz, C. Markey, J. Carpten, and J. Trent. Mayo Clinic Group: USPHS CA72818. Michigan Group: USPHS CA079596. University of Tampere Group: The Competitive Research Funding of the Pirkanmaa Hospital District, Reino Lahtikari Foundation, Finnish Cancer Organisations, Sigrid Juselius Foundation, and Academy of Finland grant 211123. University of Ulm Group: Deutsche Krebshilfe, grant number 70-3111-V03. University of Umea Group: Work was supported by the Swedish Cancer Society and a Spear grant from the Umea University Hospital, Umea, Sweden. University of Utah Group: Data collection was supported by USPHS CA90752 (to L.A.C.-A.) and by the Utah Cancer Registry, which is funded by contract #N01-PC-35141 from the National Cancer Institute's Surveillance, Epidemiology, and End-Results Program with additional support from the Utah State Department of Heath and the University of Utah. Partial support for all datasets within the Utah Population Database was provided by the University of Utah Huntsman Cancer Institute and also by the USPHS M01-RR00064 from the National Center for Research Resources. Genotyping services were provided by the Center for Inherited Disease Research (N01-HG-65403). DCC: The study is partially supported by USPHS CA106523 (to J.X.), USPHS CA95052 (to J.X.), and Department of Defense grant PC051264 (to J.X.). NR 27 TC 16 Z9 16 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD MAY 15 PY 2010 VL 70 IS 7 BP 735 EP 744 DI 10.1002/pros.21106 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 591XM UT WOS:000277338800006 PM 20333727 ER PT J AU Johnston, JJ Teer, JK Cherukuri, PE Hansen, NF Loftus, SK Chong, K Mullikin, JC Biesecker, LG AF Johnston, Jennifer J. Teer, Jamie K. Cherukuri, Praveen E. Hansen, Nancy F. Loftus, Stacie K. Chong, Karen Mullikin, James C. Biesecker, Leslie G. CA NIH Intramural Sequencing Ctr TI Massively Parallel Sequencing of Exons on the X Chromosome Identifies RBM10 as the Gene that Causes a Syndromic Form of Cleft Palate SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID INACTIVATION; EXPRESSION; MUTATIONS AB Micrognathia, glossoptosis, and cleft palate comprise one of the most common malformation sequences, Robin sequence. It is a component of the TARP syndrome, talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava. This disorder is X-linked and severe, with apparently 100% pre- or postnatal lethality in affected males. Here we characterize a second family with TARP syndrome, confirm linkage to Xp11.23-q13.3, perform massively parallel sequencing of X chromosome exons, filter the results via a number of criteria including the linkage region, use a unique algorithm to characterize sequence changes, and show that TARP syndrome is caused by mutations in the RBM10 gene, which encodes RNA binding motif 10. We further show that this previously uncharacterized gene is expressed in midgestation mouse embryos in the branchial arches and limbs, consistent with the human phenotype. We conclude that massively parallel sequencing is useful to characterize large candidate linkage intervals and that it can be used successfully to allow identification of disease-causing gene mutations. C1 [Johnston, Jennifer J.; Teer, Jamie K.; Cherukuri, Praveen E.; Loftus, Stacie K.; Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Teer, Jamie K.; Cherukuri, Praveen E.; Hansen, Nancy F.; Mullikin, James C.; Biesecker, Leslie G.; NIH Intramural Sequencing Ctr] NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Chong, Karen] Mt Sinai Hosp, Prenatal Diag & Med Genet Program, Toronto, ON M5G 1X5, Canada. RP Biesecker, LG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov FU National Human Genome Research Institute, National Institutes of Health FX This research was supported by Intramural Funds of the National Human Genome Research Institute, National Institutes of Health. The authors thank Joyce T. Turner for the initial consenting and records gathering for the family and Emma J. Spaulding for technical support. This paper is in memory of Robert J. Gorlin, the lead author of the paper describing family 1 and a generous, good-humored supporter of the work of L.G.B. NR 15 TC 66 Z9 68 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 14 PY 2010 VL 86 IS 5 BP 743 EP 748 DI 10.1016/j.ajhg.2010.04.007 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 601GC UT WOS:000278045300010 PM 20451169 ER PT J AU Miller, DT Adam, MP Aradhya, S Biesecker, LG Brothman, AR Carter, NP Church, DM Crolla, JA Eichler, EE Epstein, CJ Faucett, WA Feuk, L Friedman, JM Hamosh, A Jackson, L Kaminsky, EB Kok, K Krantz, ID Kuhn, RM Lee, C Ostell, JM Rosenberg, C Scherer, SW Spinner, NB Stavropoulos, DJ Tepperberg, JH Thorland, EC Vermeesch, JR Waggoner, DJ Watson, MS Martin, CL Ledbetter, DH AF Miller, David T. Adam, Margaret P. Aradhya, Swaroop Biesecker, Leslie G. Brothman, Arthur R. Carter, Nigel P. Church, Deanna M. Crolla, John A. Eichler, Evan E. Epstein, Charles J. Faucett, W. Andrew Feuk, Lars Friedman, Jan M. Hamosh, Ada Jackson, Laird Kaminsky, Erin B. Kok, Klaas Krantz, Ian D. Kuhn, Robert M. Lee, Charles Ostell, James M. Rosenberg, Carla Scherer, Stephen W. Spinner, Nancy B. Stavropoulos, Dimitri J. Tepperberg, James H. Thorland, Erik C. Vermeesch, Joris R. Waggoner, Darrel J. Watson, Michael S. Martin, Christa Lese Ledbetter, David H. TI Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; IDIOPATHIC MENTAL-RETARDATION; COPY-NUMBER VARIATIONS; 17Q21.31 MICRODELETION SYNDROME; ARRAY-BASED TECHNOLOGY; LOW-LEVEL MOSAICISM; STRUCTURAL VARIATION; DYSMORPHIC FEATURES; CYTOGENETIC SURVEY; OLIGONUCLEOTIDE MICROARRAY AB Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype (similar to 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages. C1 [Miller, David T.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Miller, David T.] Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Miller, David T.] Harvard Univ, Sch Med, Boston, MA USA. [Adam, Margaret P.; Faucett, W. Andrew; Kaminsky, Erin B.; Martin, Christa Lese; Ledbetter, David H.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Adam, Margaret P.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Aradhya, Swaroop] GeneDx, Gaithersburg, MD USA. [Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Brothman, Arthur R.] Univ Utah, Sch Med, Dept Pediat, Human Genet Lab, Salt Lake City, UT USA. [Brothman, Arthur R.] Univ Utah, Sch Med, Dept Pediat, Pathol Lab, Salt Lake City, UT USA. [Brothman, Arthur R.] Univ Utah, Sch Med, Dept Pediat, ARUP Lab, Salt Lake City, UT USA. [Carter, Nigel P.] Wellcome Trust Sanger Inst, Cambridge, England. [Church, Deanna M.; Ostell, James M.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Crolla, John A.] Natl Genet Reference Lab Wessex, Salisbury, Wilts, England. [Eichler, Evan E.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA. [Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Sch Med, Seattle, WA 98195 USA. [Epstein, Charles J.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Epstein, Charles J.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Feuk, Lars] Uppsala Univ, Rudbeck Lab, Uppsala, Sweden. [Friedman, Jan M.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Friedman, Jan M.] Child & Family Res Inst, Vancouver, BC, Canada. [Hamosh, Ada] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Hamosh, Ada] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Jackson, Laird] Drexel Univ, Coll Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Kok, Klaas] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 AB Groningen, Netherlands. [Krantz, Ian D.; Spinner, Nancy B.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Pediat Human Genet, Philadelphia, PA 19104 USA. [Kuhn, Robert M.] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Lee, Charles] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Rosenberg, Carla] Univ Sao Paulo, Dept Genet & Evolutionary Biol, BR-05508 Sao Paulo, Brazil. [Scherer, Stephen W.] Univ Toronto, Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5S 1A1, Canada. [Scherer, Stephen W.] Univ Toronto, Hosp Sick Children, Program Genet & Genet Biol, Toronto, ON M5S 1A1, Canada. [Scherer, Stephen W.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada. [Stavropoulos, Dimitri J.] Hosp Sick Children, Dept Pediat Lab Med, Toronto, ON M5G 1X8, Canada. [Tepperberg, James H.] Lab Corp Amer, Res Triangle Pk, NC USA. [Thorland, Erik C.] Mayo Clin, Rochester, MN USA. [Vermeesch, Joris R.] Katholieke Univ Leuven, Ctr Human Genet, Leuven, Belgium. [Waggoner, Darrel J.] Univ Chicago, Dept Human Genet & Pediat, Chicago, IL 60637 USA. [Watson, Michael S.] Amer Coll Med Genet, Bethesda, MI USA. RP Miller, DT (reprint author), Childrens Hosp, Div Genet, 300 Longwood Ave, Boston, MA 02115 USA. EM david.miller2@childrens.harvard.edu; david.ledbetter@emory.edu RI Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013; Oncogenomica, Inct/H-9999-2013; Cetgen, Inct/I-2412-2013; rosenberg, carla/N-4148-2015 OI Scherer, Stephen /0000-0002-8326-1999; rosenberg, carla/0000-0003-3253-4448 FU National Institutes of Health [RC2FID064525, MH074090]; Simons Foundation [137578]; ACMG Foundation; Luminex FX Workshops and conference calls related to the ISCA Consortium were funded through a grant from the ACMG Foundation and Luminex to D.H.L. and C.L.M., and ongoing standards and database development are funded in part by grants from the National Institutes of Health (RC2FID064525 and MH074090 to D.H.L. and C.L.M.). This work was also supported by Simons Foundation grant 137578 (to FEE.). E.E.E. is an investigator of the Howard Hughes Medical Institute. The opinions expressed here are those of the authors and the ISCA Consortium and do not necessarily reflect the views of the institutions to which the authors are affiliated, the ACMG, or the American Society of Human Genetics (ASHG). The authors would like to thank Dr. Omer Gokcumen for his assistance with summary of population CNV data. Regarding conflict of interest, the majority of authors are involved in CMA testing and/or cytogenetic testing, either as clinicians who order the testing, laboratory professionals who perform the testing, or researchers in the genomics field. S.A. is a director of clinical cytogenetics at GeneDx, a subsidiary of BioReference Laboratories; A.R.B. is a director of clinical cytogenetics and molecular cytogenetics at ARUP Laboratories; E.E.E. is a member of the Pacific Biosciences Scientific Advisory Board. S.W.S. is on the Scientific Advisory Board of Combimatrix Diagnostics and the Scientific Advisory Committee of Autism Speaks. J.T. is a director of clinical cytogenetics at Laboratory Corporation of America. J.V. is on the board of directors of Cartagenia. M.W. raises funds from industry to support the educational activities of the ACMG Foundation. NR 107 TC 797 Z9 855 U1 4 U2 64 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 14 PY 2010 VL 86 IS 5 BP 749 EP 764 DI 10.1016/j.ajhg.2010.04.006 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 601GC UT WOS:000278045300011 PM 20466091 ER PT J AU Riazuddin, SA Iqbal, M Wang, Y Masuda, T Chen, Y Bowne, S Sullivan, LS Waseem, NH Bhattacharya, S Daiger, SP Zhang, K Khan, SN Riazuddin, S Hejtmancik, JF Sieving, PA Zack, DJ Katsanis, N AF Riazuddin, S. Amer Iqbal, Muhammad Wang, Yue Masuda, Tomohiro Chen, Yuhng Bowne, Sara Sullivan, Lori S. Waseem, Naushin H. Bhattacharya, Shomi Daiger, Stephen P. Zhang, Kang Khan, Shaheen N. Riazuddin, Sheikh Hejtmancik, J. Fielding Sieving, Paul A. Zack, Donald J. Katsanis, Nicholas TI A Splice-Site Mutation in a Retina-Specific Exon of BBS8 Causes Nonsyndromic Retinitis Pigmentosa SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID BARDET-BIEDL-SYNDROME; GENES; TRANSCRIPTION AB Tissue-specific alternative splicing is an important mechanism for providing spatiotemporal protein diversity. Here we show that an in-frame splice mutation in BBS8, one of the genes involved in pleiotropic Bardet-Biedl syndrome (BBS), is sufficient to cause nonsyndromic retinitis pigmentosa (RP). A genome-wide scan of a consanguineous RP pedigree mapped the trait to a 5.6 Mb region; subsequent systematic sequencing of candidate transcripts identified a homozygous splice-site mutation in a previously unknown BBS8 exon. The allele segregated with the disorder, was absent from controls, was completely invariant across evolution, and was predicted to lead to the elimination of a 10 amino acid sequence from the protein. Subsequent studies showed the exon to be expressed exclusively in the retina and enriched significantly in the photoreceptor layer. Importantly, we found this exon to represent the major BBS8 mRNA species in the mammalian photoreceptor, suggesting that the encoded 10 amino acids play a pivotal role in the function of BBS8 in this organ. Understanding the role of this additional sequence might therefore inform the mechanism of retinal degeneration in patients with syndromic BBS or other related ciliopathies. C1 [Riazuddin, S. Amer; Wang, Yue; Katsanis, Nicholas] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Riazuddin, S. Amer; Masuda, Tomohiro; Zack, Donald J.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Iqbal, Muhammad; Khan, Shaheen N.; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. [Chen, Yuhng; Zhang, Kang] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Chen, Yuhng; Zhang, Kang] Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92093 USA. [Bowne, Sara; Sullivan, Lori S.; Daiger, Stephen P.] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX 77030 USA. [Waseem, Naushin H.; Bhattacharya, Shomi] UCL, Inst Ophthalmol, Dept Genet, London EC1V 9EL, England. [Hejtmancik, J. Fielding; Sieving, Paul A.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Katsanis, Nicholas] Duke Univ, Ctr Human Dis Modeling, Durham, NC 27710 USA. RP Katsanis, N (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. EM katsanis@cellbio.duke.edu RI Katsanis, Nicholas/E-1837-2012; Waseem, Naushin/C-9573-2013; Nasim Khan, Shaheen/F-2135-2015; Wang, Julia/M-4516-2016; OI Wang, Julia/0000-0003-2641-6904; Zack, Don/0000-0002-7966-1973; Katsanis, Nicholas/0000-0002-2480-0171 FU Ministry of Science and Technology, Islamabad Pakistan; National Institutes of Health [R01HD04260, R01DK072301, R01DK075972, R01EY007142]; Macular Vision Research Foundation; Foundation Fighting Blindness FX We gratefully acknowledge the family members who donated samples to make this work possible. Financial support was provided by the Ministry of Science and Technology, Islamabad Pakistan, National Institutes of Health grants R01HD04260, R01DK072301, R01DK075972 (N.K.), and R01EY007142 (S.P.D.), the Macular Vision Research Foundation, and the Foundation Fighting Blindness (N.K.). N.K. is the George R. Brumley Professor. NR 16 TC 45 Z9 47 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 14 PY 2010 VL 86 IS 5 BP 805 EP 812 DI 10.1016/j.ajhg.2010.04.001 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 601GC UT WOS:000278045300017 PM 20451172 ER PT J AU Chen, MH Larson, MG Hsu, YH Peloso, GM Guo, CY Fox, CS Atwood, LD Yang, QO AF Chen, Ming-Huei Larson, Martin G. Hsu, Yi-Hsiang Peloso, Gina M. Guo, Chao-Yu Fox, Caroline S. Atwood, Larry D. Yang, Qiong TI A three-stage approach for genome-wide association studies with family data for quantitative traits SO BMC GENETICS LA English DT Article ID POPULATION STRATIFICATION; LINKAGE DISEQUILIBRIUM; TESTS; POWERFUL; LOCI AB Background: Genome-wide association (GWA) studies that use population-based association approaches may identify spurious associations in the presence of population admixture. In this paper, we propose a novel three-stage approach that is computationally efficient and robust to population admixture and more powerful than the family-based association test (FBAT) for GWA studies with family data. We propose a three-stage approach for GWA studies with family data. The first stage is to perform linear regression ignoring phenotypic correlations among family members. SNPs with a first stage p-value below a liberal cut-off (e. g. 0.1) are then analyzed in the second stage that employs a linear mixed effects (LME) model that accounts for within family correlations. Next, SNPs that reach genome-wide significance (e. g. 10(-6) for 34,625 genotyped SNPs in this paper) are analyzed in the third stage using FBAT, with correction of multiple testing only for SNPs that enter the third stage. Simulations are performed to evaluate type I error and power of the proposed method compared to LME adjusting for 10 principal components (PC) of the genotype data. We also apply the three-stage approach to the GWA analyses of uric acid in Framingham Heart Study's SNP Health Association Resource (SHARe) project. Results: Our simulations show that whether or not population admixture is present, the three-stage approach has no inflated type I error. In terms of power, using LME adjusting PC is only slightly more powerful than the three-stage approach. When applied to the GWA analyses of uric acid in the SHARe project of FHS, the three-stage approach successfully identified and confirmed three SNPs previously reported as genome-wide significant signals. Conclusions: For GWA analyses of quantitative traits with family data, our three-stage approach provides another appealing solution to population admixture, in addition to LME adjusting for genetic PC. C1 [Peloso, Gina M.; Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Chen, Ming-Huei; Atwood, Larry D.] Boston Univ, Sch Med, Dept Neurol & Framingham Heart Study, Boston, MA 02118 USA. [Larson, Martin G.; Atwood, Larry D.] NHLBIs Framingham Heart Study, Framingham, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02118 USA. [Hsu, Yi-Hsiang] Hebrew Senior Life Inst Aging Res, Genet Epidemiol Program, Boston, MA USA. [Hsu, Yi-Hsiang] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hsu, Yi-Hsiang] Harvard Univ, Sch Publ Hlth, Mol & Integrat Physiol Sci Program, Boston, MA 02115 USA. [Guo, Chao-Yu] Childrens Hosp Boston, Clin Res Program, Boston, MA USA. [Guo, Chao-Yu] Childrens Hosp Boston, Dept Med, Program Genom, Boston, MA USA. [Guo, Chao-Yu] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Fox, Caroline S.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Yang, QO (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. EM qyang@bu.edu RI Yang, Qiong/G-5438-2014; OI Yang, Qiong/0000-0002-3658-1375; Larson, Martin/0000-0002-9631-1254 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center FX This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. NR 19 TC 2 Z9 2 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD MAY 14 PY 2010 VL 11 AR 40 DI 10.1186/1471-2156-11-40 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 624YQ UT WOS:000279858600003 PM 20470424 ER PT J AU Hailey, DW Rambold, AS Satpute-Krishnan, P Mitra, K Sougrat, R Kim, PK Lippincott-Schwartz, J AF Hailey, Dale W. Rambold, Angelika S. Satpute-Krishnan, Prasanna Mitra, Kasturi Sougrat, Rachid Kim, Peter K. Lippincott-Schwartz, Jennifer TI Mitochondria Supply Membranes for Autophagosome Biogenesis during Starvation SO CELL LA English DT Article ID ENDOPLASMIC-RETICULUM; MAMMALIAN-CELLS; SUBCELLULAR-LOCALIZATION; PROTEIN; TRANSPORT; YEAST; PATHWAYS; DEATH; PHOSPHATIDYLETHANOLAMINE; PHOSPHATIDYLSERINE AB Starvation-induced autophagosomes engulf cytosol and/or organelles and deliver them to lysosomes for degradation, thereby resupplying depleted nutrients. Despite advances in understanding the molecular basis of this process, the membrane origin of autophagosomes remains unclear. Here, we demonstrate that, in starved cells, the outer membrane of mitochondria participates in autophagosome biogenesis. The early autophagosomal marker, Atg5, transiently localizes to punctae on mitochondria, followed by the late autophagosomal marker, LC3. The tail-anchor of an outer mitochondrial membrane protein also labels autophagosomes and is sufficient to deliver another outer mitochondrial membrane protein, Fis1, to autophagosomes. The fluorescent lipid NBD-PS (converted to NBD-phos-photidylethanolamine in mitochondria) transfers from mitochondria to autophagosomes. Photo-bleaching reveals membranes of mitochondria and autophagosomes are transiently shared. Disruption of mitochondria/ER connections by mitofusin2 depletion dramatically impairs starvation-induced autophagy. Mitochondria thus play a central role in starvation-induced autophagy, contributing membrane to autophagosomes. C1 [Hailey, Dale W.; Rambold, Angelika S.; Satpute-Krishnan, Prasanna; Mitra, Kasturi; Sougrat, Rachid; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Kim, Peter K.] Hosp Sick Children, Cell Biol Program, Toronto, ON M5G 1X8, Canada. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 18 Lib Dr, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov OI Sougrat, Rachid/0000-0001-6476-1886 FU Intramural NIH HHS [ZIA HD001609-16] NR 57 TC 558 Z9 580 U1 12 U2 78 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAY 14 PY 2010 VL 141 IS 4 BP 656 EP 667 DI 10.1016/j.cell.2010.04.009 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 595PH UT WOS:000277623600018 PM 20478256 ER PT J AU Larrea, AA Lujan, SA Kunkel, TA AF Larrea, Andres A. Lujan, Scott A. Kunkel, Thomas A. TI SnapShot: DNA Mismatch Repair SO CELL LA English DT Editorial Material ID MECHANISMS C1 [Larrea, Andres A.; Lujan, Scott A.; Kunkel, Thomas A.] NIEHS, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Larrea, AA (reprint author), NIEHS, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 9 TC 21 Z9 21 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAY 14 PY 2010 VL 141 IS 4 DI 10.1016/j.cell.2010.05.002 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 595PH UT WOS:000277623600025 ER PT J AU Kumar, A Hou, X Lee, C Li, Y Maminishkis, A Tang, ZS Zhang, F Langer, HF Arjunan, P Dong, LJ Wu, ZJ Zhu, LY Wang, LC Min, W Colosi, P Chavakis, T Li, X AF Kumar, Anil Hou, Xu Lee, Chunsik Li, Yang Maminishkis, Arvydas Tang, Zhongshu Zhang, Fan Langer, Harald F. Arjunan, Pachiappan Dong, Lijin Wu, Zhijian Zhu, Linda Y. Wang, Lianchun Min, Wang Colosi, Peter Chavakis, Triantafyllos Li, Xuri TI Platelet-derived Growth Factor-DD Targeting Arrests Pathological Angiogenesis by Modulating Glycogen Synthase Kinase-3 beta Phosphorylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMOOTH-MUSCLE-CELLS; PDGF BETA-RECEPTOR; CHOROIDAL NEOVASCULARIZATION; MACULAR DEGENERATION; RETINAL NEOVASCULARIZATION; INTRAVITREAL INJECTION; FACTOR VEGF; ISCHEMIC RETINOPATHY; PEGAPTANIB SODIUM; EXPRESSION AB Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3 beta (GSK3 beta) Ser(9) phosphorylation and Tyr(216) dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3 beta activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3 beta and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases. C1 [Kumar, Anil; Hou, Xu; Lee, Chunsik; Li, Yang; Maminishkis, Arvydas; Tang, Zhongshu; Zhang, Fan; Arjunan, Pachiappan; Dong, Lijin; Wu, Zhijian; Zhu, Linda Y.; Colosi, Peter; Li, Xuri] NEI, NIH, Rockville, MD 20852 USA. [Langer, Harald F.; Chavakis, Triantafyllos] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hou, Xu] Fourth Mil Med Univ, Xijing Hosp, Eye Inst Chinese PLA, Dept Ophthalmol, Xian 710032, Peoples R China. [Wang, Lianchun] Univ Georgia, Complex Carbohydrate Res Ctr, Dept Biochem & Mol Biol, Athens, GA 30602 USA. [Min, Wang] Yale Univ, Dept Pathol Vasc Biol & Therapeut, New Haven, CT 06520 USA. [Langer, Harald F.] Univ Tubingen, Dept Cardiovasc Med, D-72076 Tubingen, Germany. RP Li, X (reprint author), NEI, NIH, 5635 Fishers Lane, Rockville, MD 20852 USA. EM lixur@nei.nih.gov RI Kumar, Anil/K-8504-2012 FU NEI; American Health Assistance Foundation FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NEI. This work was also supported by the Macular Degeneration Research program of the American Health Assistance Foundation. NR 80 TC 13 Z9 13 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 14 PY 2010 VL 285 IS 20 BP 15500 EP 15510 DI 10.1074/jbc.M110.113787 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592SB UT WOS:000277399000069 PM 20231273 ER PT J AU Lee, SB Park, JH Woster, PM Casero, RA Park, MH AF Lee, Seung Bum Park, Jong Hwan Woster, Patrick M. Casero, Robert A., Jr. Park, Myung Hee TI Suppression of Exogenous Gene Expression by Spermidine/Spermine N-1-Acetyltransferase 1 (SSAT1) Cotransfection SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENHANCES CELL-MIGRATION; POLYAMINE CATABOLISM; LUNG-CARCINOMA; ANALOGS; METABOLISM; INDUCTION; SPERMIDINE/SPERMINE-N-1-ACETYLTRANSFERASE-2; UBIQUITINATION; IDENTIFICATION; ACETYLATION AB Spermidine/spermine N-1-acetyltransferase 1 (SSAT1), which catalyzes the N-1-acetylation of spermidine and spermine to form acetyl derivatives, is a rate-limiting enzyme in polyamine catabolism. We now report a novel activity of transiently transfected SSAT1 in suppressing the exogenous expression of other proteins, i.e. green fluorescent protein (GFP) or GFP-eIF5A. Spermidine/spermine N-1-acetyltransferase 2 (SSAT2) or inactive SSAT1 mutant enzymes (R101A or R101K) were without effect. The loss of exogenous gene expression is not due to accelerated protein degradation, because various inhibitors of proteases, lysosome, or autophagy did not mitigate the effects. This SSAT1 effect cannot be attributed to the depletion of overall cellular polyamines or accumulation of N-1-acetylspermidine (N-1-AcSpd) because of the following: (i) addition of putrescine, spermidine, spermine, or N-1-AcSpd did not restore the expression of GFP or GFP-eIF5A; (ii) depletion of cellular polyamines with alpha-difluoromethylornithine, an inhibitor of ornithine decarboxylase, did not inhibit exogenous gene expression; and (iii) N-1, N-11-bis(ethyl)norspermine caused a drastic depletion of cellular polyamines through induction of endogenous SSAT1 but did not block exogenous gene expression. SSAT1 transient transfection did not affect stable expression of GFP, and stably expressed SSAT1 did not affect exogenous expression of GFP, suggesting that only transiently (episomally) expressed SSAT1 blocks exogenous (episomal) expression of other proteins. SSAT1 may regulate exogenous gene expression by blocking steps involved in transcription/translation from an episomal vector by targeting non-polyamine substrate(s) critical for this pathway. C1 [Park, Myung Hee] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Woster, Patrick M.] Wayne State Univ, Dept Pharmaceut Sci, Detroit, MI 48201 USA. [Casero, Robert A., Jr.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. RP Park, MH (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bldg 30,Rm 211, Bethesda, MD 20892 USA. EM mhpark@nih.gov OI Woster, Patrick/0000-0002-9471-1916 FU National Institutes of Health [CA51085]; NIDCR FX This work was supported, in whole or in part, by National Institutes of Health Grant CA51085 (extramural) and the NIDCR Intramural Research Program. NR 32 TC 5 Z9 5 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 14 PY 2010 VL 285 IS 20 BP 15548 EP 15556 DI 10.1074/jbc.M109.092007 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592SB UT WOS:000277399000073 PM 20212040 ER PT J AU Ramakrishnan, B Qasba, PK AF Ramakrishnan, Boopathy Qasba, Pradman K. TI Crystal Structure of the Catalytic Domain of Drosophila beta 1,4-Galactosyltransferase-7 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EHLERS-DANLOS-SYNDROME; GALACTOSYLTRANSFERASE-I BETA-4GALT-7; ALPHA-LACTALBUMIN; HEPARAN-SULFATE; BOVINE BETA-1,4-GALACTOSYLTRANSFERASE; LACTOSE SYNTHETASE; GENE FAMILY; PROTEIN; IDENTIFICATION; MECHANISM AB The beta 1,4-galactosyltransferase-7 (beta 4Gal-T7) enzyme, one of seven members of the beta 4Gal-T family, transfers in the presence of manganese Gal from UDP-Gal to an acceptor sugar (xylose) that is attached to a side chain hydroxyl group of Ser/Thr residues of proteoglycan proteins. It exhibits the least protein sequence similarity with the other family members, including the well studied family member beta 4Gal-T1, which, in the presence of manganese, transfers Gal from UDP-Gal to GlcNAc. We report here the crystal structure of the catalytic domain of beta 4Gal-T7 from Drosophila in the presence of manganese and UDP at 1.81 angstrom resolution. In the crystal structure, a new manganese ion-binding motif (HXH) has been observed. Superposition of the crystal structures of beta 4Gal-T7 and beta 4Gal-T1 shows that the catalytic pocket and the substrate-binding sites in these proteins are similar. Compared with GlcNAc, xylose has a hydroxyl group (instead of anN-acetyl group) at C2 and lacks the CH(2)OH group at C5; thus, these protein structures show significant differences in their acceptor-binding site. Modeling of xylose in the acceptor-binding site of the beta 4Gal-T7 crystal structure shows that the aromatic side chain of Tyr(177) interacts strongly with the C5 atom of xylose, causing steric hindrance to any additional group at C5. Because Drosophila Cd7 has a 73% protein sequence similarity to human Cd7, the present crystal structure offers a structure-based explanation for the mutations in human Cd7 that have been linked to Ehlers-Danlos syndrome. C1 [Qasba, Pradman K.] NCI, Struct Glycobiol Sect, SAIC Frederick Inc, CCRNP,CCR,NIH, Frederick, MD 21702 USA. [Ramakrishnan, Boopathy] NCI, Basic Res Program, SAIC Frederick Inc, CCRNP,CCR,NIH, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, Struct Glycobiol Sect, SAIC Frederick Inc, CCRNP,CCR,NIH, Bldg 469,Rm 221, Frederick, MD 21702 USA. EM qasba@helix.nih.gov FU National Institutes of Health, NCI, Center for Cancer Research [HHSN261200800001E]; United States Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This work was supported, in whole or in part, by National Institutes of Health Contract HHSN261200800001E from NCI and by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research. Use of beam line 22-ID/BM of the Southeast Regional Collaborative Access Team (SER-CAT), located at the Advanced Photon Source, Argonne National Laboratory, was supported by Contract W-31-109-Eng-38 from the United States Department of Energy, Office of Science, Office of Basic Energy Sciences. NR 43 TC 11 Z9 11 U1 2 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 14 PY 2010 VL 285 IS 20 BP 15619 EP 15626 DI 10.1074/jbc.M109.099564 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592SB UT WOS:000277399000080 PM 20236943 ER PT J AU Shibusawa, Y Shoji, A Suzuka, C Yanagida, A Ito, Y AF Shibusawa, Yoichi Shoji, Atsushi Suzuka, Chihiro Yanagida, Akio Ito, Yoichiro TI Counter-current chromatographic separation of nucleic acid constituents with a hydrophilic solvent system SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Counter-current chromatography; Nucleic acid constituents; Hydrophilic solvent system; Type J coil planet centrifuge ID COIL PLANET CENTRIFUGE AB Nucleic acid constituents such as nucleobases, nucleosides and nucleotides were separated by countercurrent chromatography using type J coil planet centrifuge. The separation was performed with a hydrophilic solvent system composed of 1-propano1/800 mM potassium phosphate buffer (pH 7.4) (1:1, v/v) by eluting the lower aqueous phase at a flow-rate of 0.5 ml/min. Eight selected nucleic acid constituents (4.0 mg, 0.5 mg of each), uridine monophosphate (UMP), adenosine monophosphate (AMP), deoxyadenosine monophosphate (dAMP), uridine, urasile, deoxy uridine, adenosine and adenine were well resolved within 160 min. (C) 2010 Elsevier B.V. All rights reserved. C1 [Shibusawa, Yoichi; Suzuka, Chihiro; Yanagida, Akio] Tokyo Univ Pharm & Life Sci, Sch Pharm, Div Pharmaceut & Biomed Anal, Tokyo 1920392, Japan. [Shoji, Atsushi] Nihon Univ, Dept Chem, Coll Humanities & Sci, Setagaya Ku, Tokyo 1568550, Japan. [Ito, Yoichiro] NHLBI, Bioseparat Technol Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Shibusawa, Y (reprint author), Tokyo Univ Pharm & Life Sci, Sch Pharm, Div Pharmaceut & Biomed Anal, 1432-1 Horinouchi, Tokyo 1920392, Japan. EM sibusawa@toyaku.ac.jp FU Intramural NIH HHS [Z99 HL999999] NR 7 TC 7 Z9 7 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD MAY 14 PY 2010 VL 1217 IS 20 BP 3457 EP 3460 DI 10.1016/j.chroma.2010.03.010 PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 599EM UT WOS:000277893500016 PM 20362294 ER PT J AU Roy, S Musselman, CA Kachirskaia, I Hayashi, R Glass, KC Nix, JC Gozani, O Appella, E Kutateladze, TG AF Roy, Siddhartha Musselman, Catherine A. Kachirskaia, Ioulia Hayashi, Ryo Glass, Karen C. Nix, Jay C. Gozani, Or Appella, Ettore Kutateladze, Tatiana G. TI Structural Insight into p53 Recognition by the 53BP1 Tandem Tudor Domain SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Tudor domain; methylated p53; 53BP1; structure; cancer ID LYSINE METHYLATION; BINDING-PROTEIN-1 53BP1; HISTONE H2AX; DNA; REPRESSION; CHECKPOINT; PROTEINS AB The tumor suppressor p53 and the DNA repair factor 53BP1 (p53 binding protein 1) regulate gene transcription and responses to genotoxic stresses. Upon DNA damage, p53 undergoes dimethylation at Lys382 (p53K382me2), and this posttranslational modification is recognized by 53BP1. The molecular mechanism of nonhistone methyl-lysine mark recognition remains unknown. Here we report a 1. 6-angstrom-resolution crystal structure of the tandem Tudor domain of human 53BP1 bound to a p53K382me2 peptide. In the complex, dimethylated Lys382 is restrained by a set of hydrophobic and cation-pi interactions in a cage formed by four aromatic residues and an aspartate of 53BP1. The signature HKKme2 motif of p53, which defines specificity, is identified through a combination of NMR resonance perturbations, mutagenesis, measurements of binding affinities and docking simulations, and analysis of the crystal structures of 53BP1 bound to p53 peptides containing other dimethyl-lysine marks, p53K370me2 (p53 dimethylated at Lys370) and p53K372me2 (p53 dimethylated at Lys372). Binding of the 53BP1 Tudor domain to p53K382me2 may facilitate p53 accumulation at DNA damage sites and promote DNA repair as suggested by chromatin immunoprecipitation and DNA repair assays. Together, our data detail the molecular mechanism of p53-53BP1 association and provide the basis for deciphering the role of this interaction in the regulation of p53 and 53BP1 functions. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Roy, Siddhartha; Musselman, Catherine A.; Glass, Karen C.; Kutateladze, Tatiana G.] Univ Colorado Denver, Dept Pharmacol, Sch Med, Aurora, CO 80045 USA. [Kachirskaia, Ioulia; Gozani, Or] Stanford Univ, Dept Biol Sci, Stanford, CA 94305 USA. [Hayashi, Ryo; Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Nix, Jay C.] Univ Calif Berkeley, Lawrence Berkeley Lab, Adv Light Source Beamline 4 2 2, Mol Biol Consortium, Berkeley, CA 94720 USA. RP Kutateladze, TG (reprint author), Univ Colorado Denver, Dept Pharmacol, Sch Med, 12801 E 17th Ave, Aurora, CO 80045 USA. EM Tatiana.Kutateladze@UCDenver.edu OI Glass, Karen/0000-0002-2761-733X FU National Institutes of Health [CA113472, GM071424] FX We thank A.M.J.J. Bonvin, K. Walters, and L. Jenkins for helping with the experiments, and T. Hong and K. Chua for the I-SceI stable cell lines. This research was supported by National Institutes of Health grants CA113472 and GM071424 (T.G.K.). C.A.M. and K.C.G. are recipients of National Institutes of Health National Research Service Award postdoctoral fellowships. NR 25 TC 25 Z9 25 U1 0 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 14 PY 2010 VL 398 IS 4 BP 489 EP 496 DI 10.1016/j.jmb.2010.03.024 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 599FD UT WOS:000277895500003 PM 20307547 ER PT J AU Watts, NR Vethanayagam, JG Ferns, RB Tedder, RS Harris, A Stahl, SJ Steven, AC Wingfield, PT AF Watts, Norman R. Vethanayagam, Joe G. Ferns, R. Bridget Tedder, Richard S. Harris, Audray Stahl, Stephen J. Steven, Alasdair C. Wingfield, Paul T. TI Molecular Basis for the High Degree of Antigenic Cross-Reactivity between Hepatitis B Virus Capsids (HBcAg) and Dimeric Capsid-Related Protein (HBeAg): Insights into the Enigmatic Nature of the e-Antigen SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE hepatitis B virus; surface plasmon resonance; monoclonal antibody; e-antigen; core antigen ID SURFACE-PLASMON RESONANCE; CORE ANTIGEN; MONOCLONAL-ANTIBODIES; IMMUNOCHEMICAL STRUCTURE; PRECORE REGION; BINDING; EPITOPE; IDENTIFICATION; DETERMINANTS; DIVERSITY AB The hepatitis B virus core gene codes for two closely related antigens: a 21-kDa protein that forms dimers that assemble as multimegadalton capsids, and a 17-kDa protein that also forms dimers but that do not assemble. The proteins, respectively referred to as core antigen (HBcAg) and e-antigen (HBeAg), share a sequence of 149 residues but have different amino- and carboxy-termini. Their structural and serological relationship has long been unclear. With insights gained from recent structural studies on immune complexes of the capsids, the relationship was reassessed using recombinant forms of the antigens and a panel of monoclonal antibodies (mAbs) commonly believed to discriminate between core and e-antigen. Surface plasmon resonance (SPR) was used to measure the affinities, in contrast to previous studies that used more error-prone and less sensitive plate-type assays. Four of the six mAbs did not discriminate between core and e-antigen, nor did they discriminate between e-antigen and dimers of dissociated core antigen capsids. One mAb (3120) was specific for assembled capsids and one (e6) was specific for unassembled dimers. Epitope valency of the e-antigen was also studied, using a sandwich SPR assay where e-antigen was captured with one mAb and probed with a second. The e-antigen is often considered to be a monomeric protein on the basis of monovalent reactivity with antibody pairs specific for either an a or epitope (in a prior nomenclature for e-antigen specificity). This model, however, is incorrect, because recombinant e-antigen is a stable dimer and its apparent monovalency is due to steric blockage. This was proven by the formation of a 2:1 Fab e6-e-antigen complex. These results suggest new approaches for the isolation of the authentic e-antigen, its biological assay, and its stabilization as an immune complex for structural studies. Published by Elsevier Ltd. C1 [Watts, Norman R.; Vethanayagam, Joe G.; Stahl, Stephen J.; Wingfield, Paul T.] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [Ferns, R. Bridget] UCL, Dept Infect, Ctr Virol, London W1T 4JF, England. [Tedder, Richard S.] Hlth Protect Agcy Colindale, Ctr Infect, Virus Reference Dept, London NW9 5EQ, England. [Harris, Audray; Steven, Alasdair C.] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Watts, NR (reprint author), NIAMSD, Prot Express Lab, NIH, Bldg 50,Room 1517, Bethesda, MD 20892 USA. EM Norman_Watts@nih.gov FU National Institutes of Health FX We thank Joshua Kaufman and Ira Palmer [National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)] for expert technical assistance. This research was supported by the NIAMS Intramural Research Program of the National Institutes of Health. NR 40 TC 11 Z9 12 U1 1 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 14 PY 2010 VL 398 IS 4 BP 530 EP 541 DI 10.1016/j.jmb.2010.03.026 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 599FD UT WOS:000277895500007 PM 20307545 ER PT J AU Hwang, JH Voortman, J Giovannetti, E Steinberg, SM Leon, LG Kim, YT Funel, N Park, JK Kim, MA Kang, GH Kim, SW Del Chiaro, M Peters, GJ Giaccone, G AF Hwang, Jin-Hyeok Voortman, Johannes Giovannetti, Elisa Steinberg, Seth M. Leon, Leticia G. Kim, Yong-Tae Funel, Niccola Park, Joo Kyung Kim, Min A. Kang, Gyeong Hoon Kim, Sun-Whe Del Chiaro, Marco Peters, Godefridus J. Giaccone, Giuseppe TI Identification of MicroRNA-21 as a Biomarker for Chemoresistance and Clinical Outcome Following Adjuvant Therapy in Resectable Pancreatic Cancer SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TUMOR-SUPPRESSOR GENE; HUMAN CHOLANGIOCARCINOMA; DUCTAL ADENOCARCINOMA; PROGNOSTIC MARKERS; ACTIVATED AKT; EXPRESSION; CELLS; GEMCITABINE; SURVIVAL AB Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The high risk of recurrence following surgical resection provides the rationale for adjuvant therapy. However, only a subset of patients benefit from adjuvant therapy. Identification of molecular markers to predict treatment outcome is therefore warranted. The aim of the present study was to evaluate whether expression of novel candidate biomarkers, including microRNAs, can predict clinical outcome in PDAC patients treated with adjuvant therapy. Methodology/Principal Findings: Formalin-fixed paraffin embedded specimens from a cohort of 82 resected Korean PDAC cases were analyzed for protein expression by immunohistochemistry and for microRNA expression using quantitative Real-Time PCR. Cox proportional hazards model analysis in the subgroup of patients treated with adjuvant therapy (N = 52) showed that lower than median miR-21 expression was associated with a significantly lower hazard ratio (HR) for death (HR = 0.316; 95% CI = 0.166-0.600; P = 0.0004) and recurrence (HR = 0.521; 95% CI = 0.280-0.967; P = 0.04). MiR-21 expression status emerged as the single most predictive biomarker for treatment outcome among all 27 biological and 9 clinicopathological factors evaluated. No significant association was detected in patients not treated with adjuvant therapy. In an independent validation cohort of 45 frozen PDAC tissues from Italian cases, all treated with adjuvant therapy, lower than median miR-21 expression was confirmed to be correlated with longer overall as well as disease-free survival. Furthermore, transfection with anti-miR-21 enhanced the chemosensitivity of PDAC cells. Conclusions Significance: Low miR-21 expression was associated with benefit from adjuvant treatment in two independent cohorts of PDAC cases, and anti-miR-21 increased anticancer drug activity in vitro. These data provide evidence that miR-21 may allow stratification for adjuvant therapy, and represents a new potential target for therapy in PDAC. C1 [Hwang, Jin-Hyeok; Voortman, Johannes; Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Hwang, Jin-Hyeok] Seoul Natl Univ, Bundang Hosp, Dept Internal Med, Songnam, South Korea. [Hwang, Jin-Hyeok; Kim, Yong-Tae; Park, Joo Kyung] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea. [Voortman, Johannes; Giovannetti, Elisa; Leon, Leticia G.; Peters, Godefridus J.] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Giovannetti, Elisa] Univ Pisa, Dept Internal Med, Pisa, Italy. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Funel, Niccola; Del Chiaro, Marco] Hosp Pisa, Div Chirurg Gen & Trapianti Urem & Diabet, Pisa, Italy. [Kim, Min A.; Kang, Gyeong Hoon] Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 151, South Korea. [Kim, Sun-Whe] Seoul Natl Univ, Coll Med, Dept Surg, Seoul 151, South Korea. RP Hwang, JH (reprint author), NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giovannetti, Elisa/F-4261-2011; Kang, Gyeong Hoon/F-1051-2010; Seoul National University, Pathology/B-6702-2012; Kim, Yong-Tae/E-4148-2012; Hwang, Jin-Hyeok/J-5735-2012; Kim, Sun-Whe/J-2741-2012; Giaccone, Giuseppe/E-8297-2017; OI Kang, Gyeong Hoon/0000-0003-2380-6675; Giaccone, Giuseppe/0000-0002-5023-7562; Giovannetti, Elisa/0000-0002-7565-7504; Funel, Niccola/0000-0002-5028-2363 FU National Institutes of Health, National Cancer Institute FX In part funded by the National Institutes of Health, National Cancer Institute intramural program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 158 Z9 169 U1 3 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 MAY 14 PY 2010 VL 5 IS 5 AR e10630 DI 10.1371/journal.pone.0010630 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 597PU UT WOS:000277771600004 PM 20498843 ER PT J AU Russell, DG Barry, CE Flynn, JL AF Russell, David G. Barry, Clifton E., III Flynn, JoAnne L. TI Tuberculosis: What We Don't Know Can, and Does, Hurt Us SO SCIENCE LA English DT Review ID MYCOBACTERIUM-BOVIS BCG; CHRONIC MURINE TUBERCULOSIS; BACILLE CALMETTE-GUERIN; NECROSIS-FACTOR-ALPHA; ENVIRONMENTAL MYCOBACTERIA; PROTECTIVE IMMUNITY; METHYLCITRATE CYCLE; VACCINE DEVELOPMENT; INFECTED PATIENTS; TB VACCINE AB Mycobacterium tuberculosis has a penetrance of its host population that would be the envy of most human pathogens. About one-third of the human population would have a positive skin test for the infection and is thus thought to harbor the bacterium. Globally, 22 "high-burden" countries account for more than 80% of the active tuberculosis cases in the world, which shows the inequitable distribution of the disease. There is no effective vaccine against infection, and current drug therapies are fraught with problems, predominantly because of the protracted nature of the treatment and the increasing occurrence of drug resistance. Here we focus on the biology of the host-pathogen interaction and discuss new and evolving strategies for intervention. C1 [Russell, David G.] Cornell Univ, Coll Vet Med, Dept Microbiol & Immunol, Ithaca, NY 14853 USA. [Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Flynn, JoAnne L.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15261 USA. RP Russell, DG (reprint author), Cornell Univ, Coll Vet Med, Dept Microbiol & Immunol, Ithaca, NY 14853 USA. EM dgr8@cornell.edu RI Russell, David/D-4533-2009; Barry, III, Clifton/H-3839-2012 FU NIH [AI067027, AI057086, AI080651, HL055936, HL100928, AI50732, HL71241, HL092883, HL075845]; NIAID, NIH; Bill and Melinda Gates Foundation FX Research in the authors' laboratories is supported by NIH grants AI067027, AI057086, AI080651, HL055936, and HL100928 (D. G. R.) and AI50732, HL71241, HL092883, and HL075845 (J.L.F.) and by the Intramural Research Program of the NIAID, NIH (C. E. B.). All three authors receive support from the Bill and Melinda Gates Foundation. NR 61 TC 258 Z9 269 U1 19 U2 107 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 14 PY 2010 VL 328 IS 5980 BP 852 EP 856 DI 10.1126/science.1184784 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 595NT UT WOS:000277618800038 PM 20466922 ER PT J AU Mikovits, JA Ruscetti, FW AF Mikovits, Judy A. Ruscetti, Francis W. TI Response to Comments on "Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome" SO SCIENCE LA English DT Editorial Material ID DEFICIENCY SYNDROME AIDS; VIRUS-RELATED VIRUS; LEUKEMIA-VIRUS AB We reported the detection of the human gammaretrovirus XMRV in 67% of 101 patients with chronic fatigue syndrome (CFS) and in 3.7% of 218 healthy controls, but we did not claim that XMRV causes CFS. Here, we explain why the criticisms of Sudlow et al., Lloyd et al., and van der Meer et al. regarding the selection of patients and controls in our study are unwarranted. C1 [Mikovits, Judy A.] Whittemore Peterson Inst, Reno, NV 89557 USA. [Ruscetti, Francis W.] NCI, Expt Immunol Lab, Frederick, MD 21701 USA. RP Mikovits, JA (reprint author), Whittemore Peterson Inst, Reno, NV 89557 USA. EM judym@wpinstitute.org NR 14 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 14 PY 2010 VL 328 IS 5980 DI 10.1126/science.1184548 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 595NT UT WOS:000277618800020 ER PT J AU Sierra, MD Sakakibara, S Gasperini, P Salvucci, O Jiang, K McCormick, PJ Segarra, M Stone, J Maric, D Zhu, JF Qian, XL Lowy, DR Tosato, G AF Sierra, Maria de la Luz Sakakibara, Shuhei Gasperini, Paola Salvucci, Ombretta Jiang, Kan McCormick, Peter J. Segarra, Marta Stone, Jim Maric, Dragan Zhu, Jinfang Qian, Xiaolan Lowy, Douglas R. Tosato, Giovanna TI The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1 SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; ZINC-FINGER PROTEIN; HEMATOPOIETIC STEM-CELLS; FACTOR-RECEPTOR; REPRESSOR GFI1; MICE LACKING; GRANULOCYTE; MYC; DIFFERENTIATION; PROLIFERATION AB The transcription factor growth factor independence 1 (Gfi1) and the growth factor granulocyte colony-stimulating factor (G-CSF) are individually essential for neutrophil differentiation from myeloid progenitors. Here, we provide evidence that the functions of Gfi1 and G-CSF are linked in the regulation of granulopoiesis. We report that Gfi1 promotes the expression of Ras guanine nucleotide releasing protein 1 (RasGRP1), an exchange factor that activates Ras, and that RasGRP1 is required for G-CSF signaling through the Ras/mitogen-activated protein/extracellular signal-regulated kinase (MEK/Erk) pathway. Gfi1-null mice have reduced levels of RasGRP1 mRNA and protein in thymus, spleen, and bone marrow, and Gfi1 transduction in myeloid cells promotes RasGRP1 expression. When stimulated with G-CSF, Gfi1-null myeloid cells are selectively defective at activating Erk1/2, but not signal transducer and activator of transcription 1 (STAT1) or STAT3, and fail to differentiate into neutrophils. Expression of RasGRP1 in Gfi1-deficient cells rescues Erk1/2 activation by G-CSF and allows neutrophil maturation by G-CSF. These results uncover a previously unknown function of Gfi1 as a regulator of RasGRP1 and link Gfi1 transcriptional control to G-CSF signaling and regulation of granulopoiesis. (Blood. 2010; 115(19): 3970-3979) C1 [Sierra, Maria de la Luz; Sakakibara, Shuhei; Gasperini, Paola; Salvucci, Ombretta; Jiang, Kan; McCormick, Peter J.; Segarra, Marta; Qian, Xiaolan; Lowy, Douglas R.; Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stone, Jim] Univ Alberta, Dept Biochem, Edmonton, AB, Canada. [Maric, Dragan] Natl Inst Neurol Disorders & Stroke, Neurophysiol Lab, Bethesda, MD USA. [Zhu, Jinfang] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Tosato, G (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bldg 37,Rm 4124, Bethesda, MD 20892 USA. EM tosatog@mail.nih.gov RI Zhu, Jinfang/B-7574-2012; McCormick, Peter/E-7387-2012 OI McCormick, Peter/0000-0002-2225-5181 FU NIH, NCI, Center for Cancer Research; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; JSPS; Ministerio de Educacion y Ciencia (MEC) FX This work was supported by the Intramural Research Program at NIH, NCI, Center for Cancer Research and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. S. S. is the recipient of a JSPS fellowship; M. S. is the recipient of a Ministerio de Educacion y Ciencia (MEC)-Fulbright fellowship. NR 43 TC 14 Z9 14 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 13 PY 2010 VL 115 IS 19 BP 3970 EP 3979 PG 10 WC Hematology SC Hematology GA 595NV UT WOS:000277619000020 ER PT J AU Calleri, E Ceruti, S Cristalli, G Martini, C Temporini, C Parravicini, C Volpini, R Daniele, S Caccialanza, G Lecca, D Lambertucci, C Trincavelli, ML Marucci, G Wainer, IW Ranghino, G Fantucci, P Abbracchio, MP Massolini, G AF Calleri, Enrica Ceruti, Stefania Cristalli, Gloria Martini, Claudia Temporini, Caterina Parravicini, Chiara Volpini, Rosaria Daniele, Simona Caccialanza, Gabriele Lecca, Davide Lambertucci, Catia Trincavelli, Maria Letizia Marucci, Gabriella Wainer, Irving W. Ranghino, Graziella Fantucci, Piercarlo Abbracchio, Maria P. Massolini, Gabriella TI Frontal Affinity Chromatography-Mass Spectrometry Useful for Characterization of New Ligands for GPR17 Receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DRUG DISCOVERY; PHARMACOLOGICAL CHARACTERIZATION; P2Y(13) RECEPTOR; STATIONARY-PHASE; P2Y RECEPTORS; MS DETECTION; FAC-MS; DERIVATIVES; ADENOSINE; AGONISTS AB The application of frontal affinity chromatography mass spectrometry (FAC-MS), along with molecular modeling studies, to the screening of potential drug candidates toward the recently deorphanized G-protein-coupled receptor (GPCR) GPR17 is shown. GPR17 is dually activated by uracil nucleotides and cysteinyl-leukotrienes, and is expressed in organs typically undergoing ischemic damage (i.e., brain, heart and kidney), thus representing a new pharmacological target for acute and chronic neurodegeneration. GPR17 was entrapped on an immobilized artificial membrane (IAM), and this stationary phase was used to screen a library of nucleotide derivatives by FAC-MS to select high affinity ligands. The chromatographic results have been validated with a reference functional assay ([(35)S]GTP gamma S binding assay). The receptor nucleotide-binding site was studied by setting up a column where a mutated GPR17 receptor (Arg255Ile) has been immobilized. The chromatographic behavior of the tested nucleotide derivatives together with in silico studies have been used to gain insights into the structure requirement of GPR17 ligands. C1 [Calleri, Enrica; Temporini, Caterina; Caccialanza, Gabriele; Massolini, Gabriella] Univ Pavia, Dept Pharmaceut Chem, I-27100 Pavia, Italy. [Ceruti, Stefania; Parravicini, Chiara; Lecca, Davide; Abbracchio, Maria P.] Univ Milan, Dept Pharmacol Sci, Lab Cellular & Mol Pharmacol Purinerg Transmiss, I-20133 Milan, Italy. [Cristalli, Gloria; Volpini, Rosaria; Lambertucci, Catia; Marucci, Gabriella] Univ Camerino, Dept Chem Sci, I-62032 Camerino, Italy. [Martini, Claudia; Daniele, Simona; Trincavelli, Maria Letizia] Univ Pisa, Dept Psychiat Neurobiol Pharmacol & Biotechnol, I-56126 Pisa, Italy. [Wainer, Irving W.] NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Ranghino, Graziella; Fantucci, Piercarlo] Delos Srl, Bresso, MI, Italy. [Fantucci, Piercarlo] Univ Milano Bicocca, Dept Biosci & Biotechnol, I-20126 Milan, Italy. RP Massolini, G (reprint author), Univ Pavia, Dept Pharmaceut Chem, Via Taramelli 12, I-27100 Pavia, Italy. EM g.massolini@unipv.it RI Lecca, Davide/A-8850-2010; Abbracchio, Maria Pia/B-9342-2014; OI Lecca, Davide/0000-0002-3258-363X; Abbracchio, Maria Pia/0000-0002-7833-3388; Lambertucci, Catia/0000-0003-2004-1531; CALLERI, ENRICA/0000-0002-4246-460X; Temporini, Caterina/0000-0003-1925-7845; Trincavelli, Maria Letizia/0000-0001-8124-977X; Ceruti, Stefania/0000-0003-1663-4211; Martini, Claudia/0000-0001-9379-3027 FU Italian Ministry for University and Research [RBN503YA3L] FX Cangrelor was a kind gift from The Medicine Company (Parsippany, NJ). This work was supported by a grant from the Italian Ministry for University and Research (Project FIRB RBN503YA3L). NR 38 TC 30 Z9 33 U1 1 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 13 PY 2010 VL 53 IS 9 BP 3489 EP 3501 DI 10.1021/jm901691y PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 592CN UT WOS:000277352800006 PM 20394377 ER PT J AU Carlsson, J Yoo, L Gao, ZG Irwin, JJ Shoichet, BK Jacobson, KA AF Carlsson, Jens Yoo, Lena Gao, Zhan-Guo Irwin, John J. Shoichet, Brian K. Jacobson, Kenneth A. TI Structure-Based Discovery of A(2A) Adenosine Receptor Ligands SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; BETA(2)-ADRENERGIC RECEPTOR; MOLECULAR DOCKING; BETA-LACTAMASE; CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURE; PARTIAL AGONISTS; NUCLEIC-ACIDS; CELL-CULTURE; FORCE-FIELD AB The recent determination of X-ray structures of pharmacologically relevant GPCRs has made these targets accessible to structure-based ligand discovery. Here we explore whether novel chemotypes may be discovered for the A(2A) adenosine receptor, based on complementarity to its recently determined structure. The A(2A) adenosine receptor signals in the periphery and the CNS, with agonists explored as anti-inflammatory drugs and antagonists explored for neurodegenerative diseases. We used molecular docking to screen a 1.4 million compound database against the X-ray structure computationally and tested 20 high-ranking, previously unknown molecules experimentally. Of these 35% showed substantial activity with affinities between 200 nM and 9 mu M. For the most potent of these new inhibitors, over 50-fold specificity was observed for the A(2A) versus the related A(1) and A(3) subtypes. These high hit rates and affinities at least partly reflect the bias of commercial libraries toward GPCR-like chemotypes, an issue that we attempt to investigate quantitatively. Despite this bias, many of the most potent new ligands were novel, dissimilar from known ligands, providing new lead structures for modulation of this medically important target. C1 [Carlsson, Jens; Irwin, John J.; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. [Yoo, Lena; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Shoichet, BK (reprint author), Univ Calif San Francisco, Dept Pharmaceut Chem, 1700 4th St,Box 2550, San Francisco, CA 94158 USA. EM shoichet@cgl.ucsf.edu; kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Irwin, John/0000-0002-1195-6417; Carlsson, Jens/0000-0003-4623-2977 FU NIH [GM 59957]; NIDDK; Knut and Alice Wallenberg Foundation FX This work is supported by NIH Grant GM 59957 (to B.K.S.), NIDDK Intramural Research Program (to K.A.J.), and a fellowship from the Knut and Alice Wallenberg Foundation (to J.C.). We thank A. Doak for aggregation assays and members of the Shoichet lab for docking "hit-list" evaluation. We thank Tudor Oprea for access to the WOMBAT database and John Overington for a prerelease version of the ChEMBL database. NR 54 TC 130 Z9 132 U1 1 U2 9 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 MAY 13 PY 2010 VL 53 IS 9 BP 3748 EP 3755 DI 10.1021/jm100240h PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 592CN UT WOS:000277352800028 PM 20405927 ER PT J AU Salome, C Salome-Grosjean, E Stables, JP Kohna, H AF Salome, Christophe Salome-Grosjean, Elise Stables, James P. Kohna, Harold TI Merging the Structural Motifs of Functionalized Amino Acids and alpha-Aminoamides: Compounds with Significant Anticonvulsant Activities SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID N-BENZYLACETAMIDE DERIVATIVES; GATED SODIUM-CHANNELS; ANTIEPILEPTIC DRUGS; NEUROPATHIC PAIN; FORMALIN TEST; EPILEPSY; MODEL; PNU-151774E; DISCOVERY; AGENTS AB Functional amino acids (FAAs) and alpha-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4'-((3 ''-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED(50) values of 13, 14, similar to 10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases. C1 [Salome, Christophe; Salome-Grosjean, Elise; Kohna, Harold] Univ N Carolina, UNC Eshelman Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. [Stables, James P.] NINDS, Epilepsy Branch, NIH, Bethesda, MD 20892 USA. [Kohna, Harold] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Kohna, H (reprint author), Univ N Carolina, UNC Eshelman Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. EM hkohn@email.unc.edu FU National Center for Research Resources [UL1RR025747]; National Institute of Neurological Disorders and Stroke [R01NS054112] FX We thank the NINDS and the ASP at the National Institutes of Health with Drs. Tracy Chen and Jeffrey Jiang for kindly performing the pharmacological studies via the ASP's contract site at the University of Utah with Drs. H. Wolfe, H. S. White, and K. Wilcox. The project was supported by award no. UL1RR025747 from the National Center for Research Resources and grant R01NS054112 (H.K.) from the National Institute of Neurological Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources, National Institute of Neurological Disorders and Stroke, or the National Institutes of Health. Harold Kohn has a royalty-stake position in (R)-3. NR 66 TC 17 Z9 19 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 13 PY 2010 VL 53 IS 9 BP 3756 EP 3771 DI 10.1021/jm100185c PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 592CN UT WOS:000277352800029 PM 20394379 ER PT J AU Liu, SB Hu, H Pederset, LG AF Liu, Shubin Hu, Hao Pederset, Lee G. TI Steric, Quantum, and Electrostatic Effects on S(N)2 Reaction Barriers in Gas Phase SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID INTERNAL-ROTATION BARRIERS; DENSITY-FUNCTIONAL THEORY; CORRELATION-ENERGY; KINETIC-ENERGY; FISHER INFORMATION; TRANSITION-STATES; IONIC REACTIONS; SN2 REACTIONS; SQUARE-ROOT; TERMS AB Biomolecular nucleophilic substitution reactions, S(N)2, are fundamental and commonplace in chemistry. It is the well-documented experimental finding in the literature that vicinal substitution with bulkier groups near the reaction center significantly slows the reaction due to steric hindrance, but theoretical understanding in the quantitative manner about factors dictating the S(N)2 reaction barrier height is still controversial. In this work, employing the new quantification approach that we recently proposed for the steric effect from the density functional theory framework, we investigate the relative contribution of three independent effects steric, electrostatic, and quantum to the S(N)2 barrier heights in gas phase for substituted methyl halide systems, R1R2R3CX, reacting with the fluorine anion, where R-1, R-2, and R-3 denote substituting groups and X = F or Cl. We found that in accordance with the experimental finding, for these systems, the steric effect dominates the transition state barrier, contributing positively to barrier heights, but this contribution is largely compensated by the negative, stabilizing contribution from the quantum effect due to the exchange-correlation interactions. Moreover, we find that it is the component from the electrostatic effect that is linearly correlated with the S(N)2 barrier height for the systems investigated in the present study. In addition, we compared our approach with the conventional method of energy decomposition in density functional theory as well as examined the steric effect from the wave function theory for these systems via natural bond orbital analysis. C1 [Liu, Shubin] Univ N Carolina, Ctr Res Comp, Chapel Hill, NC 27599 USA. [Hu, Hao] Univ Hong Kong, Dept Chem, Hong Kong, Hong Kong, Peoples R China. [Pederset, Lee G.] Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Pederset, Lee G.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Liu, SB (reprint author), Univ N Carolina, Ctr Res Comp, Chapel Hill, NC 27599 USA. EM shubin@email.unc.edu RI Liu, Shubin/B-1502-2009; Hu, Hao/A-2307-2008 OI Liu, Shubin/0000-0001-9331-0427; FU UNC EFRC; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-SC0001011]; National Institute of Health [HL-06350]; NSF [FRG DMR-0804549]; NIH, NIEHS FX Helpful discussion with Daniel Ess, Robert G. Parr, and Cynthia K. Schauer of University of North Carolina at Chapel Hill; Robert C. Morrison of East Carolina University; Paul W. Ayer of McMaster University, Canada; and Stephen L. Craig of Duke University is gratefully acknowledged. This work was supported in part by UNC EFRC: Solar Fuels and Next Generation Photovoltaics, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Award No. DE-SC0001011; the National Institute of Health (HL-06350); NSF (FRG DMR-0804549); and the Intramural Research Program of NIH, NIEHS. We acknowledge the use of the computational resources provided by the Research Computing Center at University of North Carolina at Chapel Hill. Part of the work was presented in the 50th Sanibel Symposium at St. Thomas Island, GA. NR 60 TC 37 Z9 37 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 MAY 13 PY 2010 VL 114 IS 18 BP 5913 EP 5918 DI 10.1021/jp101329f PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 591DX UT WOS:000277280400035 PM 20377265 ER PT J AU Franks, PW Knowler, WC Looker, HC AF Franks, Paul W. Knowler, William C. Looker, Helen C. TI Childhood Obesity, Other Cardiovascular Risk Factors, and Premature Death REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Franks, Paul W.] Umea Univ Hosp, S-90185 Umea, Sweden. [Knowler, William C.] NIDDKD, Phoenix, AZ USA. [Looker, Helen C.] Mt Sinai Sch Med, New York, NY USA. RP Franks, PW (reprint author), Umea Univ Hosp, S-90185 Umea, Sweden. EM paul.franks@medicin.umu.se NR 1 TC 0 Z9 0 U1 1 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 13 PY 2010 VL 362 IS 19 BP 1841 EP 1842 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 594RQ UT WOS:000277555500018 ER PT J AU Narayanan, S Silva, R Peruzzi, G Alvarez, Y Simhadri, VR Debell, K Coligan, JE Borrego, F AF Narayanan, Sriram Silva, Rodolfo Peruzzi, Giovanna Alvarez, Yelina Simhadri, Venkateswara R. Debell, Karen Coligan, John E. Borrego, Francisco TI Human Th1 Cells That Express CD300a Are Polyfunctional and After Stimulation Up-Regulate the T-Box Transcription Factor Eomesodermin SO PLOS ONE LA English DT Article ID RECEPTOR IRP60 CD300A; IFN-GAMMA PRODUCTION; INHIBITORY RECEPTOR; INTERFERON-GAMMA; HELPER LYMPHOCYTES; LEISHMANIA-MAJOR; DENDRITIC CELLS; BET; DIFFERENTIATION; EFFECTOR AB Human naive CD4 T cells express low levels of the immunomodulatory receptor CD300a, whereas effector/memory CD4 cells can be either CD300a(+) or CD300a(-). This suggested that CD300a expression could define a specific subset within the effector/memory CD4 T cell subpopulations. In fact, ex vivo analysis of the IFN-gamma producing CD4 T cells showed that they are enriched in the CD300a(+) subset. Moreover, stimulated CD4 T cells producing TNF-alpha and IL-2 besides IFN-gamma (polyfunctional) are predominantly CD300a(+). In addition to producing markedly higher levels of Th1-associated cytokines, the stimulated CD300a(+) CD4 T cells are distinguished by a striking up-regulation of the T-box transcription factor eomesodermin (Eomes), whereas T-bet is up-regulated in both CD300a+ and CD300a(-) activated CD4 T cells to similar levels. The pleiotropic cytokine TGF-beta 1 has a determinant role in dictating the development of this Th1 subset, as its presence inhibits the expression of CD300a and down-regulates the expression of Eomes and IFN-gamma. We conclude that CD300a+ human Th1 cells tend to be polyfunctional and after stimulation up-regulate Eomes. C1 [Narayanan, Sriram; Silva, Rodolfo; Peruzzi, Giovanna; Alvarez, Yelina; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD USA. [Simhadri, Venkateswara R.; Debell, Karen; Borrego, Francisco] US FDA, Ctr Biol Evaluat & Res, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Bethesda, MD USA. RP Narayanan, S (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD USA. EM Francisco.Borrego@fda.hhs.gov OI Narayanan, Sriram/0000-0002-6484-2800; Peruzzi, Giovanna/0000-0002-6517-9107 FU Food and Drug Administration (FDA); National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by the intramural programs of Food and Drug Administration (FDA) and the National Institute of Allergy and Infectious Diseases (NIAID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 22 Z9 22 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 13 PY 2010 VL 5 IS 5 AR e10636 DI 10.1371/journal.pone.0010636 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 595SN UT WOS:000277633500020 PM 20498708 ER PT J AU Squarize, CH Castilho, RM Bugge, TH Gutkind, JS AF Squarize, Cristiane H. Castilho, Rogerio M. Bugge, Thomas H. Gutkind, J. Silvio TI Accelerated Wound Healing by mTOR Activation in Genetically Defined Mouse Models SO PLOS ONE LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; RENAL-ALLOGRAFT REJECTION; CHROMOSOME-10 PTEN; CANCER; SIROLIMUS; TARGET; DISEASE; PROLIFERATION; PHOSPHATASE; MECHANISMS AB Background: The management of slow or non-healing ulcerations constitutes an increasing clinical challenge in the developed world because of the ageing of the population and the pandemic rise in type II diabetes. Recent studies suggest that molecular circuitries deployed by tumor cells to promote cancerous growth may also contribute to tissue regeneration. Here, we exploited this emerging information to search for novel molecular targets to accelerate wound healing. Methodology/Principal Findings: We found that the activation of the PI3K-Akt-mTOR pathway, whose aberrant function is a frequent event in human neoplasia, represents an integral component of the normal wound healing process. By the use of genetically defined approaches, including the epithelial-specific ablation of Pten and Tsc1, we show that mTOR activation can dramatically increase epithelial cell proliferation, migration, and cutaneous wound healing, while pharmacological inhibition of mTOR with rapamycin delays wound closure. Conclusions/Significance: Overall, our findings indicate that the transient pharmacologic activation of the PI3K-Akt-mTOR signaling axis may represent a novel clinical intervention strategy to accelerate the healing of debilitating and life-threatening wounds. C1 [Squarize, Cristiane H.; Castilho, Rogerio M.; Bugge, Thomas H.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Squarize, Cristiane H.; Castilho, Rogerio M.] Univ Michigan, Sch Dent, Dept Periodont & Oral Med, Div Oral Pathol Med Radiol, Ann Arbor, MI 48109 USA. RP Squarize, CH (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Castilho, Rogerio/E-4987-2010 FU NIH, National Institute of Dental and Craniofacial Research FX This research was supported by the Intramural Research Program of NIH, National Institute of Dental and Craniofacial Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 52 Z9 53 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 13 PY 2010 VL 5 IS 5 AR e10643 DI 10.1371/journal.pone.0010643 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 595SN UT WOS:000277633500022 PM 20498714 ER PT J AU Funkenstein, B Olekh, E Jakowlew, SB AF Funkenstein, Bruria Olekh, Elena Jakowlew, Sonia B. TI Identification of a novel transforming growth factor-beta (TGF-beta 6) gene in fish: regulation in skeletal muscle by nutritional state SO BMC MOLECULAR BIOLOGY LA English DT Article ID DEOXYRIBONUCLEIC-ACID CLONING; TROUT ONCORHYNCHUS-MYKISS; BREAM SPARUS-AURATA; MESSENGER RIBONUCLEIC-ACID; BASS DICENTRARCHUS-LABRAX; POLYMERASE-CHAIN-REACTION; TGF-BETA; RAINBOW-TROUT; MOLECULAR-CLONING; COMPLEMENTARY-DNA AB Background: The transforming growth factor-beta (TGF-beta) family constitutes of dimeric proteins that regulate the growth, differentiation and metabolism of many cell types, including that of skeletal muscle in mammals. The potential role of TGF-beta s in fish muscle growth is not known. Results: Here we report the molecular characterization, developmental and tissue expression and regulation by nutritional state of a novel TGF-beta gene from a marine fish, the gilthead sea bream Sparus aurata. S. aurata TGF-beta 6 is encoded by seven exons 361, 164, 133, 111, 181, 154, and 156 bp in length and is translated into a 420-amino acid peptide. The exons are separated by six introns: >643, 415, 93, 1250, 425 and >287 bp in length. Although the gene organization is most similar to mouse and chicken TGF-beta 2, the deduced amino acid sequence represents a novel TGF-beta that is unique to fish that we have named TGF-beta 6. The molecule has conserved putative functional residues, including a cleavage motif (RXXR) and nine cysteine residues that are characteristic of TGF-beta. Semi-quantitative analysis of TGF-beta 6 expression revealed differential expression in various tissues of adult fish with high levels in skin and muscle, very low levels in liver, and moderate levels in other tissues including brain, eye and pituitary. TGF-beta 6 is expressed in larvae on day of hatching and increases as development progresses. A fasting period of five days of juvenile fish resulted in increased levels of TGF-beta 6 expression in white skeletal muscle compared to that in fed fish, which was slightly attenuated by one injection of growth hormone. Conclusion: Our findings provide valuable insights about genomic information and nutritional regulation of TGF-beta 6 which will aid the further investigation of the S. aurata TGF-beta 6 gene in association with muscle growth. The finding of a novel TGF-beta 6 molecule, unique to fish, will contribute to the understanding of the evolution of the TGF-beta family of cytokines in vertebrates. C1 [Funkenstein, Bruria; Olekh, Elena] Natl Inst Oceanog, IL-31080 Haifa, Israel. [Jakowlew, Sonia B.] NCI, Ctr Canc Training, Canc Training Branch, Bethesda, MD 20892 USA. RP Funkenstein, B (reprint author), Natl Inst Oceanog, POB 8030, IL-31080 Haifa, Israel. EM bruriaf@gmail.com RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X FU United States-Israel Binational Agricultural Research and Development- (BARD) [IS-3703-05] FX We wish to thank the staff at The National Center of Mariculture, Eilat, The Salt Company, Atlit, Kibbutz Ma'agan Michael and Mevo'ot-Yam School, Michmoret for fish samples. We are also grateful to A. Dyman for technical assistance in carrying out the growth hormone experiments and E. Re'em for his help with the Statistical Analysis. This project was conceived and initiated while Dr. Funkenstein was on sabbatical leave from the Israel Oceanographic and Limnological Research, Haifa, Israel from Feb 1994 to Jan 1995 and working in Dr. S. Jakowlew's laboratory at the National Cancer Institute; we wish to thank Drs. T. Moody and J. Mulshine for their support of this project during Dr. Funkenstein's stay at NCI, Rockville. This work was supported in part by a grant from the United States-Israel Binational Agricultural Research and Development- (BARD, Project No. IS-3703-05). Lastly, the constructive comments from three anonymous reviewers, leading to a much improved manuscript, are greatly appreciated. NR 77 TC 14 Z9 18 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2199 J9 BMC MOL BIOL JI BMC Mol. Biol. PD MAY 12 PY 2010 VL 11 AR 37 DI 10.1186/1471-2199-11-37 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 625XV UT WOS:000279931000001 PM 20459854 ER PT J AU Makhnovskii, YA Berezhkovskii, AM Zitserman, VY AF Makhnovskii, Yu. A. Berezhkovskii, A. M. Zitserman, V. Yu. TI Diffusion in a tube of alternating diameter SO CHEMICAL PHYSICS LA English DT Article DE Diffusion in confined media; Entropic transport; Boundary homogenization ID CROSS-SECTION; BOUNDARY HOMOGENIZATION; VENTRICULAR MYOCARDIUM; RELEASE; PORE; MEDIA; WATER AB The paper deals with diffusion of a particle in a tube that consists of alternating wide and narrow sections. At sufficiently long times the particle motion can be coarse-grained and described as effective free-diffusion along the tube axis. In the coarse-grained description all the details of the tube geometry are packed into the effective diffusion coefficient of the particle. We derive a formula for the effective diffusion coefficient, which shows how it depends on the geometric parameters of the tube. To test the accuracy of this formula we compare its predictions with the values of the effective diffusion coefficient found in Brownian dynamics simulations. The comparison shows that the formula is applicable at arbitrary values of the length and radius of the narrow sections on condition that the radius of the wide sections does not exceed their length. (C) 2010 Elsevier B. V. All rights reserved. C1 [Makhnovskii, Yu. A.] Russian Acad Sci, Topchiev Inst Petrochem Synth, Moscow 117912, Russia. [Berezhkovskii, A. M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Zitserman, V. Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. RP Makhnovskii, YA (reprint author), Russian Acad Sci, Topchiev Inst Petrochem Synth, Leninskii Pr 29, Moscow 117912, Russia. EM yuam@ips.ac.ru RI Makhnovskii, Yurii/B-1223-2014 OI Makhnovskii, Yurii/0000-0002-1517-536X FU NIH, Center for Information Technology FX A.M.B. was supported by the Intramural Research Program of the NIH, Center for Information Technology. NR 36 TC 5 Z9 5 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0104 J9 CHEM PHYS JI Chem. Phys. PD MAY 12 PY 2010 VL 370 IS 1-3 BP 238 EP 243 DI 10.1016/j.chemphys.2010.04.012 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 593OR UT WOS:000277468900032 ER PT J AU Berezhkovskii, AM AF Berezhkovskii, A. M. TI Variance of residence time spent by diffusing particle in a sub-domain: Path integral based approach SO CHEMICAL PHYSICS LA English DT Article DE Diffusion; Residence time; Fluctuations ID FLUORESCENCE AB Path integral based approach is used to analyze the variance of the residence time spent in a sub-domain by a particle diffusing in the presence of an arbitrary potential in a larger domain containing the subdomain. It is assumed that there is no absorption of the particle within the domain or at its boundaries. Because of the ergodisity, the mean residence time in the sub-domain is a product of the observation time and the equilibrium probability of finding the particle in the sub-domain. We show that the variance also grows linearly with the observation time at large times and explain how the slope of this linear dependence can be found. The general approach is illustrated by simple examples, in which explicit formulas for the variance can be obtained. Published by Elsevier B.V. C1 NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM berezh@mail.nih.gov FU NIH, Center for Information Technology FX The author is greatly obliged to his colleagues at NIH, Sergey Bezrukov, Irina Gopich, Attila Szabo, and George Weiss, as well as his colleagues in Israel, Mexico and Russia, Noam Agmon, Leonardo Dagdug, Yurii Makhnovskii, and Vladimir Zitserman, for very useful and illuminating discussions of different aspects of the residence time distribution and related problems. This study was supported by the Intramural Research Program of the NIH, Center for Information Technology. NR 18 TC 9 Z9 9 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0104 J9 CHEM PHYS JI Chem. Phys. PD MAY 12 PY 2010 VL 370 IS 1-3 BP 253 EP 257 DI 10.1016/j.chemphys.2009.10.020 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 593OR UT WOS:000277468900034 PM 20532189 ER PT J AU Maison, SF Liu, XP Vetter, DE Eatock, RA Nathanson, NM Wess, J Liberman, MC AF Maison, Stephane F. Liu, Xiao-Ping Vetter, Douglas E. Eatock, Ruth Anne Nathanson, Neil M. Wess, Juergen Liberman, M. Charles TI Muscarinic Signaling in the Cochlea: Presynaptic and Postsynaptic Effects on Efferent Feedback and Afferent Excitability SO JOURNAL OF NEUROSCIENCE LA English DT Article ID OUTER HAIR-CELLS; RECEPTOR KNOCKOUT MICE; NICOTINIC CHOLINERGIC-RECEPTOR; GUINEA-PIG COCHLEA; CROSSED-OLIVOCOCHLEAR-BUNDLE; SPIRAL GANGLION NEURONS; ACETYLCHOLINE-RECEPTOR; MAMMALIAN COCHLEA; RAT COCHLEA; ACOUSTIC INJURY AB Acetylcholine is the major neurotransmitter of the olivocochlear efferent system, which provides feedback to cochlear hair cells and sensory neurons. To study the role of cochlear muscarinic receptors, we studied receptor localization with immunohistochemistry and reverse transcription-PCR and measured olivocochlear function, cochlear responses, and histopathology in mice with targeted deletion of each of the five receptor subtypes. M(2), M(4), and M(5) were detected in microdissected immature (postnatal days 10-13) inner hair cells and spiral ganglion cells but not outer hair cells. In the adult (6 weeks), the same transcripts were found in microdissected organ of Corti and spiral ganglion samples. M(2) protein was found, by immunohistochemistry, in olivocochlear fibers in both outer and inner hair cell areas. M(3) mRNA was amplified only from whole cochleas, and M(1) message was never seen in wild-type ears. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were unaffected by loss of G(q)-coupled receptors (M(1), M(3), or M(5)), as were shock-evoked olivocochlear effects and vulnerability to acoustic injury. In contrast, loss of G(i)-coupled receptors (M(2) and/or M(4)) decreased neural responses without affecting DPOAEs (at low frequencies). This phenotype and the expression pattern are consistent with excitatory muscarinic signaling in cochlear sensory neurons. At high frequencies, both ABRs and DPOAEs were attenuated by loss of M(2) and/or M(4), and the vulnerability to acoustic injury was dramatically decreased. This aspect of the phenotype and the expression pattern are consistent with a presynaptic role for muscarinic autoreceptors in decreasing ACh release from olivocochlear terminals during high-level acoustic stimulation and suggest that muscarinic antagonists could enhance the resistance of the inner ear to noise-induced hearing loss. C1 [Maison, Stephane F.; Liu, Xiao-Ping; Eatock, Ruth Anne; Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Maison, Stephane F.; Eatock, Ruth Anne; Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Maison, Stephane F.; Liu, Xiao-Ping; Eatock, Ruth Anne; Liberman, M. Charles] Harvard Massachusetts Inst Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Vetter, Douglas E.] Tufts Univ, Sch Med, Dept Neurosci, Boston, MA 02111 USA. [Nathanson, Neil M.] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Wess, Juergen] NIDDKD, Mol Signaling Sect, Bioorgan Chem Lab, US Dept HHS, Bethesda, MD 20892 USA. RP Maison, SF (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM stephane_maison@meei.harvard.edu RI Eatock, Ruth/F-6404-2013; OI Eatock, Ruth Anne/0000-0001-7547-2051 FU National Institutes of Health [RO1 DC0188, RO1 DC006258, RO1 DC02290, RO1 NS026920, P30 DC5029, P30 NS047243]; National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by National Institutes of Health Grants RO1 DC0188 (M. C. L.), RO1 DC006258 (D. E. V.), RO1 DC02290 (R. A. E.), RO1 NS026920 (N.M.N.), P30 DC5029 (M. C. L.), and P30 NS047243 (D. E. V.). J.W. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The skillful assistance of Leslie Dodds is gratefully acknowledged, as is the generous gift of the anti-CHT antibody from Dr. Randy Blakely of Vanderbilt University. NR 71 TC 11 Z9 11 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 12 PY 2010 VL 30 IS 19 BP 6751 EP 6762 DI 10.1523/JNEUROSCI.5080-09.2010 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 595ZS UT WOS:000277653600028 PM 20463237 ER PT J AU Subach, FV Patterson, GH Renz, M Lippincott-Schwartz, J Verkhusha, VV AF Subach, Fedor V. Patterson, George H. Renz, Malte Lippincott-Schwartz, Jennifer Verkhusha, Vladislav V. TI Bright Monomeric Photoactivatable Red Fluorescent Protein for Two-Color Super-Resolution sptPALM of Live Cells SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID LOCALIZATION MICROSCOPY; CRYSTAL-STRUCTURE; FRET MICROSCOPY; LIVING CELLS; CHROMOPHORE; COLOR; RESOLUTION; CORAL; GFP; ISOMERIZATION AB Rapidly emerging techniques of super-resolution single-molecule microscopy of living cells rely on the continued development of genetically encoded photoactivatable fluorescent proteins. On the basis of monomeric TagRFP, we have developed a photoactivatable TagRFP protein that is initially dark but becomes red fluorescent after violet light irradiation. Compared to other monomeric dark-to-red photoactivatable proteins including PAmCherry, PATagRFP has substantially higher molecular brightness, better pH stability, substantially less sensitivity to blue light, and better photostability in both ensemble and single-molecule modes. Spectroscopic analysis suggests that PATagRFP photoactivation is a two-step photochemical process involving sequential one-photon absorbance by two distinct chromophore forms. True monomeric behavior, absence of green fluorescence, and single-molecule performance in live cells make PATagRFP an excellent protein tag for two-color imaging techniques, including conventional diffraction-limited photoactivation microscopy, super-resolution photoactivated localization microscopy (PALM), and single particle tracking PALM (sptPALM) of living cells. Two-color sptPALM imaging was demonstrated using several PATagRFP tagged transmembrane proteins together with PAGFP-tagged clathrin light chain. Analysis of the resulting sptPALM images revealed that single-molecule transmembrane proteins, which are internalized into a cell via endocytosis, colocalize in space and time with plasma membrane domains enriched in clathrin light-chain molecules. C1 [Subach, Fedor V.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Dept Anat, Bronx, NY 10461 USA. [Subach, Fedor V.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Struct Biol & Gruss Lipper Biophoton Ctr, Bronx, NY 10461 USA. [Patterson, George H.] Natl Inst Biomed Imaging & Bioengn, Biophoton Sect, NIH, Bethesda, MD 20892 USA. [Renz, Malte; Lippincott-Schwartz, Jennifer] NICHHD, Sect Organelle Biol, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Verkhusha, VV (reprint author), Albert Einstein Coll Med, Dept Anat, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM vladislav.verkhusha@einstein.yu.edu RI Subach, Fedor/K-7080-2014 FU National Institutes of Health [GM073913] FX We thank Dmitry Chudakov (Institute of Bioorganic Chemistry, Russia) for the TagRFP gene, Alexander Sorkin (University of Colorado at Denver) for the EGFR gene, Jinghang Zhang (Albert Einstein College of Medicine) for assistance with flow cytometry, Harald Hess (Howard Hughes Medical Institute, Janelia Farm Research Campus) for PALM analysis assistance, Suliana Manley (Ecole Polytechnique Federale de Lausanne, Switzerland) for the sptPALM analysis code, and Daniel Blair and Eric Dufresne for sharing their Mat Lab particle tracking code (http://www.physics.georgetown.edu/matlab). This work was supported by the Grant GM073913 from the National Institutes of Health to V.V.V. NR 49 TC 111 Z9 114 U1 6 U2 53 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 MAY 12 PY 2010 VL 132 IS 18 BP 6481 EP 6491 DI 10.1021/ja100906g PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 593IB UT WOS:000277445400039 PM 20394363 ER PT J AU Shaukat, AM Breman, JG McKenzie, FE AF Shaukat, Ayesha M. Breman, Joel G. McKenzie, F. Ellis TI Using the entomological inoculation rate to assess the impact of vector control on malaria parasite transmission and elimination SO MALARIA JOURNAL LA English DT Article ID PLASMODIUM-FALCIPARUM; WESTERN KENYA; REDUCES MALARIA; TREATED NETS; AFRICA; CONSEQUENCES; PREVALENCE; MANAGEMENT; INFECTION; MOSQUITOS AB Background: Prior studies have shown that annual entomological inoculation rates (EIRs) must be reduced to less than one to substantially reduce the prevalence of malaria infection. In this study, EIR values were used to quantify the impact of insecticide-treated bed nets (ITNs), indoor residual spraying (IRS), and source reduction (SR) on malaria transmission. The analysis of EIR was extended through determining whether available vector control tools can ultimately eradicate malaria. Method: The analysis is based primarily on a review of all controlled studies that used ITN, IRS, and/or SR and reported their effects on the EIR. To compare EIRs between studies, the percent difference in EIR between the intervention and control groups was calculated. Results: Eight vector control intervention studies that measured EIR were found: four ITN studies, one IRS study, one SR study, and two studies with separate ITN and IRS intervention groups. In both the Tanzania study and the Solomon Islands study, one community received ITNs and one received IRS. In the second year of the Tanzania study, EIR was 90% lower in the ITN community and 93% lower in the IRS community, relative to the community without intervention; the ITN and IRS effects were not significantly different. In contrast, in the Solomon Islands study, EIR was 94% lower in the ITN community and 56% lower in the IRS community. The one SR study, in Dar es Salaam, reported a lower EIR reduction (47%) than the ITN and IRS studies. All of these vector control interventions reduced EIR, but none reduced it to zero. Conclusion: These studies indicate that current vector control methods alone cannot ultimately eradicate malaria because no intervention sustained an annual EIR less than one. While researchers develop new tools, integrated vector management may make the greatest impact on malaria transmission. There are many gaps in the entomological malaria literature and recommendations for future research are provided. C1 [Shaukat, Ayesha M.; Breman, Joel G.; McKenzie, F. Ellis] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Shaukat, AM (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM amsha2@bu.edu NR 31 TC 34 Z9 35 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD MAY 12 PY 2010 VL 9 AR 122 DI 10.1186/1475-2875-9-122 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 617DU UT WOS:000279261900001 PM 20459850 ER PT J AU Effantin, G Ishikawa, T De Donatis, GM Maurizi, MR Steven, AC AF Effantin, Gregory Ishikawa, Takashi De Donatis, Gian Marco Maurizi, Michael R. Steven, Alasdair C. TI Local and Global Mobility in the ClpA AAA plus Chaperone Detected by Cryo-Electron Microscopy: Functional Connotations SO STRUCTURE LA English DT Article ID ATP-DEPENDENT PROTEASES; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; SUBSTRATE-BINDING; MOLECULAR CHAPERONE; ELECTRON-MICROSCOPY; MUTATIONAL ANALYSIS; COMPLEX-FORMATION; HSP100 CHAPERONE; PROTEINS AB The ClpA chaperone combines with the CIpP peptidase to perform targeted proteolysis in the bacterial cytoplasm. ClpA monomer has an N-terminal substrate-binding domain and two AAA+ ATPase domains (D1 and D2). ClpA hexamers stack axially on CIpP heptamers to form the symmetry-mismatched protease. We used cryo-electron microscopy to visualize the ClpA-ATP gamma S hexamer, in the context of ClpAP complexes. Two segments lining the axial channel show anomalously low density, indicating that these motifs, which have been implicated in substrate translocation, are mobile. We infer that ATP hydrolysis is accompanied by substantial structural changes in the D2 but not the D1 tier. The entire N domain is rendered invisible by large-scale fluctuations. When deletions of 10 and 15 residues were introduced into the linker, N domain mobility was reduced but not eliminated and changes were observed in enzymatic activities. Based on these observations, we present a pseudo-atomic model of ClpAP holoenzyme, a dynamic proteolytic nanomachine. C1 [Effantin, Gregory; Ishikawa, Takashi; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Ishikawa, Takashi] Eidgenoss Tech Hsch Zurich, Dept Biol, CH-8093 Zurich, Switzerland. [De Donatis, Gian Marco; Maurizi, Michael R.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov RI Ishikawa, Takashi/E-5023-2017 OI Ishikawa, Takashi/0000-0002-1976-7477 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Cancer Institute at the National Institutes of Health FX We thank N. Cheng and D. Winkler for their help with electron microscopes and B. Heymann for his support in computational matters. This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Cancer Institute at the National Institutes of Health. NR 57 TC 19 Z9 20 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAY 12 PY 2010 VL 18 IS 5 BP 553 EP 562 DI 10.1016/j.str.2010.02.016 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 595XW UT WOS:000277648400003 PM 20462489 ER PT J AU Yoon, SI Jones, BC Logsdon, NJ Harris, BD Deshpande, A Radaeva, S Halloran, BA Gao, B Walter, MR AF Yoon, Sung-il Jones, Brandi C. Logsdon, Naomi J. Harris, Bethany D. Deshpande, Ashlesha Radaeva, Svetlana Halloran, Brian A. Gao, Bin Walter, Mark R. TI Structure and Mechanism of Receptor Sharing by the IL-10R2 Common Chain SO STRUCTURE LA English DT Article ID VERSUS-HOST-DISEASE; CRYSTAL-STRUCTURE; INTERLEUKIN-10 RECEPTOR; ERYTHROPOIETIN RECEPTOR; CELL TRANSPLANTATION; GENETIC-VARIATION; GROWTH-HORMONE; CUTTING EDGE; COMPLEX; BINDING AB IL-10R2 is a shared cell surface receptor required for the activation of five class 2 cytokines (IL-10, IL-22, IL-26, IL-28, and IL-29) that play critical roles in host defense. To define the molecular mechanisms that regulate its promiscuous binding, we have determined the crystal structure of the IL-10R2 ectodomain at 2.14 angstrom resolution. IL-10R2 residues required for binding were identified by alanine scanning and used to derive computational models of IL-10/IL-10R1/IL-10R2 and IL-22/IL-22R1/IL-10R2 ternary complexes. The models reveal a conserved binding epitope that is surrounded by two clefts that accommodate the structural and chemical diversity of the cytokines. These results provide a structural framework for interpreting IL-10R2 single nucleotide polymorphisms associated with human disease. C1 [Yoon, Sung-il; Jones, Brandi C.; Logsdon, Naomi J.; Deshpande, Ashlesha; Halloran, Brian A.; Walter, Mark R.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Harris, Bethany D.; Walter, Mark R.] Univ Alabama, Ctr Biophys Sci & Engn, Birmingham, AL 35294 USA. [Radaeva, Svetlana; Gao, Bin] NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Walter, MR (reprint author), Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. EM walter@uab.edu FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Institutes of Health [AI043700, AI043700-08S1] FX Use of the Advance Photon Source (SER-CAT, ID-22) was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract W-31-109-Eng-38. This work was funded by grants AI043700 and AI043700-08S1 from the National Institutes of Health. NR 59 TC 28 Z9 29 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAY 12 PY 2010 VL 18 IS 5 BP 638 EP 648 DI 10.1016/j.str.2010.02.009 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 595XW UT WOS:000277648400011 PM 20462497 ER PT J AU Kim, HC Greenland, P Rossouw, JE Manson, JE Cochrane, BB Lasser, NL Limacher, MC Lloyd-Jones, DM Margolis, KL Robinson, JG AF Kim, Hyeon Chang Greenland, Philip Rossouw, Jacques E. Manson, JoAnn E. Cochrane, Barbara B. Lasser, Norman L. Limacher, Marian C. Lloyd-Jones, Donald M. Margolis, Karen L. Robinson, Jennifer G. TI Multimarker Prediction of Coronary Heart Disease Risk The Women's Health Initiative SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary heart disease; prediction; biomarker ID C-REACTIVE PROTEIN; INCIDENT CARDIOVASCULAR EVENTS; RANDOMIZED CONTROLLED-TRIAL; ESTROGEN PLUS PROGESTIN; FIBRIN D-DIMER; ATHEROSCLEROSIS RISK; POSTMENOPAUSAL WOMEN; LEUKOCYTE COUNT; MYOCARDIAL-INFARCTION; INFLAMMATORY MARKERS AB Objectives The aim of this study was to investigate whether multiple biomarkers contribute to improved coronary heart disease (CHD) risk prediction in post-menopausal women compared with assessment using traditional risk factors (TRFs) only. Background The utility of newer biomarkers remains uncertain when added to predictive models using only TRFs for CHD risk assessment. Methods The Women's Health Initiative Hormone Trials enrolled 27,347 post-menopausal women ages 50 to 79 years. Associations of TRFs and 18 biomarkers were assessed in a nested case-control study including 321 patients with CHD and 743 controls. Four prediction equations for 5-year CHD risk were compared: 2 Framingham risk score covariate models; a TRF model including statin treatment, hormone treatment, and cardiovascular disease history as well as the Framingham risk score covariates; and an additional biomarker model that additionally included the 5 significantly associated markers of the 18 tested (interleukin-6, D-dimer, coagulation factor VIII, von Willebrand factor, and homocysteine). Results The TRF model showed an improved C-statistic (0.729 vs. 0.699, p = 0.001) and net reclassification improvement (6.42%) compared with the Framingham risk score model. The additional biomarker model showed additional improvement in the C-statistic (0.751 vs. 0.729, p = 0.001) and net reclassification improvement (6.45%) compared with the TRF model. Predicted CHD risks on a continuous scale showed high agreement between the TRF and additional biomarker models (Spearman's coefficient = 0.918). Among the 18 biomarkers measured, C-reactive protein level did not significantly improve CHD prediction either alone or in combination with other biomarkers. Conclusions Moderate improvement in CHD risk prediction was found when an 18-biomarker panel was added to predictive models using TRFs in post-menopausal women. (J Am Coll Cardiol 2010;55:2080-91) (C) 2010 by the American College of Cardiology Foundation C1 [Greenland, Philip] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Kim, Hyeon Chang] Yonsei Univ, Dept Prevent Med, Seoul 120749, South Korea. [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20892 USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Cochrane, Barbara B.] Univ Washington, Family & Child Nursing Dept, Seattle, WA 98195 USA. [Lasser, Norman L.] Univ Med & Dent New Jersey, New Jersey Med Sch, Prevent Cardiol Program, Newark, NJ 07103 USA. [Limacher, Marian C.] Univ Florida, Div Cardiovasc Med, Gainesville, FL USA. [Margolis, Karen L.] Hlth Partners Res Fdn, Minneapolis, MN USA. [Robinson, Jennifer G.] Univ Iowa, Dept Epidemiol & Med, Iowa City, IA USA. RP Greenland, P (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 750 N Lake Shore Dr,11th Floor, Chicago, IL 60611 USA. EM p-greenland@northwestern.edu RI Lloyd-Jones, Donald/C-5899-2009; OI Kim, Hyeon Chang/0000-0001-7867-1240 FU National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; Rose Stamler Fund for Young Investigators at Northwestern University; Abbott Laboratories; Aegerion Pharmaceuticals; AstraZeneca; Bristol-Myers Squibb; Daiichi Sankyo; GlaxoSmithKline; Hoffmann-La Roche; Merck; Merck/Schering-Plough FX From the *Department of Preventive Medicine, Northwestern University, Chicago, Illinois; dagger Department of Preventive Medicine, Yonsei University, Seoul, Korea; double dagger National Heart, Lung, and Blood Institute, Bethesda, Maryland; Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; parallel to Family and Child Nursing Department, University of Washington, Seattle, Washington; Preventive Cardiology Program, New Jersey Medical School, Newark, New Jersey; #Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida; **Health Partners Research Foundation, Minneapolis, Minnesota; and the dagger dagger Departments of Epidemiology and Medicine, University of Iowa, Iowa City, Iowa. The Women's Health Initiative is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The National Institutes of Health had input into the design and conduct of the study and in the review and approval of this article. Dr. Kim was partially supported by the Rose Stamler Fund for Young Investigators at Northwestern University. Dr. Robinson has received grants to institution from Abbott Laboratories, Aegerion Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Hoffmann-La Roche, Merck, and Merck/Schering-Plough; and is a consultant or advisory board member for AstraZeneca and Merck. NR 76 TC 67 Z9 69 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 11 PY 2010 VL 55 IS 19 BP 2080 EP 2091 DI 10.1016/j.jacc.2009.12.047 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 591LW UT WOS:000277303100008 PM 20447530 ER PT J AU Kalogeropoulos, A Georgiopoulou, V Psaty, BM Rodondi, N Smith, AL Harrison, DG Liu, YM Hoffmann, U Bauer, DC Newman, AB Kritchevsky, SB Harris, TB Butler, J AF Kalogeropoulos, Andreas Georgiopoulou, Vasiliki Psaty, Bruce M. Rodondi, Nicolas Smith, Andrew L. Harrison, David G. Liu, Yongmei Hoffmann, Udo Bauer, Douglas C. Newman, Anne B. Kritchevsky, Stephen B. Harris, Tamara B. Butler, Javed CA Hlth ABC Study Investigators TI Inflammatory Markers and Incident Heart Failure Risk in Older Adults The Health ABC (Health, Aging, and Body Composition) Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE elderly; heart failure; inflammation ID TUMOR-NECROSIS-FACTOR; C-REACTIVE PROTEIN; PATHOPHYSIOLOGICALLY RELEVANT CONCENTRATIONS; EXPERIMENTAL DIABETIC CARDIOMYOPATHY; LEFT-VENTRICULAR DYSFUNCTION; FACTOR-ALPHA; TNF-ALPHA; MYOCARDIAL-INFARCTION; MULTIPLE IMPUTATION; EJECTION FRACTION AB Objectives The purpose of this study was to evaluate the association between inflammation and heart failure (HF) risk in older adults. Background Inflammation is associated with HF risk factors and also directly affects myocardial function. Methods The association of baseline serum concentrations of interleukin (IL)-6, tumor necrosis factor-alpha, and C-reactive protein (CRP) with incident HF was assessed with Cox models among 2,610 older persons without prevalent HF enrolled in the Health ABC (Health, Aging, and Body Composition) study (age 73.6 +/- 2.9 years; 48.3% men; 59.6% white). Results During follow-up (median 9.4 years), HF developed in 311 (11.9%) participants. In models controlling for clinical characteristics, ankle-arm index, and incident coronary heart disease, doubling of IL-6, tumor necrosis factor-alpha, and CRP concentrations was associated with 29% (95% confidence interval: 13% to 47%; p < 0.001), 46% (95% confidence interval: 17% to 84%; p = 0.001), and 9% (95% confidence interval: -1% to 24%; p = 0.087) increase in HF risk, respectively. In models including all 3 markers, IL-6, and tumor necrosis factor-alpha, but not CRP, remained significant. These associations were similar across sex and race and persisted in models accounting for death as a competing event. Post-HF ejection fraction was available in 239 (76.8%) cases; inflammatory markers had stronger association with HF with preserved ejection fraction. Repeat IL-6 and CRP determinations at 1-year follow-up did not provide incremental information. Addition of IL-6 to the clinical Health ABC HF model improved model discrimination (C index from 0.717 to 0.734; p = 0.001) and fit (decreased Bayes information criterion by 17.8; p < 0.001). Conclusions Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification. (J Am Coll Cardiol 2010;55:2129-37) (C) 2010 by the American College of Cardiology Foundation C1 [Kalogeropoulos, Andreas; Georgiopoulou, Vasiliki; Smith, Andrew L.; Harrison, David G.; Butler, Javed] Emory Univ, Atlanta, GA 30322 USA. [Psaty, Bruce M.] Univ Washington, Seattle, WA 98195 USA. [Rodondi, Nicolas] Univ Lausanne, Lausanne, Switzerland. [Liu, Yongmei; Kritchevsky, Stephen B.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Bauer, Douglas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Newman, Anne B.] Univ Pittsburgh, Pittsburgh, PA USA. [Harris, Tamara B.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Butler, J (reprint author), Emory Univ Hosp, Div Cardiol, 1365 Clifton Rd NE,Suite AT 430, Atlanta, GA 30322 USA. EM javed.butler@emory.edu RI Newman, Anne/C-6408-2013; Kalogeropoulos, Andreas/A-9494-2009; OI Newman, Anne/0000-0002-0106-1150; Kalogeropoulos, Andreas/0000-0002-1284-429X; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institute of Aging, National Institutes of Health, Bethesda, Maryland [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; Emory University Heart and Vascular Board FX From the *Emory University, Atlanta, Georgia; dagger University of Washington, Seattle, Washington; double dagger University of Lausanne, Lausanne, Switzerland; Wake Forest University, Winston-Salem, North Carolina; parallel to Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; University of California San Francisco, San Francisco, California; #University of Pittsburgh, Pittsburgh, Pennsylvania; and the **Intramural Research Program, National Institute of Aging, National Institutes of Health, Bethesda, Maryland. This research was supported in part by the Intramural Research Program of the National Institute of Aging, National Institutes of Health, Bethesda, Maryland, and by grants N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. Support for this research was also partially funded through an Emory University Heart and Vascular Board grant titled "Novel Risk Markers and Prognosis Determination in Heart Failure." NR 55 TC 111 Z9 116 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 11 PY 2010 VL 55 IS 19 BP 2129 EP 2137 DI 10.1016/j.jacc.2009.12.045 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 591LW UT WOS:000277303100015 PM 20447537 ER PT J AU Ho, JE Levy, D AF Ho, Jennifer E. Levy, Daniel TI B-Type Natriuretic Peptide Testing in the General Population Are We Ready for Prime Time? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE natriuretic peptide; prognosis; heart failure; mortality; myocardial infarction ID HEART-FAILURE; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; MULTIPLE BIOMARKERS; MORTALITY; DEATH; DYSFUNCTION; PREDICTION; COMMUNITY; BRAIN C1 [Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. NHLBI, Ctr Populat Studies, Framingham, MA 01702 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM levyd@nhlbi.nih.gov OI Ho, Jennifer/0000-0002-7987-4768 FU Intramural NIH HHS [Z01 HL006001-02, Z01 HL006001-01, Z99 HL999999] NR 13 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 11 PY 2010 VL 55 IS 19 BP 2148 EP 2149 DI 10.1016/j.jacc.2010.01.030 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 591LW UT WOS:000277303100018 PM 20447540 ER PT J AU Tsang, KM Starost, MF Nesterova, M Boikos, SA Watkins, T Almeida, MQ Harran, M Li, A Collins, MT Cheadle, C Mertz, EL Leikin, S Kirschner, LS Robey, P Stratakis, CA AF Tsang, Kit Man Starost, Matthew F. Nesterova, Maria Boikos, Sosipatros A. Watkins, Tonya Almeida, Madson Q. Harran, Michelle Li, Andrew Collins, Michael T. Cheadle, Christopher Mertz, Edward L. Leikin, Sergey Kirschner, Lawrence S. Robey, Pamela Stratakis, Constantine A. TI Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE catalytic subunit; mesenchymal cells; regulatory subunit; tumor; sarcoma ID FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; MESENCHYMAL STEM-CELLS; SUBUNIT TYPE 1A; FIBROUS DYSPLASIA; CARNEY COMPLEX; IN-VIVO; REGULATORY SUBUNIT; GROWTH-PLATE; PROGENITOR CELLS; DOWN-REGULATION AB A population of stromal cells that retains osteogenic capacity in adult bone (adult bone stromal cells or aBSCs) exists and is under intense investigation. Mice heterozygous for a null allele of prkar1a (Prkar1a(+/-)), the primary receptor for cyclic adenosine monophosphate (cAMP) and regulator of protein kinase A (PKA) activity, developed bone lesions that were derived from cAMP-responsive osteogenic cells and resembled fibrous dysplasia (FD). Prkar1a(+/) mice were crossed with mice that were heterozygous for catalytic subunit Ca (Prkaca(+/-)), the main PKA activity-mediating molecule, to generate a mouse model with double heterozygosity for prkar1a and prkaca (Prkar1a(+/-) Prkaca(+/-)). Unexpectedly, Prkar1a(+/-) Prkaca(+/) mice developed a greater number of osseous lesions starting at 3 months of age that varied from the rare chondromas in the long bones and the ubiquitous osteochondrodysplasia of vertebral bodies to the occasional sarcoma in older animals. Cells from these lesions originated from an area proximal to the growth plate, expressed osteogenic cell markers, and showed higher PKA activity that was mostly type II (PKA-II) mediated by an alternate pattern of catalytic subunit expression. Gene expression profiling confirmed a preosteoblastic nature for these cells but also showed a signature that was indicative of mesenchymal-to-epithelial transition and increased Wnt signaling. These studies show that a specific subpopulation of aBSCs can be stimulated in adult bone by alternate PKA and catalytic subunit activity; abnormal proliferation of these cells leads to skeletal lesions that have similarities to human FD and bone tumors. C1 [Tsang, Kit Man; Nesterova, Maria; Boikos, Sosipatros A.; Almeida, Madson Q.; Harran, Michelle; Li, Andrew; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Inter Inst Training Program, NIH, Bethesda, MD 20892 USA. [Tsang, Kit Man] Chinese Univ Hong Kong, Sch Biomed Sci, Div Biochem Med, Hong Kong 00852, Hong Kong, Peoples R China. [Starost, Matthew F.] NIH, Off Res Serv, Div Vet Resources, Bethesda, MD 20892 USA. [Watkins, Tonya; Cheadle, Christopher] Johns Hopkins Univ, Sch Med, Div Clin Immunol & Allergy, Baltimore, MD 21224 USA. [Collins, Michael T.; Robey, Pamela] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Mertz, Edward L.; Leikin, Sergey] NICHHD, Sect Phys Biochem, Off Sci Director, NIH, Bethesda, MD 20892 USA. [Kirschner, Lawrence S.] Ohio State Univ, Dept Mol Virol Immunol & Mol Genet, Columbus, OH 43210 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. EM stratakc@cc1.nichd.nih.gov RI Robey, Pamela/H-1429-2011; Leikin, Sergey/A-5518-2008 OI Robey, Pamela/0000-0002-5316-5576; Leikin, Sergey/0000-0001-7095-0739 FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development [Z01-HD-000642-04] FX We thank Dr. J. Aidan Carney (Mayo Clinic, Rochester, MN) for examples of human tumors associated with CNC; Dr. Nicholas Patronas (Department of Diagnostic Radiology, National Institutes of Health Clinical Center) for sharing the clinical imaging of bone lesions from CNC patients; Dr. Kenn Holmbeck and Dr. Joanne Shi (National Institute of Dental and Craniofacial Research) for technical expertise in mu CT experiment; Drs. Jean-Charles Grivel (National Institute of Child Health and Human Development), Iusta Caminha (National Institute of Allergy and Infectious Diseases, Bethesda, MD), and Joao Bosco Oliveira (National Institute of Allergy and Infectious Diseases) for technical expertise in flow cytometry study; and Dr. Robert M. Kotin (National Heart, Lung, and Blood Institute, Bethesda, MD) for generously providing us with the Prkx antibody. This work was supported by National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Project Z01-HD-000642-04 (to C.A.S.). NR 51 TC 27 Z9 28 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 11 PY 2010 VL 107 IS 19 BP 8683 EP 8688 DI 10.1073/pnas.1003680107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 595DP UT WOS:000277591200036 PM 20421483 ER PT J AU Hodgkinson, CA Enoch, MA Srivastava, V Cummins-Oman, JS Ferrier, C Iarikova, P Sankararaman, S Yamini, G Yuan, QP Zhou, ZF Albaugh, B White, KV Shen, PH Goldman, D AF Hodgkinson, Colin A. Enoch, Mary-Anne Srivastava, Vibhuti Cummins-Oman, Justine S. Ferrier, Cherisse Iarikova, Polina Sankararaman, Sriram Yamini, Goli Yuan, Qiaoping Zhou, Zhifeng Albaugh, Bernard White, Kenneth V. Shen, Pei-Hong Goldman, David TI Genome-wide association identifies candidate genes that influence the human electroencephalogram SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE alcoholism; electroencephalogram; endophenotype; genetics; whole-genome association ID LINKAGE DISEQUILIBRIUM; ALCOHOL DEPENDENCE; EEG POWER; SCHIZOPHRENIA; DISORDERS; PHENOTYPE; FREQUENCY; PROTEIN; BETA; HERITABILITY AB Complex psychiatric disorders are resistant to whole-genome analysis due to genetic and etiological heterogeneity. Variation in resting electroencephalogram (EEG) is associated with common, complex psychiatric diseases including alcoholism, schizophrenia, and anxiety disorders, although not diagnostic for any of them. EEG traits for an individual are stable, variable between individuals, and moderately to highly heritable. Such intermediate phenotypes appear to be closer to underlying molecular processes than are clinical symptoms, and represent an alternative approach for the identification of genetic variation that underlies complex psychiatric disorders. We performed a whole-genome association study on alpha (alpha), beta (beta), and theta (theta) EEG power in a Native American cohort of 322 individuals to take advantage of the genetic and environmental homogeneity of this population isolate. We identified three genes (SGIP1, ST6GALNAC3, and UGDH) with nominal association to variability of theta or alpha power. SGIP1 was estimated to account for 8.8% of variance in theta power, and this association was replicated in US Caucasians, where it accounted for 3.5% of the variance. Bayesian analysis of prior probability of association based upon earlier linkage to chromosome 1 and enrichment for vesicle-related transport proteins indicates that the association of SGIP1 with theta power is genuine. We also found association of SGIP1 with alcoholism, an effect that may be mediated via the same brain mechanisms accessed by theta EEG, and which also provides validation of the use of EEG as an endophenotype for alcoholism. C1 [Hodgkinson, Colin A.; Enoch, Mary-Anne; Srivastava, Vibhuti; Cummins-Oman, Justine S.; Ferrier, Cherisse; Iarikova, Polina; Yamini, Goli; Yuan, Qiaoping; Zhou, Zhifeng; White, Kenneth V.; Shen, Pei-Hong; Goldman, David] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. [Sankararaman, Sriram] Univ Calif Berkeley, Dept Comp Sci, Berkeley, CA 94720 USA. [Albaugh, Bernard] Ctr Human Behav Studies, Weatherford, OK 73096 USA. RP Hodgkinson, CA (reprint author), NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. EM chodg@mail.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institute on Alcohol Abuse and Alcoholism FX We thank the study participants for their contributions, and Longina Akhtar and Elisa Moore for technical assistance. This study was funded by the intramural program of National Institute on Alcohol Abuse and Alcoholism. NR 49 TC 36 Z9 38 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 MAY 11 PY 2010 VL 107 IS 19 BP 8695 EP 8700 DI 10.1073/pnas.0908134107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 595DP UT WOS:000277591200038 PM 20421487 ER PT J AU Farci, P Diaz, G Chen, Z Govindarajan, S Tice, A Agulto, L Pittaluga, S Boon, D Yu, C Engle, RE Haas, M Simon, R Purcell, RH Zamboni, F AF Farci, Patrizia Diaz, Giacomo Chen, Zhaochun Govindarajan, Sugantha Tice, Ashley Agulto, Liane Pittaluga, Stefania Boon, Denali Yu, Claro Engle, Ronald E. Haas, Mark Simon, Richard Purcell, Robert H. Zamboni, Fausto TI B cell gene signature with massive intrahepatic production of antibodies to hepatitis B core antigen in hepatitis B virus-associated acute liver failure SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE fulminant hepatitis B; pathogenesis; gene expression profiling; B cell immunity; phage display Fab library ID FULMINANT VIRAL-HEPATITIS; NEGATIVE REGULATOR; T-CELLS; INFECTION; MEMBRANE; FAMILY; ACTIVATION; REJECTION; DISEASE; PROTEIN AB Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a dramatic clinical syndrome due to a sudden loss of hepatic cells leading to multiorgan failure. The mechanisms whereby HBV induces ALF are unknown. Here, we show that liver tissue collected at the time of liver transplantation in two patients with HBV-associated ALF is characterized by an overwhelming B cell response apparently centered in the liver with massive accumulation of plasma cells secreting IgG and IgM, accompanied by complement deposition. We demonstrate that the molecular target of these antibodies is the hepatitis B core antigen (HBcAg); that these antibodies display a restricted variable heavy chain (V-H) repertoire and lack somatic mutations; and that these two unrelated individuals with ALF use an identical predominant VH gene with unmutated variable domain (IGHV1-3) for both IgG and IgM anti-HBc antibodies, indicating that HBcAg is the target of a germline human VH gene. These data suggest that humoral immunity may exert a primary role in the pathogenesis of HBV-associated ALF. C1 [Farci, Patrizia; Chen, Zhaochun; Tice, Ashley; Agulto, Liane; Boon, Denali; Yu, Claro; Engle, Ronald E.; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Diaz, Giacomo] Univ Cagliari, Dept Biomed Sci & Technol, I-09123 Cagliari, Italy. [Govindarajan, Sugantha] Univ So Calif, Rancho Los Amigos Hosp, Dept Pathol, Downey, CA 90242 USA. [Pittaluga, Stefania] NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Haas, Mark] Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90048 USA. [Simon, Richard] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Zamboni, Fausto] Brotzu Hosp, Liver Transplantat Ctr, I-09134 Cagliari, Italy. RP Farci, P (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM pfarci@niaid.nih.gov; rpurcell@niaid.nih.gov FU National Institutes of Health; National Institute of Allergy and Infectious Diseases FX We thank P. Lusso, F. Marincola, and R. Dalla-Favera for their valuable comments; H.J. Alter for critically reviewing the manuscript; S. Dedola for taking care of the patients; V. Congias, M. Cuccuru, R. Strazzera, S. Farci, D. Cao, and R. Scioscia for their technical help; and K. Prims for editorial assistance. W. H. Gerlich generously supplied prototype monoclonal antibodies against pre-S1 and pre-S2. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 34 TC 50 Z9 52 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 11 PY 2010 VL 107 IS 19 BP 8766 EP 8771 DI 10.1073/pnas.1003854107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 595DP UT WOS:000277591200050 PM 20421498 ER PT J AU Brown, AP Chung, EJ Urick, ME Shield, WP Sowers, AL Thetford, A Shankavaram, UT Mitchell, JB Citrin, DE AF Brown, Aaron P. Chung, Eun Joo Urick, Mary Ellen Shield, William P., III Sowers, Anastasia L. Thetford, Angela Shankavaram, Uma T. Mitchell, James B. Citrin, Deborah E. TI Evaluation of the fullerene compound DF-1 as a radiation protector SO RADIATION ONCOLOGY LA English DT Article ID RADIOPROTECTIVE AGENTS; CARBON NANOTUBES; DAMAGE; ANTIOXIDANT; INHIBITION; AMIFOSTINE; EFFICACY; BIOLOGY; TEMPOL; ALPHA AB Background: Fullerene compounds are known to possess antioxidant properties, a common property of chemical radioprotectors. DF-1 is a dendrofullerene nanoparticle with antioxidant properties previously found to be radioprotective in a zebrafish model. The purpose of this study was to evaluate the radioprotective effects of DF-1 in a murine model of lethal total body irradiation and to assess for selective radioprotection of normal cells versus tumor cells. Methods: In vitro radioresponse was evaluated with clonogenic assays with human tumor cells and fibroblast lines in the presence of varying concentrations of DF-1 or vehicle. DNA double strand break induction and repair was evaluated with immunocytochemistry for gamma H2AX. Lethal total body irradiation was delivered with 137Cs after intraperitoneal delivery of DF-1 or vehicle control. Bone marrow hypoxia was evaluated with piminidazole uptake assessed by flow cytometry. Results: DF-1 provided modest radioprotection of human cancer cell lines and fibroblast cell lines when delivered prior to irradiation (dose modifying factor or 1.1). There was no evidence of selective protection of fibroblasts versus tumor cells. Cells treated with DF-1 at radioprotective doses were found to have fewer gamma H2AX foci at 1 and 6 hours after irradiation compared to vehicle treated controls. The LD50/30 for C57Bl6/Ncr mice treated with a single 300 mg/kg dose of DF-1 pre-irradiation was 10.09 Gy (95% CI 9.58-10.26) versus 8.29 Gy (95% CI, 8.21-8.32) for control mice. No protective effects were seen with a single 200 mg/kg dose. No increase in pimonidazole uptake was appreciated in bone marrow of mice treated with DF-1 compared to vehicle controls. Conclusions: DF-1 has modest activity as a radiation protector in vivo. There was no evidence of selective protection from irradiation of normal versus tumor cells with DF-1. C1 [Brown, Aaron P.] NIH, Off Director, Bethesda, MD 20892 USA. [Sowers, Anastasia L.; Thetford, Angela; Mitchell, James B.] NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Citrin, DE (reprint author), NCI, Radiat Oncol Branch, Bldg 10,CRC B2-3500, Bethesda, MD 20892 USA. EM citrind@mail.nih.gov FU NIH, NCI, Office of the Director; NIH Clinical Center; NIH; Pfizer Inc FX This research was supported by the Intramural Research Program of the NIH, NCI, Office of the Director and the NIH Clinical Center.; Aaron Brown's research year was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc (via a grant to the Foundation for NIH from Pfizer Inc). NR 39 TC 13 Z9 15 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD MAY 11 PY 2010 VL 5 AR 34 DI 10.1186/1748-717X-5-34 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 605DF UT WOS:000278327000002 PM 20459795 ER PT J AU Cao, C Huang, XS Han, YY Wan, YS Birnbaumer, L Feng, GS Marshall, J Jiang, MS Chu, WM AF Cao, Cong Huang, Xuesong Han, Yuyuan Wan, Yinsheng Birnbaumer, Lutz Feng, Geng-Sheng Marshall, John Jiang, Meisheng Chu, Wen-Ming TI G alpha(i1) and G alpha(i3) Are Required for Epidermal Growth Factor-Mediated Activation of the Akt-mTORC1 Pathway (vol 266, pg 249, 2008) SO SCIENCE SIGNALING LA English DT Correction ID FOXO TRANSCRIPTION FACTORS; HETEROTRIMERIC G-PROTEINS; PERTUSSIS-TOXIN; FACTOR RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE HYDROLYSIS; SIGNALING PATHWAYS; KINASE ACTIVATION; TYROSINE KINASE; RAT HEPATOCYTES AB The precise mechanism whereby epidermal growth factor (EGF) activates the serine-threonine kinase Akt and the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) remains elusive. Here, we report that the alpha subunits of the heterotrimeric guanine nucleotide-binding proteins (G proteins) G alpha(i1) and G alpha(i3) are critical for this activation process. Both G alpha(i1) and G alpha(i3) formed complexes with growth factor receptor binding 2 (Grb2)-associated binding protein 1 (Gab1) and the EGF receptor (EGFR) and were required for the phosphorylation of Gab1 and its subsequent interaction with the p85 subunit of phosphatidylinositol 3-kinase in response to EGF. Loss of G alpha(i1) and G alpha(i3) severely impaired the activation of Akt and of p70 S6 kinase and 4E-BP1, downstream targets of mTORC1, in response to EGF, heparin-binding EGF-like growth factor, and transforming growth factor alpha, but not insulin, insulin-like growth factor, or platelet-derived growth factor. In addition, ablation of G alpha(i1) and G alpha(i3) largely inhibited EGF-induced cell growth, migration, and survival, and the accumulation of cyclin D1. Overall, this study suggests that G alpha(i1) and G alpha(i3) lie downstream of EGFR, but upstream of Gab1-mediated activation of Akt and mTORC1, thus revealing a role for G(alpha i) proteins in mediating EGFR signaling. C1 [Cao, Cong; Huang, Xuesong; Han, Yuyuan; Chu, Wen-Ming] Brown Univ, Dept Mol Microbiol & Immunol, Providence, RI 02912 USA. [Cao, Cong; Chu, Wen-Ming] Brown Univ, Pathobiol Grad Program, Providence, RI 02912 USA. [Wan, Yinsheng] Providence Coll, Dept Biol, Providence, RI 02918 USA. [Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Neurobiol Lab, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Feng, Geng-Sheng] Burnham Inst Med Res, La Jolla, CA 92037 USA. [Marshall, John] Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Providence, RI 02912 USA. [Jiang, Meisheng] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Chu, WM (reprint author), Brown Univ, Dept Mol Microbiol & Immunol, Providence, RI 02912 USA. EM wen-ming_chu@brown.edu NR 1 TC 0 Z9 0 U1 0 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAY 11 PY 2010 VL 3 IS 121 AR er2 DI 10.1126/scisignal.3121er2 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 594UQ UT WOS:000277564900005 ER PT J AU Arslan, AA Helzlsouer, KJ Kooperberg, C Shu, XO Steplowski, E Bueno-de-Mesquita, HB Fuchs, CS Gross, MD Jacobs, EJ LaCroix, AZ Petersen, GM Stolzenberg-Solomon, RZ Zheng, W Albanes, D Amundadottir, L Bamlet, WR Barricarte, A Bingham, SA Boeing, H Boutron-Ruault, MC Buring, JE Chanock, SJ Clipp, S Gaziano, JM Giovannucci, EL Hankinson, SE Hartge, P Hoover, RN Hunter, DJ Hutchinson, A Jacobs, KB Kraft, P Lynch, SM Manjer, J Manson, JE McTiernan, A McWilliams, RR Mendelsohn, JB Michaud, DS Palli, D Rohan, TE Slimani, N Thomas, G Tjonneland, A Tobias, GS Trichopoulos, D Virtamo, J Wolpin, BM Yu, K Zeleniuch-Jacquotte, A Patel, AV AF Arslan, Alan A. Helzlsouer, Kathy J. Kooperberg, Charles Shu, Xiao-Ou Steplowski, Emily Bueno-de-Mesquita, H. Bas Fuchs, Charles S. Gross, Myron D. Jacobs, Eric J. LaCroix, Andrea Z. Petersen, Gloria M. Stolzenberg-Solomon, Rachael Z. Zheng, Wei Albanes, Demetrius Amundadottir, Laufey Bamlet, William R. Barricarte, Aurelio Bingham, Sheila A. Boeing, Heiner Boutron-Ruault, Marie-Christine Buring, Julie E. Chanock, Stephen J. Clipp, Sandra Gaziano, J. Michael Giovannucci, Edward L. Hankinson, Susan E. Hartge, Patricia Hoover, Robert N. Hunter, David J. Hutchinson, Amy Jacobs, Kevin B. Kraft, Peter Lynch, Shannon M. Manjer, Jonas Manson, JoAnn E. McTiernan, Anne McWilliams, Robert R. Mendelsohn, Julie B. Michaud, Dominique S. Palli, Domenico Rohan, Thomas E. Slimani, Nadia Thomas, Gilles Tjonneland, Anne Tobias, Geoffrey S. Trichopoulos, Ditnitrios Virtamo, Jarmo Wolpin, Brian M. Yu, Kai Zeleniuch-Jacquotte, Anne Patel, Alpa V. TI Anthropometric Measures, Body Mass Index, and Pancreatic Cancer A Pooled Analysis From the Pancreatic Cancer Cohort Consortium (PanScan) SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID BASE-LINE CHARACTERISTICS; LIFE-STYLE FACTORS; PHYSICAL-ACTIVITY; NUTRITIONAL FACTORS; WOMENS HEALTH; RISK-FACTORS; OBESITY; INSULIN; MORTALITY; DESIGN AB Background: Obesity has been proposed as a risk factor for pancreatic cancer. Methods: Pooled data were analyzed from the National Cancer Institute Pancreatic Cancer Cohort Consortium (PanScan) to study the association, between prediagnostic anthropometric measures and risk of pancreatic cancer. PanScan applied a nested case-control study design and included 2170 cases and 2209 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression for cohort-specific quartiles of body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), weight, height, waist circumference, and waist to hip ratio as well as conventional BMI categories (underweight, <18.5; normal weight, 18.5-24.9; overweight, 25.0-29.9; obese, 30.0-34.9; and severely obese, >= 35.0). Models were adjusted for potential confounders. Results: In all of the participants, a positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs lowest BMI guartile, 1.33; 95% Cl, 1.12-1.58; P-trend<.001). In men, the adjusted OR for pancreatic cancer for the highest vs lowest quartile of BMI was 1.33 (95% Cl, 1.04-1.69; P-trend<.03), and in women it was 1.34 (95% Cl, 1.05-1.70; P-trend=.01). Increased waist to hip ratio was associated with increased risk of pancreatic cancer in women (adjusted OR for the highest vs lowest quartile, 1.87; 95% Cl, 1.31-2.69; P-trend=.003) but less so in men. Conclusions: These findings provide strong support for a positive association between BMI and pancreatic cancer risk. In addition, centralized fat distribution may increase pancreatic cancer risk, especially in women. Arch Intern Med. 2010;170(9):791 -802 C1 [Arslan, Alan A.] NYU, Dept Obstet & Gynecol, Sch Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Dept Environm Med, Sch Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Inst Canc, New York, NY 10016 USA. [Helzlsouer, Kathy J.] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Kooperberg, Charles; LaCroix, Andrea Z.; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Dept Med, Div Epidemiol, Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Steplowski, Emily] Informat Management Serv Inc, Silver Spring, MD USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.; Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Wolpin, Brian M.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Prevent Med, Phys Hlth Study, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Phys Hlth Study, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Cardiovasc Med, Phys Hlth Study, Boston, MA 02115 USA. [Manson, JoAnn E.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [Gross, Myron D.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Jacobs, Eric J.; Patel, Alpa V.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [Petersen, Gloria M.; Bamlet, William R.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [McWilliams, Robert R.] Mayo Clin, Dept Oncol, Coll Med, Rochester, MN USA. [Stolzenberg-Solomon, Rachael Z.; Albanes, Demetrius; Amundadottir, Laufey; Chanock, Stephen J.; Hartge, Patricia; Hoover, Robert N.; Hutchinson, Amy; Jacobs, Kevin B.; Mendelsohn, Julie B.; Thomas, Gilles; Tobias, Geoffrey S.; Yu, Kai] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Amundadottir, Laufey; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lynch, Shannon M.] NCI, Div Canc Control & Populat Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Barricarte, Aurelio] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Barricarte, Aurelio] Publ Hlth Inst Navarra, Pamplona, Spain. [Bingham, Sheila A.] Univ Cambridge, MRC Ctr Nutr & Canc, Cambridge, England. [Boeing, Heiner] German Inst Human Nutr, Potsdam, Nuthetal, Germany. [Boutron-Ruault, Marie-Christine] INSERM, Villejuif, France. [Boutron-Ruault, Marie-Christine] Inst Gustave Roussy, Villejuif, France. [Clipp, Sandra] George W Comstock Ctr Publ Hlth Res & Prevent, Hagerstown, MD USA. [Gaziano, J. Michael] Harvard Univ, Sch Publ Hlth, Massachusetts Vet Epidemiol Res & Informat Ctr, Vet Affairs Boston Healthcare Syst, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Kraft, Peter; Manson, JoAnn E.; Trichopoulos, Ditnitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Hutchinson, Amy; Jacobs, Kevin B.] NCI, Core Genotyping Facil, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv LLC, Gaithersburg, MD USA. [Manjer, Jonas] Malmo Univ Hosp, Dept Surg, Malmo, Sweden. [Michaud, Dominique S.] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, London, England. [Palli, Domenico] Canc Res & Prevent Inst, Mol & Nutr Epidemiol Unit, Florence, Italy. [Rohan, Thomas E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Slimani, Nadia] Int Agcy Res Canc, F-69372 Lyon, France. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulos, Ditnitrios] Univ Athens, Sch Med, Dept Hyg & Epidemiol, Athens, Greece. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Arslan, AA (reprint author), NYU, Dept Obstet & Gynecol, Sch Med, 550 1st Ave,TH 528, New York, NY 10016 USA. EM alan.arslan@nyumc.org RI Boutron Ruault, Marie-Christine/G-3705-2013; Boutron, Marie-Christine/K-8168-2013; Michaud, Dominique/I-5231-2014; Albanes, Demetrius/B-9749-2015; Boutron-Ruault, Marie-Christine/H-3936-2014; Amundadottir, Laufey/L-7656-2016; Tobias, Geoffrey/M-4135-2016; OI Amundadottir, Laufey/0000-0003-1859-8971; Tobias, Geoffrey/0000-0002-2878-8253; PALLI, Domenico/0000-0002-5558-2437 FU NCI, National Institutes of Health [HHSN261200800001E]; ATBC [N01-CN-45165, N01-RC-45035]; Intramural Research Program of the NCI [N01-RC37004]; US Public Health Service; National Institute on Aging [5U01AG018033]; NCI [CA105069, CA73790]; Associazione Italiana per la Ricerca sul Cancro FX This project was funded in whole or in part by contract HHSN261200800001E from the NCI, National Institutes of Health. The ATBC was supported by contracts N01-CN-45165, N01-RC-45035, and N01-RC37004 from the Intramural Research Program of the NCI and the US Public Health Service. CLUE II was supported by grant 5U01AG018033 from the National Institute on Aging and by grants CA105069 and CA73790 from the NCI. The EPIC was supported by the European Commission: Public Health and Consumer Protection Directorate 1993-2004; Research Directorate-General 2005; Ligue contre le Cancer; Societe 3M; Mutuelle Generale de l'Education Nationale; Institut National de la Sante et de la Recherche Medicale (France); German Cancer Aid, German Cancer Research Center, Federal Ministry of Education and Research (Germany); Danish Cancer Society (Denmark); Health Research Fund of the Spanish Ministry of Health, participating regional governments and institutions (Spain); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, the Wellcome Trust (United Kingdom); Greek Ministry of Health and Social Solidarity, Hellenic Health Foundation and Stavros Niarchos Foundation (Greece); Italian Association for Research on Cancer (Italy); Dutch Ministry of Public Health, Welfare and Sports, Dutch Prevention Funds, LK Research Funds, Dutch ZON (Zorg Onderzoek Nederland) (the Netherlands); Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane and Vasterbotten (Sweden); and World Cancer Research Fund. The New York University Women's Health Study is supported by research grants R01CA034588, R01CA098661, and P3OCA016087 from the NCI and by grant ES000260 from the National Institute of Environmental Health Sciences. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial was supported by contracts from the NCI (University of Colorado: NOICN-25514; Georgetown University: NO I-CN-25522; Pacific Health Research Institute: NOI-CN-25515; Henry Ford Health System: NO1-CN-25512; University of Minnesota: NO I-CN-25513; Washington University: NO1-CN-25516; University of Pittsburgh: NO1-CN25511; University of Utah: NO1-CN-25524; Marshfield Clinic Research Foundation: NO1-CN-25518; University of Alabama at Birmingham: NO1-CN-75022; Westat Inc: NO1-CN-25476; and University of California, Los Angeles: NO1-CN-25404). The SMWHS were supported by extramural research grants RO1 CA82729 and RO1 CA70867 from the NCI and by the Intramural Research Program of the NCI (Division of Cancer Epidemiology and Genetics). The Women's Health Initiative is funded by contracts NO1WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 3211832119, 32122, 42107-26, 42129-32, and 44221 from the National Heart, Lung, and Blood Institute. NR 57 TC 117 Z9 122 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 EI 1538-3679 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAY 10 PY 2010 VL 170 IS 9 BP 791 EP 802 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 592EE UT WOS:000277357800009 PM 20458087 ER PT J AU Schindler, CW Panlilio, LV Gilman, JP Justinova, Z Vemuri, VK Makriyannis, A Goldberg, SR AF Schindler, Charles W. Panlilio, Leigh V. Gilman, Joanne P. Justinova, Zuzana Vemuri, V. Kiran Makriyannis, Alex Goldberg, Steven R. TI Effects of cannabinoid receptor antagonists on maintenance and reinstatement of methamphetamine self-administration in rhesus monkeys SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Cannabinoid; Receptor antagonist; Methamphetamine; Self-administration; Reinstatement; Rhesus monkey ID ENDOCANNABINOID SYSTEM; SQUIRREL-MONKEYS; COCAINE DEPENDENCE; SEEKING BEHAVIOR; DRUG-ABUSE; RELAPSE; RATS; BRAIN; INVOLVEMENT; MECHANISMS AB Cannabinoid receptor antagonists have shown some promise as treatments capable of reducing abuse and relapse to a number of abused drugs. In rodents, such effects have been observed with methamphetamine self-administration. However, the effects of cannabinoid receptor antagonists on methamphetamine self-administration and relapse have not been studied in primates. In the present study, rhesus monkeys were trained to respond on a three-component operant schedule. During the first 5-min component, fixed-ratio responses were reinforced by food, during the second 90- or 180-min component fixed-ratio responses were reinforced by iv. methamphetamine. The third component was identical to the first. There was a 5-min timeout between each component. The effects of the cannabinoid receptor antagonists AM 251 and rimonabant were tested at various doses against self-administration of 3 mu g/kg/injection methamphetamine, and 1 mg/kg AM 251 and 0.3 mg/kg rimonabant were tested against the methamphetamine dose-effect function. The 1 mg/kg dose of AM 251 was also tested for its ability to alter reinstatement of extinguished self-administration responding. The cannabinoid receptor antagonist AM 251 was found to reduce methamphetamine self-administration at doses that did not affect food-reinforced responding. The cannabinoid receptor antagonist rimonabant had similar, but less robust effects. AM 251 also prevented reinstatement of extinguished methamphetamine seeking that was induced by re-exposure to a combination of methamphetamine and methamphetamine-associated cues. These results indicate that cannabinoid receptor antagonists might have therapeutic effects for the treatment of methamphetamine dependence. (C) 2010 Published by Elsevier B.V. C1 [Schindler, Charles W.; Panlilio, Leigh V.; Gilman, Joanne P.; Justinova, Zuzana; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, DHHS,NIH,Intramural Res Program, Baltimore, MD 21224 USA. [Justinova, Zuzana] Univ Maryland, Sch Med, Dept Psychiat, MPRC, Baltimore, MD 21201 USA. [Vemuri, V. Kiran; Makriyannis, Alex] Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. RP Schindler, CW (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, DHHS,NIH,Intramural Res Program, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM cschindl@helix.nih.gov RI Justinova, Zuzana/A-9109-2011 OI Justinova, Zuzana/0000-0001-5793-7484 FU NIH, NIDA FX This research was supported by the Intramural Research Program of the NIH, NIDA. NR 27 TC 10 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAY 10 PY 2010 VL 633 IS 1-3 BP 44 EP 49 DI 10.1016/j.ejphar.2010.02.005 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 583TA UT WOS:000276701500007 PM 20153314 ER PT J AU Lam, ET Ringel, MD Kloos, RT Prior, TW Knopp, MV Liang, J Sammet, S Hall, NC Wakely, PE Vasko, VV Saji, M Snyder, PJ Wei, L Arbogast, D Collamore, M Wright, JJ Moley, JF Villalona-Calero, MA Shah, MH AF Lam, Elaine T. Ringel, Matthew D. Kloos, Richard T. Prior, Thomas W. Knopp, Michael V. Liang, Jiachao Sammet, Steffen Hall, Nathan C. Wakely, Paul E., Jr. Vasko, Vasyl V. Saji, Motoyasu Snyder, Pamela J. Wei, Lai Arbogast, Daria Collamore, Minden Wright, John J. Moley, Jeffrey F. Villalona-Calero, Miguel A. Shah, Manisha H. TI Phase II Clinical Trial of Sorafenib in Metastatic Medullary Thyroid Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RET PROTOONCOGENE MUTATIONS; SOLID TUMORS; CARCINOMA; ANGIOGENESIS; TARGETS; INHIBITION; EXPRESSION; PATHWAY; RECIST AB Purpose Mutations in the RET proto-oncogene and vascular endothelial growth factor receptor (VEGFR) activity are critical in the pathogenesis of medullary thyroid cancer (MTC). Sorafenib, a multikinase inhibitor targeting Ret and VEGFR, showed antitumor activity in preclinical studies of MTC. Patients and Methods In this phase II trial of sorafenib in patients with advanced MTC, the primary end point was objective response. Secondary end points included toxicity assessment and response correlation with tumor markers, functional imaging, and RET mutations. Using a two-stage design, 16 or 25 patients were to be enrolled onto arms A (hereditary) and B (sporadic). Patients received sorafenib 400 mg orally twice daily. Results Of 16 patients treated in arm B, one achieved partial response (PR; 6.3%; 95% CI, 0.2% to 30.2%), 14 had stable disease (SD; 87.5%; 95% CI, 61.7% to 99.5%), and one was nonevaluable. In a post hoc analysis of 10 arm B patients with progressive disease (PD) before study, one patient had PR of 21 + months, four patients had SD >= 15 months, four patients had SD <= 6 months, and one patient had clinical PD. Median progression-free survival was 17.9 months. Arm A was prematurely terminated because of slow accrual. Common adverse events (AEs) included diarrhea, hand-foot-skin reaction, rash, and hypertension. Although serious AEs were rare, one death was seen. Tumor markers decreased in the majority of patients, and RET mutations were detected in 10 of 12 sporadic MTCs analyzed. Conclusion Sorafenib is reasonably well tolerated, with suggestion of clinical benefit for patients with sporadic MTC. Caution should be taken because of the rare but fatal toxicity potentially associated with sorafenib. C1 Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. Ohio State Univ, Dept Mol Virol, Columbus, OH 43210 USA. Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. Ohio State Univ, Dept Radiol, Columbus, OH 43210 USA. Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. Washington Univ, Sch Med, St Louis, MO USA. NCI, Ctr Therapy & Evaluat Program, Rockville, MD USA. RP Shah, MH (reprint author), A438 Starling Loving Hall,320 W 10th Ave, Columbus, OH 43210 USA. EM manisha.shah@osumc.edu RI Saji, Motoyasu/E-4007-2011; Sammet, Steffen/E-4009-2011 OI Sammet, Steffen/0000-0001-6564-9132 FU National Cancer Institute (NCI) [N01-CM-62207]; NCI/SAIC-Frederick; Diagnostic Hybrids; Exelixis; Daichi Sankyo; Eisai; Bayer HealthCare; Onyx Pharmaceuticals; AstraZeneca FX Supported by Grant No. N01-CM-62207 from the National Cancer Institute (NCI) and by Translational Research Initiative Funds through NCI/SAIC-Frederick.; Research Funding: Matthew D. Ringel, Diagnostic Hybrids, Exelixis, Daichi Sankyo, Eisai; Richard T. Kloos, Bayer HealthCare, Onyx Pharmaceuticals, Exelixis, Eisai; Jeffrey F. Moley, Exelixis, AstraZeneca; Miguel A. Villalona-Calero, Onyx Pharmaceuticals; Manisha H. Shah, Exelixis, Eisai NR 30 TC 193 Z9 195 U1 0 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 10 PY 2010 VL 28 IS 14 BP 2323 EP 2330 DI 10.1200/JCO.2009.25.0068 PG 8 WC Oncology SC Oncology GA 592OT UT WOS:000277389600003 PM 20368568 ER PT J AU Schonfeld, SJ Pee, D Greenlee, RT Hartge, P Lacey, JV Park, Y Schatzkin, A Visvanathan, K Pfeiffer, RM AF Schonfeld, Sara J. Pee, David Greenlee, Robert T. Hartge, Patricia Lacey, James V., Jr. Park, Yikyung Schatzkin, Arthur Visvanathan, Kala Pfeiffer, Ruth M. TI Effect of Changing Breast Cancer Incidence Rates on the Calibration of the Gail Model SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RECEPTOR STATUS; UNITED-STATES; RISK; TAMOXIFEN; WOMEN; VALIDATION; CHEMOPREVENTION; RALOXIFENE; ESTROGEN; THERAPY AB Purpose The Gail model combines relative risks (RRs) for five breast cancer risk factors with age-specific breast cancer incidence rates and competing mortality rates from the Surveillance, Epidemiology, and End Results (SEER) program from 1983 to 1987 to predict risk of invasive breast cancer over a given time period. Motivated by changes in breast cancer incidence during the 1990s, we evaluated the model's calibration in two recent cohorts. Methods We included white, postmenopausal women from the National Institutes of Health (NIH) -AARP Diet and Health Study (NIH-AARP, 1995 to 2003), and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO, 1993 to 2006). Calibration was assessed by comparing the number of breast cancers expected from the Gail model with that observed. We then evaluated calibration by using an updated model that combined Gail model RRs with 1995 to 2003 SEER invasive breast cancer incidence rates. Results Overall, the Gail model significantly underpredicted the number of invasive breast cancers in NIH-AARP, with an expected-to-observed ratio of 0.87 (95% CI, 0.85 to 0.89), and in PLCO, with an expected-to-observed ratio of 0.86 (95% CI, 0.82 to 0.90). The updated model was well-calibrated overall, with an expected-to-observed ratio of 1.03 (95% CI, 1.00 to 1.05) in NIH-AARP and an expected-to-observed ratio of 1.01 (95% CI: 0.97 to 1.06) in PLCO. Of women age 50 to 55 years at baseline, 13% to 14% had a projected Gail model 5-year risk lower than the recommended threshold of 1.66% for use of tamoxifen or raloxifene but >= 1.66% when using the updated model. The Gail model was well calibrated in PLCO when the prediction period was restricted to 2003 to 2006. Conclusion This study highlights that model calibration is important to ensure the usefulness of risk prediction models for clinical decision making. C1 [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD USA. Informat Management Syst, Rockville, MD USA. Marshfield Clin Res Fdn, Epidemiol Res Ctr, Marshfield, WI USA. RP Pfeiffer, RM (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM pfeiffer@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; OI Park, Yikyung/0000-0002-6281-489X FU National Institutes of Health; National Cancer Institute FX Supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. NR 21 TC 22 Z9 22 U1 0 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 10 PY 2010 VL 28 IS 14 BP 2411 EP 2417 DI 10.1200/JCO.2009.25.2767 PG 7 WC Oncology SC Oncology GA 592OT UT WOS:000277389600014 PM 20368565 ER PT J AU Santos, MA Huen, MSY Jankovic, M Chen, HT Lopez-Contreras, AJ Klein, IA Wong, N Barbancho, JLR Fernandez-Capetillo, O Nussenzweig, MC Chen, JJ Nussenzweig, A AF Santos, Margarida Almeida Huen, Michael S. Y. Jankovic, Mila Chen, Hua-Tang Lopez-Contreras, Andres J. Klein, Isaac A. Wong, Nancy Barbancho, Juan L. R. Fernandez-Capetillo, Oscar Nussenzweig, Michel C. Chen, Junjie Nussenzweig, Andre TI Class switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; GENOMIC INSTABILITY; HISTONE H2AX; REGION RECOMBINATION; CHROMOSOME BREAKS; REPAIR PROTEINS; IN-VIVO; SITES; 53BP1 AB 53BP1 is a well-known mediator of the cellular response to DNA damage. Two alternative mechanisms have been proposed to explain 53BP1's interaction with DNA double-strand breaks (DSBs), one by binding to methylated histones and the other via an RNF8 E3 ligase-dependent ubiquitylation pathway. The formation of RNF8 and 53BP1 irradiation-induced foci are both dependent on histone H2AX. To evaluate the contribution of the RNF8-dependent pathway to 53BP1 function, we generated RNF8 knockout mice. We report that RNF8 deficiency results in defective class switch recombination (CSR) and accumulation of unresolved immunoglobulin heavy chain-associated DSBs. The CSR DSB repair defect is milder than that observed in the absence of 53BP1 but similar to that found in H2AX(-/-) mice. Moreover, similar to H2AX but different from 53BP1 deficiency, RNF8(-/-) males are sterile, and this is associated with defective ubiquitylation of the XY chromatin. Combined loss of H2AX and RNF8 does not cause further impairment in CSR, demonstrating that the two genes function epistatically. Importantly, although 53BP1 foci formation is RNF8 dependent, its binding to chromatin is preserved in the absence of RNF8. This suggests a two-step mechanism for 53BP1 association with chromatin in which constitutive loading is dependent on interactions with methylated histones, whereas DNA damage-inducible RNF8-dependent ubiquitylation allows its accumulation at damaged chromatin. C1 [Santos, Margarida Almeida; Chen, Hua-Tang; Wong, Nancy; Nussenzweig, Andre] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Huen, Michael S. Y.] Univ Hong Kong, Dept Anat, Pokfulam, Hong Kong, Peoples R China. [Huen, Michael S. Y.] Univ Hong Kong, Ctr Canc Res, Pokfulam, Hong Kong, Peoples R China. [Jankovic, Mila; Klein, Isaac A.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Jankovic, Mila; Klein, Isaac A.; Nussenzweig, Michel C.] Howard Hughes Med Inst, New York, NY 10065 USA. [Lopez-Contreras, Andres J.; Barbancho, Juan L. R.; Fernandez-Capetillo, Oscar] Spanish Natl Canc Res Ctr, Genom Instabil Grp, Madrid 28029, Spain. [Chen, Junjie] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA. RP Nussenzweig, A (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov RI Huen, Michael/E-9862-2010; Fernandez-Capetillo, Oscar/H-3508-2015; OI Fernandez-Capetillo, Oscar/0000-0002-2690-6885; Lopez-Contreras, Andres Joaquin/0000-0002-5517-7327 FU Medical Scientist Training Program [GM07739]; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX I.A. Klein was supported by Medical Scientist Training Program grant GM07739 and is a predoctoral fellow of the Cancer Research Institute. This work was supported by the Intramural Research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 32 TC 55 Z9 57 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 10 PY 2010 VL 207 IS 5 BP 973 EP 981 DI 10.1084/jem.20092308 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 593KB UT WOS:000277452100010 PM 20385748 ER PT J AU Liu, WL Meckel, T Tolar, P Sohn, HW Pierce, SK AF Liu, Wanli Meckel, Tobias Tolar, Pavel Sohn, Hae Won Pierce, Susan K. TI Antigen affinity discrimination is an intrinsic function of the B cell receptor SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID RESONANCE ENERGY-TRANSFER; RESPONSES IN-VIVO; IMMUNE-RESPONSE; LIVING CELLS; LYMPH-NODE; SUBCAPSULAR SINUS; MOLECULAR EVENTS; PLASMA-CELL; T-CELLS; ACTIVATION AB Antibody affinity maturation, a hallmark of adaptive immune responses, results from the selection of B cells expressing somatically hypermutated B cell receptors (BCRs) with increased affinity for antigens. Despite the central role of affinity maturation in antibody responses, the molecular mechanisms by which the increased affinity of a B cell for antigen is translated into a selective advantage for that B cell in immune responses is incompletely understood. We use high resolution live-cell imaging to provide evidence that the earliest BCR-intrinsic events that follow within seconds of BCR-antigen binding are highly sensitive to the affinity of the BCR for antigen. High affinity BCRs readily form oligomers and the resulting microclusters grow rapidly, resulting in enhanced recruitment of Syk kinase and calcium fluxes. Thus, B cells are able to read the affinity of antigen by BCR-intrinsic mechanisms during the earliest phases of BCR clustering, leading to the initiation of B cell responses. C1 [Liu, Wanli; Sohn, Hae Won; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Meckel, Tobias] Tech Univ Darmstadt, Dept Biol Membrane Biophys, D-64287 Darmstadt, Germany. [Tolar, Pavel] Natl Inst Med Res, London NW7 1AA, England. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM spierce@nih.gov RI Meckel, Tobias/F-4372-2010; liu, wanli/H-5690-2011 OI Meckel, Tobias/0000-0003-0759-2072; liu, wanli/0000-0003-2624-6802 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work has been supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 46 TC 60 Z9 62 U1 1 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 10 PY 2010 VL 207 IS 5 BP 1095 EP 1111 DI 10.1084/jem.20092123 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 593KB UT WOS:000277452100019 PM 20404102 ER PT J AU Allende, ML Tuymetova, G Lee, BG Bonifacino, E Wu, YP Proia, RL AF Allende, Maria L. Tuymetova, Galina Lee, Bridgin G. Bonifacino, Eliana Wu, Yun-Ping Proia, Richard L. TI S1P1 receptor directs the release of immature B cells from bone marrow into blood SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID PROTEIN-COUPLED-RECEPTOR; SPHINGOSINE 1-PHOSPHATE RECEPTOR; PROGENITOR CELLS; MARGINAL-ZONE; LYMPHOCYTE EGRESS; FUNCTIONAL-CHARACTERISTICS; PERIPHERAL-TISSUES; T-CELLS; IN-VIVO; SPHINGOSINE-1-PHOSPHATE AB S1P1 receptor expression is required for the egress of newly formed T cells from the thymus and exit of mature T and B cells from secondary lymphoid organs. In this study, we deleted the expression of the S1P1 receptor gene (S1pr1) in developing B cells in the bone marrow. Although B cell maturation within the bone marrow was largely normal in the B cell-specific S1pr1 knockout (B-S1pr1KO) mice, their newly generated immature B cells appeared in the blood at abnormally low numbers as compared with control mice. In the bone marrow of B-S1pr1KO mice, immature B cells in contact with the vascular compartment displayed increased apoptosis as compared with control mice. Forced expression of CD69, a negative regulator of S1P1 receptor expression, in developing bone marrow B cells also reduced the number of immature B cells in the blood. Attenuation of CXCR4 signaling, which is required for the proper retention of developing B cells in bone marrow, did not release immature B cells into the blood of B-S1pr1KO mice as effectively as in control mice. Our results indicate that the S1P1 receptor provides a signal necessary for the efficient transfer of newly generated immature B cells from the bone marrow to the blood. C1 [Allende, Maria L.; Tuymetova, Galina; Lee, Bridgin G.; Bonifacino, Eliana; Wu, Yun-Ping; Proia, Richard L.] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Proia, RL (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. EM proia@nih.gov RI Proia, Richard/A-7908-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 58 TC 80 Z9 80 U1 1 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 10 PY 2010 VL 207 IS 5 BP 1113 EP 1124 DI 10.1084/jem.20092210 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 593KB UT WOS:000277452100020 PM 20404103 ER PT J AU Siberry, GK Williams, PL Lujan-Zilbermann, J Warshaw, MG Spector, SA Decker, MD Heckman, BE Demske, EF Read, JS Jean-Philippe, P Kabat, W Nachman, S AF Siberry, George K. Williams, Paige L. Lujan-Zilbermann, Jorge Warshaw, Meredith G. Spector, Stephen A. Decker, Michael D. Heckman, Barbara E. Demske, Emily F. Read, Jennifer S. Jean-Philippe, Patrick Kabat, William Nachman, Sharon CA IMPAACT P1065 Protocol Team TI Phase I/II, Open-Label Trial of Safety and Immunogenicity of Meningococcal (Groups A, C, Y, and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine in Human Immunodeficiency Virus-Infected Adolescents SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE adolescent; HIV; meningococcal vaccine; immunization ID ACTIVE ANTIRETROVIRAL THERAPY; SEROGROUP-C; PNEUMOCOCCAL CONJUGATE; ANTIBODY-RESPONSE; BACTERICIDAL ANTIBODY; HEALTHY ADOLESCENTS; CHILDREN; SEROPREVALENCE; RECONSTITUTION; DISEASE AB Background: Quadrivalent meningococcal polysaccharide conjugate vaccine (MCV4) is routinely recommended for healthy youth in the United States, but there are no data about its use in HIV-infected people. Methods: P1065 is a Phase I/II trial of MCV4 safety and immunogenicity in HIV-infected children and youth performed at 27 US sites of the IMPAACT network. All youth (11-24 years old) received 1 dose of open-label MCV4 at entry. Standardized questionnaires were used to evaluate safety. Baseline protective immunity was defined as rabbit serum bactericidal antibody (rSBA) titer >= 1:128. Immunogenic response was defined as a >= 4-fold rise in rSBA against each meningococcal serogroup. Multivariable logistic regression analysis was used to evaluate the association of demographic and clinical characteristics on immunogenic response to serogroup C. Results: Among 319 subjects who received MCV4, 10 (3.1%) reported immediate adverse events which were local and mild, and 7 (2.2%) experienced Grade >= 3 adverse events, unrelated to vaccine. The 305 subjects with serologic data had a median age of 17 years and were 59% male, 50% Black, and 38% Latino. Subjects were stratified by entry CD4%: 12%, CD4 <15%; 40%, 15% to 24%; and 48%, >= 25%. Baseline protective immunity varied by serogroup: A, 41%; C, 11%; W-135, 15%; Y, 35% The immunogenic response rates to serogroups A, C, W-135, and Y were 68%, 52%, 73%, and 63%, respectively. In multivariable logistic regression models, lower entry CD4%, higher entry viral load, and CDC Class B/C diagnosis were associated with significantly lower odds of response to serogroup C. Conclusion: Many HIV-infected youth naturally acquire meningococcal immunity. MCV4 is safe and immunogenic in HIV-infected youth, but response rates are lower than in healthy youth, particularly for those with more advanced HIV clinical, immunologic, and virologic status. C1 [Siberry, George K.; Read, Jennifer S.] NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. [Williams, Paige L.; Warshaw, Meredith G.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Lujan-Zilbermann, Jorge] Univ S Florida, Coll Med, Dept Pediat, Div Infect Dis, Tampa, FL 33612 USA. [Spector, Stephen A.] Univ Calif San Diego, Dept Pediat, Div Infect Dis, San Diego, CA 92103 USA. [Spector, Stephen A.] Rady Childrens Hosp San Diego, La Jolla, CA USA. [Decker, Michael D.] Sanofi Pasteur Inc, Swiftwater, PA USA. [Decker, Michael D.] Vanderbilt Univ, Dept Prevent Med, Nashville, TN USA. [Heckman, Barbara E.] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Demske, Emily F.] Social & Sci Syst Inc, Silver Spring, MD USA. [Jean-Philippe, Patrick] NIAID, Henry Jackson Fdn Advancement Mil Med, Div Aids, Bethesda, MD USA. [Kabat, William] Childrens Mem Hosp, Div Infect Dis & Pathol, Special Infect Dis Lab, Chicago, IL USA. [Nachman, Sharon] SUNY Stony Brook, Dept Pediat, Stony Brook, NY 11794 USA. RP Siberry, GK (reprint author), NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, 6100 Execut Blvd,Room 4B11H, Bethesda, MD 20892 USA. EM siberryg@mail.nih.gov OI Decker, Michael/0000-0003-1008-7472; Frenkel, Lisa M/0000-0001-9566-8959 FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [AI068632]; Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases [5 U01 AI41110]; Pediatric AIDS Clinical Trials Group (PACTG) [1 U01 AI068616]; IMPAACT Group; NICHD [N01-DK-9-001/HHSN267200800001C]; National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C] FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (AI068632). This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and #1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). Additional support for this work was provided with Federal funds from the National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800014C. Sanofi-Pasteur Inc. provided study vaccine and performed meningococcal serum bactericidal antibody activity assays. NR 26 TC 25 Z9 26 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD MAY 10 PY 2010 VL 29 IS 5 BP 391 EP 396 DI 10.1097/INF.0b013e3181c38f3b PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 590IJ UT WOS:000277218600001 PM 20431379 ER PT J AU Maertens, JA Madero, L Reilly, AF Lehrnbecher, T Groll, AH Jafri, HS Green, M Nania, JJ Bourque, MR Wise, BA Strohmaier, KM Taylor, AF Kartsonis, NA Chow, JW Arndt, CAS dePauw, BE Walsh, TJ AF Maertens, Johan A. Madero, Luis Reilly, Anne F. Lehrnbecher, Thomas Groll, Andreas H. Jafri, Hasan S. Green, Michael Nania, Joseph J. Bourque, Michael R. Wise, Beth Ann Strohmaier, Kim M. Taylor, Arlene F. Kartsonis, Nicholas A. Chow, Joseph W. Arndt, Carola A. S. dePauw, Ben E. Walsh, Thomas J. CA Caspofungin Pediat Study Grp TI A Randomized, Double-Blind, Multicenter Study of Caspofungin Versus Liposomal Amphotericin B for Empiric Antifungal Therapy in Pediatric Patients With Persistent Fever and Neutropenia SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE caspofungin; liposomal amphotericin B; empiric antifungal therapy; pediatric patients; fever and neutropenia ID INVASIVE FUNGAL-INFECTIONS; PULMONARY ASPERGILLOSIS; TRANSPLANT RECIPIENTS; CLINICAL-TRIALS; CANCER; CHILDREN; EXPERIENCE; EFFICACY; CANDIDA; PHARMACOKINETICS AB Background: Persistently febrile neutropenic children at risk for invasive fungal infections receive empiric antifungal therapy as a standard of care. However, little is known about the role of echinocandins and liposomal amphotericin B (L-AmB) for empiric antifungal therapy in pediatric patients. Methods: Patients between the ages of 2 to 17 years with persistent fever and neutropenia were randomly assigned to receive caspofungin (70 mg/m(2) loading dose on day 1, then 50 mg/m2 daily [maximum 70 mg/d]) or L-AmB (3 mg/kg daily) in a 2: 1 ratio. Evaluation of safety was the primary objective of the study. Efficacy was also evaluated, with a successful outcome defined as fulfilling all components of a prespecified 5-part composite endpoint. Suspected invasive fungal infections were evaluated by an independent, treatment-blinded adjudication committee. Results: Eighty-two patients received study therapy (caspofungin 56, L-AmB 26), and 81 were evaluated for efficacy (caspofungin 56; L-AmB 25). Outcomes for safety and efficacy endpoints were similar for both study arms. Adverse drug-related event rates [95% confidence interval] were similar between the caspofungin and L-AmB groups (clinical 48.2% [34.7-62.0] versus 46.2% [26.6-66.6]; laboratory 10.7% [4.0-21.9] versus 19.2% [6.6-39.4]). Serious drug-related adverse events occurred in 1 (1.8%) of caspofungin-treated patients and 3 (11.5%) of L-AmB-treated patients. Overall success rates [95% CI] were 46.4% [33.4-59.5] for caspofungin and 32.0% [13.7-50.3] for L-AmB. Conclusions: Caspofungin and L-AmB were comparable in tolerability, safety, and efficacy as empiric antifungal therapy for persistently febrile neutropenic pediatric patients. C1 [Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Maertens, Johan A.] Univ Hosp Leuven, Dept Hematol, Acute Leukemia & Stem Cell Transplantat Unit, Louvain, Belgium. [Madero, Luis] Hosp Univ Nino Jesus, Madrid, Spain. [Reilly, Anne F.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Lehrnbecher, Thomas] Goethe Univ Frankfurt, Frankfurt, Germany. [Groll, Andreas H.] Univ Childrens Hosp Munster, Dept Pediat Hematol Oncol, Infect Dis Res Program, Munster, Germany. [Jafri, Hasan S.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Div Pediat Infect Dis, Dallas, TX 75390 USA. [Green, Michael] Childrens Hosp Pittsburgh, Dept Pediat, Div Infect Dis, Pittsburgh, PA 15213 USA. [Green, Michael] Childrens Hosp Pittsburgh, Dept Surg, Pittsburgh, PA 15213 USA. [Green, Michael] Childrens Hosp Pittsburgh, Dept Clin & Translat Sci, Pittsburgh, PA 15213 USA. [Nania, Joseph J.] Vanderbilt Univ, Nashville, TN USA. [Bourque, Michael R.; Wise, Beth Ann; Strohmaier, Kim M.; Taylor, Arlene F.; Kartsonis, Nicholas A.; Chow, Joseph W.] Merck Res Labs, Clin Res Infect Dis, N Wales, PA USA. [Arndt, Carola A. S.] Mayo Clin, Dept Pediat & Adolescent Med, Rochester, MN USA. [dePauw, Ben E.] Radboud Univ Nijmegen, Nijmegen Med Ctr, Nijmegen, Netherlands. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, CRC 1-5750,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov FU Merck Co., Inc FX The authors thank all the patients and their caregivers who participated in this study, as well as all members of the Protocol 044 Study Group. The authors also thank Alfred Saah, Hedy Teppler, and Anne Henry for their contributions to the design and conduct of the study. Funding for this study was provided in part by Merck & Co., Inc. The industrial sponsor provided assistance with study design, data acquisition, and statistical analyses. Authors had full access to data and data analysis. NR 36 TC 68 Z9 71 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD MAY 10 PY 2010 VL 29 IS 5 BP 415 EP 420 DI 10.1097/INF.0b013e3181da2171 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 590IJ UT WOS:000277218600006 PM 20431381 ER PT J AU Klein, MA AF Klein, Marguerite A. TI The National Institutes of Health (NIH) Sponsored a Scientific Workshop, "Soy Protein/Isoflavone Research: Challenges in Designing and Evaluating Intervention Studies," July 28-29, 2009 SO PHARMACEUTICAL BIOLOGY LA English DT Meeting Abstract C1 [Klein, Marguerite A.] Natl Inst Hlth, Off Dietary Supplements, Bethesda, MD 21779 USA. EM kleinm@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1388-0209 J9 PHARM BIOL JI Pharm. Biol. PD MAY 10 PY 2010 VL 48 SU 1 BP 3 EP 4 PG 2 WC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy SC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy GA 620MC UT WOS:000279503000008 ER PT J AU Cardellina, JH Betz, JM AF Cardellina, John H., II Betz, Joseph M. TI Analytical Chemistry of Vitamin D in Clinical Samples: State of the Art and Current Challenges SO PHARMACEUTICAL BIOLOGY LA English DT Meeting Abstract C1 [Cardellina, John H., II; Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. EM jhcardellina@aol.com NR 0 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1388-0209 J9 PHARM BIOL JI Pharm. Biol. PD MAY 10 PY 2010 VL 48 SU 1 BP 13 EP 13 PG 1 WC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy SC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy GA 620MC UT WOS:000279503000032 ER PT J AU Rosenberg, ES Graham, BS Chan, ES Bosch, RJ Stocker, V Maenza, J Markowitz, M Little, S Sax, PE Collier, AC Nabel, G Saindon, S Flynn, T Kuritzkes, D Barouch, DH AF Rosenberg, Eric S. Graham, Barney S. Chan, Ellen S. Bosch, Ronald J. Stocker, Vicki Maenza, Janine Markowitz, Martin Little, Susan Sax, Paul E. Collier, Ann C. Nabel, Gary Saindon, Suzanne Flynn, Theresa Kuritzkes, Daniel Barouch, Dan H. CA ACTG A5187 Team TI Safety and Immunogenicity of Therapeutic DNA Vaccination in Individuals Treated with Antiretroviral Therapy during Acute/Early HIV-1 Infection SO PLOS ONE LA English DT Article ID VIREMIA AB Background: An effective therapeutic vaccine that could augment immune control of HIV-1 replication may abrogate or delay the need for antiretroviral therapy. AIDS Clinical Trials Group (ACTG) A5187 was a phase I/II, randomized, placebocontrolled, double-blinded trial to evaluate the safety and immunogenicity of an HIV-1 DNA vaccine (VRC-HVDNA 009-00-VP) in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. (clinicaltrials.gov NCT00125099) Methods: Twenty healthy HIV-1 infected subjects who were treated with antiretroviral therapy during acute/early HIV-1 infection and had HIV-1 RNA, 50 copies/mL were randomized to receive either vaccine or placebo. The objectives of this study were to evaluate the safety and immunogenicity of the vaccine. Following vaccination, subjects interrupted antiretroviral treatment, and set-point HIV-1 viral loads and CD4 T cell counts were determined 17-23 weeks after treatment discontinuation. Results: Twenty subjects received all scheduled vaccinations and discontinued antiretroviral therapy at week 30. No subject met a primary safety endpoint. No evidence of differences in immunogenicity were detected in subjects receiving vaccine versus placebo. There were also no significant differences in set-point HIV-1 viral loads or CD4 T cell counts following treatment discontinuation. Median set-point HIV-1 viral loads after treatment discontinuation in vaccine and placebo recipients were 3.5 and 3.7 log10 HIV-1 RNA copies/mL, respectively. Conclusions: The HIV-1 DNA vaccine (VRC-HIVDNA 009-00-VP) was safe but poorly immunogenic in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. Viral set-points were similar between vaccine and placebo recipients following treatment interruption. However, median viral load set-points in both groups were lower than in historical controls, suggesting a possible role for antiretroviral therapy in persons with acute or early HIV-1 infection and supporting the safety of discontinuing treatment in this group. C1 [Rosenberg, Eric S.; Saindon, Suzanne; Flynn, Theresa] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Graham, Barney S.; Nabel, Gary] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Chan, Ellen S.; Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Stocker, Vicki] Social & Sci Syst, Silver Spring, MD USA. [Maenza, Janine; Collier, Ann C.] Univ Washington, Seattle, WA 98195 USA. [Markowitz, Martin] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [Little, Susan] Univ Calif San Diego, San Diego, CA 92103 USA. [Sax, Paul E.; Kuritzkes, Daniel] Brigham & Womens Hosp, Boston, MA 02115 USA. [Barouch, Dan H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Rosenberg, ES (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM erosenberg1@mgh.harvard.edu FU NIH [ACTG, AI068636, AI068634, AI038858, AI038855, AI058727, AI066305, AI066924, AI078526, AI 40873]; Doris Duke Clinical Scientist Development Award FX NIH AIDS Clinical Trials Group (ACTG, AI068636, AI068634, AI038858, AI038855), Doris Duke Clinical Scientist Development Award (D. H. B.), and NIH grants AI058727, AI066305, AI066924, AI078526 (D. H. B.) and AI 40873 (E. S. R). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 10 TC 21 Z9 21 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 10 PY 2010 VL 5 IS 5 AR e10555 DI 10.1371/journal.pone.0010555 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 593OJ UT WOS:000277467900011 PM 20479938 ER PT J AU Rubinstein, LV Steinberg, SM Kummar, S Kinders, R Parchment, RE Murgo, AJ Tomaszewski, JE Doroshow, JH AF Rubinstein, Larry V. Steinberg, Seth M. Kummar, Shivaani Kinders, Robert Parchment, Ralph E. Murgo, Anthony J. Tomaszewski, Joseph E. Doroshow, James H. TI The statistics of phase 0 trials SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT Annual Conference on Statistical Issues in Clinical Trials-Early, Translational and Proof of Concept Studies - The Go/No Go Decisions CY APR 08, 2008 CL Philadelphia, PA DE first-in-man study; PD-driven phase 0 trial; pharmacodynamic assay; phase 1 clinical trial; phase 2 clinical trial ID CLINICAL-TRIALS; DRUG DEVELOPMENT; ADVANCED MALIGNANCIES; TUMOR SIZE; END-POINT; CANCER; INHIBITOR; ABT-888 AB The PD-driven phase 0 trial is a new form, designed to be a first-in-man study, often of a new agent, conducted to assess drug effect on a molecular target, by means of a pharmacodynamic (PD) assay, in a very small number (10-15) of patients. Such a study is meant to be a proof of principle trial to determine whether the agent yields the PD effect predicted by pre-clinical studies. The dosage is meant to be pharmacologically active, but is neither toxic nor likely to yield clinical benefit. Such a trial may be used to serve as a very early test of an agent's biologic effect, allowing for early weeding out of ineffective agents, or as an early means of determining the most promising of competing analogue agents. This manuscript will present designs for such PD-driven studies that are statistically efficient and rigorous, focusing on non-comparative trials. The phase 0 trial promises to become an increasingly important tool for facilitating and speeding the development of new therapeutic agents, particularly in oncology. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Rubinstein, Larry V.; Tomaszewski, Joseph E.; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Steinberg, Seth M.; Kummar, Shivaani; Doroshow, James H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Kinders, Robert; Parchment, Ralph E.] NCI, Lab Human Toxicol & Pharmacol, Appl Dev Res Support Directorate, SAIC Frederick Inc, Frederick, MD 21702 USA. [Murgo, Anthony J.] US FDA, Off Oncol Drug Prod, Silver Spring, MD USA. RP Rubinstein, LV (reprint author), NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. EM rubinsteinl@ctep.nci.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 10 TC 11 Z9 12 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAY 10 PY 2010 VL 29 IS 10 BP 1072 EP 1076 DI 10.1002/sim.3840 PG 5 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 597DI UT WOS:000277735900003 PM 20419759 ER PT J AU Mbulaiteye, SM Talisuna, AO Ogwang, MD McKenzie, FE Ziegler, JL Parkin, DM AF Mbulaiteye, Sam M. Talisuna, Ambrose O. Ogwang, Martin D. McKenzie, F. Ellis Ziegler, John L. Parkin, Donald M. TI African Burkitt's lymphoma: could collaboration with HIV-1 and malaria programmes reduce the high mortality rate? SO LANCET LA English DT Editorial Material ID CHILDREN; UGANDA; INFECTION; PEPFAR; BURDEN; MALAWI C1 [Talisuna, Ambrose O.] Uganda Malaria Surveillance Programme, Kampala, Uganda. [Ogwang, Martin D.] St Marys Hosp, Dept Surg, Lacor, Gulu, Uganda. [McKenzie, F. Ellis] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Ziegler, John L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Parkin, Donald M.] Univ Oxford, Clin Trial Serv Unit, Oxford, England. RP Mbulaiteye, SM (reprint author), 2302 Cranberry Terrace, Silver Spring, MD 20906 USA. EM sammwiidu@hotmail.com NR 22 TC 11 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD MAY 8 PY 2010 VL 375 IS 9726 BP 1661 EP 1663 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 597CX UT WOS:000277734700032 PM 20452522 ER PT J AU Makarova, KS Koonin, EV AF Makarova, Kira S. Koonin, Eugene V. TI Two new families of the FtsZ-tubulin protein superfamily implicated in membrane remodeling in diverse bacteria and archaea SO BIOLOGY DIRECT LA English DT Article ID STRUCTURAL INSIGHTS; CELL-DIVISION; PSI-BLAST; EVOLUTION; CYTOSKELETON; OMPA; ALIGNMENTS; SULFOLOBUS; SEQUENCES; FILAMENTS AB Several recent discoveries reveal unexpected versatility of the bacterial and archaeal cytoskeleton systems that are involved in cell division and other processes based on membrane remodeling. Here we apply methods for distant protein sequence similarity detection, phylogenetic approaches, and genome context analysis to described two previously unnoticed families of the FtsZ-tubulin superfamily. One of these families is limited in its spread to Proteobacteria whereas the other is represented in diverse bacteria and archaea, and might be the key component of a novel, multicomponent membrane remodeling system that also includes a Von Willebrand A domain-containing protein, a distinct GTPase and membrane transport proteins of the OmpA family. This article was reviewed by Purificacion Lopez-Garcia and Gaspar Jekely; for complete reviews, see the Reviewers Reports section. C1 [Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU National Institutes of Health, National Library of Medicine FX The authors' research is supported by intramural funds of the Department of Health and Human Services (National Institutes of Health, National Library of Medicine) NR 44 TC 20 Z9 21 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD MAY 7 PY 2010 VL 5 AR 33 DI 10.1186/1745-6150-5-33 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 605PM UT WOS:000278359500001 PM 20459678 ER PT J AU Kim, JI Cali, I Surewicz, K Kong, QZ Raymond, GJ Atarashi, R Race, B Qing, LT Gambetti, P Caughey, B Surewicz, WK AF Kim, Jae-Il Cali, Ignazio Surewicz, Krystyna Kong, Qingzhong Raymond, Gregory J. Atarashi, Ryuichiro Race, Brent Qing, Liuting Gambetti, Pierluigi Caughey, Byron Surewicz, Witold K. TI Mammalian Prions Generated from Bacterially Expressed Prion Protein in the Absence of Any Mammalian Cofactors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IN-VITRO; SCRAPIE; DISEASE; STRAINS; ANIMALS; HUMANS; MICE AB Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases that are associated with the conformational conversion of a normal prion protein, PrP(C), to a misfolded aggregated form, PrP(Sc). The protein-only hypothesis asserts that PrP(Sc) itself represents the infectious TSE agent. Although this model is supported by rapidly growing experimental data, unequivocal proof has been elusive. The protein misfolding cyclic amplification reactions have been recently shown to propagate prions using brain-derived or recombinant prion protein, but only in the presence of additional cofactors such as nucleic acids and lipids. Here, using a protein misfolding cyclic amplification variation, we show that prions causing transmissible spongiform encephalopathy in wild-type hamsters can be generated solely from highly purified, bacterially expressed recombinant hamster prion protein without any mammalian or synthetic cofactors (other than buffer salts and detergent). These findings provide strong support for the protein-only hypothesis of TSE diseases, as well as argue that cofactors such as nucleic acids, other polyanions, or lipids are nonobligatory for prion protein conversion to the infectious form. C1 [Kim, Jae-Il; Surewicz, Krystyna; Surewicz, Witold K.] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Cali, Ignazio; Kong, Qingzhong; Qing, Liuting; Gambetti, Pierluigi] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Raymond, Gregory J.; Atarashi, Ryuichiro; Race, Brent; Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Surewicz, WK (reprint author), Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA. EM witold.surewicz@case.edu OI cali, ignazio/0000-0001-5770-3848 FU National Institutes of Health [NS44158, AG14359]; NIAID FX This work was supported, in whole or in part, by National Institutes of Health Grants NS44158 (to W. K. S.) and AG14359 (to P. G., W. K. S., and Q. K.) and by the Intramural Research Program of the NIAID. NR 29 TC 123 Z9 124 U1 0 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 7 PY 2010 VL 285 IS 19 BP 14083 EP 14087 DI 10.1074/jbc.C110.113464 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591KQ UT WOS:000277299700003 PM 20304915 ER PT J AU Selvanathan, SP Thakurta, AG Dhakshnamoorthy, J Zhou, M Veenstra, TD Dhar, R AF Selvanathan, Saravana P. Thakurta, Anjan G. Dhakshnamoorthy, Jothy Zhou, Ming Veenstra, Timothy D. Dhar, Ravi TI Schizosaccharomyces pombe Dss1p Is a DNA Damage Checkpoint Protein That Recruits Rad24p, Cdc25p, and Rae1p to DNA Double-strand Breaks SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA EXPORT; FISSION YEAST; SACCHAROMYCES-CEREVISIAE; NUCLEAR-LOCALIZATION; POLY(A)(+) RNA; RAD51 HOMOLOG; CELL-CYCLE; COMPLEX; GENE; REPLICATION AB Schizosaccharomyces pombe Dss1p and its homologs function in multiple cellular processes including recombinational repair of DNA and nuclear export of messenger RNA. We found that Tap-tagged Rad24p, a member of the 14-3-3 class of proteins, co-purified Dss1p along with mitotic activator Cdc25p, messenger RNA export/cell cycle factor Rae1p, 19 S proteasomal factors, and recombination protein Rhp51p (a Rad51p homolog). Using chromatin immunoprecipitation, we found that Dss1p recruited Rad24p and Rae1p to the double-strand break (DSB) sites. Furthermore, Cdc25p also recruited to the DSB site, and its recruitment was dependent on Dss1p, Rad24p, and the protein kinase Chk1p. Following DSB, all nuclear Cdc25p was found to be chromatin-associated. We found that Dss1p and Rae1p have a DNA damage checkpoint function, and upon treatment with UV light Delta dss1 cells entered mitosis prematurely with indistinguishable timing from Delta rad24 cells. Taken together, these results suggest that Dss1p plays a critical role in linking repair and checkpoint factors to damaged DNA sites by specifically recruiting Rad24p and Cdc25p to the DSBs. We suggest that the sequestration of Cdc25p to DNA damage sites could provide a mechanism for S. pombe cells to arrest at G(2)/M boundary in response to DNA damage. C1 [Selvanathan, Saravana P.; Thakurta, Anjan G.; Dhakshnamoorthy, Jothy; Dhar, Ravi] NCI, Basic Res Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zhou, Ming; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, Sci Applicat Int Corp Frederick Inc,NIH, Frederick, MD 21702 USA. RP Dhar, R (reprint author), NCI, Basic Res Lab, Ctr Canc Res, NIH, Bldg 37,Rm 5016,37 Convent Dr,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dharr@mail.nih.gov FU National Institutes of Health NCI FX This work was supported, in whole or in part, by National Institutes of Health NCI intramural program. NR 51 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 7 PY 2010 VL 285 IS 19 BP 14122 EP 14133 DI 10.1074/jbc.M109.083485 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591KQ UT WOS:000277299700008 PM 20231270 ER PT J AU Ryu, H Al-Ani, G Deckert, K Kirkpatrick, D Gygi, SP Dasso, M Azuma, Y AF Ryu, Hyunju Al-Ani, Gada Deckert, Katelyn Kirkpatrick, Donald Gygi, Steven P. Dasso, Mary Azuma, Yoshiaki TI PIASy Mediates SUMO-2/3 Conjugation of Poly(ADP-ribose) Polymerase 1 (PARP1) on Mitotic Chromosomes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TOPOISOMERASE-II; SACCHAROMYCES-CEREVISIAE; PROTEIN SUMOYLATION; ACTIVE CENTROMERES; ENZYME; INTERACTS; CENPB; YEAST; BUB3 AB PIASy is a small ubiquitin-related modifier (SUMO) ligase that modifies chromosomal proteins in mitotic Xenopus egg extracts and plays an essential role in mitotic chromosome segregation. We have isolated a novel SUMO-2/3-modified mitotic chromosomal protein and identified it as poly(ADP-ribose) polymerase 1 (PARP1). PARP1 was robustly conjugated to SUMO-2/ 3 on mitotic chromosomes but not on interphase chromatin. PIASy promotes SUMOylation of PARP1 both in egg extracts and in vitro reconstituted SUMOylation assays. Through tandem mass spectrometry analysis of mitotically SUMOylated PARP1, we identified a residue within the BRCA1 C-terminal domain of PARP1 (lysine 482) as its primary SUMOylation site. Mutation of this residue significantly reduced PARP1 SUMOylation in egg extracts and enhanced the accumulation of species derived from modification of secondary lysine residues in assays using purified components. SUMOylation of PARP1 did not alter in vitro PARP1 enzyme activity, poly-ADP-ribosylation (PARylation), nor did inhibition of SUMOylation of PARP1 alter the accumulation of PARP1 on mitotic chromosomes, suggesting that SUMOylation regulates neither the intrinsic activity of PARP1 nor its localization. However, loss of SUMOylation increased PARP1-dependent PARylation on isolated chromosomes, indicating SUMOylation controls the capacity of PARP1 to modify other chromatin-associated proteins. C1 [Azuma, Yoshiaki] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA. [Kirkpatrick, Donald; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Dasso, Mary] NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20852 USA. RP Azuma, Y (reprint author), 1200 Sunnyside Ave,Haworth Hall,Rm 3037, Lawrence, KS 66045 USA. EM azumay@ku.edu OI Kirkpatrick, Donald/0000-0003-3091-2804; Dasso, Mary/0000-0002-5410-1371 FU National Institutes of Health [P20 RR015563, GM80278, GM67945]; Department of Molecular Biosciences at University of Kansas FX This work was supported, in whole or in part, by National Institutes of Health Grants P20 RR015563 (National Center for Research Resources COBRE-Center for Cancer Experimental Therapeutics) and GM80278 and GM67945 (NIGMS to S. P. G.). This work was also supported in part by a start-up grant from Department of Molecular Biosciences at University of Kansas. NR 36 TC 19 Z9 20 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 7 PY 2010 VL 285 IS 19 BP 14415 EP 14423 DI 10.1074/jbc.M109.074583 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591KQ UT WOS:000277299700038 PM 20228053 ER PT J AU Kim, MS Yoon, SK Bollig, F Kitagaki, J Hur, W Whye, NJ Wu, YP Rivera, MN Park, JY Kim, HS Malik, K Bell, DW Englert, C Perantoni, AO Lee, SB AF Kim, Myoung Shin Yoon, Seung Kew Bollig, Frank Kitagaki, Jirouta Hur, Wonhee Whye, Nathan J. Wu, Yun-Ping Rivera, Miguel N. Park, Jik Young Kim, Ho-Shik Malik, Karim Bell, Daphne W. Englert, Christoph Perantoni, Alan O. Lee, Sean Bong TI A Novel Wilms Tumor 1 (WT1) Target Gene Negatively Regulates the WNT Signaling Pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-CATENIN; KIDNEY DEVELOPMENT; CTNNB1 MUTATIONS; SUPPRESSOR; ZEBRAFISH; IDENTIFICATION; INHIBITION; EXPRESSION; SCLEROSIS; IDAX AB Mammalian kidney development requires the functions of the Wilms tumor gene WT1 and the WNT/beta-catenin signaling pathway. Recent studies have shown that WT1 negatively regulates WNT/beta-catenin signaling, but the molecular mechanisms by which WT1 inhibits WNT/beta-catenin signaling are not completely understood. In this study, we identified a gene, CXXC5, which we have renamed WID (WT1-induced Inhibitor of Dishevelled), as a novel WT1 transcriptional target that negatively regulates WNT/beta-catenin signaling. WT1 activates WID transcription through the upstream enhancer region. In the developing kidney, Wid and Wt1 are coexpressed in podocytes of maturing nephrons. Structure-function analysis demonstrated that WID interacts with Dishevelled via its C-terminal CXXC zinc finger and Dishevelled binding domains and potently inhibits WNT/beta-catenin signaling in vitro and in vivo. WID is evolutionarily conserved, and ablation of wid in zebrafish embryos with antisense morpholino oligonucleotides perturbs embryonic kidney development. Taken together, our results demonstrate that the WT1 negatively regulates WNT/beta-catenin pathway via its target gene WID and further suggest a role for WID in nephrogenesis. C1 [Kim, Myoung Shin; Whye, Nathan J.; Wu, Yun-Ping; Park, Jik Young; Kim, Ho-Shik; Lee, Sean Bong] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Yoon, Seung Kew; Hur, Wonhee] Catholic Univ Korea, Dept Internal Med, World Hlth Org,Catholic Res Inst Med Sci, Collaborating Ctr Viral Hepatitis, Seoul 137701, South Korea. [Bollig, Frank; Englert, Christoph] Fritz Lipmann Inst, Leibniz Inst Age Res, D-07745 Jena, Germany. [Kitagaki, Jirouta; Perantoni, Alan O.] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. [Rivera, Miguel N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA. [Malik, Karim] Univ Bristol, Canc & Leukaemia Childhood Sargent Unit, Dept Cellular & Mol Med, Bristol BS8 1TD, Avon, England. [Bell, Daphne W.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Lee, SB (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 9000 Rockville Pike,Bldg 10,9D11, Bethesda, MD 20892 USA. EM seanL@mail.nih.gov FU National Institutes of Health, NIDDK; National Human Genome Research Institute; NCI; Deutsche Forschungsgemeinschaft; 21st Century Frontier Functional Human Genome Project in Korea [FG06-11-11] FX This work was supported, in whole or in part, by National Institutes of Health grants from the Intramural Research Program, NIDDK (to S. B. L.), National Human Genome Research Institute (to D. W. B.), and NCI (to A.O.P.). This work was also supported by the Deutsche Forschungsgemeinschaft (to C. E.) and Grant FG06-11-11 of the 21st Century Frontier Functional Human Genome Project in Korea (to S.K.Y.). NR 36 TC 42 Z9 43 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 7 PY 2010 VL 285 IS 19 BP 14585 EP 14593 DI 10.1074/jbc.M109.094334 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591KQ UT WOS:000277299700055 PM 20220130 ER PT J AU Radaev, S Zou, ZC Huang, T Lafer, EM Hinck, AP Sun, PD AF Radaev, Sergei Zou, Zhongcheng Huang, Tao Lafer, Eileen M. Hinck, Andrew P. Sun, Peter D. TI Ternary Complex of Transforming Growth Factor-beta 1 Reveals Isoform-specific Ligand Recognition and Receptor Recruitment in the Superfamily SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TGF-BETA-ISOFORMS; CRYSTAL-STRUCTURE; SIGNALING COMPLEXES; BINDING-SPECIFICITY; STRUCTURAL BASIS; KNOCKOUT MICE; CLEFT-PALATE; II-RECEPTOR; SYSTEM; SOFTWARE AB Transforming growth factor (TGF)-beta 1, -beta 2, and -beta 3 are 25-kDa homodimeric polypeptides that play crucial nonover-lapping roles in embryogenesis, tissue development, carcinogenesis, and immune regulation. Here we report the 3.0-angstrom resolution crystal structure of the ternary complex between human TGF-beta 1 and the extracellular domains of its type I and type II receptors, T beta RI and T beta RII. The TGF-beta 1 ternary complex structure is similar to previously reported TGF-beta 3 complex except with a 10 degrees rotation in T beta RI docking orientation. Quantitative binding studies showed distinct kinetics between the receptors and the isoforms of TGF-beta. T beta RI showed significant binding to TGF-beta 2 and TGF-beta 3 but not TGF-beta 1, and the binding to all three isoforms of TGF-beta was enhanced considerably in the presence of T beta RII. The preference of TGF-beta 2 to T beta RI suggests a variation in its receptor recruitment in vivo. Although TGF-beta 1 and TGF-beta 3 bind and assemble their ternary complexes in a similar manner, their structural differences together with differences in the affinities and kinetics of their receptor binding may underlie their unique biological activities. Structural comparisons revealed that the receptor-ligand pairing in the TGF-beta superfamily is dictated by unique insertions, deletions, and disulfide bonds rather than amino acid conservation at the interface. The binding mode of T beta RII on TGF-beta is unique to TGF-beta s, whereas that of type II receptor for bone morphogenetic protein on bone morphogenetic protein appears common to all other cytokines in the superfamily. Further, extensive hydrogen bonds and salt bridges are present at the high affinity cytokine-receptor interfaces, whereas hydrophobic interactions dominate the low affinity receptor-ligand interfaces. C1 [Radaev, Sergei; Zou, Zhongcheng; Sun, Peter D.] NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Huang, Tao; Lafer, Eileen M.; Hinck, Andrew P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. RP Sun, PD (reprint author), 12441 Parklawn Dr, Rockville, MD 20852 USA. EM psun@nih.gov FU National Institutes of Health [GM58670]; NIAID; Robert A. Welch Foundation [AQ1431] FX This work was supported, in whole or in part, by National Institutes of Health Grant GM58670 (to A. P. H.). This work was also supported by NIAID intramural research funding and by Robert A. Welch Foundation Grant AQ1431 (to A. P. H.). NR 50 TC 56 Z9 58 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 7 PY 2010 VL 285 IS 19 BP 14806 EP 14814 DI 10.1074/jbc.M109.079921 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591KQ UT WOS:000277299700077 PM 20207738 ER PT J AU Shakoury-Elizeh, M Protchenko, O Berger, A Cox, J Gable, K Dunn, TM Prinz, WA Bard, M Philpott, CC AF Shakoury-Elizeh, Minoo Protchenko, Olga Berger, Alvin Cox, James Gable, Kenneth Dunn, Teresa M. Prinz, William A. Bard, Martin Philpott, Caroline C. TI Metabolic Response to Iron Deficiency in Saccharomyces cerevisiae SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEME-BINDING PROTEIN; SQUALENE EPOXIDASE; FERRIC REDUCTASE; LIPID PARTICLES; BUDDING YEAST; RESISTANCE; STORAGE; BIOSYNTHESIS; DEPRIVATION; ERGOSTEROL AB Iron is an essential cofactor for enzymes involved in numerous cellular processes, yet little is known about the impact of iron deficiency on cellular metabolism or iron proteins. Previous studies have focused on changes in transcript and proteins levels in iron-deficient cells, yet these changes may not reflect changes in transport activity or flux through a metabolic pathway. We analyzed the metabolomes and transcriptomes of yeast grown in iron-rich and iron-poor media to determine which bio-synthetic processes are altered when iron availability falls. Iron deficiency led to changes in glucose metabolism, amino acid biosynthesis, and lipid biosynthesis that were due to deficiencies in specific iron-dependent enzymes. Iron-sulfur proteins exhibited loss of iron cofactors, yet amino acid synthesis was maintained. Ergosterol and sphingolipid biosynthetic pathways had blocks at points where heme and diiron enzymes function, whereas Ole1, the essential fatty acid desaturase, was resistant to iron depletion. Iron-deficient cells exhibited depletion of most iron enzyme activities, but loss of activity during iron deficiency did not consistently disrupt metabolism. Amino acid homeostasis was robust, but iron deficiency impaired lipid synthesis, altering the properties and functions of cellular membranes. C1 [Philpott, Caroline C.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Prinz, William A.] NIDDK, Lab Cell Biol & Biochem, NIH, Bethesda, MD 20892 USA. [Berger, Alvin] Metabolon Inc, Durham, NC 27713 USA. [Cox, James] Univ Utah, Metabol Core Res Facil, Salt Lake City, UT 84132 USA. [Gable, Kenneth; Dunn, Teresa M.] Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. [Bard, Martin] Indiana Univ Purdue Univ, Dept Biol, Indianapolis, IN 46202 USA. RP Philpott, CC (reprint author), Bldg 10,Rm 9B-16,10 Ctr Dr, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov FU National Institutes of Health, NIDDK [P30 DK072437]; NIH [GM62104]; Center of Excellence in Molecular Hematology; United States Public Health Service, NINDS, NIH [NS47717] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of NIDDK (to M. S.-E., O.P., W. A. P., and C. C. P.), by NIH Grant NIDDK P30 DK072437 (to J.C.), and by NIH Grant GM62104 (to M. B.). This work was also supported by the Center of Excellence in Molecular Hematology and by United States Public Health Service Grant NS47717 awarded by NINDS, NIH (to T. M. D.). NR 50 TC 62 Z9 66 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 7 PY 2010 VL 285 IS 19 BP 14823 EP 14833 DI 10.1074/jbc.M109.091710 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591KQ UT WOS:000277299700079 PM 20231268 ER PT J AU Effantin, G Maurizi, MR Steven, AC AF Effantin, Gregory Maurizi, Michael R. Steven, Alasdair C. TI Binding of the ClpA Unfoldase Opens the Axial Gate of ClpP Peptidase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ATP-DEPENDENT PROTEASES; AAA PLUS PROTEINS; ESCHERICHIA-COLI; ELECTRON-MICROSCOPY; COMPLEX-FORMATION; HSP100 CHAPERONE; SERINE PROTEASES; 20S PROTEASOMES; N-TERMINUS; PROTEOLYSIS AB ClpP is a serine protease whose active sites are sequestered in a cavity enclosed between two heptameric rings of subunits. The ability of ClpP to process folded protein substrates depends on its being partnered by an AAA+ ATPase/unfoldase, ClpA or ClpX. In active complexes, substrates are unfolded and fed along an axial channel to the degradation chamber inside ClpP. We have used cryoelectron microscopy at similar to 11-angstrom resolution to investigate the three-dimensional structure of ClpP complexed with either one or two end-mounted ClpA hexamers. In the absence of ClpA, the apical region of ClpP is sealed; however, it opens on ClpA binding, creating an access channel. This region is occupied by the N-terminal loops (residues 1-17) of ClpP, which tend to be poorly visible in crystal structures, indicative of conformational variability. Nevertheless, we were able to model the closed-to-open transition that accompanies ClpA binding in terms of movements of these loops; in particular, "up" conformations of the loops correlate with the open state. The main part of ClpP, the barrel formed by 14 copies of residues 18-193, is essentially unchanged by the interaction with ClpA. Using difference mapping, we localized the binding site for ClpA to a peripheral pocket between adjacent ClpP subunits. Based on these observations, we propose that access to the ClpP degradation chamber is controlled allosterically by hinged movements of its N-terminal loops, which the symmetry-mismatched binding of ClpA suffices to induce. C1 [Steven, Alasdair C.] NIAMS, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Maurizi, Michael R.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMS, Struct Biol Res Lab, NIH, Bldg 50,Rm 1517, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov FU NIAMS; NCI of the National Institutes of Health FX This work was supported by the Intramural Research Programs of NIAMS and NCI of the National Institutes of Health. NR 45 TC 21 Z9 21 U1 0 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 7 PY 2010 VL 285 IS 19 BP 14834 EP 14840 DI 10.1074/jbc.M109.090498 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591KQ UT WOS:000277299700080 PM 20236930 ER PT J AU Green, RE Krause, J Briggs, AW Maricic, T Stenzel, U Kircher, M Patterson, N Li, H Zhai, WW Fritz, MHY Hansen, NF Durand, EY Malaspinas, AS Jensen, JD Marques-Bonet, T Alkan, C Prufer, K Meyer, M Burbano, HA Good, JM Schultz, R Aximu-Petri, A Butthof, A Hober, B Hoffner, B Siegemund, M Weihmann, A Nusbaum, C Lander, ES Russ, C Novod, N Affourtit, J Egholm, M Verna, C Rudan, P Brajkovic, D Kucan, Z Gusic, I Doronichev, VB Golovanova, LV Lalueza-Fox, C de la Rasilla, M Fortea, J Rosas, A Schmitz, RW Johnson, PLF Eichler, EE Falush, D Birney, E Mullikin, JC Slatkin, M Nielsen, R Kelso, J Lachmann, M Reich, D Paabo, S AF Green, Richard E. Krause, Johannes Briggs, Adrian W. Maricic, Tomislav Stenzel, Udo Kircher, Martin Patterson, Nick Li, Heng Zhai, Weiwei Fritz, Markus Hsi-Yang Hansen, Nancy F. Durand, Eric Y. Malaspinas, Anna-Sapfo Jensen, Jeffrey D. Marques-Bonet, Tomas Alkan, Can Pruefer, Kay Meyer, Matthias Burbano, Hernan A. Good, Jeffrey M. Schultz, Rigo Aximu-Petri, Ayinuer Butthof, Anne Hoeber, Barbara Hoeffner, Barbara Siegemund, Madlen Weihmann, Antje Nusbaum, Chad Lander, Eric S. Russ, Carsten Novod, Nathaniel Affourtit, Jason Egholm, Michael Verna, Christine Rudan, Pavao Brajkovic, Dejana Kucan, Zeljko Gusic, Ivan Doronichev, Vladimir B. Golovanova, Liubov V. Lalueza-Fox, Carles de la Rasilla, Marco Fortea, Javier Rosas, Antonio Schmitz, Ralf W. Johnson, Philip L. F. Eichler, Evan E. Falush, Daniel Birney, Ewan Mullikin, James C. Slatkin, Montgomery Nielsen, Rasmus Kelso, Janet Lachmann, Michael Reich, David Paeaebo, Svante TI A Draft Sequence of the Neandertal Genome SO SCIENCE LA English DT Article ID ANCIENT DNA; ENZYMATIC AMPLIFICATION; MODERN HUMANS; MITOCHONDRIAL GENOME; HUMAN-POPULATIONS; HUMAN-EVOLUTION; HOMO-SAPIENS; GENE; PATTERNS; NUCLEOTIDE AB Neandertals, the closest evolutionary relatives of present-day humans, lived in large parts of Europe and western Asia before disappearing 30,000 years ago. We present a draft sequence of the Neandertal genome composed of more than 4 billion nucleotides from three individuals. Comparisons of the Neandertal genome to the genomes of five present-day humans from different parts of the world identify a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. We show that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other. C1 [Green, Richard E.; Krause, Johannes; Briggs, Adrian W.; Maricic, Tomislav; Stenzel, Udo; Kircher, Martin; Pruefer, Kay; Meyer, Matthias; Burbano, Hernan A.; Good, Jeffrey M.; Schultz, Rigo; Aximu-Petri, Ayinuer; Butthof, Anne; Hoeber, Barbara; Hoeffner, Barbara; Siegemund, Madlen; Weihmann, Antje; Kelso, Janet; Lachmann, Michael; Paeaebo, Svante] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, D-04103 Leipzig, Germany. [Patterson, Nick; Li, Heng; Nusbaum, Chad; Lander, Eric S.; Russ, Carsten; Novod, Nathaniel] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Zhai, Weiwei; Durand, Eric Y.; Malaspinas, Anna-Sapfo; Slatkin, Montgomery; Nielsen, Rasmus] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Fritz, Markus Hsi-Yang; Birney, Ewan] European Bioinformat Inst, European Mol Biol Lab, Hinxton CB10 1SD, Cambs, England. [Hansen, Nancy F.; Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Jensen, Jeffrey D.] Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA 01655 USA. [Alkan, Can; Eichler, Evan E.] Univ Washington, Dept Genome Sci, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Good, Jeffrey M.] Univ Montana, Div Biol Sci, Missoula, MT 59812 USA. [Brajkovic, Dejana] Croatian Acad Sci & Arts, Inst Quaternary Paleontol & Geol, HR-10000 Zagreb, Croatia. [Affourtit, Jason; Egholm, Michael] 454 Life Sci, Branford, CT 06405 USA. [Doronichev, Vladimir B.; Golovanova, Liubov V.] ANO Lab Prehist, St Petersburg, Russia. [Marques-Bonet, Tomas; Lalueza-Fox, Carles] Inst Evolutionary Biol UPF CSIC, Barcelona 08003, Spain. [de la Rasilla, Marco; Fortea, Javier] Univ Oviedo, Dept Hist, Area Prehist, Oviedo, Spain. [Rosas, Antonio] CSIC, Museo Nacl Ciencias Nat, Dept Paleobiol, E-28006 Madrid, Spain. [Schmitz, Ralf W.] Landschaftverband Rheinlund Landesmuseum Bonn, D-53115 Bonn, Germany. [Schmitz, Ralf W.] Univ Bonn, Abt Vor & Fruhgeschichtl Archaol, D-5300 Bonn, Germany. [Johnson, Philip L. F.] Emory Univ, Dept Biol, Atlanta, GA 30322 USA. [Falush, Daniel] Univ Coll Cork, Dept Microbiol, Cork, Ireland. [Verna, Christine] Max Planck Inst Evolutionary Anthropol, Dept Human Evolut, D-04103 Leipzig, Germany. [Reich, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Green, RE (reprint author), Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. EM green@eva.mpg.de; reich@genetics.med.harvard.edu; paabo@eva.mpg.de RI VERNA, Christine/A-2366-2017; Li, Heng/D-9344-2011; Nielsen, Rasmus/D-4405-2009; Alkan, Can/D-2982-2009; Burbano, Hernan/F-2952-2010; VERNA, Christine/H-3235-2013; Marques-Bonet, Tomas/I-4618-2014; Lalueza-Fox, Carles/G-9762-2015; Krause, Johannes/E-6640-2015; Rosas, Antonio/D-9742-2016 OI Jensen, Jeffrey/0000-0002-4786-8064; Birney, Ewan/0000-0001-8314-8497; Kircher, Martin/0000-0001-9278-5471; Burbano, Hernan A./0000-0003-3433-719X; VERNA, Christine/0000-0002-4217-5736; Li, Heng/0000-0003-4874-2874; Nielsen, Rasmus/0000-0003-0513-6591; Alkan, Can/0000-0002-5443-0706; Malaspinas, Anna-Sapfo/0000-0003-1001-7511; de la RASILLA, Marco/0000-0002-5505-0625; Marques-Bonet, Tomas/0000-0002-5597-3075; Krause, Johannes/0000-0001-5475-4690; Rosas, Antonio/0000-0002-5829-9952 FU Ministerio de Ciencia e Innovacion; Janggen-Pohn fellowship; National Human Genome Research Institute, National Institutes of Health; Burroughs Wellcome Career Development Award; [GM40282] FX We thank E. Buglione, A. Burke, Y.-J. Chen, J. Salem, P. Schaffer, E. Szekeres, and C. Turcotte at 454 Life Sciences Corp. for production sequencing on the 454 platform; S. Fisher, J. Wilkinson, J. Blye, R. Hegarty, A. Allen, S. K. Young, and J. L. Chang for nine Illumina sequencing runs performed at the Broad Institute; J. Rothberg and E. Rubin for input leading up to this project; O. Bar-Yosef, L. Excoffier, M. Gralle, J.-J. Hublin, D. Lieberman, M. Stoneking, and L. Vigilant for constructive criticism; I. Jankovic for assistance with the Vindija collection; S. Ptak, M. Siebauer, and J. Visagie for help with data analysis, M. Richards and S. Talamo for carbon dating; J. Dabney for editorial assistance; the Genome Center at Washington University for prepublication use of the orangutan genome assembly; and K. Finstermeier for expert graphical design. Neandertal bone extract sequence data have been deposited at European Bioinformatics Institute under STUDY accession ERP000119, alias Neandertal Genome project. HGDP sequence data have been deposited at EBI under STUDY accession ERP000121, alias Human Genome Diversity Project. We are grateful to the Max Planck Society, and particularly the Presidential Innovation Fund, for making this project possible. C. L.-F. was supported by a grant from the Ministerio de Ciencia e Innovacion; E. Y. D. and M. S. were supported in part by grant GM40282; A.-S. M. was supported by a Janggen-Pohn fellowship; N. F. H. and J. C. M. were supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; and D. R. by a Burroughs Wellcome Career Development Award in the Biomedical Sciences. Author contributions: S. P. conceived and coordinated the project; D. R. coordinated population genetic analyses; R. E. G. and J. Ke. coordinated bioinformatic aspects; R. E. G., J. Kr., A. W. B., M. E., and S. P. developed the initial project strategies; J. Kr. and T. M. collected and analyzed fossil samples; J. Kr., T. M., A. W. B., and M. M. developed the DNA extraction and library preparation protocols and performed laboratory work prior to sequencing; K. P. designed the restriction enzyme enrichment method; A. A.-P., A. B., B. Hb., B. Hff., M. Sg., R. S., A. W., J. A., M. E., and M. K. performed and coordinated DNA sequencing on the 454 and Illumina platforms; J. A. and M. E. organized and coordinated sequence production on the 454 platform; C. N., E. S. L., C. R., and N. N. organized and performed nine sequencing runs on the Illumina platform at the Broad Institute; M. K. and J. Ke. compiled the catalog of human-specific genomic features; U. S., M. K., N. H., J. M., J. Ke., K. P., and R. E. G. developed and implemented the primary sequence alignment and analysis methodologies; R. E. G., U. S., J. Kr., A. W. B., H. B., P. L. F. J. and M. L. developed and implemented the wet lab and bioinformatic assays for human DNA contamination; C. A., T. M.-B., and E. E. E. performed structural variation analyses; H. L., J. M., and D. R. designed and implemented analyses of population divergences; R. E. G., N. P., W. Z., J. M., H. L., M. H.-Y. F., E. Y. D., A. S.-M., P. L. F. J., J. J., J. G., M. L., D. F., M. S., E. B., R. N., S. P., and D. R. developed and implemented population genetics comparisons; R. E. G., M. L., J. G., D. F., J. D. J., D. R., and S. P. designed and implemented the screen for selective sweeps; P. R., D. B., Z. K., I. G., C. V., V. B. D., L. V. G., C. L.-F., M. R., J. F., A. R., and R. S.; provided samples, analyses, and paleontological expertise; . R. and S. P. edited the manuscript. NR 88 TC 1134 Z9 1177 U1 75 U2 567 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 7 PY 2010 VL 328 IS 5979 BP 710 EP 722 DI 10.1126/science.1188021 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 592DZ UT WOS:000277357100030 PM 20448178 ER PT J AU Mehta, N Cunningham, CK Flynn, P Pepe, J Obaro, S Kapogiannis, BG Bethel, J Luzuriaga, K AF Mehta, Nishaki Cunningham, Coleen K. Flynn, Patricia Pepe, Joyce Obaro, Stephen Kapogiannis, Bill G. Bethel, James Luzuriaga, Katherine CA Adolescent Trials Network HIV AIDS TI Impaired generation of hepatitis B virus-specific memory B cells in HIV infected individuals following vaccination SO VACCINE LA English DT Article DE HIV; Hepatitis B vaccines; Memory B cells ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; HOMOSEXUAL-MEN; SURFACE-ANTIGEN; CHILDREN; ANTIBODY; IMMUNOGENICITY; PERSISTENCE; RESPONSES; VACCINES AB Hepatitis B-specific memory B cell (HSMBC) frequencies were measured following hepatitis B vaccination 10 15 HIV uninfected and 12 HIV infected adolescents. HSMBC were detected at significantly lower frequencies in HIV infected than in HIV uninfected individuals. The detection of HBsAb >10 mIU/mlat study week 28 was strongly associated with the detection of HSMBC and a direct correlation between HBsAb titers and HSMBC frequencies was observed. In HIV uninfected individuals, antibody titers >1000 mIU/ml were associated with higher HSMC frequencies. Lower HSMBC frequencies, reduced memory B cell (MBC) proliferation, and altered B cell phenotypes were measured in viremic HIV infected individuals compared with aviremic HIV infected or HIV uninfected individuals. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Mehta, Nishaki; Pepe, Joyce; Luzuriaga, Katherine] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA 01605 USA. [Mehta, Nishaki; Pepe, Joyce; Luzuriaga, Katherine] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA. [Cunningham, Coleen K.] Duke Univ, Sch Med, Dept Pediat, Div Infect Dis, Durham, NC USA. [Flynn, Patricia] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38101 USA. [Obaro, Stephen] Michigan State Univ, Dept Pediat & Human Dev, Div Pediat Infect Dis, E Lansing, MI 48824 USA. [Kapogiannis, Bill G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. [Bethel, James] WESTAT Corp, Rockville, MD 20850 USA. RP Luzuriaga, K (reprint author), Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA 01605 USA. EM katherine.luzuriaga@umassmed.edu FU Pediatric AIDS Clinical Trials Group (PACTG)/International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) [5 U01 AI068632-02]; National Institutes of Health [R01-AI032391, K24-HD001489, P30-AI042845, U01 HD 040533, U01 HD 040474]; National Institutes on Drug Abuse; Mental Health; Duke Center for AIDS Research [P30 AI064518-04]; National Center for Research Resources, National Institutes of Health, Department of Health and Human Services; Children's National Medical Center [M01RR020359]; University of California at San Francisco [M01RR00083-42]; Pediatric Clinical Research [M01RR01271]; Tulane/LSU Clinical Trial Research Center FX We acknowledge the contribution of the investigators and staff at the following ATN sites that participated and enrolled subjects into this study: Children's Diagnostic and Treatment Center, Fort Lauderdale, FL (Puga, Leonard, Eysallanne, Inman); Children's Hospital of Los Angeles, Los Angeles, CA (Belzer, Tucker); Children's National Medical Center, Washington, DC (D'Angelo, Trexler, Hagler, Klamberg); John H. Stroger Jr. Hospital of Cook County and the Ruth M. Rothstein CORE Center, Chicago, IL (Martinez, Bojan, Jackson); Montefiore Medical Center, Bronx, NY (Futterman, Enriquez-Bruce, Campos); Mount Sinai Medical Center, New York, NY (Levin, Geiger, Lee); St. Jude Children's Research Hospital, Memphis, TN (Flynn, Gaur, Dillard, McKinley); Tulane University Health Sciences Center, New Orleans, LA (Abdalian, Baker, Kozina); University of Maryland, Baltimore, MD (Peralta, Flores, Gorle, Collinetti); University of Puerto Rico, San Juan, PR (Febo, Ayala-Flores, Fuentes); University of South Florida, Tampa, FL (Emmanuel, Lujan-Zilbermann, Callejas, Julian). Additional support was provided by the Pediatric AIDS Clinical Trials Group (PACTG)/International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) funded by grant No. 5 U01 AI068632-02. The following PACTG/IMPAACT sites also participated and enrolled subjects into this study: Hospital San Juan, Rio Piedras, Puerto Rico (Acevedo, Gonzalez, Angeli, Marrero, Perez); St. Jude Children's Research Hospital, Memphis, TN (Flynn, Patel, Dillard, Wride); University of Alabama at Birmingham, Birmingham, AL (Pass, Craine, Beatty); University of California at San Diego, San Diego, CA (Spector, Viani, Norris, Stangl).; We also thank Nancy Liu and Sushma Ahmad (Westat) for protocol support; Robin Brody, Erik Larson, Linda Lambrecht, James Coderre, and the UMass Pediatric Immunology staff for technical assistance; Margaret McManus for data analysis; and Wanda DePasquale for preparation of the manuscript.; Conflict of interest: All authors have contributed significantly to the work, have approved the manu:script, and concur with its submission. The manuscript material has not been previously reported, nor is it under consideration for publication elsewhere. There are no conflicting financial interests; This work was supported by the National Institutes of Health Grants R01-AI032391, K24-HD001489, and P30-AI042845 (to K.L.) and by The Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) from the National Institutes of Health (U01 HD 040533 and U01 HD 040474) through the National Institute of Child Health and Human Development (B. Kapogiannis, R. Hazra, S. Lee, C. Worrell), with supplemental funding from the National Institutes on Drug Abuse (N. Borek) and Mental Health (P. Brouwers, S. Allison). The study was scientifically reviewed by the ATN's Therapeutic Leadership Group. Network, scientific and logistical support was provided by the ATN Coordinating Center (C. Wilson, C. Partlow) at The University of Alabama at Birmingham. Network operations and analytic support was provided by the ATN Data and Operations Center at Westat, Incorporated U. Korelitz, B. Driver). Additional support for this study was provided by the P30 AI064518-04 (Duke Center for AIDS Research; CKC) and by grants from the General Clinical Research Center (GCRC) Program of the National Center for Research Resources, National Institutes of Health, Department of Health and Human Services. The following grants provided support: Children's National Medical Center, GCRC Grant M01RR020359 and University of California at San Francisco, GCRC Grant M01RR00083-42 and Pediatric Clinical Research Grant M01RR01271. The Tulane/LSU Clinical Trial Research Center was supported in part or in full by the Louisiana Board of Regents Clinical and Translational Research, Education, and Commercialization Project. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agencies NR 45 TC 15 Z9 15 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAY 7 PY 2010 VL 28 IS 21 BP 3672 EP 3678 DI 10.1016/j.vaccine.2010.03.022 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 602HC UT WOS:000278128800008 PM 20356567 ER PT J AU Ferrucci, L Semba, RD Guralnik, JM Ershler, WB Bandinelli, S Patel, KV Sun, K Woodman, RC Andrews, NC Cotter, RJ Ganz, T Nemeth, E Longo, DL AF Ferrucci, Luigi Semba, Richard D. Guralnik, Jack M. Ershler, William B. Bandinelli, Stefania Patel, Kushang V. Sun, Kai Woodman, Richard C. Andrews, Nancy C. Cotter, Robert J. Ganz, Tomas Nemeth, Elizabeta Longo, Dan L. TI Proinflammatory state, hepcidin, and anemia in older persons SO BLOOD LA English DT Article ID IRON-DEFICIENCY ANEMIA; CHRONIC DISEASE; SERUM HEPCIDIN; INFLAMMATION; HYPOFERREMIA; POPULATION; PREVALENCE; HUMANS AB patients with overt inflammatory diseases, up-regulated hepcidin impairs iron absorption and macrophage release, causing anemia. Whether the mild pro-inflammatory state of aging is associated with increased hepcidin is unknown. We characterized the relationships between urinary hepcidin, iron status, anemia, and inflammation in 582 patients 65 years or older participating in the InCHIANTI (Invecchiare in Chianti, "Aging in the Chianti Area") study, a population-based study of aging in Tuscany, Italy. Compared with nonanemic persons, urinary hepcidin (nanograms/milligram of urinary creatinine) was significantly lower in iron deficiency and inflammation anemia compared with no anemia or other anemia types. Urinary hepcidin was positively correlated with log(ferritin) and negatively correlated with the soluble transferrin receptor/log(ferritin) ratio but not correlated with markers of inflammation: interleukin-6 (IL-6), IL-1 beta, tumor necrosis factor-alpha, and C-reactive protein (CRP). Lower iron was significantly correlated with higher IL-6 and CRP. Adjusting for confounders, IL-6 and CRP remained significantly associated with serum iron, with no evidence that such a relationship was accounted for by variability in urinary hepcidin. In conclusion, elevated pro-inflammatory markers were associated with anemia and low iron status, but not with higher urinary hepcidin. Future studies should test whether hepcidin production becomes up-regulated only in situations of overt inflammation. (Blood. 2010; 115(18):3810-3816) C1 [Ferrucci, Luigi; Ershler, William B.; Longo, Dan L.] Harbor Hosp Ctr, Clin Res Branch, Natl Inst Aging, Intramural Res Program, Baltimore, MD 21225 USA. [Semba, Richard D.; Sun, Kai] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Guralnik, Jack M.; Patel, Kushang V.] Epidemiol Demog & Biometry Lab, Bethesda, MD USA. [Bandinelli, Stefania] ASF, Geriatr Rehabil Unit, Florence, Italy. [Woodman, Richard C.] Novartis Pharmaceut, Global Med Affairs, E Hanover, NJ USA. [Andrews, Nancy C.] Duke Univ, Sch Med, Durham, NC USA. [Cotter, Robert J.] Johns Hopkins Univ, Sch Med, Mass Spectrometry Lab, Baltimore, MD USA. Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90024 USA. RP Ferrucci, L (reprint author), Harbor Hosp Ctr, Clin Res Branch, Natl Inst Aging, Intramural Res Program, 5th Fl,3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov OI Andrews, Nancy/0000-0003-0243-4462 FU National Institute on Aging; National Institute on Aging, National Institutes of Health; Italian Ministry of Health [ICS-110.1/RS97.71]; US National Institute on Aging [N01-AG-919413, N01-AG-821336, R01 AG027012, R01 AG029148]; Orthobiotech FX This work was supported by National Institute on Aging and the Intramural Research Program, National Institute on Aging, National Institutes of Health. The InCHIANTI study was supported as a targeted project (ICS-110.1/RS97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (contracts N01-AG-919413 and N01-AG-821336; grants R01 AG027012 and R01 AG029148). Measures of hepcidin were supported by an unrestricted grant from Orthobiotech. NR 25 TC 70 Z9 74 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 6 PY 2010 VL 115 IS 18 BP 3810 EP 3816 DI 10.1182/blood-2009-02-201087 PG 7 WC Hematology SC Hematology GA 591WM UT WOS:000277335900025 PM 20081092 ER PT J AU Fishelovitch, D Shaik, S Wolfson, HJ Nussinov, R AF Fishelovitch, Dan Shaik, Sason Wolfson, Haim J. Nussinov, Ruth TI How Does the Reductase Help To Regulate the Catalytic Cycle of Cytochrome P450 3A4 Using the Conserved Water Channel? SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MOLECULAR-DYNAMICS; BINDING-SITE; SUBSTRATE-BINDING; CRYSTAL-STRUCTURE; SIDE-CHAIN; P450CAM; MECHANISM; IDENTIFICATION; RESOLUTION; PROTEINS AB Water molecules play a major role in the P450 catalytic cycle. Here, we locate the preferred water pathways and their gating mechanisms for the human cytochrome P450 3A4 (CYP3A4) and elucidate the role of the cytochrome P450 reductase (CPR) in turning on and activating these water channels. We perform explicit solvent molecular dynamic simulations of CYP3A4, unbound and bound to two substrates, and with and without the flavin mononucleotide (FMN)-binding domain of CPR. We observe in/out passage of water molecules via a water-specific and conserved channel (aqueduct) located between the active site and the heme proximal side. We find that the aqueduct gating mechanism is mediated by R375, the conserved arginine that salt bridges with the heme 7-propionate. When R375 rotates, it opens the aqueduct and establishes a connection between a cluster of active site water molecules network and the bulk solvent, The aqueduct region overlaps with the CPR binding-site to CYP3A4. Indeed, we find that when the RAN domain of CPR binds to CYP3A4, the aqueduct fully opens up, thereby allowing a flow of water molecules. The aqueduct's opening can permit proton transfer, shuttling the protons to the active site through ordered water molecules. In addition, the expulsion of water molecules via the aqueduct contributes to substrate binding. As such, the CPR binding has a function: it triggers the aqueduct's opening and thereby enables a proton shuttle pathway, which is needed for the dioxygen activation. This mechanism could be a general paradigm in P450s. C1 [Fishelovitch, Dan; Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. [Shaik, Sason] Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel. [Shaik, Sason] Hebrew Univ Jerusalem, Lise Meitner Minerva Ctr Computat Quantum Chem, IL-91904 Jerusalem, Israel. [Wolfson, Haim J.] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth] NCI, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. RP Nussinov, R (reprint author), Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. EM ruthn@helix.nih.gov RI Wolfson, Haim/A-1837-2011 FU National Cancer Institute; National Institutes of Health [HHSN26120080000 IE]; HU [ISF (53/09)] FX This project has been funded in whole or in part by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN26120080000 IE. 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 pail) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The research at the HU was supported in parts by ISF (53/09) and DIP (DIP-F.7.1) grants to S.S. This study utilized the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 55 TC 27 Z9 27 U1 2 U2 12 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 MAY 6 PY 2010 VL 114 IS 17 BP 5964 EP 5970 DI 10.1021/jp101894k PG 7 WC Chemistry, Physical SC Chemistry GA 588FR UT WOS:000277053900043 PM 20387782 ER PT J AU Mantilla-Beniers, NB Bjornstad, ON Grenfell, BT Rohani, P AF Mantilla-Beniers, N. B. Bjornstad, O. N. Grenfell, B. T. Rohani, P. TI Decreasing stochasticity through enhanced seasonality in measles epidemics SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE disease ecology; measles; seasonality; stochasticity; epidemiology; resonance ID INFANT-MORTALITY DECLINE; TIME-SERIES ANALYSIS; INFECTIOUS-DISEASES; CHILDHOOD DISEASES; DYNAMICAL-SYSTEMS; POPULATION; ENGLAND; MODEL; FLUCTUATIONS; VARIABILITY AB Seasonal changes in the environment are known to be important drivers of population dynamics, giving rise to sustained population cycles. However, it is often difficult to measure the strength and shape of seasonal forces affecting populations. In recent years, statistical time-series methods have been applied to the incidence records of childhood infectious diseases in an attempt to estimate seasonal variation in transmission rates, as driven by the pattern of school terms. In turn, school-term forcing was used to show how susceptible influx rates affect the interepidemic period. In this paper, we document the response of measles dynamics to distinct shifts in the parameter regime using previously unexplored records of measles mortality from the early decades of the twentieth century. We describe temporal patterns of measles epidemics using spectral analysis techniques, and point out a marked decrease in birth rates over time. Changes in host demography alone do not, however, suffice to explain epidemiological transitions. By fitting the time-series susceptible-infected-recovered model to measles mortality data, we obtain estimates of seasonal transmission in different eras, and find that seasonality increased over time. This analysis supports theoretical work linking complex population dynamics and the balance between stochastic and deterministic forces as determined by the strength of seasonality. C1 [Mantilla-Beniers, N. B.] Univ Nacl Autonoma Mexico, C3, Mexico City 04510, DF, Mexico. [Mantilla-Beniers, N. B.] Univ Nacl Autonoma Mexico, Inst Fis, Mexico City 04510, DF, Mexico. [Mantilla-Beniers, N. B.] Univ Nacl Autonoma Mexico, Fac Ciencias, Mexico City 04510, DF, Mexico. [Bjornstad, O. N.; Grenfell, B. T.] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Bjornstad, O. N.; Grenfell, B. T.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Rohani, P.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, P.] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Bjornstad, O. N.; Grenfell, B. T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Mantilla-Beniers, NB (reprint author), Univ Nacl Autonoma Mexico, C3, Mexico City 04510, DF, Mexico. EM nmantilla@cantab.net RI Bjornstad, Ottar/I-4518-2012; Mantilla-Beniers, Natalia/F-6081-2013 FU Gates Foundation; Science and Technology Directorate; Department of Homeland Security; Fogarty International Center; National Institutes of Health; CONACyT; DGAPA (UNAM) FX O.N.B., B.T.G. and P.R. were supported by the Gates Foundation, the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. N.B.M.B. received funding from CONACyT for part of this research and as a PROFIP scholar from DGAPA (UNAM). NR 84 TC 9 Z9 9 U1 1 U2 11 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD MAY 6 PY 2010 VL 7 IS 46 BP 727 EP 739 DI 10.1098/rsif.2009.0317 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 573PY UT WOS:000275927900002 PM 19828508 ER PT J AU Sanyal, AJ Chalasani, N Kowdley, KV McCullough, A Diehl, AM Bass, NM Neuschwander-Tetri, BA Lavine, JE Tonascia, J Unalp, A Van Natta, M Clark, J Brunt, EM Kleiner, DE Hoofnagle, JH Robuck, PR AF Sanyal, Arun J. Chalasani, Naga Kowdley, Kris V. McCullough, Arthur Diehl, Anna Mae Bass, Nathan M. Neuschwander-Tetri, Brent A. Lavine, Joel E. Tonascia, James Unalp, Aynur Van Natta, Mark Clark, Jeanne Brunt, Elizabeth M. Kleiner, David E. Hoofnagle, Jay H. Robuck, Patricia R. CA NASH CRN TI Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FATTY LIVER-DISEASE; FOLLOW-UP; ROSIGLITAZONE; METAANALYSIS; VARIABILITY; STEATOSIS; HISTORY; TRIAL; NAFLD AB Background: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. Methods: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. Results: Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Conclusions: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT0063622.) N Engl J Med 2010;362:1675-85. C1 [Sanyal, Arun J.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Chalasani, Naga] Indiana Univ, Indianapolis, IN 46204 USA. [Kowdley, Kris V.] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [McCullough, Arthur] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Diehl, Anna Mae] Duke Univ, Durham, NC USA. [Bass, Nathan M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Neuschwander-Tetri, Brent A.] St Louis Univ, St Louis, MO 63103 USA. [Brunt, Elizabeth M.] Washington Univ, St Louis, MO 63130 USA. [Lavine, Joel E.] Univ Calif San Diego, San Diego, CA 92103 USA. [Tonascia, James; Unalp, Aynur; Van Natta, Mark; Clark, Jeanne] Johns Hopkins Univ, Baltimore, MD USA. [Kleiner, David E.] NCI, Bethesda, MD 20892 USA. [Hoofnagle, Jay H.; Robuck, Patricia R.] NIDDKD, Bethesda, MD 20892 USA. RP Sanyal, AJ (reprint author), MCV Box 980342, Richmond, VA 23298 USA. EM asanyal@mcvh-vcu.edu OI Kleiner, David/0000-0003-3442-4453 FU National Institutes of Health (NIH) [U01DK61718, U01DK61728, U01DK61731, U01DK61732, U01DK61734, U01DK61737, U01DK61738, U01DK61730, U01DK61713, UL1RR024989, UL1RR024128, UL1RR000750, UL1RR024131, M01RR000827, UL1RR025014, M01RR600065]; Takeda Pharmaceuticals North America through a Cooperative Research and Development Agreement with the NIH FX Supported by grants (U01DK61718, U01DK61728, U01DK61731, U01DK61732, U01DK61734, U01DK61737, U01DK61738, U01DK61730, and U01DK61713) from the National Institutes of Health (NIH), by the intramural program of the National Cancer Institute, and by NIH General Clinical Research Center grants or Clinical and Translational Science Awards (UL1RR024989, UL1RR024128, UL1RR000750, UL1RR024131, M01RR000827, UL1RR025014, and M01RR600065). Additional funding was provided by Takeda Pharmaceuticals North America through a Cooperative Research and Development Agreement with the NIH. The vitamin E softgels and matching placebo were provided by Pharmavite through a Clinical Trial Agreement with the NIH. NR 29 TC 827 Z9 858 U1 7 U2 42 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 6 PY 2010 VL 362 IS 18 BP 1675 EP 1685 DI 10.1056/NEJMoa0907929 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 591OQ UT WOS:000277311200005 PM 20427778 ER PT J AU Kimmel, PL Malozowski, S AF Kimmel, Paul L. Malozowski, Saul TI Reevaluating Erythropoiesis-Stimulating Agents SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Kimmel, Paul L.; Malozowski, Saul] NIDDKD, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), NIDDKD, Bethesda, MD 20892 USA. EM sm007@nih.gov NR 4 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 6 PY 2010 VL 362 IS 18 BP 1742 EP 1743 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 591OQ UT WOS:000277311200023 PM 20449880 ER PT J AU Castilho, RM Squarize, CH Leelahavanichkul, K Zheng, Y Bugge, T Gutkind, JS AF Castilho, Rogerio M. Squarize, Cristiane H. Leelahavanichkul, Kantima Zheng, Yi Bugge, Thomas Gutkind, J. Silvio TI Rac1 Is Required for Epithelial Stem Cell Function during Dermal and Oral Mucosal Wound Healing but Not for Tissue Homeostasis in Mice SO PLOS ONE LA English DT Article ID HAIR FOLLICLE; HUMAN KERATINOCYTES; RHO-GTPASES; SKIN; EXPRESSION; EPIDERMIS; ACTIVATION; DIFFERENTIATION; TRANSFORMATION; MECHANISMS AB Background: The regenerative capacity of the skin, including the continuous replacement of exfoliated cells and healing of injuries relies on the epidermal stem cells and their immediate cell descendants. The relative contribution of the hair follicle stem cells and the interfollicular stem cells to dermal wound healing is an area of active investigation. Recent studies have revealed that the small GTPase Rac1, which regulates cell migration and nuclear gene expression, is required for hair follicle stem function but not for the normal homeostasis of the interfollicular skin. Methodology/Principal Findings: Here we explored whether Rac1 contributes to wound healing in the skin and in the oral mucosa, the latter an anatomical site that presents similar architecture to that of the skin but is devoid of any hair follicle structures, and hence lacks hair follicle stem cells. Epidermal Rac1 gene excision led to the clearly delayed closure of cutaneous wounds. Remarkably, genetic ablation of Rac1 from the oral mucosa resulted in the complete inability of oral wounds to heal. We present evidence that the lack of oral mucosal re-epithelization may result from the reduced migratory capacity of cells lacking Rac1 together with altered expression of injury-induced proliferative and cellular stress-related expression programs. Conclusions/Significance: Together, these observations support that while the normal development and homeostasis of the interfollicular skin and oral mucosa do not require Rac1 function, the interfollicular and oral epithelial stem cells may require a Rac1-dependent program to orchestrate the tissue response to injury and ultimate for wound closure. Ultimately, these findings may enable the molecular characterization of the acute tissue regenerative response of these stem cell populations, thus facilitating the identification of novel molecular-targeted strategies aimed at accelerating wound closure. C1 [Castilho, Rogerio M.; Squarize, Cristiane H.; Leelahavanichkul, Kantima; Bugge, Thomas; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Zheng, Yi] Univ Cincinnati, Med Ctr, Div Expt Hematol, Childrens Hosp, Cincinnati, OH 45267 USA. [Castilho, Rogerio M.; Squarize, Cristiane H.] Univ Michigan, Dept Periodont & Oral Med, Ann Arbor, MI 48109 USA. RP Castilho, RM (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. EM sg39v@nih.gov RI Castilho, Rogerio/E-4987-2010; Gutkind, J. Silvio/A-1053-2009; Zheng, Yi/J-7235-2015 OI Zheng, Yi/0000-0001-7089-6074 FU Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research [Z01DE00558-18] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research, project Z01DE00558-18. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 29 Z9 30 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 6 PY 2010 VL 5 IS 5 AR e10503 DI 10.1371/journal.pone.0010503 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 592LG UT WOS:000277379800002 PM 20463891 ER PT J AU Schuck, P AF Schuck, Peter TI Sedimentation Patterns of Rapidly Reversible Protein Interactions SO BIOPHYSICAL JOURNAL LA English DT Article ID VELOCITY ANALYTICAL ULTRACENTRIFUGATION; PYRUVATE-DEHYDROGENASE COMPLEX; COEFFICIENT DISTRIBUTIONS C(S); SIZE-DISTRIBUTION ANALYSIS; SELF-ASSOCIATING SOLUTES; GILBERT-JENKINS THEORY; LAMM EQUATION; WEIGHT AVERAGE; SYSTEMS; EQUILIBRIUM AB The transport behavior of macromolecular mixtures with rapidly reversible complex formation is of great interest in the study of protein interactions by many different methods. Complicated transport patterns arise even for simple bimolecular reactions, when all species exhibit different migration velocities. Although partial differential equations are available to describe the spatial and temporal evolution of the interacting system given particular initial conditions, a general overview of the phase behavior of the systems in parameter space has not yet been reported. In the case of sedimentation of two-component mixtures, this study presents simple analytical solutions that solve the underlying equations in the diffusion-free limit previously subject to Gilbert-Jenkins theory. The new expressions describe, with high precision, the average sedimentation coefficients and composition of each boundary, which allow the examination of features of the whole parameter space at once, and may be used for experimental design and robust analysis of experimental boundary patterns to derive the stoichiometry and affinity of the complex. This study finds previously unrecognized features, including a phase transition between boundary patterns. The model reveals that the time-average velocities of all components in the reaction mixture must match-a condition that suggests an intuitive physical picture of an effective particle of the coupled cosedimentation of an interacting system. Adding to the existing numerical solutions of the relevant partial differential equations, the effective particle model provides physical insights into the relationships of the parameters that govern sedimentation patterns. C1 Natl Inst Biomed Imaging & Bioengn, Dynam Macromolecular Assembly, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromolecular Assembly, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. EM schuckp@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 36 TC 36 Z9 36 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY 5 PY 2010 VL 98 IS 9 BP 2005 EP 2013 DI 10.1016/j.bpj.2009.12.4336 PG 9 WC Biophysics SC Biophysics GA 592KH UT WOS:000277377300035 PM 20441765 ER PT J AU Anderson, WF Camargo, MC Fraumeni, JF Correa, P Rosenberg, PS Rabkin, CS AF Anderson, William F. Camargo, M. Constanza Fraumeni, Joseph F., Jr. Correa, Pelayo Rosenberg, Philip S. Rabkin, Charles S. TI Age-Specific Trends in Incidence of Noncardia Gastric Cancer in US Adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HELICOBACTER-PYLORI INFECTION; UNITED-STATES; TEMPORAL VARIATION; COHORT MODELS; RATES; PERIOD; EPIDEMIOLOGY; ESOPHAGEAL; RISK AB Context For the last 50 years, overall age-standardized incidence rates for noncardia gastric cancer have steadily declined in most populations. However, overall rates are summary measures that may obscure important age-specific trends. Objective To examine effects of age at diagnosis on noncardia gastric cancer incidence trends in the United States. Design, Setting, and Participants Descriptive study with age-period-cohort analysis of cancer registration data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, which covers approximately 26% of the US population. From 1977 through 2006, there were 83 225 adults with incident primary gastric cancer, including 39 003 noncardia cases. Main Outcome Measures Overall and age-specific incidence rates, adjusted for period and cohort effects using age-period-cohort models. Results were stratified by race, sex, and socioeconomic status. Results Overall age-standardized annual incidence per 100 000 population declined during the study period from 5.9 (95% confidence interval [CI], 5.7-6.1) to 4.0 (95% CI, 3.9-4.1) in whites, from 13.7 (95% CI, 12.5-14.9) to 9.5 (95% CI, 9.1-10.0) in blacks, and from 17.8 (95% CI, 16.1-19.4) to 11.7 (95% CI, 11.2-12.1) in other races. Age-specific trends among whites varied significantly between older and younger age groups (P < .001 for interaction by age): incidence per 100 000 declined significantly from 19.8 (95% CI, 19.0-20.6) to 12.8 (95% CI, 12.5-13.1) for ages 60 to 84 years and from 2.6 (95% CI, 2.4-2.8) to 2.0 (95% CI, 1.9-2.1) for ages 40 to 59 years but increased significantly from 0.27 (95% CI, 0.19-0.35) to 0.45 (95% CI, 0.39-0.50) for ages 25 to 39 years. Conversely, rates for all age groups declined or were stable among blacks and other races. Age-period-cohort analysis confirmed a significant increase in whites among younger cohorts born since 1952 (P < .001). Conclusions From 1977 through 2006, the incidence rate for noncardia gastric cancer declined among all race and age groups except for whites aged 25 to 39 years, for whom it increased. Additional surveillance and analytical studies are warranted to identify risk factors that may explain this unfavorable trend. JAMA. 2010;303(17):1723-1728 www.jama.com C1 [Rabkin, Charles S.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Camargo, M. Constanza] Univ Illinois, Div Epidemiol & Biostat, Chicago, IL USA. [Correa, Pelayo] Vanderbilt Univ, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Nashville, TN 37212 USA. RP Rabkin, CS (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Ste 7082, Rockville, MD 20852 USA. EM rabkinc@mail.nih.gov RI Camargo, M. Constanza/R-9891-2016 FU National Cancer Institute, National Institutes of Health FX This study was funded by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 31 TC 128 Z9 134 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 5 PY 2010 VL 303 IS 17 BP 1723 EP 1728 DI 10.1001/jama.2010.496 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 591CR UT WOS:000277276600025 PM 20442388 ER PT J AU Maitland, ML Bakris, GL Black, HR Chen, HX Durand, JB Elliott, WJ Ivy, SP Leier, CV Lindenfeld, J Liu, G Remick, SC Steingart, R Tang, WHW AF Maitland, Michael L. Bakris, George L. Black, Henry R. Chen, Helen X. Durand, Jean-Bernard Elliott, William J. Ivy, S. Percy Leier, Carl V. Lindenfeld, JoAnn Liu, Glenn Remick, Scot C. Steingart, Richard Tang, W. H. Wilson CA Natl Canc Inst TI Initial Assessment, Surveillance, and Management of Blood Pressure in Patients Receiving Vascular Endothelial Growth Factor Signaling Pathway Inhibitors SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID TYROSINE KINASE INHIBITOR; RENAL-CELL CARCINOMA; ANGIOGENESIS INHIBITOR; ARTERIAL-HYPERTENSION; CLINICAL TOXICITY; EUROPEAN-SOCIETY; SUNITINIB MALATE; CANCER; THERAPY; BEVACIZUMAB AB Hypertension is a mechanism-based toxic effect of drugs that inhibit the vascular endothelial growth factor signaling pathway (VSP). Substantial evidence exists for managing hypertension as a chronic condition, but there are few prospectively collected data on managing acute hypertension caused by VSP inhibitors. The Investigational Drug Steering Committee of the National Cancer Institute convened an interdisciplinary cardiovascular toxicities expert panel to evaluate this problem, to make recommendations to the Cancer Therapy Evaluation Program on further study, and to structure an approach for safe management by treating physicians. The panel reviewed: the published literature on blood pressure (BP), hypertension, and specific VSP inhibitors; abstracts from major meetings; shared experience with the development of VSP inhibitors; and established principles of hypertension care. The panel generated a consensus report including the recommendations on clinical concerns summarized here. To support the greatest possible number of patients to receive VSP inhibitors safely and effectively, the panel had four recommendations: 1) conduct and document a formal risk assessment for potential cardiovascular complications, 2) recognize that preexisting hypertension will be common in cancer patients and should be identified and addressed before initiation of VSP inhibitor therapy, 3) actively monitor BP throughout treatment with more frequent assessments during the first cycle of treatment, and 4) manage BP with a goal of less than 140/90 mmHg for most patients (and to lower, prespecified goals in patients with specific preexisting cardiovascular risk factors). Proper agent selection, dosing, and scheduling of follow-up should enable maintaining VSP inhibition while avoiding the complications associated with excessive or prolonged elevation in BP. C1 [Maitland, Michael L.] Univ Chicago, Ctr Comprehens Canc, Comm Clin Pharmacol & Pharmacogenom, Dept Med,Sect Hematol Oncol, Chicago, IL 60637 USA. [Bakris, George L.] Univ Chicago, Dept Med, Endocrinol Sect, Chicago, IL 60637 USA. [Black, Henry R.] NYU, Sch Med, Ctr Prevent Cardiovasc Dis, Div Cardiol, New York, NY USA. [Chen, Helen X.; Ivy, S. Percy] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Durand, Jean-Bernard] Univ Texas MD Anderson Canc Ctr, Dept Cardiol, Houston, TX 77030 USA. [Elliott, William J.] Pacific NW Univ Hlth Sci, Div Pharmacol, Yakima, WA USA. [Leier, Carl V.] Ohio State Univ, Dorothy M Davis Heart & Lung Res Inst, Div Cardiovasc Med, Columbus, OH 43210 USA. [Lindenfeld, JoAnn] Univ Colorado, Dept Med, Div Cardiol, Denver, CO USA. [Liu, Glenn] Univ Wisconsin Carbone Canc, Dept Med, Hematol Oncol Sect, Madison, WI USA. [Remick, Scot C.] W Virginia Univ, Sch Med, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. [Steingart, Richard] Mem Sloan Kettering Canc Ctr, Dept Med, Serv Cardiol, New York, NY 10021 USA. [Tang, W. H. Wilson] Cleveland Clin, Inst Heart & Vasc, Sect Heart Failure & Cardiac Transplantat Med, Cleveland, OH 44106 USA. RP Maitland, ML (reprint author), Univ Chicago, Med Ctr, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM mmaitlan@medicine.bsd.uchicago.edu RI Tang, Wai Hong/I-1238-2013 FU NCI NIH HHS [5K23CA124802] NR 42 TC 137 Z9 142 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAY 5 PY 2010 VL 102 IS 9 BP 596 EP 604 DI 10.1093/jnci/djq091 PG 9 WC Oncology SC Oncology GA 593IZ UT WOS:000277448700008 PM 20351338 ER PT J AU Bromberg-Martin, ES Hikosaka, O Nakamura, K AF Bromberg-Martin, Ethan S. Hikosaka, Okihide Nakamura, Kae TI Coding of Task Reward Value in the Dorsal Raphe Nucleus SO JOURNAL OF NEUROSCIENCE LA English DT Article ID JUXTACELLULAR LABELING METHODS; BASAL GANGLIA; MONOAMINERGIC INNERVATION; SEROTONERGIC NEURONS; GENETIC-VARIATION; LATERAL AMYGDALA; FIRING NEURONS; FUTURE REWARDS; SENSORY INPUTS; EYE-MOVEMENTS AB The dorsal raphe nucleus and its serotonin-releasing neurons are thought to regulate motivation and reward-seeking. These neurons are known to be active during motivated behavior, but the underlying principles that govern their activity are unknown. Here we show that a group of dorsal raphe neurons encode behavioral tasks in a systematic manner, tracking progress toward upcoming rewards. We analyzed dorsal raphe neuron activity recorded while animals performed two reward-oriented saccade tasks. There was a strong correlation between the tonic activity level of a neuron during behavioral tasks and its encoding of reward-related cues and outcomes. Neurons that were tonically excited during the task predominantly carried positive reward signals. Neurons that were tonically inhibited during the task predominantly carried negative reward signals. Neurons that did not change their tonic activity levels during the task had weak reward signals with no tendency for a positive or negative direction. This form of correlated task and reward coding accounted for the majority of systematic variation in dorsal raphe response patterns in our tasks. A smaller component of neural activity reflected detection of reward delivery. Our data suggest that the dorsal raphe nucleus encodes participation in a behavioral task in terms of its future motivational outcomes. C1 [Bromberg-Martin, Ethan S.; Hikosaka, Okihide] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Nakamura, Kae] Kansai Med Univ, Sch Med, Dept Physiol, Moriguchi, Osaka 5708506, Japan. [Nakamura, Kae] Japan Sci & Technol Agcy, Kawaguchi, Saitama 3320012, Japan. RP Bromberg-Martin, ES (reprint author), NEI, Sensorimotor Res Lab, NIH, 49 Convent Dr,Bldg 49,Room 2A50, Bethesda, MD 20892 USA. EM bromberge@mail.nih.gov FU Intramural Research; Precursory Research for Embryonic Science and Technology; Takeda Foundation; Nakayama Foundation; Grant-in-Aid for Scientific Research B; Grant-in-Aid for Scientific Research on Priority Areas FX This research was supported by the Intramural Research Program at the National Eye Institute. K.N. is supported by Precursory Research for Embryonic Science and Technology, the Takeda Foundation, the Nakayama Foundation, a Grant-in-Aid for Scientific Research B, and a Grant-in-Aid for Scientific Research on Priority Areas. NR 56 TC 63 Z9 64 U1 2 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 5 PY 2010 VL 30 IS 18 BP 6262 EP 6272 DI 10.1523/JNEUROSCI.0015-10.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 592EH UT WOS:000277358300012 PM 20445052 ER PT J AU Berman, RA Wurtz, RH AF Berman, Rebecca A. Wurtz, Robert H. TI Functional Identification of a Pulvinar Path from Superior Colliculus to Cortical Area MT SO JOURNAL OF NEUROSCIENCE LA English DT Article ID OLD-WORLD MONKEYS; FRONTAL EYE FIELD; INFERIOR PULVINAR; MACAQUE MONKEY; RHESUS-MONKEY; VISUAL-CORTEX; MACACA-MULATTA; ARCHITECTONIC SUBDIVISIONS; TOPOGRAPHIC ORGANIZATION; PARABIGEMINAL NUCLEUS AB The idea of a second visual pathway, in which visual signals travel from brainstem to cortex via the pulvinar thalamus, has had considerable influence as an alternative to the primary geniculo-striate pathway. Existence of this second pathway in primates, however, is not well established. A major question centers on whether the pulvinar acts as a relay, particularly in the path from the superior colliculus (SC) to the motion area in middle temporal cortex (MT). We used physiological microstimulation to identify pulvinar neurons belonging to the path from SC to MT in the macaque. We made three salient observations. First, we identified many neurons in the visual pulvinar that received input from SC or projected to MT, as well as a largely separate set of neurons that received input from MT. Second, and more importantly, we identified a subset of neurons as relay neurons that both received SC input and projected to MT. The identification of these relay neurons demonstrates a continuous functional path from SC to MT through the pulvinar in primates. Third, we histologically localized a subset of SC-MT relay neurons to the subdivision of inferior pulvinar known to project densely to MT but also localized SC-MT relay neurons to an adjacent subdivision. This pattern indicates that the pulvinar pathway is not limited to a single anatomically defined region. These findings bring new perspective to the functional organization of the pulvinar and its role in conveying signals to the cerebral cortex. C1 [Berman, Rebecca A.; Wurtz, Robert H.] NEI, Sensorimotor Res Lab, NIH, Bethesda 20982, MD USA. RP Berman, RA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda 20982, MD USA. EM bermanr@nei.nih.gov FU National Eye Institute Intramural Research FX This work was supported by the National Eye Institute Intramural Research Program at the National Institutes of Health. We are grateful to Mitchell Smith for processing and analysis of the histological sections, to John McClurkin for assistance in modifying the computer programs to control microstimulation, and to Altah Nichols and Tom Ruffner for machine shop support. NR 60 TC 71 Z9 72 U1 2 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 5 PY 2010 VL 30 IS 18 BP 6342 EP 6354 DI 10.1523/JNEUROSCI.6176-09.2010 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 592EH UT WOS:000277358300020 PM 20445060 ER PT J AU Ryabov, Y Clore, GM Schwieters, CD AF Ryabov, Yaroslav Clore, G. Marius Schwieters, Charles D. TI Direct Use of N-15 Relaxation Rates as Experimental Restraints on Molecular Shape and Orientation for Docking of Protein-Protein Complexes SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ROTATIONAL DIFFUSION; DISTANCE RESTRAINTS; GLOBULAR-PROTEINS; DIPOLAR COUPLINGS; CRYSTAL-STRUCTURE; TERMINAL DOMAIN; ENZYME I; NMR; HPR; INFORMATION AB N-15 relaxation rates contain information on overall molecular shape and size, as well as residue specific orientations of N-H bond vectors relative to the axes of the diffusion tensor. Here we describe a pseudopotential E-relax that permits direct use of N-15 relaxation rates, in the form of R-2/R-1 ratios, as experimental restraints in structure calculations without requiring prior information to be extracted from a known molecular structure. The elements of the rotational diffusion tensor are calculated from the atomic coordinates at each step of the structure calculation and then used together with the N-H bond vector orientations to compute the N-15 R-2/R-1 ratios. We show that the E-relax term can be reliably used for protein-protein docking of complexes and illustrate its applicability to the 40 kDa complex of the N-terminal domain of enzyme I and the histidine phosphocarrier protein HPr and to the symmetric HIV-1 protease dimer. C1 [Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Ryabov, Yaroslav; Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov; charles.schwieters@nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU NIDDK; CIT FX Y.R. acknowledges a National Research Council Research Associateship. This work was supported by the NIH Intramural Research Programs of NIDDK (G.M.C.) and CIT (C.D.S.). NR 26 TC 13 Z9 13 U1 0 U2 3 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 MAY 5 PY 2010 VL 132 IS 17 BP 5987 EP + DI 10.1021/ja101842n PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA 589OA UT WOS:000277158500030 PM 20392103 ER PT J AU Tokar, EJ Qu, W Liu, J Liu, W Webber, MM Phang, JM Waalkes, MP AF Tokar, Erik J. Qu, Wei Liu, Jie Liu, Wei Webber, Mukta M. Phang, James M. Waalkes, Michael P. TI Arsenic-Specific Stem Cell Selection During Malignant Transformation SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID PROSTATE EPITHELIAL-CELLS; GLUTATHIONE-S-TRANSFERASE; MULTIDRUG-RESISTANCE; APOPTOTIC RESISTANCE; ANTICANCER AGENTS; OXIDATIVE STRESS; LOW-LEVEL; IN-UTERO; CANCER; EXPOSURE AB Arsenic is a carcinogen that targets the urogenital system, including the prostate. Although the mechanisms for arsenic-induced carcinogenesis are undefined, arsenic drives overaccumulation of stem cells and cancer stem cells (CSCs) in vivo and in vitro, indicating that these cells are a key target population. Disruption of stem cell population dynamics may be critical to acquisition of cancer phenotype. We tested the hypothesis that prostate stem cells have a survival selection advantage during arsenic exposure that favors their accumulation and facilitates their malignant transformation. Innate and acquired resistance to acute (24-72 hours of exposure) and chronic (6 weeks of exposure) arsenite-induced cytolethality and apoptosis were assessed in a human prostate stem cell line (WPE-stem) and the mature parental cell line (RWPE-1). Real-time reverse transcription-polymerase chain reaction and/or Western blot analysis was used to measure the expression of apoptosis-, stress-, and arsenic-related genes. Arsenic-, cadmium-, and N-methyl-N-nitrosourea-induced isogenic malignant transformants of RWPE-1 cells were compared for acquisition of CSC-like qualities by holoclone and sphere formation assays, growth in soft agar, and expression of CSC biomarkers. All statistical tests were two-sided. WPE-stem cells showed innate resistance to arsenic-induced cytolethality (arsenite concentration lethal to 50% of the cells [LC(50)] = 32.4 mu M, 95% confidence interval [CI] = 31.5 to 33.3 mu M) and apoptosis compared with parental RWPE-1 cells (LC(50) = 10.4 mu M, 95% CI = 7.4 to 13.4 mu M). Compared with RWPE-1 cells, WPE-stem cells showed noticeably higher expression of antiapoptotic (ie, BCL2, MT), stress-related (ie, NFE2L2, SOD1, PRODH), and arsenic adaptation (ie, ABCC1, GSTP1) factors and noticeably lower expression of proapoptotic factors (ie, BAX, caspases 3, 7, 8, and 9). WPE-stem cells also showed hyper-adaptability to chronic arsenite exposure (5 mu M, 6 weeks) compared with RWPE-1 cells (LC(50) = 94.7 vs 32.1 mu M, difference = 62.6 mu M, 95% CI = 53.3 to 71.9 mu M) at levels that in previous work induced a malignant phenotype in RWPE-1 after 30 weeks of exposure. Quantification of CSC-like cells in isogenic RWPE-1 transformants showed that marked overproduction was unique to a malignant phenotype acquired in response to arsenic exposure but not in response to cadmium or N-methyl-N-nitrosourea exposure. An apparent stem cell survival advantage with regard to arsenic causes selection during malignant transformation that manifests itself as an overabundance of CSC-like cells specifically after arsenic-driven acquisition of malignant phenotype. The increased resistance to apoptosis and arsenite hyper-adaptability of WPE-stem cells suggests that arsenite transformation of RWPE-1 cells involves an increase in the number of CSC-like cells. C1 [Tokar, Erik J.; Qu, Wei; Liu, Jie; Waalkes, Michael P.] NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. [Liu, Wei; Phang, James M.] NCI, Metab & Canc Susceptibil Sect, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. [Webber, Mukta M.] Michigan State Univ, Dept Zool, E Lansing, MI 48824 USA. [Webber, Mukta M.] Michigan State Univ, Dept Med, E Lansing, MI 48824 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, 111 Alexander Dr,MD F0-09, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [NO1-CO-12400] FX This research was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and also, in part, with federal funds from the National Cancer Institute, National Institutes of Health, under Contract NO1-CO-12400. NR 59 TC 42 Z9 45 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 5 PY 2010 VL 102 IS 9 BP 638 EP 649 DI 10.1093/jnci/djq093 PG 12 WC Oncology SC Oncology GA 593IZ UT WOS:000277448700012 PM 20339138 ER PT J AU Azzato, EM Tyrer, J Fasching, PA Beckmann, MW Ekici, AB Schulz-Wendtland, R Bojesen, SE Nordestgaard, BG Flyger, H Milne, RL Arias, JI Menendez, P Benitez, J Chang-Claude, J Hein, R Wang-Gohrke, S Nevanlinna, H Heikkinen, T Aittomaki, K Blomqvist, C Margolin, S Mannermaa, A Kosma, VM Kataja, V Beesley, J Chen, XQ Chenevix-Trench, G Couch, FJ Olson, JE Fredericksen, ZS Wang, XS Giles, GG Severi, G Baglietto, L Southey, MC Devilee, P Tollenaar, RAEM Seynaeve, C Garcia-Closas, M Lissowska, J Sherman, ME Bolton, KL Hall, P Czene, K Cox, A Brock, IW Elliott, GC Reed, MWR Greenberg, D Anton-Culver, H Ziogas, A Humphreys, M Easton, DF Caporaso, NE Pharoah, PDP AF Azzato, Elizabeth M. Tyrer, Jonathan Fasching, Peter A. Beckmann, Matthias W. Ekici, Arif B. Schulz-Wendtland, Ruediger Bojesen, Stig E. Nordestgaard, Borge G. Flyger, Henrik Milne, Roger L. Arias, Jose Ignacio Menendez, Primitiva Benitez, Javier Chang-Claude, Jenny Hein, Rebecca Wang-Gohrke, Shan Nevanlinna, Heli Heikkinen, Tuomas Aittomaki, Kristiina Blomqvist, Carl Margolin, Sara Mannermaa, Arto Kosma, Veli-Matti Kataja, Vesa Beesley, Jonathan Chen, Xiaoqing Chenevix-Trench, Georgia Couch, Fergus J. Olson, Janet E. Fredericksen, Zachary S. Wang, Xianshu Giles, Graham G. Severi, Gianluca Baglietto, Laura Southey, Melissa C. Devilee, Peter Tollenaar, Rob A. E. M. Seynaeve, Caroline Garcia-Closas, Montserrat Lissowska, Jolanta Sherman, Mark E. Bolton, Kelly L. Hall, Per Czene, Kamila Cox, Angela Brock, Ian W. Elliott, Graeme C. Reed, Malcolm W. R. Greenberg, David Anton-Culver, Hoda Ziogas, Argyrios Humphreys, Manjeet Easton, Douglas F. Caporaso, Neil E. Pharoah, Paul D. P. CA Kathleen Cuningham Fdn Consortium TI Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor-Negative Breast Cancer Survival SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; GENOME-WIDE ASSOCIATION; GENETIC-VARIATION; OVARIAN-CANCER; TUMOR CHARACTERISTICS; COMMON POLYMORPHISMS; BRCA1 MUTATIONS; REPAIR GENES; RISK; POPULATION AB Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. We evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5' nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. In the hypothesis-generating dataset, SNP rs4778137 (C > G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 x 10(-5)). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 x 10(-4)). The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer. C1 [Azzato, Elizabeth M.; Tyrer, Jonathan; Pharoah, Paul D. P.] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cambridge, England. [Azzato, Elizabeth M.; Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Fasching, Peter A.; Beckmann, Matthias W.] Univ Breast Ctr, Bavarian Breast Canc Cases & Controls BBCC, Erlangen, Germany. [Schulz-Wendtland, Ruediger] Univ Hosp Erlangen, Inst Diagnost Radiol, BBCC, Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, BBCC, D-8520 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, BBCC, Los Angeles, CA 90095 USA. [Bojesen, Stig E.; Nordestgaard, Borge G.; Flyger, Henrik] Univ Copenhagen, Herlev Univ Hosp, Copenhagen Breast Canc Study, Copenhagen, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.; Flyger, Henrik] Univ Copenhagen, Herlev Univ Hosp, CGPS, Dept Clin Biochem, Copenhagen, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.; Flyger, Henrik] Univ Copenhagen, Herlev Univ Hosp, CGPS, Dept Breast Surg, Copenhagen, Denmark. [Milne, Roger L.] Spanish Natl Canc Ctr, Breast Canc Study CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Genet Grp, CNIO BCS, Madrid, Spain. [Arias, Jose Ignacio] Hosp Monte Naranco, CNIO BCS, Oviedo, Spain. [Menendez, Primitiva] HUCA Oviedo, CNIO BCS, Oviedo, Spain. [Chang-Claude, Jenny; Hein, Rebecca] German Canc Res Ctr, Div Canc Epidemiol, Genet Epidemiol Study Breast Canc Age GESBC 50, D-6900 Heidelberg, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, GESBC, Ulm, Germany. [Nevanlinna, Heli; Heikkinen, Tuomas] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, Helsinki Breast Canc Study HEBCS, FIN-00290 Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, HEBCS, FIN-00290 Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Dept Oncol, HEBCS, FIN-00290 Helsinki, Finland. [Margolin, Sara; Mannermaa, Arto] Karolinska Inst, Dept Pathol & Oncol, Karolinska Breast Canc Study KARBAC, Stockholm, Sweden. [Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa] Univ Kuopio, Inst Clin Med Pathol & Forens Med, Kuopio Breast Canc Project, FIN-70211 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti] Kuopio Univ Hosp, Dept Pathol, KBCP, SF-70210 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa] Kuopio Univ Hosp, Dept Oncol, KBCP, SF-70210 Kuopio, Finland. Vaasa Cent Hosp, Dept Oncol, KBCP, Vaasa, Finland. [Kathleen Cuningham Fdn Consortium] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Beesley, Jonathan; Chen, Xiaoqing; Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Couch, Fergus J.; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, MCBCS, Rochester, MN USA. [Couch, Fergus J.; Olson, Janet E.; Fredericksen, Zachary S.] Mayo Clin, Dept Hlth Sci Res, MCBCS, Rochester, MN USA. [Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, MCCS, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, MCCS, Melbourne, Vic, Australia. [Devilee, Peter] Leiden Univ, Med Ctr, Breast Canc Study ORIGO, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, ORIGO, Dept Pathol, Leiden, Netherlands. [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, ORIGO, Leiden, Netherlands. [Seynaeve, Caroline] Erasmus MC Daniel den Hoed Canc Ctr, Rotterdam Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Garcia-Closas, Montserrat; Sherman, Mark E.; Bolton, Kelly L.] NCI, PBCS, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, PBCS, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Hall, Per; Czene, Kamila] Karolinska Inst, Dept Med Epidemiol & Biostat, Singapore & Swedish Breast Canc Study SASBAC, Stockholm, Sweden. [Cox, Angela; Brock, Ian W.; Elliott, Graeme C.] Univ Sheffield, Dept Oncol, Inst Canc Studies, SBCS, Sheffield, S Yorkshire, England. [Reed, Malcolm W. R.] Univ Sheffield, Acad Unit Surg Oncol, SBCS, Sheffield, S Yorkshire, England. [Greenberg, David] Eastern Canc Registrat & Informat Ctr, Unit Magog Court C, Cambridge, England. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, UCIBCS, Irvine, CA USA. [Humphreys, Manjeet; Easton, Douglas F.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England. RP Azzato, EM (reprint author), 6120 Executive Plaza,Rm 7106, Rockville, MD 20852 USA. EM azzatoe2@mail.nih.gov RI Ekici, Arif/C-3971-2013; Garcia-Closas, Montserrat /F-3871-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Czene, Kamila/0000-0002-3233-5695; Lissowska, Jolanta/0000-0003-2695-5799; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099 FU National Cancer Institute and the National Institutes of Health (NIH)-Cambridge; ELAN Fonds of the University of Erlangen; Dr Mildred Scheel Stiftung; Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Copenhagen University Hospital; Herlev Hospital; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario [PI081120, PI081583]; Deutsche Krebshilfe e.V. [70492]; Helsinki University Central Hospital; Academy of Finland [110663]; Finnish Cancer Society; Sigrid Juselius Foundation; Kuopio University Hospital; Vaasa Central Hospital; Finnish Cancer Foundation; National Breast Cancer Foundation and the National Health and Medical Research Council (NHMRC) [145684, 288704, 454508, 209057, 251533, 396414]; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; Cancer Foundation of Western Australia; NIH [P50 CA116201, R01 CA122340]; VicHealth; Prostate Cancer Foundation of Australia; Dutch Cancer Society; National Cancer Institute, Department of Health and Human Services; Agency for Science, Technology and Research of Singapore (A*STAR); US NIH; Susan G. Komen Breast Cancer Foundation; Yorkshire Cancer Research and the Breast Cancer Campaign; NIH, National Cancer Institute [CA-58860]; Lon V. Smith Foundation [LVS-18840] FX Cancer Research UK (C1287 and A7497 to D. F. E.). E. M. A. is supported by the National Cancer Institute and the National Institutes of Health (NIH)-Cambridge Graduate Partnership Program. Bavarian Breast Cancer Cases and Controls (BBCC) was supported by the ELAN Fonds of the University of Erlangen, and P. A. F. is funded by Dr Mildred Scheel Stiftung and Deutsche Krebshilfe e.V. CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Copenhagen University Hospital, Herlev Hospital. Spanish National Cancer Centre Breast Cancer Study (CNIO-BCS) was supported by the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer, and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI081120 to J. Ben., PI081583 to R. L. M.]. Genetic Epidemiology Study of Breast Cancer by Age 50 (GESBC) was supported by the Deutsche Krebshilfe e. V. (70492) and GESBC genotyping in part by the state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm (P. 685). Helsinki Breast Cancer Study (HEBCS) has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (110663), the Finnish Cancer Society, and the Sigrid Juselius Foundation. Kuopio Breast Cancer Project (KBCP) is supported by grants from erityisvaltionosuus (EVO) funds of Kuopio University Hospital, EVO funds of Vaasa Central Hospital, the Finnish Cancer Foundation, and the Academy of Finland. The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer is supported by grants from the National Breast Cancer Foundation and the National Health and Medical Research Council (NHMRC) (145684, 288704, and 454508) and by the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. Mayo Clinic Breast Cancer Study (MCBCS) was supported by grants from the NIH (P50 CA116201 and R01 CA122340). Melbourne Collaborative Cohort Study (MCCS) was supported by NHMRC (209057, 251533, 396414, and 504711). Infrastructure support for the MCCS recruitment and follow-up is provided by the Cancer Council Victoria, whereas cohort recruitment was partly funded by VicHealth. Genotyping was in part supported by the Prostate Cancer Foundation of Australia. Leiden University Medical Centre Breast Cancer Study (ORIGO) was supported by the Dutch Cancer Society. Polish Breast Cancer Study was funded by intramural research funds of the National Cancer Institute, Department of Health and Human Services. SASBAC was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US NIH, and the Susan G. Komen Breast Cancer Foundation. Sheffield Breast Cancer Study (SBCS) was supported by Yorkshire Cancer Research and the Breast Cancer Campaign. University of California Irvine Breast Cancer Study (UCIBCS) is supported by the NIH, National Cancer Institute (CA-58860), and the Lon V. Smith Foundation (LVS-18840). NR 59 TC 31 Z9 31 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 5 PY 2010 VL 102 IS 9 BP 650 EP 662 DI 10.1093/jnci/djq057 PG 13 WC Oncology SC Oncology GA 593IZ UT WOS:000277448700013 PM 20308648 ER PT J AU Kiyatkin, EA AF Kiyatkin, E. A. TI DIFFERENTIAL EFFECTS OF DOPAMINE AND OPIOID RECEPTOR BLOCKADE ON MOTIVATED COCA-COLA DRINKING BEHAVIOR AND ASSOCIATED CHANGES IN BRAIN, SKIN AND MUSCLE TEMPERATURES SO NEUROSCIENCE LA English DT Article DE brain metabolism; dopamine antagonists; naloxone; neural activation; motivation; reward ID NUCLEUS-ACCUMBENS DOPAMINE; FREELY MOVING RATS; SELECTIVE BLOCKADE; FEEDING-BEHAVIOR; REWARD; NALOXONE; FOOD; HYPERTHERMIA; INVOLVEMENT; RESPONSES AB Although pharmacological blockade of both dopamine (DA) and opiate receptors has an inhibiting effect on appetitive motivated behaviors, it is still unclear which physiological mechanisms affected by these treatments underlie the behavioral deficit. To clarify this issue, we examined how pharmacological blockade of either DA (SCH23390+eticlopride at 0.2 mg/kg each) or opioid receptors (naloxone 1 mg/kg) affects motor activity and temperature fluctuations in the nucleus accumbens (NAcc), temporal muscle, and facial skin associated with motivated Coca-Cola drinking behavior in rats. In drug-free conditions, presentation of a cup containing 5 ml of Coca-Cola induced locomotor activation and rapid NAcc temperature increases, which both transiently decreased during drinking, and phasically increased again after the cup was emptied. Muscle temperatures followed this pattern, but increases were weaker and more delayed than those in the NAcc. Skin temperature rapidly dropped after cup presentation, remained at low levels during consumption, and slowly restored during post-consumption behavioral activation. By itself, DA receptor blockade induced robust decrease in spontaneous locomotion, moderate increases in brain and muscle temperatures, and a relative increase in skin temperatures, suggesting metabolic activation coupled with adynamia. Following this treatment (similar to 180 min), motor activation to cup presentation and Coca-Cola consumption were absent, but rats showed NAcc and muscle temperature increases following cup presentation comparable to control. Therefore, DA receptor blockade does not affect significantly central and peripheral autonomic responses to appetitive stimuli, but eliminates their behavior-activating effects, thus disrupting appetitive behavior and blocking consumption. Naloxone alone slightly decreased brain and muscle temperatures and increased skin temperatures, pointing at the enhanced heat loss and possible minor inhibition of basal metabolic activity. This treatment (similar to 60 min) had minimal effects on the latencies of drinking, but increased its total duration, with licking interrupted by pauses and retreats. This behavioral attenuation was coupled with weaker than in control locomotor activation and diminished temperature fluctuations in each recording location. Therefore, attenuation of normal behavioral and physiological responses to appetitive stimuli appears to underlie modest inhibiting effects of opiate receptor blockade on motivated behavior and consumption. Published by Elsevier Ltd on behalf of IBRO. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov FU NIH, NIDA FX This research was supported by the Intramural Research Program of the NIH, NIDA. I wish to thank Michael S. Smirnov for participation in this study. Dr. Mary Pfeiffer and Jeremy Tang for language assistance, and Dr. Maria Flavia Barbano for helpful critique of this study's results and their conceptual interpretation. NR 57 TC 2 Z9 2 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD MAY 5 PY 2010 VL 167 IS 2 BP 439 EP 455 DI 10.1016/j.neuroscience.2010.02.032 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 584AI UT WOS:000276722000023 PM 20167257 ER PT J AU Miller, JC Danon, L O'Hagan, JJ Goldstein, E Lajous, M Lipsitch, M AF Miller, Joel C. Danon, Leon O'Hagan, Justin J. Goldstein, Edward Lajous, Martin Lipsitch, Marc TI Student Behavior during a School Closure Caused by Pandemic Influenza A/H1N1 SO PLOS ONE LA English DT Article ID TRANSMISSION AB Background: Many schools were temporarily closed in response to outbreaks of the recently emerged pandemic influenza A/H1N1 virus. The effectiveness of closing schools to reduce transmission depends largely on student/family behavior during the closure. We sought to improve our understanding of these behaviors. Methodology/Principal Findings: To characterize this behavior, we surveyed students in grades 9-12 and parents of students in grades 5-8 about student activities during a weeklong closure of a school during the first months after the disease emerged. We found significant interaction with the community and other students-though less interaction with other students than during school-with the level of interaction increasing with grade. Conclusions: Our results are useful for the future design of social distancing policies and to improving the ability of modeling studies to accurately predict their impact. C1 [Miller, Joel C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Miller, Joel C.; Danon, Leon; O'Hagan, Justin J.; Goldstein, Edward; Lajous, Martin; Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Danon, Leon] Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. [Lajous, Martin] Natl Inst Publ Hlth, Ctr Populat Hlth Res, Cuernavaca, Morelos, Mexico. [Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Miller, JC (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM joel.c.miller.research@gmail.com RI Danon, Leon/J-6324-2012; Miller, Joel/C-4229-2015; OI Danon, Leon/0000-0002-7076-1871; Miller, Joel/0000-0003-4426-0405; Lipsitch, Marc/0000-0003-1504-9213 FU United States National Institutes of Health [5U01GM076497]; Mexican National Council for Science and Technology (CONACyT); Ministry of Health of Mexico; Department of Epidemiology, Harvard School of Public Health; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Medical Research Council, United Kingdom FX This work was supported by the United States National Institutes of Health cooperative agreement 5U01GM076497 "Models of Infectious Disease Agent Study'' (M. Lipsitch, J.J.O'H. and E. G.), the Mexican National Council for Science and Technology (CONACyT), the Ministry of Health of Mexico (M.Lajous) and the Department of Epidemiology, Harvard School of Public Health (M.Lajous and J.J.O'H.), the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (J.C.M.), and the Medical Research Council, United Kingdom (L. D.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 13 TC 17 Z9 19 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 5 PY 2010 VL 5 IS 5 AR e10425 DI 10.1371/journal.pone.0010425 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 592LC UT WOS:000277379400007 PM 20463960 ER PT J AU Martensen, R AF Martensen, Robert TI Institutional Review Boards, Professionalism, and the Internet SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article AB Even as the Internet generates pressures that erode professional authorities of all kinds, it also provides opportunities for researchers and their institutional review boards to bolster their status as trusted sources. To this end, we must work to improve clinical protocol design and approval procedures and maintain the integrity of the study participant recruitment process in clinical trials. C1 Off NIH Hist, Bethesda, MD 20892 USA. RP Martensen, R (reprint author), Off NIH Hist, Bethesda, MD 20892 USA. EM martensenr@mail.nih.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAY 5 PY 2010 VL 2 IS 30 AR 30cm15 DI 10.1126/scitranslmed.3000884 PG 4 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 591ZA UT WOS:000277342900001 PM 20445198 ER PT J AU Simberkoff, MS Arbeit, RD Johnson, GR Oxman, MN Boardman, KD Williams, HM Levin, MJ Schmader, KE Gelb, LD Keay, S Neuzil, K Greenberg, RN Griffin, MR Davis, LE Morrison, VA Annunziato, PW AF Simberkoff, Michael S. Arbeit, Robert D. Johnson, Gary R. Oxman, Michael N. Boardman, Kathy D. Williams, Heather M. Levin, Myron J. Schmader, Kenneth E. Gelb, Lawrence D. Keay, Susan Neuzil, Kathleen Greenberg, Richard N. Griffin, Marie R. Davis, Larry E. Morrison, Vicki A. Annunziato, Paula W. CA Shingles Prevention Study Grp TI Safety of Herpes Zoster Vaccine in the Shingles Prevention Study A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID POSTHERPETIC NEURALGIA; SMALLPOX VACCINATION; ROTAVIRUS VACCINE; OLDER-ADULTS; VIRUS; INTUSSUSCEPTION; EVENTS; HEALTH AB Background: The herpes zoster vaccine is effective in preventing herpes zoster and postherpetic neuralgia in immunocompetent older adults. However, its safety has not been described in depth. Objective: To describe local adverse effects and short-and long-term safety profiles of herpes zoster vaccine in immunocompetent older adults. Design: Randomized, placebo-controlled trial with enrollment from November 1998 to September 2001 and follow-up through April 2004 (mean, 3.4 years). A Veterans Affairs Coordinating Center generated the permutated block randomization scheme, which was stratified by site and age. Participants and follow-up study personnel were blinded to treatment assignments. (ClinicalTrials.gov registration number: NCT00007501) Setting: 22 U.S. academic centers. Participants: 38 546 immunocompetent adults 60 years or older, including 6616 who participated in an adverse events substudy. Intervention: Single dose of herpes zoster vaccine or placebo. Measurements: Serious adverse events and rashes in all participants and inoculation-site events in substudy participants during the first 42 days after inoculation. Thereafter, vaccination-related serious adverse events and deaths were monitored in all participants, and hospitalizations were monitored in substudy participants. Results: After inoculation, 255 (1.4%) vaccine recipients and 254 (1.4%) placebo recipients reported serious adverse events. Local inoculation-site side effects were reported by 1604 (48%) vaccine recipients and 539 (16%) placebo recipients in the substudy. A total of 977 (56.6%) of the vaccine recipients reporting local side effects were aged 60 to 69 years, and 627 (39.2%) were older than 70 years. After inoculation, herpes zoster occurred in 7 vaccine recipients versus 24 placebo recipients. Long-term follow-up (mean, 3.39 years) showed that rates of hospitalization or death did not differ between vaccine and placebo recipients. Limitations: Participants in the substudy were not randomly selected. Confirmation of reported serious adverse events with medical record data was not always obtained. Conclusion: Herpes zoster vaccine is well tolerated in older, immunocompetent adults. C1 [Simberkoff, Michael S.] Vet Affairs New York Harbor Healthcare Syst, New York, NY 10010 USA. NYU, Sch Med, New York, NY USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Vet Affairs Cooperat Studies Program Coordinating, West Haven, CT USA. Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. Univ Calif San Diego, San Diego, CA 92103 USA. New Mexico Vet Affairs Hlth Care Syst, Albuquerque, NM USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Colorado Denver, Aurora, CO USA. Durham Vet Affairs Med Ctr, GRECC, Durham, NC USA. St Louis Vet Affairs Med Ctr, St Louis, MO USA. Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Univ Washington, Sch Med, Seattle, WA USA. Lexington Vet Affairs Med Ctr, Lexington, KY USA. Vet Affairs Tennessee Valley Healthcare Syst, GRECC, Nashville, TN USA. Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. Minneapolis Vet Affairs Med Ctr, Minneapolis, MN USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. Merck & Co Inc, Whitehouse Stn, NJ USA. RP Simberkoff, MS (reprint author), Vet Affairs New York Harbor Healthcare Syst, 423 E 23rd St, New York, NY 10010 USA. EM Mike.SimberkoffMD@va.gov RI Irwin, Michael/H-4870-2013 OI Irwin, Michael/0000-0002-1502-8431 FU Department of Veterans Affairs, Office of Research and Development; Merck; James R. and Jesse V. Scott Fund FX Grant Support: By the Cooperative Studies Program of the Department of Veterans Affairs, Office of Research and Development; Merck; and the James R. and Jesse V. Scott Fund for Shingles Research. NR 21 TC 49 Z9 50 U1 0 U2 10 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 MAY 4 PY 2010 VL 152 IS 9 BP 545 EP + DI 10.7326/0003-4819-152-9-201005040-00004 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 595IN UT WOS:000277604000001 PM 20439572 ER PT J AU Pohlhaus, JR Jiang, H Sutton, J AF Pohlhaus, Jennifer Reineke Jiang, Hong Sutton, Jennifer TI Sex Differences in Career Development Awardees' Subsequent Grant Attainment SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Pohlhaus, Jennifer Reineke; Jiang, Hong; Sutton, Jennifer] NIH, Bethesda, MD 20892 USA. RP Pohlhaus, JR (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 6 TC 6 Z9 6 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAY 4 PY 2010 VL 152 IS 9 BP 616 EP 617 DI 10.7326/0003-4819-152-9-201005040-00019 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 595IN UT WOS:000277604000014 PM 20439584 ER PT J AU Metifiot, M Maddali, K Naumova, A Zhang, XM Marchand, C Pommier, Y AF Metifiot, Mathieu Maddali, Kasthuraiah Naumova, Alena Zhang, Xuemin Marchand, Christophe Pommier, Yves TI Biochemical and Pharmacological Analyses of HIV-1 Integrase Flexible Loop Mutants Resistant to Raltegravir SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; TREATMENT-NAIVE PATIENTS; IN-VITRO; CATALYTIC DOMAIN; RETROVIRAL INTEGRASE; COMBINATION THERAPY; ACTIVE-SITE; DNA-BINDING; INHIBITORS; INFECTION AB Resistance to raltegravir (RAL), the first HIV-1 integrase (IN) inhibitor approved by the FDA, involves three genetic pathways: IN mutations N155H, Q148H/R/K, and Y143H/R/C. Those mutations are generally associated with secondary point mutations. The resulting mutant viruses show a high degree of resistance against RAL but somehow are affected in their replication capacity. Clinical and virological data indicate the high relevance of the combination G140S + Q148H because of its limited impact on HIV replication and very high resistance to RAE. Here, we report how mutations at the amino acid residues 140, 148, and 155 affect IN enzymatic activity and RA L resistance. We show that single mutations at position 140 have limited impact on 3'-processing (3'-P) but severely inactivate strand transfer (ST). On the other hand, single mutations at position 148 have a more profound effect and inactivate both 3'-P and ST. By examining systematically all of the double mutants at the 140 and 148 positions, we demonstrate that only the combination G140S + Q148H is able to restore the catalytic properties of IN. This rescue only operates in cis when both the 140S and 148H mutations are in the same IN polypeptide flexible loop. Finally, we show that the G140S-Q148H double mutant exhibits the highest resistance to RAL. It also confers cross-resistance to elvitegravir but less to G-quadraduplex inhibitors such as zintevir. Our results demonstrate that IN mutations at positions 140 and 148 in the IN flexible loop can account for the phenotype of RAL-resistant viruses. C1 [Metifiot, Mathieu; Maddali, Kasthuraiah; Naumova, Alena; Zhang, Xuemin; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU NIH; National Cancer Institute (NCI); Center for Cancer Research (CCR) FX These studies were supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute (NCI), Center for Cancer Research (CCR). NR 55 TC 45 Z9 46 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 4 PY 2010 VL 49 IS 17 BP 3715 EP 3722 DI 10.1021/bi100130f PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 586ZP UT WOS:000276955600023 PM 20334344 ER PT J AU Tanaka, S Cao, K Niimi, A Limsirichaikul, S Miao, HQ Nakamura, N Murate, T Hasegawa, Y Takahashi, T Suzuki, M AF Tanaka, Shigeru Cao, Ke Niimi, Atsuko Limsirichaikul, Siripan Miao, Huang Qin Nakamura, Noriko Murate, Takashi Hasegawa, Yoshinori Takahashi, Takashi Suzuki, Motoshi TI Functions of base selection step in human DNA polymerase alpha SO DNA REPAIR LA English DT Article DE Genomic instability; DNA polymerase; HNPCC; Mismatch repair; Mutation ID SACCHAROMYCES-CEREVISIAE; TRANSLESION SYNTHESIS; REPLICATION FIDELITY; EXONUCLEASE ACTIVITY; AMINO-ACID; MOTIF-A; O-HELIX; DELTA; MUTANTS; REPAIR AB Recent studies have revealed that the base selection step of DNA polymerases (pol) plays a role in prevention of DNA replication errors. We investigated whether base selection is required for the DNA replication fidelity of pol alpha and genomic stability in human cells. We introduced an Leu864 to Phe substitution (L864F) into human pol alpha and performed an in vitro LacZ alpha forward mutation assay. Our results showed that the overall mutation rate was increased by 180-fold as compared to that of the wild-type. Furthermore, steady state kinetics analyses consistently showed that L864F pol alpha had a decreased discrimination ability between correct and incorrect nucleotide incorporation, as well as between matched and mismatched primer termini. L864F pol alpha also exhibited increased translesion activity over the abasic, etheno-A, O(4)-methyl-T, and O(6)-methyl-G sites. In addition, our steady state kinetics analyses supported the finding of increased translesion activity of L864F pol alpha over O(6)-methyl-G. We also established stable clones transfected with pola1L864F utilizing the human cancer cell line HCT116. Using the HPRT gene as a reporter, the spontaneous mutation rate of pola1L864F cells was determined to be 2.4-fold greater than that of wild-type cells. Mutation assays were also carried out using cells transiently transfected with the wild-type or pola1L864F, and increased mutant frequencies were observed in pola1L864F cells under both spontaneous and methyl methanesulfonate-induced conditions. Together, our results indicate that the base selection step in human pol alpha functions to prevent DNA replication errors and maintain genomic integrity in HCT116 cells. (C) 2010 Elsevier B.V. All rights reserved. C1 [Suzuki, Motoshi] Nagoya Univ, Grad Sch Med, Div Mol Carcinogenesis, Ctr Neurol Dis & Canc,Showa Ku, Nagoya, Aichi 4668550, Japan. [Tanaka, Shigeru; Hasegawa, Yoshinori] Nagoya Univ, Grad Sch Med, Dept Resp Med, Nagoya, Aichi 4668550, Japan. [Limsirichaikul, Siripan] Silpakorn Univ, Fac Pharm, Dept Biopharm, Nakhon Pathom 73000, Thailand. [Nakamura, Noriko] NIEHS, Gamete Biol Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Murate, Takashi] Nagoya Univ, Sch Hlth Sci, Nagoya, Aichi 4618673, Japan. RP Suzuki, M (reprint author), Nagoya Univ, Grad Sch Med, Div Mol Carcinogenesis, Ctr Neurol Dis & Canc,Showa Ku, Tsurumai Cho 65, Nagoya, Aichi 4668550, Japan. EM msuzuki@med.nagoya-u.ac.jp RI Takahashi, Takashi/I-7262-2014; Suzuki, Motoshi/I-7246-2014 OI Suzuki, Motoshi/0000-0003-0682-5006 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan; Japan Society for the Promotion of Science; Aichi Cancer Research Foundation; Novartis Foundation (Japan) for the Promotion of Science FX We thank Drs. Hiro-o Ishihara, Kiyoshi Yanagisawa, and Tomoya Yamaguchi for their critical discussion. We are also grateful for the generous assistance of Sachiko Takahashi and Kumiko Kobayashi. This work was supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas, a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, the Aichi Cancer Research Foundation, and the Novartis Foundation (Japan) for the Promotion of Science. NR 27 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAY 4 PY 2010 VL 9 IS 5 BP 534 EP 541 DI 10.1016/j.dnarep.2010.02.002 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 606YZ UT WOS:000278466400008 PM 20202915 ER PT J AU Buck, AJ Vena, JE McGuinness, BM Cooney, MA Louis, GM AF Buck, Alexandra J. Vena, John E. McGuinness, Bridget M. Cooney, Maureen A. Louis, Germaine M. TI Communicating serum chemical concentrations to study participants: follow up survey SO ENVIRONMENTAL HEALTH LA English DT Article ID ENVIRONMENTAL CHEMICALS; ANGLER COHORT; EXPOSURE; HEALTH; RISK AB Background: A considerable literature now supports the importance of effective communication with study participants, including how best to develop communication plans focusing on the uncertainty of health risks associated with particular environmental exposures. Strategies for communicating individual concentrations of environmental chemicals in human biological samples in the absence of clearly established safe or hazardous levels have been discussed from a conceptual basis and to a lesser extent from an empirical basis. We designed and evaluated an empirically based communication strategy for women of reproductive age who previously participated in a prospective study focusing on persistent environmental chemicals and reproductive outcomes. Methods: A cohort of women followed from preconception through pregnancy or up to 12 menstrual cycles without pregnancy was given their individual serum concentrations for lead, dichloro-2,2-bisp-chlorophenyl ethylene, and select polychlorinated biphenyl congeners. Two versions of standardized letters were prepared depending upon women's exposure status, which was characterized as low or high. Letters included an introduction, individual concentrations, population reference values and guidance for minimizing future exposures. Participants were actively monitored for any questions or concerns following receipt of letters. Results: Ninety-eight women were sent letters informing them of their individual concentrations to select study chemicals. None of the 89 (91%) participating women irrespective of exposure status contacted the research team with questions or concerns about communicated exposures despite an invitation to do so. Conclusions: Our findings suggest that study participants can be informed about their individual serum concentrations without generating unnecessary concern. C1 [Cooney, Maureen A.; Louis, Germaine M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Buck, Alexandra J.] SUNY Buffalo, Sch Law, Buffalo, NY 14260 USA. [Vena, John E.] Univ Georgia, Dept Epidemiol & Biostat, Coll Publ Hlth, Athens, GA 30602 USA. [McGuinness, Bridget M.] SUNY Buffalo, Dept Social & Prevent Med, Sch Publ Hlth & Hlth Profess, Buffalo, NY 14214 USA. RP Cooney, MA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd, Rockville, MD 20852 USA. EM cooneyma@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health & Human Development; Agency for Toxic Substances and Disease Registry [H751 ATH 298338] FX Supported, in part, by Intramural Funding of the Eunice Kennedy Shriver National Institute of Child Health & Human Development and the Agency for Toxic Substances and Disease Registry (H751 ATH 298338). NR 23 TC 3 Z9 3 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD MAY 4 PY 2010 VL 9 AR 20 DI 10.1186/1476-069X-9-20 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 611DR UT WOS:000278791700001 PM 20441591 ER PT J AU Ivanov, V Mizuuchi, K AF Ivanov, Vassili Mizuuchi, Kiyoshi TI Multiple modes of interconverting dynamic pattern formation by bacterial cell division proteins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell division; min system; oscillations and waves; self-organization; septum localization ID TO-POLE OSCILLATION; ESCHERICHIA-COLI; MIN-PROTEINS; IN-VITRO; TOPOLOGICAL REGULATION; PROPER PLACEMENT; INHIBITOR MINC; RAPID POLE; BINDING; RING AB Min proteins of the Escherichia coli cell division system oscillate between the cell poles in vivo. In vitro on a solid-surface supported lipid bilayer, these proteins exhibit a number of interconverting modes of collective ATP-driven dynamic pattern formation including not only the previously described propagating waves, but also near uniformity in space surface concentration oscillation, propagating filament like structures with a leading head and decaying tail and moving and dividing amoeba-like structures with sharp edges. We demonstrate that the last behavior most closely resembles in vivo system behavior. The simple reaction-diffusion models previously proposed for the Min system fail to explain the results of the in vitro self-organization experiments. We propose the hypotheses that initiation of MinD binding to the surface is controlled by counteraction of initiation and dissociation complexes; the binding of MinD/E is stimulated by MinE and involves polymerization-depolymerization dynamics; polymerization of MinE over MinD oligomers triggers dynamic instability leading to detachment from the membrane. The physical properties of the lipid bilayer are likely to be one of the critical determinants of certain aspects of the dynamic patterns observed. C1 [Ivanov, Vassili; Mizuuchi, Kiyoshi] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Mizuuchi, K (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM kmizu@helix.nih.gov FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Min Li (National Institute of Diabetes and Digestive and Kidney Diseases) for help with protein expression, Dominic Esposito (Science Applications International Corporation-Frederick Inc.) for preparation of part of expression vectors, and Robert Craigie (National Institute of Diabetes and Digestive and Kidney Diseases) for help with editing of the manuscript. This research was supported by the Intramural Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 38 TC 46 Z9 49 U1 1 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 MAY 4 PY 2010 VL 107 IS 18 BP 8071 EP 8078 DI 10.1073/pnas.0911036107 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 591OK UT WOS:000277310400008 PM 20212106 ER PT J AU Szentpetery, Z Varnai, P Balla, T AF Szentpetery, Zsofia Varnai, Peter Balla, Tamas TI Acute manipulation of Golgi phosphoinositides to assess their importance in cellular trafficking and signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE phosphatidylinositol 4-phosphate; PI 4-kinase; Sac1 phosphatase; vesicular trafficking; green fluorescent protein ID PHOSPHATIDYLINOSITOL TRANSFER PROTEINS; ADP-RIBOSYLATION FACTOR; BIOLOGICAL FUNCTIONS; ACID PHOSPHOLIPIDS; MEMBRANE DYNAMICS; LIPID PHOSPHATASE; SECRETION; 4-KINASE; CELLS; 4,5-BISPHOSPHATE AB Phosphoinositides are essential lipid regulators of trafficking and signaling pathways of all eukaryotic cells. Phosphatidylinositol 4-phosphate (PtdIns4P) is an intermediate in the synthesis of several important phosphoinositide species but also serves as a regulatory molecule in its own right. Phosphatidylinositol 4-kinases are most abundant in the Golgi but are also found in the plasma membrane and in endocytic compartments. To investigate the role of Golgi PtdIns4P in orchestrating trafficking events, we used a unique drug-inducible molecular approach to rapidly deplete PtdIns4P from Golgi membranes by a recruitable Sac1 phosphatase enzyme. The utility of the system was shown by the rapid loss of Golgi localization of PH domains known to bind PtdIns4P after Sac1 recruitment to the Golgi. Acute PtdIns4P depletion prevented the exit of cargo from the Golgi destined to both the plasma membrane and the late endosomes and led to the loss of some but not all clathrin adaptors from the Golgi membrane. Rapid PtdIns4P depletion in the Golgi also impaired but did not eliminate the replenishment of the plasma membrane PtdIns(4,5)P-2 during phospholipase C activation revealing a hitherto unrecognized contribution of Golgi PtdIns4P to this process. This unique approach will allow further studies on the role of phosphoinositides in endocytic compartments that have evaded detection using the conventional long-term manipulations of inositide kinase and phosphatase activities. C1 [Szentpetery, Zsofia; Balla, Tamas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Varnai, Peter] Semmelweis Univ, Sch Med, Dept Physiol, H-1094 Budapest, Hungary. RP Balla, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov OI Balla, Tamas/0000-0002-9077-3335 FU Hungarian Scientific Research Fund [OTKA NF-68563]; Medical Research Council of Hungary [ETT 494/2009]; Eunice Kennedy Shriver NICHD of NIH FX We are grateful to Drs. Juan Bonifacino, Julie Donaldson, Lois Greene, Mark Lemmon, Jennifer Lippincott-Schwartz, Philip W. Majerus (Washington University School of Medicine, St. Louis, MO), Jeffry Pessin, Alexander Sorkin, and Roger Y. Tsien (University of California at San Diego, La Jolla, CA) for DNA constructs. Confocal imaging was performed at the Microscopy and Imaging Core of the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), with the kind assistance of Drs. Vincent Schram and James T. Russell. P. V. was supported by grants from the Hungarian Scientific Research Fund (OTKA NF-68563) and the Medical Research Council (ETT 494/2009) of Hungary. This research was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver NICHD of NIH. NR 40 TC 68 Z9 68 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 4 PY 2010 VL 107 IS 18 BP 8225 EP 8230 DI 10.1073/pnas.1000157107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 591OK UT WOS:000277310400034 PM 20404150 ER PT J AU Chang, J Voorhees, TJ Liu, YS Zhao, YG Chang, CH AF Chang, JiHoon Voorhees, Timothy J. Liu, Yusen Zhao, Yongge Chang, Cheong-Hee TI Interleukin-23 production in dendritic cells is negatively regulated by protein phosphatase 2A SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cytokine; NF-kappa B; TLR ID NF-KAPPA-B; TUMOR-SUPPRESSOR CYLD; IL-23; CYTOKINE; KINASE; INFLAMMATION; IL-10; DIFFERENTIATION; EXPRESSION; DISTINCT AB IL-12 and IL-23 are produced by activated antigen-presenting cells but the two induce distinct immune responses by promoting Th1 and Th17 cell differentiation, respectively. IL-23 is a heterodimeric cytokine consisting of two subunits: p40 that is shared with IL-12 and p19 unique to IL-23. In this study, we showed that the production of IL-23 but not IL-12 was negatively regulated by protein phosphatase 2A (PP2A) in dendritic cells (DC). PP2A inhibits IL-23 production by suppressing the expression of the IL-23p19 gene. Treating DC with okadaic acid that inhibits the PP2A activity or knocking down the catalytic subunit of PP2A with siRNA enhanced IL-23 but not IL-12 production. Unlike PP2A, MAP kinase phosphatase-1 or CYLD did not show an effect on IL-23 production supporting the specificity of PP2A. PP2A-mediated inhibition requires a newly made protein that is likely responsible for bringing PP2A and IKK beta together upon LPS stimulation, which then results in the termination of IKK phosphorylation. Thus, our results uncovered an important role of the protein phosphatase in the regulation of IL-23 production and identified PP2A as a previously uncharacterized inhibitor of IL-23p19 expression in DC. C1 [Chang, JiHoon; Voorhees, Timothy J.; Chang, Cheong-Hee] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Liu, Yusen] Ohio State Univ, Coll Med, Dept Pediat,Ctr Perinatal Res, Nationwide Childrens Hosp,Res Inst, Columbus, OH 43205 USA. [Zhao, Yongge] NIAID, Host Def Lab, NIH, Bethesda, MD 20817 USA. RP Chang, CH (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. EM heechang@umich.edu RI Liu, Yusen/E-3527-2011 FU National Institutes of Health [AI070448, AI057798] FX We thank Dr. Philip King (University of Michigan, Ann Arbor) and Dr. Mark Kaplan (Indiana University, Indianapolis) for critical reading of the manuscript. This work was partly supported by National Institutes of Health Grants AI070448 (to C.-H. C.) and AI057798 (to Y.L.). NR 33 TC 14 Z9 14 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 4 PY 2010 VL 107 IS 18 BP 8340 EP 8345 DI 10.1073/pnas.0914703107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 591OK UT WOS:000277310400054 PM 20404153 ER PT J AU Das, U Kumar, J Mayer, ML Plested, AJR AF Das, Utpal Kumar, Janesh Mayer, Mark L. Plested, Andrew J. R. TI Domain organization and function in GluK2 subtype kainate receptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE crystal structure; glutamate receptors; ligand gated ion channels ID AMINO-TERMINAL DOMAIN; IONOTROPIC GLUTAMATE RECEPTORS; GATED ION-CHANNEL; X-RAY-STRUCTURE; CRYSTAL-STRUCTURE; AMPA RECEPTOR; 3-DIMENSIONAL STRUCTURE; CONFORMATIONAL-CHANGES; DESENSITIZATION; SUBUNIT AB Glutamate receptor ion channels (iGluRs) are excitatory neurotransmitter receptors with a unique molecular architecture in which the extracellular domains assemble as a dimer of dimers. The structure of individual dimer assemblies has been established previously for both the isolated ligand-binding domain (LBD) and more recently for the larger amino terminal domain (ATD). How these dimers pack to form tetrameric assemblies in intact iGluRs has remained controversial. Using recently solved crystal structures for the GluK2 kainate receptor ATD as a guide, we performed cysteine mutant cross-linking experiments in full-length tetrameric GluK2 to establish how the ATD packs in a dimer of dimers assembly. A similar approach, using a full-length AMPA receptor GluA2 crystal structure as a guide, was used to design cysteine mutant cross-links for the GluK2 LBD dimer of dimers assembly. The formation of cross-linked tetramers in full-length GluK2 by combinations of ATD and LBD mutants which individually produce only cross-linked dimers suggests that subunits in the ATD and LBD layers swap dimer partners. Functional studies reveal that cross-linking either the ATD or the LBD inhibits activation of GluK2 and that, in the LBD, cross-links within and between dimers have different effects. These results establish that kainate and AMPA receptors have a conserved extracellular architecture and provide insight into the role of individual dimer assemblies in activation of ion channel gating. C1 [Das, Utpal; Kumar, Janesh; Mayer, Mark L.] NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Plested, Andrew J. R.] Leibniz Inst Mol Pharmacol, D-13125 Berlin, Germany. [Plested, Andrew J. R.] Charite, D-10117 Berlin, Germany. RP Mayer, ML (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM mlm@helix.nih.gov; plested@fmp-berlin.de RI Das, Utpal/E-4692-2013; Mayer, Mark/H-5500-2013; OI Plested, Andrew/0000-0001-6062-0832 FU National Institute of Child Health and Human Development; National Institutes of Health; Department of Health and Human Services; Neurocure Cluster of Excellence; Deutsche Forschungsgemeinschaft FX We thank Carla Glasser for preparing cDNAs; Marcus Wietstruk and Dr. Anna Carbone for assistance with cell culture; Dr. C. Rosenmund for the loan of a piezoelectric stack; Dr. E. Gouaux for sharing GluA2 coordinates before publication, and the National Institute of Neurological Disorders and Stroke DNA sequencing facility. This work was supported by the intramural research program of the National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services ( M. L. M.) and the Neurocure Cluster of Excellence, Deutsche Forschungsgemeinschaft ( A.J.R.P.). NR 38 TC 33 Z9 33 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 4 PY 2010 VL 107 IS 18 BP 8463 EP 8468 DI 10.1073/pnas.1000838107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 591OK UT WOS:000277310400075 PM 20404149 ER PT J AU Djouad, F Jackson, WM Bobick, BE Janjanin, S Song, YJ Huang, GTJ Tuan, RS AF Djouad, Farida Jackson, Wesley M. Bobick, Brent E. Janjanin, Sasa Song, Yingjie Huang, George T. J. Tuan, Rocky S. TI Activin A expression regulates multipotency of mesenchymal progenitor cells SO STEM CELL RESEARCH & THERAPY LA English DT Article ID EMBRYONIC STEM-CELLS; IN-VITRO; DENDRITIC CELLS; GROWTH-FACTOR; SELF-RENEWAL; DIFFERENTIATION; BONE; FOLLISTATIN; TISSUE; PROLIFERATION AB Introduction: Bone marrow (BM) stroma currently represents the most common and investigated source of mesenchymal progenitor cells (MPCs); however, comparable adult progenitor or stem cells have also been isolated from a wide variety of tissues. This study aims to assess the functional similarities of MPCs from different tissues and to identify specific factor(s) related to their multipotency. Methods: For this purpose, we directly compared MPCs isolated from different adult tissues, including bone marrow, tonsil, muscle, and dental pulp. We first examined and compared proliferation rates, immunomodulatory properties, and multidifferentiation potential of these MPCs in vitro. Next, we specifically evaluated activin A expression profile and activin A: follistatin ratio in MPCs from the four sources. Results: The multidifferentiation potential of the MPCs is correlated with activin A level and/or the activin A: follistatin ratio. Interestingly, by siRNA-mediated activin A knockdown, activin A was shown to be required for the chondrogenic and osteogenic differentiation of MPCs. These findings strongly suggest that activin A has a pivotal differentiation-related role in the early stages of chondrogenesis and osteogenesis while inhibiting adipogenesis of MPCs. Conclusions: This comparative analysis of MPCs from different tissue sources also identifies bone marrow-derived MPCs as the most potent MPCs in terms of multilineage differentiation and immunosuppression, two key requirements in cell-based regenerative medicine. In addition, this study implicates the significance of activin A as a functional marker of MPC identity. C1 [Djouad, Farida; Jackson, Wesley M.; Bobick, Brent E.; Janjanin, Sasa; Song, Yingjie; Huang, George T. J.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Djouad, F (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM farida.djouad@inserm.fr OI Djouad, Farida/0000-0001-8248-6822 FU National Institute of Arthritis, and Musculoskeletal and Skin Diseases (NIAMS), NIH [ZO1 AR 41131]; [R01 DE019156-01] FX This work was supported by the National Institute of Arthritis, and Musculoskeletal and Skin Diseases (NIAMS) Intramural Research Program, NIH (ZO1 AR 41131), and in part by R01 DE019156-01 (GTJH). NR 62 TC 20 Z9 20 U1 0 U2 3 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 MAY 4 PY 2010 VL 1 AR 11 DI 10.1186/scrt11 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 794EW UT WOS:000292879300002 PM 20637060 ER PT J AU Frolov, VA Zimmerberg, J AF Frolov, Vadim A. Zimmerberg, Joshua TI Cooperative elastic stresses, the hydrophobic effect, and lipid tilt in membrane remodeling SO FEBS LETTERS LA English DT Review DE Viral infection; Influenza; Exocytosis; Endocytosis; Membrane fusion; Membrane fission; Dynamin; Molecular dynamics; Computer simulations ID VESICLE FUSION; STALK MODEL; BILAYERS; FISSION; MECHANISM; PROTEIN; INTERMEDIATE; CURVATURE; FORCES; SIMULATIONS AB One of the fundamental properties of biological membranes is the high lateral integrity provided by the lipid bilayer, the structural core and the foundation of their barrier function. This tensile strength is due to the intrinsic properties of amphiphilic lipid molecules, which spontaneously self-assemble into a stable bilayer structure due to the hydrophobic effect. In the highly dynamic life of cellular membranes systems, however, this integrity has to be regularly compromised. One of the emerging puzzles is the mechanism of localized rupture of lipid monolayer, the formation of tiny hydrophobic patches and flipping of lipid tails between closely apposed monolayers. The energy cost of such processes is prohibitively high, unless cooperative deformations in a small membrane patch are carefully organized. Here we review the latest experimental and theoretical data on how such deformations can be conducted, specifically describing how elastic stresses yield tilting of lipids leading to cooperative restructuring of lipid monolayers. Proteins specializing in membrane remodeling assemble into closely packed circular complexes to arrange these deformations in time and space. Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies. C1 [Zimmerberg, Joshua] Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Frolov, Vadim A.] Ctr Mixto CSIC UPV EHU, Unidad Biofis, Leioa 48940, Spain. [Frolov, Vadim A.] Univ Basque Country, Dept Biochim & Biol Mol, Leioa 48940, Spain. [Frolov, Vadim A.] Basque Fdn Sci, IKERBASQUE, Bilbao 48011, Spain. RP Zimmerberg, J (reprint author), Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM zimmerbj@mail.nih.gov OI Frolov, Vadim/0000-0002-0653-5669 FU NICHD, NIH FX This work was supported by the Intramural Program of the NICHD, NIH. NR 50 TC 19 Z9 20 U1 1 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAY 3 PY 2010 VL 584 IS 9 BP 1824 EP 1829 DI 10.1016/j.febslet.2010.01.039 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 583YW UT WOS:000276717600025 PM 20100479 ER PT J AU Zheng, YP John, S Pesavento, JJ Schultz-Norton, JR Schiltz, RL Baek, S Nardulli, AM Hager, GL Kelleher, NL Mizzen, CA AF Zheng, Yupeng John, Sam Pesavento, James J. Schultz-Norton, Jennifer R. Schiltz, R. Louis Baek, Sonjoon Nardulli, Ann M. Hager, Gordon L. Kelleher, Neil L. Mizzen, Craig A. TI Histone H1 phosphorylation is associated with transcription by RNA polymerases I and II SO JOURNAL OF CELL BIOLOGY LA English DT Article ID C-TERMINAL DOMAIN; S-3 CELL-CYCLE; SECONDARY STRUCTURE; MMTV PROMOTER; CHROMATIN-STRUCTURE; RIBOSOMAL GENES; BINDING; VIVO; DNA; UBF AB Histone H1 phosphorylation affects chromatin condensation and function, but little is known about how specific phosphorylations impact the function of H1 variants in higher eukaryotes. In this study, we show that specific sites in H1.2 and H1.4 of human cells are phosphorylated only during mitosis or during both mitosis and interphase. Antisera generated to individual H1.2/H1.4 interphase phosphorylations reveal that they are distributed throughout nuclei and enriched in nucleoli. Moreover, interphase phosphorylated H1.4 is enriched at active 45S preribosomal RNA gene promoters and is rapidly induced at steroid hormone response elements by hormone treatment. Our results imply that site-specific interphase H1 phosphorylation facilitates transcription by RNA polymerases I and II and has an unanticipated function in ribosome biogenesis and control of cell growth. Differences in the numbers, structure, and locations of interphase phosphorylation sites may contribute to the functional diversity of H1 variants. C1 [Zheng, Yupeng; Mizzen, Craig A.] Univ Illinois, Dept Cell & Dev Biol, Urbana, IL 61801 USA. [Pesavento, James J.; Kelleher, Neil L.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. [Schultz-Norton, Jennifer R.; Nardulli, Ann M.] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. [Kelleher, Neil L.; Mizzen, Craig A.] Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA. [John, Sam; Schiltz, R. Louis; Baek, Sonjoon; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Mizzen, CA (reprint author), Univ Illinois, Dept Cell & Dev Biol, Urbana, IL 61801 USA. EM cmizzen@illinois.edu RI Zheng, Yupeng/B-3782-2014; Schroeder, Jennifer/G-3679-2014; OI Schroeder, Jennifer/0000-0002-1975-721X; Zheng, Yupeng/0000-0002-3351-5161 FU Roy J. Carver Charitable Trust [04-76]; March of Dimes [FY05-1232]; National Science Foundation [MCB-0821893]; Packard Foundation; Sloan Foundation; Cottrell Scholar Award; National Institutes of Health [GM 067193, R01 DK53884, 5T32 GM 08276] FX This work was funded by grants from the Roy J. Carver Charitable Trust (grant 04-76), the March of Dimes (Basil O'Connor Scholar Award FY05-1232), and the National Science Foundation (MCB-0821893) to C. A. Mizzen, by grants from the Packard Foundation, the Sloan Foundation, and a Cottrell Scholar Award to N.L. Kelleher, and National Institutes of Health grants to N.L. Kelleher (GM 067193) and A. M. Nardulli (R01 DK53884). J.J. Pesavento was a recipient of a National Institutes of Health Institutional National Research Service Award in Molecular Biophysics (5T32 GM 08276). NR 66 TC 48 Z9 49 U1 1 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAY 3 PY 2010 VL 189 IS 3 BP 407 EP 415 DI 10.1083/jcb.201001148 PG 9 WC Cell Biology SC Cell Biology GA 591AJ UT WOS:000277269600006 PM 20439994 ER PT J AU Boni, MF de Jong, MD van Doorn, HR Holmes, EC AF Boni, Maciej F. de Jong, Menno D. van Doorn, H. Rogier Holmes, Edward C. TI Guidelines for Identifying Homologous Recombination Events in Influenza A Virus SO PLOS ONE LA English DT Article ID HEMAGGLUTININ GENE; ANTIGENIC DRIFT; GENOME ANALYSIS; EVOLUTION; RESISTANCE; SEQUENCE; SURVEILLANCE; REASSORTMENT; SELECTION; ALIGNMENT AB The rapid evolution of influenza viruses occurs both clonally and non-clonally through a variety of genetic mechanisms and selection pressures. The non-clonal evolution of influenza viruses comprises relatively frequent reassortment among gene segments and a more rarely reported process of non-homologous RNA recombination. Homologous RNA recombination within segments has been proposed as a third such mechanism, but to date the evidence for the existence of this process among influenza viruses has been both weak and controversial. As homologous recombination has not yet been demonstrated in the laboratory, supporting evidence, if it exists, may come primarily from patterns of phylogenetic incongruence observed in gene sequence data. Here, we review the necessary criteria related to laboratory procedures and sample handling, bioinformatic analysis, and the known ecology and evolution of influenza viruses that need to be met in order to confirm that a homologous recombination event occurred in the history of a set of sequences. To determine if these criteria have an effect on recombination analysis, we gathered 8307 publicly available full-length sequences of influenza A segments and divided them into those that were sequenced via the National Institutes of Health Influenza Genome Sequencing Project (IGSP) and those that were not. As sample handling and sequencing are executed to a very high standard in the IGSP, these sequences should be less likely to be exposed to contamination by other samples or by laboratory strains, and thus should not exhibit laboratory-generated signals of homologous recombination. Our analysis shows that the IGSP data set contains only two phylogenetically-supported single recombinant sequences and no recombinant clades. In marked contrast, the non-IGSP data show a very large amount of potential recombination. We conclude that the presence of false positive signals in the non-IGSP data is more likely than false negatives in the IGSP data, and that given the evidence to date, homologous recombination seems to play little or no role in the evolution of influenza A viruses. C1 [Boni, Maciej F.; de Jong, Menno D.; van Doorn, H. Rogier] Univ Oxford, Clin Res Unit, Ho Chi Minh City, Vietnam. [Boni, Maciej F.] Univ Oxford, Ctr Genom & Global Hlth, MRC, Oxford, England. [Boni, Maciej F.; van Doorn, H. Rogier] Univ Oxford, Ctr Trop Med, Nuffield Dept Med, Oxford, England. [de Jong, Menno D.] Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, NL-1105 AZ Amsterdam, Netherlands. [Holmes, Edward C.] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, State Coll, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Boni, MF (reprint author), Univ Oxford, Clin Res Unit, Ho Chi Minh City, Vietnam. EM mboni@oucru.org OI van Doorn, H Rogier/0000-0002-9807-1821; Holmes, Edward/0000-0001-9596-3552 FU United Kingdom Medical Research Council [G0600718]; University of Amsterdam; Wellcome Trust [081613/Z/06/Z, 077078/Z/05/Z]; National Institutes of Health [GM080533] FX MFB is supported by United Kingdom Medical Research Council grant G0600718. MDdJ is supported by the University of Amsterdam. HRvD is supported by Wellcome Trust grants 081613/Z/06/Z and 077078/Z/05/Z. ECH is supported by National Institutes of Health grant GM080533. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 32 Z9 33 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 3 PY 2010 VL 5 IS 5 AR e10434 DI 10.1371/journal.pone.0010434 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 590PW UT WOS:000277240300010 PM 20454662 ER PT J AU Lee, WJ Pollin, TI O'Connell, JR Agarwala, R Schaffer, AA AF Lee, Woei-Jyh Pollin, Toni I. O'Connell, Jeffrey R. Agarwala, Richa Schaffer, Alejandro A. TI PedHunter 2.0 and its usage to characterize the founder structure of the Old Order Amish of Lancaster County SO BMC MEDICAL GENETICS LA English DT Article ID AMERICAN ANABAPTIST GENEALOGY; GENOME-WIDE SCAN; LIFE-SPAN; COMMON VARIANTS; BLOOD-PRESSURE; GENE; CHROMOSOME; LINKAGE; REGION; LOCUS AB Background: Because they are a closed founder population, the Old Order Amish (OOA) of Lancaster County have been the subject of many medical genetics studies. We constructed four versions of Anabaptist Genealogy Database (AGDB) using three sources of genealogies and multiple updates. In addition, we developed PedHunter, a suite of query software that can solve pedigree-related problems automatically and systematically. Methods: We report on how we have used new features in PedHunter to quantify the number and expected genetic contribution of founders to the OOA. The queries and utility of PedHunter programs are illustrated by examples using AGDB in this paper. For example, we calculated the number of founders expected to be contributing genetic material to the present-day living OOA and estimated the mean relative founder representation for each founder. New features in PedHunter also include pedigree trimming and pedigree renumbering, which should prove useful for studying large pedigrees. Results: With PedHunter version 2.0 querying AGDB version 4.0, we identified 34,160 presumed living OOA individuals and connected them into a 14-generation pedigree descending from 554 founders (332 females and 222 males) after trimming. From the analysis of cumulative mean relative founder representation, 128 founders (78 females and 50 males) accounted for over 95% of the mean relative founder contribution among living OOA descendants. Discussion/Conclusions: The OOA are a closed founder population in which a modest number of founders account for the genetic variation present in the current OOA population. Improvements to the PedHunter software will be useful in future studies of both the OOA and other populations with large and computerized genealogies. C1 [Lee, Woei-Jyh; Agarwala, Richa; Schaffer, Alejandro A.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Pollin, Toni I.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [O'Connell, Jeffrey R.] ARS, Anim Improvement Programs Lab, USDA, Beltsville, MD 20705 USA. RP Schaffer, AA (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM schaffer@helix.nih.gov RI Schaffer, Alejandro/F-2902-2012 FU NIH, NLM FX This research was supported in part by the Intramural Research Program of the NIH, NLM. NR 62 TC 16 Z9 16 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD MAY 2 PY 2010 VL 11 AR 68 DI 10.1186/1471-2350-11-68 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 605YJ UT WOS:000278385000001 PM 20433770 ER PT J AU Olivera, A Eisner, C Kitamura, Y Dillahunt, S Allende, L Tuymetova, G Watford, W Meylan, F Diesner, SC Li, LL Schnermann, J Proia, RL Rivera, J AF Olivera, Ana Eisner, Christoph Kitamura, Yoshiaki Dillahunt, Sandra Allende, Laura Tuymetova, Galina Watford, Wendy Meylan, Francoise Diesner, Susanne C. Li, Lingli Schnermann, Jurgen Proia, Richard L. Rivera, Juan TI Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MAST-CELL DEGRANULATION; FC-EPSILON-RI; SYSTEMIC-ANAPHYLAXIS; VASCULAR-PERMEABILITY; S1P(1) RECEPTOR; GAMMA RIII; HISTAMINE; 1-PHOSPHATE; ACTIVATION; ASTHMA AB Sphingosine kinase 1 (SphK1) and SphK2 are ubiquitous enzymes that generate sphingosine-1-phosphate (SIP), a ligand for a family of G protein-coupled receptors (S1PR1-S1PR5) with important functions in the vascular and immune systems. Here we explore the role of these kinases and receptors in recovery from anaphylaxis in mice. We found that Sphk2(-/-) mice had a rapid recovery from anaphylaxis. In contrast, Sphk1(-/-) mice showed poor recovery from anaphylaxis and delayed histamine clearance. Injection of SIP into Sphk1(-/-) mice increased histamine clearance and promoted recovery from anaphylaxis. Adoptive cell transfer experiments demonstrated that SphK1 activity was required in both the hematopoietic and nonhematopoietic compartments for recovery from anaphylaxis. Mice lacking the SW receptor S1PR2 also showed a delay in plasma histamine clearance and a poor recovery from anaphylaxis. However, SW did not promote the recovery of S1pr2(-/-) mice from anaphylaxis, whereas S1pr2(+/-) mice showed partial recovery. Unlike Sphk2(-/-) mice, Sphk1(-/-) and S1pr2(-/-) mice had severe hypotension during anaphylaxis. Thus, SphK1-produced S1P regulates blood pressure, histamine clearance, and recovery from anaphylaxis in a manner that involves S1PR2. This suggests that specific S1PR2 agonists may serve to counteract the vasodilation associated with anaphylactic shock. C1 [Olivera, Ana; Kitamura, Yoshiaki; Dillahunt, Sandra; Diesner, Susanne C.; Rivera, Juan] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Immunogenet Mol Lab, NIH, Bethesda, MD USA. [Eisner, Christoph; Li, Lingli; Schnermann, Jurgen] NIDDK, Kidney Dis Branch, NIH, Bethesda, MD USA. [Allende, Laura; Tuymetova, Galina; Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. [Watford, Wendy] NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD USA. [Meylan, Francoise] NIAMS, Autoimmun Branch, NIH, Bethesda, MD USA. RP Olivera, A (reprint author), NIAMS, Immunogenet Mol Lab, NIH, Bldg 10,Room 13C103, Bethesda, MD 20892 USA. EM oliveraa@mail.nih.gov; juan_rivera@nih.gov RI Proia, Richard/A-7908-2012 FU NIAMS; NIDDK, NIH; Office of Science and Technology; NIDDK FX The work herein was supported by the Intramural Research Programs of NIAMS and NIDDK, NIH. The authors thank the animal care programs of the Office of Science and Technology, NIAMS, and NIDDK for invaluable support during this work. NR 62 TC 56 Z9 57 U1 1 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2010 VL 120 IS 5 BP 1429 EP 1440 DI 10.1172/JCI40659 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 590SN UT WOS:000277248000012 PM 20407207 ER PT J AU Watanabe, T Asano, N Fichtner-Feigl, S Gorelick, PL Tsuji, Y Matsumoto, Y Chiba, T Fuss, IJ Kitani, A Strober, W AF Watanabe, Tomohiro Asano, Naoki Fichtner-Feigl, Stefan Gorelick, Peter L. Tsuji, Yoshihisa Matsumoto, Yuko Chiba, Tsutomu Fuss, Ivan J. Kitani, Atsushi Strober, Warren TI NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NF-KAPPA-B; INTESTINAL EPITHELIAL-CELLS; INDEPENDENT ANTIVIRAL RESPONSE; INNATE IMMUNE RECOGNITION; INTERFERON-ALPHA/BETA; INFLAMMATORY DISEASE; EXPERIMENTAL COLITIS; EFFECTOR-CELLS; T-LYMPHOCYTES; PROTECTS MICE AB Nucleotide-binding oligomerization domain 1 (NOD 1) is an intracellular epithelial cell protein known to play a role in host defense at mucosal surfaces. Here we show that a ligand specific for NOD 1, a peptide derived from peptidoglycan, initiates an unexpected signaling pathway in human epithelial cell lines that results in the production of type I IFN. Detailed analysis revealed the components of the signaling pathway. NOD1 binding to its ligand triggered activation of the serine-threonine kinase RICK, which was then able to bind TNF receptor-associated factor 3 (TRAF3). This in turn led to activation of TANK-binding kinase 1 (TBK1) and I kappa B kinase epsilon (IKK epsilon) and the subsequent activation of IFN regulatory factor 7 (IRF7). IRF7 induced IFN-beta production, which led to activation of a heterotrimeric transcription factor complex known as IFN-stimulated gene factor 3 (ISGF3) and the subsequent production of CXCL10 and additional type I IFN. In vivo studies showed that mice lacking the receptor for IFN-beta or subjected to gene silencing of the ISGF3 component Stat1 exhibited decreased CXCL10 responses and increased susceptibility to Helicobacter pylori infection, phenotypes observed in NOD1-deficient mice. These studies thus establish that NOD1 can activate the ISGF3 signaling pathway that is usually associated with protection against viral infection to provide mice with robust type I IFN-mediated protection from H. pylori and possibly other mucosal infections. C1 [Watanabe, Tomohiro; Asano, Naoki; Fichtner-Feigl, Stefan; Fuss, Ivan J.; Kitani, Atsushi; Strober, Warren] NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Watanabe, Tomohiro; Tsuji, Yoshihisa; Matsumoto, Yuko; Chiba, Tsutomu] Kyoto Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Kyoto 6068507, Japan. [Gorelick, Peter L.] Sci Applicat Int Corp, Anim Hlth Diagnost Lab, Lab Anim Sci Program, Natl Canc Inst Frederick, Frederick, MD USA. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bldg 10 CRC,Room 5W3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM tmhrwtnb@kuhp.kyoto-u.ac.jp; wstrober@niaid.nih.gov OI Asano, Naoki/0000-0003-4452-8459 FU Ministry of Education, Science and Culture, Japan; Japan Society for the Promotion of Science [21590532]; Takeda Science Foundation; Ichiro Kanehara Memorial Foundation for Medical Research; Astellas Foundation for Research on Metabolic Disorders; Yakult Bioscience Foundation; Sumitomo Foundation; Uehara Memorial Foundation FX This work is supported in part by grants from the Ministry of Education, Science and Culture, Japan, and the Japan Society for the Promotion of Science (grant 21590532), the Takeda Science Foundation, the Ichiro Kanehara Memorial Foundation for Medical Research, the Astellas Foundation for Research on Metabolic Disorders, the Yakult Bioscience Foundation, the Sumitomo Foundation, and the Uehara Memorial Foundation (to T. Watanabe). NR 61 TC 98 Z9 101 U1 0 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2010 VL 120 IS 5 BP 1645 EP 1662 DI 10.1172/JCI39481 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 590SN UT WOS:000277248000031 PM 20389019 ER PT J AU Corti, D Suguitan, AL Pinna, D Silacci, C Fernandez-Rodriguez, BM Vanzetta, F Santos, C Luke, CJ Torres-Velez, FJ Temperton, NJ Weiss, RA Sallusto, F Subbarao, K Lanzavecchia, A AF Corti, Davide Suguitan, Amorsolo L., Jr. Pinna, Debora Silacci, Chiara Fernandez-Rodriguez, Blanca M. Vanzetta, Fabrizia Santos, Celia Luke, Catherine J. Torres-Velez, Fernando J. Temperton, Nigel J. Weiss, Robin A. Sallusto, Federica Subbarao, Kanta Lanzavecchia, Antonio TI Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MEMORY B-CELLS; VIRUS HEMAGGLUTININ; A VIRUS; AVIAN INFLUENZA; MONOCLONAL-ANTIBODIES; H2 STRAINS; BINDING; H5N1; PROTECTION; SUBTYPE AB The target of neutralizing antibodies that protect against influenza virus infection is the viral protein HA. Genetic and antigenic variation in HA has been used to classify influenza viruses into subtypes (H1-H16). The neutralizing antibody response to influenza virus is thought to be specific for a few antigenically related isolates within a given subtype. However, while heterosubtypic antibodies capable of neutralizing multiple influenza virus subtypes have been recently isolated from phage display libraries, it is not known whether such antibodies are produced in the course of an immune response to influenza virus infection or vaccine. Here we report that, following vaccination with seasonal influenza vaccine containing H1 and H3 influenza virus subtypes, some individuals produce antibodies that cross-react with H5 HA. By immortalizing IgG-expressing B cells from 4 individuals, we isolated 20 heterosubtypic mAbs that bound and neutralized viruses belonging to several HA subtypes (H1, H2, H5, H6, and H9), including the pandemic A/California/07/09 H1N1 isolate. The mAbs used different VH genes and carried a high frequency of somatic mutations. With the exception of a mAb that bound to the HA globular head, all heterosubtypic mAbs bound to acid-sensitive epitopes in the HA stem region. Four mAbs were evaluated in vivo and protected mice from challenge with influenza viruses representative of different subtypes. These findings reveal that seasonal influenza vaccination can induce polyclonal heterosubtypic neutralizing antibodies that cross-react with the swine-origin pandemic H1N1 influenza virus and with the highly pathogenic H5N1 virus. C1 [Corti, Davide; Pinna, Debora; Silacci, Chiara; Fernandez-Rodriguez, Blanca M.; Vanzetta, Fabrizia; Sallusto, Federica; Lanzavecchia, Antonio] Inst Res Biomed, CH-6500 Bellinzona, Switzerland. [Suguitan, Amorsolo L., Jr.; Santos, Celia; Luke, Catherine J.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Rockville, MD USA. [Torres-Velez, Fernando J.] NIAID, Comparat Med Branch, NIH, Rockville, MD USA. [Temperton, Nigel J.; Weiss, Robin A.] UCL, MRC UCL Ctr Med Mol Virol, Div Infect & Immun, London, England. RP Lanzavecchia, A (reprint author), Inst Res Biomed, Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland. EM lanzavecchia@irb.unisi.ch RI Temperton, Nigel/K-5158-2013; Chiang, Vincent, Ming-Hsien/D-4312-2016 OI Temperton, Nigel/0000-0002-7978-3815; Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863 FU Swiss National Science Foundation [31003A-126027]; European Commission [201169]; Human Frontier Science Program [RGP9/2007]; National Institute of Allergy and Infection Diseases, NIH; Helmut Horten Foundation; UK Medical Research Council FX We thank David Jarrossay for cell sorting; Isabella Giacchetto-Sasselli for antibody sequence analysis; Jadon Jackson, Leatrice Vogel, and the staff of the Comparative Medicine Branch, NIAID, for assistance with the mouse studies; Lawrence Faucetre and Katherine Shea for assistance with pathology studies and IHC; and Barbara Cappechi (Novartis) for providing HA H5 genes. We thank the National Institute of Hygiene and Epidemiology (NIHE) in Hanoi, Vietnam, for the A/Viet Nam/1194/2004 HA gene. We thank Hong Jin of MedImmune for providing the ferret hyperimmune sera that were used as controls in the animal studies. This work was supported in part by the Swiss National Science Foundation (31003A-126027), the European Commission FP6 programme (IMECS, 201169), the Human Frontier Science Program (RGP9/2007), and the Intramural Research Program of National Institute of Allergy and Infection Diseases, NIH. A. Lanzavecchia is supported by the Helmut Horten Foundation. N.J. Temperton and R.A. Weiss are supported by the UK Medical Research Council. NR 36 TC 243 Z9 248 U1 2 U2 20 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2010 VL 120 IS 5 BP 1663 EP 1673 DI 10.1172/JCI41902 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 590SN UT WOS:000277248000032 PM 20389023 ER PT J AU Antonelli, LRV Rothfuchs, AG Goncalves, R Roffe, E Cheever, AW Bafica, A Salazar, AM Feng, CG Sher, A AF Antonelli, Lis R. V. Rothfuchs, Antonio Gigliotti Goncalves, Ricardo Roffe, Ester Cheever, Allen W. Bafica, Andre Salazar, Andres M. Feng, Carl G. Sher, Alan TI Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID AEROSOLIZED INTERFERON-ALPHA; T-CELL IMMUNITY; MYCOBACTERIUM-TUBERCULOSIS; DENDRITIC CELLS; LISTERIA-MONOCYTOGENES; CHEMOKINE RECEPTOR; POLYRIBOCYTIDYLIC ACID; BACTERIAL-INFECTION; IFN-ALPHA/BETA; RESISTANCE AB Type I IFN has been demonstrated to have major regulatory effects on the outcome of bacterial infections. To assess the effects of exogenously induced type I IFN on the outcome of Mycobacterium tuberculosis infection, we treated pathogen-exposed mice intranasally with polyinosinic-polycytidylic acid condensed with poly-L-lysine and carboxymethylcellulose (Poly-ICLC), an agent designed to stimulate prolonged, high-level production of type I IFN. Drug-treated, M. tuberculosis-infected WT mice, but not mice lacking IFN-alpha beta receptor 1 (IFN alpha beta R; also known as IFNAR1), displayed marked elevations in lung bacillary loads, accompanied by widespread pulmonary necrosis without detectable impairment of Th1 effector function. Importantly, lungs from Poly-ICLC-treated M. tuberculosis-infected mice exhibited a striking increase in CD11b(+)F4/80(+)Gr1(int) cells that displayed decreased MHC II expression and enhanced bacterial levels relative to the same subset of cells purified from infected, untreated controls. Moreover, both the Poly-ICLC-triggered pulmonary recruitment of the CD11b(+)F4/80(+)Gr1(int) population and the accompanying exacerbation of infection correlated with type I IFN-induced upregulation of the chemokine-encoding gene Ccl2 and were dependent on host expression of the chemokine receptor CCR2. The above findings suggest that Poly-ICLC treatment can detrimentally affect the outcome of M. tuberculosis infection, by promoting the accumulation of a permissive myeloid population in the lung. In addition, these data suggest that agents that stimulate type I IFN should be used with caution in patients exposed to this pathogen. C1 [Antonelli, Lis R. V.; Rothfuchs, Antonio Gigliotti; Cheever, Allen W.; Feng, Carl G.; Sher, Alan] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Goncalves, Ricardo] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. [Roffe, Ester] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Bafica, Andre] Univ Fed Santa Catarina, Dept Microbiol Immunol & Parasitol, Florianopolis, SC, Brazil. [Salazar, Andres M.] Oncovir Inc, Washington, DC USA. RP Antonelli, LRV (reprint author), Fiocruz MS, Ctr Pesquisas Rene Rachou, Av Augusto de Lima 1715, BR-30190002 Belo Horizonte, MG, Brazil. EM lisantonelli@cpqrr.fiocruz.br RI Roffe, Ester/H-4688-2012; Rothfuchs, Antonio/F-5981-2013; Vacinas, Inct/J-9431-2013; Antonelli, Lis/G-2907-2012 OI Rothfuchs, Antonio/0000-0001-6001-7240; FU NIAID, NIH, Department of Health and Human Services FX We are grateful to Sara Hieny, Pat Caspar, Sandy White, and Robert Thompson for excellent technical assistance and to the NIAID Flow Cytometry Section, particularly Bishop Hague for performing the FACS cell purifications and Kevin Holmes and David Stephany for their advice on multicolor flow cytometry. We also thank Stefanie Vogel and Brian Kelsall for their valuable advice and Siamon Gordon, Dragana Jankovic, Tom Wynn, and Giorgio Trinchieri for their helpful comments on this manuscript. This study was supported by the Intramural Research Program of NIAID, NIH, Department of Health and Human Services. NR 45 TC 111 Z9 112 U1 1 U2 7 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2010 VL 120 IS 5 BP 1674 EP 1682 DI 10.1172/JCI40817 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 590SN UT WOS:000277248000033 PM 20389020 ER PT J AU Ye, H Jeong, SY Ghosh, MC Kovtunovych, G Silvestri, L Ortillo, D Uchida, N Tisdale, J Camaschella, C Rouault, TA AF Ye, Hong Jeong, Suh Young Ghosh, Manik C. Kovtunovych, Gennadiy Silvestri, Laura Ortillo, Danilo Uchida, Naoya Tisdale, John Camaschella, Clara Rouault, Tracey A. TI Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID SULFUR CLUSTER BIOGENESIS; FRIEDREICH ATAXIA; MONOTHIOL GLUTAREDOXINS; REGULATORY PROTEINS; SCAFFOLD PROTEIN; GENE-EXPRESSION; SACCHAROMYCES-CEREVISIAE; RESPONSIVE ELEMENT; MICROCYTIC ANEMIA; MOLECULAR CONTROL AB Glutaredoxin 5 (GLRX5) deficiency has previously been identified as a cause of anemia in a zebrafish model and of sideroblastic anemia in a human patient. Here we report that GLRX5 is essential for iron-sulfur cluster biosynthesis and the maintenance of normal mitochondrial and cytosolic iron homeostasis in human cells. GLRX5, a mitochondrial protein that is highly expressed in erythroid cells, can homodimerize and assemble [2Fe-2S] in vitro. In GLRX5-deficient cells, [Fe-S] cluster biosynthesis was impaired, the iron-responsive element-binding (IRE-binding) activity of iron regulatory protein 1 (IRP1) was activated, and increased IRP2 levels, indicative of relative cytosolic iron depletion, were observed together with mitochondrial iron overload. Rescue of patient fibroblasts with the WT GLRX5 gene by transfection or viral transduction reversed a slow growth phenotype, reversed the mitochondrial iron overload, and increased aconitase activity. Decreased aminolevulinate delta, synthase 2 (ALAS2) levels attributable to IRP-mediated translational repression were observed in erythroid cells in which GLRX5 expression had been downregulated using siRNA along with marked reduction in ferrochelatase levels and increased ferroportin expression. Erythroblasts express both IRP-repressible ALAS2 and non-IRP-repressible ferroportin 1b. The unique combination of IRP targets likely accounts for the tissue-specific phenotype of human GLRX5 deficiency. C1 [Ye, Hong; Jeong, Suh Young; Ghosh, Manik C.; Kovtunovych, Gennadiy; Rouault, Tracey A.] NICHHD, Program Mol Med, NIH, Bethesda, MD 20892 USA. [Silvestri, Laura; Camaschella, Clara] Univ Vita Salute, Milan, Italy. [Silvestri, Laura; Camaschella, Clara] Ist Ric & Cura Carattere Sci IRCCS San Raffaele, Milan, Italy. [Ortillo, Danilo] Emory Univ, Dept Phys, Atlanta, GA 30322 USA. [Uchida, Naoya; Tisdale, John] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Program Mol Med, NIH, Bethesda, MD 20892 USA. EM trou@helix.nih.gov RI Camaschella, Clara/A-3289-2015; Silvestri, Laura/A-1417-2015; OI Silvestri, Laura/0000-0002-8726-9808; Jeong, Suh Young/0000-0002-6376-7001 FU National Institute of Child Health and Human Development; Roche Foundation for Anemia Research (ROFAR) FX We thank W.H. Tong, D. Crooks, H. Uhrigshardt, D. Zhang, and S. Cooperman for providing antibodies and cell lines. We also thank P. Kim and G. Patterson for help in confocal microscopy and W. Chen of genomics core laboratory at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) for microarray analysis. This work was supported by the intramural program of the National Institute of Child Health and Human Development (to T. Rouault) and by a grant from Roche Foundation for Anemia Research (ROFAR) (to C. Camaschella). NR 57 TC 89 Z9 93 U1 0 U2 12 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2010 VL 120 IS 5 BP 1749 EP 1761 DI 10.1172/JCI40372 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 590SN UT WOS:000277248000039 PM 20364084 ER PT J AU Spiegel, AM AF Spiegel, Allen M. TI Commentary: New Guidelines for NIH Peer Review: Improving the System or Undermining It? SO ACADEMIC MEDICINE LA English DT Editorial Material AB The National Institutes of Health (NIH) peer review system has been viewed as the best way to guarantee the scientific independence of biomedical research in the United States, and it has been emulated internationally. The system, however, is subject to a variety of stresses, and these have always been exacerbated at times of flat NIH funding, as in the past five years. To address several of these stresses, NIH first conducted a "diagnostic self-study" of the peer review system and then implemented a number of changes. Costello, in a Perspective in this issue of Academic Medicine, argues that two of these changes, special consideration for new investigators and emphasis of the criterion of "innovation," undermine the stated goal of funding the "best science by the best scientists." In this commentary on Costello's Perspective article, the author examines the issue of NIH funding of new investigators from a historical perspective, in the context of overall NIH priority setting in resource allocation. The related issue of innovation as a criterion in NIH peer review is also addressed, and the commentary concludes with an affirmation of the need to measure outcomes in assessing the impact of changes in the NIH peer review system. C1 [Spiegel, Allen M.] Albert Einstein Coll Med, Bronx, NY 10461 USA. [Spiegel, Allen M.] NIDDK, NIH, Bethesda, MD USA. RP Spiegel, AM (reprint author), Albert Einstein Coll Med, Belfer 312,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM allen.spiegel@einstein.yu.edu NR 5 TC 1 Z9 1 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD MAY PY 2010 VL 85 IS 5 BP 746 EP 748 DI 10.1097/ACM.0b013e3181d7e130 PG 3 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 618SI UT WOS:000279375600008 PM 20520019 ER PT J AU Subburaman, P Austin, BP Shaw, GX Waugh, DS Ji, XH AF Subburaman, Priadarsini Austin, Brian P. Shaw, Gary X. Waugh, David S. Ji, Xinhua TI Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of macrophage growth locus A (MglA) protein from Francisella tularensis SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS LA English DT Article ID TRANSCRIPTION; STARVATION; TULAREMIA AB Francisella tularensis, a potential bioweapon, causes a rare infectious disease called tularemia in humans and animals. The macrophage growth locus A (MglA) protein from F. tularensis associates with RNA polymerase to positively regulate the expression of multiple virulence factors that are required for its survival and replication within macrophages. The MglA protein was over-produced in Escherichia coli, purified and crystallized. The crystals diffracted to 7.5 angstrom resolution at the Advanced Photon Source, Argonne National Laboratory and belonged to the hexagonal space group P6(1) or P6(5), with unit-cell parameters a = b = 125, c = 54 angstrom. C1 [Subburaman, Priadarsini; Austin, Brian P.; Shaw, Gary X.; Waugh, David S.; Ji, Xinhua] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Ji, XH (reprint author), NCI, Macromol Crystallog Lab, 1050 Boyles St, Frederick, MD 21702 USA. EM jix@mail.nih.gov RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU NIH, National Cancer Institute, Center for Cancer Research; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Electrospray mass-spectrometry experiments were conducted on the LC/ES-MS instrument maintained by the Biophysics Resource in the Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute at Frederick. X-ray diffraction data were collected on the SER-CAT 22-ID beamline of the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at http://www.ser-cat.org/members.html. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract No. W-31-109-Eng-38. NR 11 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1744-3091 J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Cryst. Commun. PD MAY PY 2010 VL 66 BP 554 EP 557 DI 10.1107/S1744309110009711 PN 5 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 590IC UT WOS:000277217700018 PM 20445258 ER PT J AU Solomon, D AF Solomon, D. TI HPV DNA TESTING SO ACTA CYTOLOGICA LA English DT Meeting Abstract C1 [Solomon, D.] Natl Canc Inst, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0001-5547 J9 ACTA CYTOL JI Acta Cytol. PD MAY-JUN PY 2010 VL 54 IS 3 SU S BP 378 EP 378 PG 1 WC Pathology SC Pathology GA 600KZ UT WOS:000277986200046 ER PT J AU Reuschenbach, M Clad, A Doberitz, CV Wentzensen, N Rahmsdorf, J Schaffrath, F Griesser, H Freudenberg, N Doberitz, MV AF Reuschenbach, M. Clad, A. Doberitz, C. von Knebel Wentzensen, N. Rahmsdorf, J. Schaffrath, F. Griesser, H. Freudenberg, N. Doberitz, M. von Knebel TI IMPROVED DIAGNOSIS OF CERVICAL DYSPLASIA BY P16(INK4A) IMMUNOCYTOCHEAUSTRY SO ACTA CYTOLOGICA LA English DT Meeting Abstract C1 Univ Heidelberg, Inst Pathol, Dept Appl Tumor Biol, Heidelberg, Germany. Univ Freiburg, Div Obstet & Gynecol, Freiburg, Germany. Natl Canc Inst, NIH, Div Canc Epidemiol & Genet, Bethesda, MD USA. ZPZ Koln, Ctr Pathol & Cytodiagnost, Cologne, Germany. Univ Freiburg, Inst Pathol, D-7800 Freiburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0001-5547 J9 ACTA CYTOL JI Acta Cytol. PD MAY-JUN PY 2010 VL 54 IS 3 SU S BP 393 EP 393 PG 1 WC Pathology SC Pathology GA 600KZ UT WOS:000277986200096 ER PT J AU Oh, W Stevenson, DK Tyson, JE Morris, BH Ahlfors, CE Bender, GJ Wong, RJ Perritt, R Vohr, BR Van Meurs, KP Vreman, HJ Das, A Phelps, DL O'Shea, TM Higgins, RD AF Oh, W. Stevenson, D. K. Tyson, J. E. Morris, B. H. Ahlfors, C. E. Bender, G. Jesse Wong, R. J. Perritt, R. Vohr, B. R. Van Meurs, K. P. Vreman, H. J. Das, A. Phelps, D. L. O'Shea, T. Michael Higgins, R. D. CA NICHD Neonatal Res Network Bethesd TI Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants SO ACTA PAEDIATRICA LA English DT Article DE Extremely low birth weight infants; Neurodevelopmental outcomes; Plasma bilirubin; unbound bilirubin ID PREMATURE-INFANTS; SERUM BILIRUBIN; ANTIOXIDANT ACTIVITY; BINDING CAPACITY; ALBUMIN BINDING; PRETERM INFANTS; KERNICTERUS; AGE; ENCEPHALOPATHY; RISK AB Objectives: To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18-22 months corrected age in extremely low birth weight infants. Method: Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 +/- 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18-22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. Results: Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. Conclusions: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18-22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants. C1 [Oh, W.; Bender, G. Jesse; Vohr, B. R.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Stevenson, D. K.; Wong, R. J.; Van Meurs, K. P.; Vreman, H. J.] Stanford Univ, Palo Alto, CA 94304 USA. [Tyson, J. E.; Morris, B. H.] Univ Texas Houston, Houston, TX USA. [Perritt, R.; Das, A.] RTI, Res Triangle Pk, NC USA. [Phelps, D. L.] Univ Rochester, Rochester, NY USA. [O'Shea, T. Michael] Wake Forest Univ Winston Salem, Winston Salem, NC USA. [Higgins, R. D.] NICHD, Bethesda, MD USA. RP Oh, W (reprint author), Brown Univ, Warren Alpert Med Sch, 101 Dudley St, Providence, RI 02912 USA. EM woh@wihri.org RI Myers , Gary /I-4901-2013; Finer, Nick/B-9981-2009 OI Myers , Gary /0000-0003-4317-015X; Finer, Nick/0000-0003-2468-6804 FU NCATS NIH HHS [UL1 TR000454]; NCRR NIH HHS [KL2 RR024149, KL2 RR24149, M01 RR006022, M01 RR007122, M01 RR008084, M01 RR016587, M01 RR16587, M01 RR30, M01 RR32, M01 RR39, M01 RR44, M01 RR6022, M01 RR633, M01 RR70, M01 RR7122, M01 RR750, M01 RR80, M01 RR8084, UL1 RR024128, UL1 RR024148, UL1 RR24128, UL1 RR24148]; NICHD NIH HHS [U10 HD40689, U01 HD036790, U01 HD36790, U10 HD021364, U10 HD021373, U10 HD021385, U10 HD021397, U10 HD027851, U10 HD027853, U10 HD027856, U10 HD027871, U10 HD027880, U10 HD027904, U10 HD027904-09, U10 HD034216, U10 HD040461, U10 HD040492, U10 HD040498, U10 HD040521, U10 HD040689, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40521] NR 33 TC 36 Z9 37 U1 3 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PD MAY PY 2010 VL 99 IS 5 BP 673 EP 678 DI 10.1111/j.1651-2227.2010.01688.x PG 6 WC Pediatrics SC Pediatrics GA 575AG UT WOS:000276034800011 PM 20105142 ER PT J AU Narva, AS Briggs, M Jordan, R Pavkov, ME Burrows, NR Williams, DE AF Narva, Andrew S. Briggs, Michael Jordan, Regina Pavkov, Meda E. Burrows, Nilka Rios Williams, Desmond E. TI Toward a More Collaborative Federal Response to Chronic Kidney Disease SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE Chronic kidney disease; Fistula First; Surveillance; Quality improvement organizations; CDC; CMS; NIDDK; NKDEP ID CONVERTING ENZYME-INHIBITORS; NONDIABETIC RENAL-DISEASE; PROGRESSION; METAANALYSIS AB Chronic kidney disease (CKD) is a significant public health problem in the United States. However, data from the United States Renal Data System and other sources suggest that care for people with CKD does not meet recommended standards. The Federal government has developed the infrastructure to promote population-based interventions which have reduced the burden of other chronic illnesses. An effective, coordinated response by Federal health agencies to the public health challenge of CKD could have a significant effect on the morbidity, mortality, and costs associated with CKD. In recent years, initiatives undertaken by three Federal agencies have made important advances in coordinating efforts. The Centers for Disease Control and Prevention has begun to develop public health infrastructure for monitoring the burden of CKD. The Centers for Medicare and Medicaid Services has, through the successful Fistula First Breakthrough Initiative (FFBI) and inclusion of CKD in the scope of work of Quality Improvement Organizations, promoted earlier diagnosis and treatment of CKD. The National Institute of Diabetes and Digestive and Kidney Diseases, through its National Kidney Disease Education Program, has reinvigorated and expanded the Kidney Interagency Coordinating Committee so that it is a robust vehicle to share information about activities, identify and disseminate promising practices and tools, and foster cross-agency collaboration. Collaboration among Federal health agencies has the potential to enhance efforts to reduce the burden of CKD. Published by the National Kidney Foundation, Inc. C1 [Narva, Andrew S.] NIDDK, NIH, Bethesda, MD USA. [Briggs, Michael; Jordan, Regina; Pavkov, Meda E.; Burrows, Nilka Rios; Williams, Desmond E.] Ctr Dis Control, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. RP Burrows, NR (reprint author), 4770 Buford Hwy NE,Mailstop K10, Atlanta, GA 30341 USA. EM nrios@cdc.gov FU Intramural NIH HHS [Z99 DK999999] NR 26 TC 3 Z9 3 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1548-5595 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD MAY PY 2010 VL 17 IS 3 BP 282 EP 288 DI 10.1053/j.ackd.2010.03.006 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 599YE UT WOS:000277949400010 PM 20439097 ER PT J AU Kusumoto-Matsuo, R Opresko, PL Ramsden, D Tahara, H Bohr, VA AF Kusumoto-Matsuo, Rika Opresko, Patricia L. Ramsden, Dale Tahara, Hidetoshi Bohr, Vilhelm A. TI Cooperation of DNA-PKcs and WRN helicase in the maintenance of telomeric D-loops SO AGING-US LA English DT Article DE RecQ; WRN; DNA-PKcs; telomere; aging; DNA repair ID WERNER-SYNDROME PROTEIN; STRAND BREAK REPAIR; CATALYTIC SUBUNIT; IN-VITRO; KINASE; COMPLEX; DISPLACEMENT; EXONUCLEASE; CHROMATIN; GENETICS AB Werner syndrome is an inherited human progeriod syndrome caused by mutations in the gene encoding the Werner Syndrome protein, WRN. It has both 3'-5' DNA helicase and exonuclease activities, and is suggested to have roles in many aspects of DNA metabolism, including DNA repair and telomere maintenance. The DNA-PK complex also functions in both DNA double strand break repair and telomere maintenance. Interaction between WRN and the DNA-PK complex has been reported in DNA double strand break repair, but their possible cooperation at telomeres has not been reported. This study analyzes the in vitro and in vivo interaction at the telomere between WRN and DNA-PKcs, the catalytic subunit of DNA-PK. The results show that DNA-PKcs selectively stimulates WRN helicase but not WRN exonuclease in vitro, affecting that WRN helicase unwinds and promotes the release of the full-length invading strand of a telomere D-loop model substrate. In addition, the length of telomeric G-tails decreases in DNA-PKcs knockdown cells, and this phenotype is reversed by overexpression of WRN helicase. These results suggest that WRN and DNA-PKcs may cooperatively prevent G-tail shortening in vivo. C1 [Kusumoto-Matsuo, Rika; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Opresko, Patricia L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Environm & Occupat Hlth, Pittsburgh, PA 15219 USA. [Ramsden, Dale] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Ramsden, Dale] Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. [Ramsden, Dale] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Tahara, Hidetoshi] Hiroshima Univ, Grad Sch Biomed Sci, Div Integrated Med Sci, Dept Cellular & Mol Biol, Hiroshima 7348551, Japan. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM bohrv@nih.gov OI Opresko, Patricia/0000-0002-6470-2189 FU Japan Society For the Promotion of Science (Japan); NIH, National Institute on Aging [CA84442, ES0515052]; Ministry of Education, Culture, Sports, Science and Technology of Japan [20014015] FX We thank Dr. Ian D. Hickson (University of Oxford) for His-tagged BLM, Dr. Marc S. Wold (University of Iowa) for p11d-tRPA vector, Dr. Junko Oshima (University of Washington) for pBK-WRN and pBK-WRN (E84A), and Drs. Yie Liu, Chandrika Canugovi, and Avik Ghosh for their technical advice and critical reading of this manuscript. R.K. was supported by a Research Fellowship of Japan Society For the Promotion of Science (Japan). This work was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, as well as NIH grant CA84442 (to D.A.R), grant ES0515052 (P.L.O.) and Grant-in-Aid for Scientific Research No. 20014015 on priority areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to H.T). NR 44 TC 16 Z9 18 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD MAY PY 2010 VL 2 IS 5 BP 274 EP 284 PG 11 WC Cell Biology SC Cell Biology GA 605LX UT WOS:000278350200008 PM 20519774 ER PT J AU Tikkanen, R Ducci, F Goldman, D Holi, M Lindberg, N Tiihonen, J Virkkunen, M AF Tikkanen, Roope Ducci, Francesca Goldman, David Holi, Matti Lindberg, Nina Tiihonen, Jari Virkkunen, Matti TI MAOA Alters the Effects of Heavy Drinking and Childhood Physical Abuse on Risk for Severe Impulsive Acts of Violence Among Alcoholic Violent Offenders SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Violence; Alcoholism; Alcohol Consumption; Antisocial Behavior; Personality Disorder; Impulsivity; Childhood Adversity; Physical Abuse; Monoamine Oxidase A; Crime ID MONOAMINE-OXIDASE-A; BORDERLINE PERSONALITY-DISORDER; GENE PROMOTER; FUNCTIONAL POLYMORPHISM; REGULATORY POLYMORPHISM; ANTISOCIAL-BEHAVIOR; FOLLOW-UP; ASSOCIATION; GENOTYPE; ENVIRONMENT AB Background: A polymorphism in the promoter region of the monoamine oxidase A gene (MAOA) has been shown to alter the effect of persistent drinking and childhood maltreatment on the risk for violent and antisocial behaviors. These findings indicate that MAOA could contribute to inter-individual differences in stress resiliency. Methods: Recidivism in severe violent crimes was assessed after 8 years of nonincarcerated follow-up in a male sample of 174 impulsive Finnish alcoholic violent offenders, the majority of whom exhibited antisocial (ASPD) or borderline personality disorder (BPD) or both. We examined whether MAOA genotype alters the effects of heavy drinking and childhood physical abuse (CPA) on the risk for committing impulsive recidivistic violent crimes. Results: Logistic regression analyses showed that both heavy drinking and CPA were significant independent predictors of recidivism in violent behavior (OR 5.2, p = 0.004 and OR 5.3, p = 0.003) among offenders having the high MAOA activity genotype (MAOA-H), but these predictors showed no effect among offenders carrying the low MAOA activity genotype (MAOA-L). Conclusion: Carriers of the MAOA-H allele have a high risk to commit severe recidivistic impulsive violent crimes after exposure to heavy drinking and CPA. C1 [Tikkanen, Roope; Lindberg, Nina; Virkkunen, Matti] Univ Helsinki, Dept Psychiat, Inst Clin Med, Huch 00029, Finland. [Ducci, Francesca] Inst Psychiat, Div Psychol SGDP Ctr, London, England. [Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Holi, Matti] Helsinki Univ Hosp, Peijas Psychiat Hosp, Vantaa, Finland. [Tiihonen, Jari] Univ Kuopio, Dept Forens Psychiat, FIN-70211 Kuopio, Finland. [Tiihonen, Jari] Kuopio Univ Hosp, Dept Clin Physiol, SF-70210 Kuopio, Finland. [Tiihonen, Jari] Natl Inst Hlth & Welf, Helsinki, Finland. [Virkkunen, Matti] Helsinki Univ Hosp, Kellokoski Psychiat Hosp, Kellokoski, Finland. RP Tikkanen, R (reprint author), Univ Helsinki, Dept Psychiat, Inst Clin Med, POB 590, Huch 00029, Finland. EM roope.tikkanen@helsinki.fi RI Goldman, David/F-9772-2010; Tiihonen, Jari/G-3078-2012 OI Goldman, David/0000-0002-1724-5405; Tiihonen, Jari/0000-0002-0400-6798 FU National Institute on Alcohol Abuse and Alcoholism, NIH; Janssen-Cilag; Eli Lilly; Lundbeck FX This research benefited from the support of the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH.. Jari Tiihonen has been a Faculty member of the Lundbeck International Neuroscience Foundation since 1997, a consult/expert member of Advisory Board of Janssen-Cilag since 2006, a member of Eli Lilly Advisory Board since October 2006, has conducted research collaboration with Organon since 2007, and has received lecture fees from Janssen-Cilag, Eli Lilly, and Lundbeck. All other authors report no competing interests. No financial support was received from anyone benefiting from these results. NR 47 TC 19 Z9 21 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2010 VL 34 IS 5 BP 853 EP 860 DI 10.1111/j.1530-0277.2010.01157.x PG 8 WC Substance Abuse SC Substance Abuse GA 587NO UT WOS:000276999600011 PM 20201935 ER PT J AU Rotman, Y Borg, BB Soza, A Feld, JJ Modi, AA Loomba, R Lutchman, G Rivera, E Doo, E Ghany, MG Heller, T Neumann, AU Liang, TJ Hoofnagle, JH AF Rotman, Y. Borg, B. B. Soza, A. Feld, J. J. Modi, A. A. Loomba, R. Lutchman, G. Rivera, E. Doo, E. Ghany, M. G. Heller, T. Neumann, A. U. Liang, T. J. Hoofnagle, J. H. TI Low- and standard-dose peginterferon alfa-2a for chronic hepatitis C, genotype 2 or 3: efficacy, tolerability, viral kinetics and cytokine response SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PLUS RIBAVIRIN; INITIAL TREATMENT; GENE-EXPRESSION; PEGYLATED INTERFERON; ANTIVIRAL THERAPY; INFECTED PATIENTS; HCV GENOTYPE-2; COMBINATION; VIRUS AB P>Background Chronic infection with hepatitis C, genotype 2/3, responds better than other genotypes to peginterferon and ribavirin treatment. We hypothesized that a lower dose of peginterferon would be as effective, but less toxic than standard doses. Aim To test the hypothesis that a lower dose of peginterferon would be as effective as, but less toxic than, standard doses. Methods A total of 30 patients were treated with low-dose peginterferon alfa-2a (90 mu g/week) and 27 patients with standard doses (180 mu g/week) for 24 weeks in combination with 800 mg/day of ribavirin. Patients who failed treatment were offered 48 weeks of standard-dose treatment. Viral and serum inducible protein 10 (IP-10) levels were measured and early viral kinetic parameters were calculated. Results Sustained virological response was achieved in 68% of the low-dose and 87% of the standard-dose patients (per protocol, P = 0.79 for non-inferiority). Re-treatment was successful in all patients who tolerated full dose and duration. The standard-dose group had greater first-phase declines of viral levels and faster time to negativity. The second-phase slope was not dose-dependent. IP-10 induction was significantly greater with the standard dose. Although fatigue and general feeling during treatment were worse for standard dose, haematological toxicity and depression did not differ between groups. Conclusion A lower dose of peginterferon is associated with some symptomatic benefit, but the response is not equivalent to standard dosing. C1 [Rotman, Y.; Borg, B. B.; Soza, A.; Feld, J. J.; Modi, A. A.; Loomba, R.; Lutchman, G.; Rivera, E.; Doo, E.; Ghany, M. G.; Heller, T.; Liang, T. J.; Hoofnagle, J. H.] NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Soza, A.] Pontificia Univ Catolica Chile, Dept Gastroenterol, Santiago, Chile. [Neumann, A. U.] Bar Ilan Univ, Goodman Fac Life Sci, Ramat Gan, Israel. RP Rotman, Y (reprint author), NIDDKD, Liver Dis Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9C434, Bethesda, MD 20892 USA. EM rotmany@mail.nih.gov RI Soza, Alejandro/C-2907-2009 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX Declaration of personal interests: None. Declaration of funding interests: This study was funded by the intramural research programme of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The medications for the study were kindly supplied by Roche Pharmaceuticals, Nutley, NJ, under a Clinical Trial Agreement with the National Institutes of Health. NR 30 TC 5 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD MAY 1 PY 2010 VL 31 IS 9 BP 1018 EP 1027 DI 10.1111/j.1365-2036.2010.04263.x PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 579GL UT WOS:000276356900010 PM 20163377 ER PT J AU Velagaleti, RS Pencina, MJ Vasan, RS Benjamin, EJ Massaro, JM Pencina, K Levy, D AF Velagaleti, Raghava S. Pencina, Michael J. Vasan, Ramachandran S. Benjamin, Emelia J. Massaro, Joseph M. Pencina, Karol Levy, Daniel TI Cross-Sectional Relations of Lipid Concentrations to Left Ventricular Structural Attributes SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY HEART-DISEASE; SERUM-CHOLESTEROL; HYPERCHOLESTEROLEMIA; HYPERTROPHY AB Although previous investigations reported on the associations of lipid concentrations with left ventricular remodeling in specific subpopulations, few data exist on these associations in a community-based sample of subjects without cardiovascular disease. In this study, 3,554 Framingham Heart Study participants (mean age 47 years, 53% women) without preexisting clinical cardiovascular disease were examined, and no meaningful associations of high-density lipoprotein cholesterol or non high-density lipoprotein cholesterol with echocardiographic indexes of left ventricular structure were observed. In conclusion, these data do not support an independent association between lipid concentrations and left ventricular structure. Published by Elsevier Inc. (Am J Cardiol 2010;105:1297-1299) C1 [Velagaleti, Raghava S.; Pencina, Michael J.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Massaro, Joseph M.; Pencina, Karol; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Pencina, Michael J.; Massaro, Joseph M.; Pencina, Karol] Boston Univ, Dept Stat, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM levyd@nih.gov OI Massaro, Joseph/0000-0002-2682-4812; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health, Bethesda, Maryland [NO1-HIC-25195]; National Heart, Lung, and Blood Institute [RO1 HL 080124, 2K24HL 04334] FX The Framingham Heart Study is supported by Contract NO1-HIC-25195 from the National Institutes of Health, Bethesda, Maryland. Dr. Vasan was supported by Grants RO1 HL 080124 and 2K24HL 04334 from the National Heart, Lung, and Blood Institute. NR 12 TC 2 Z9 2 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 1 PY 2010 VL 105 IS 9 BP 1297 EP 1299 DI 10.1016/j.amjcard.2009.12.050 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 594ZF UT WOS:000277579600016 PM 20403482 ER PT J AU Vidula, H Tian, L Liu, K Criqui, MH Ferrucci, L Guralnik, JM Green, D Ridker, P McDermott, MM AF Vidula, Himabindu Tian, Lu Liu, Kiang Criqui, Michael H. Ferrucci, Luigi Guralnik, Jack M. Green, David Ridker, Paul McDermott, Mary M. TI Comparison of Effects of Statin Use on Mortality in Patients With Peripheral Arterial Disease With Versus Without Elevated C-Reactive Protein and D-Dimer Levels SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ANKLE BRACHIAL INDEX; INFLAMMATORY MARKERS; ATHEROSCLEROSIS; ASSOCIATION; PREVALENCE; SERUM AB We determined whether statin use was associated with lower all-cause and cardiovascular disease (CVD) mortality in 579 participants with lower extremity peripheral arterial disease (PAD) according to the presence and absence of elevated C-reactive protein (CRP) and D-dimer levels. Statin use was determined at baseline and at each annual visit. The CRP and D-dimer levels were measured at baseline. The mean follow-up was 3.7 years. The analyses were adjusted for age, gender, race, co-morbidities, ankle brachial index, cholesterol, and other confounders. Of the 579 participants, 242 (42%) were taking a statin at baseline and 129 (22%) died during follow-up. Statin use was associated with lower all-cause mortality (hazard ratio 0.51, 95% confidence interval [CI] 0.30 to 0.86, p = 0.012) and CVD mortality (hazard ratio 0.36, 95% CI 0.14 to 0.89, p = 0.027) compared to statin nonuse. No statistically significant interaction was found for the baseline CRP or D-dimer level with the association of statin use and mortality. However, statin therapy was associated with significantly lower all-cause and total mortality only among participants with baseline CRP values greater than the median and not among those with CRP values less than the median (hazard ratio 0.44, 95% CI 0.23 to 0.88 vs hazard ratio 0.73, 95% CI 0.31 to 1.75 for all-cause mortality and hazard ratio 0.20, 95% CI 0.063 to 0.65 vs hazard ratio 0.59, 95% CI 0.093 to 3.79 for CVD mortality). In conclusion, among those with PAD, statin use was associated with lower all-cause and CVD mortality compared to no statin use. The favorable association of statin use with mortality was not influenced significantly by the baseline CRP or D-dimer level. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:1348-1352) C1 [Vidula, Himabindu; Liu, Kiang; Green, David; McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Tian, Lu] Stanford Univ, Palo Alto, CA 94304 USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Ferrucci, Luigi; Guralnik, Jack M.] NIA, Bethesda, MD 20892 USA. [Ridker, Paul] Harvard Univ, Sch Med, Boston, MA USA. RP McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. EM Mdm608@northwestern.edu FU National Heart and Lung and Blood Institute (Bethesda, Maryland) [R01-HL58099, R01-FIL64739, R01-HL071223, R01-HL076298]; National Heart and Lung and Blood Institute (Bethesda, Maryland); National Center for Research Resources, National Institutes of Health (Bethesda, Maryland) [RR-00048]; National Institute on Aging, National Institutes of Health (Bethesda, Maryland) FX This study was supported by grants R01-HL58099, R01-FIL64739, R01-HL071223, and R01-HL076298 from the National Heart and Lung and Blood Institute (Bethesda, Maryland) and by grant RR-00048 from the National Center for Research Resources, National Institutes of Health (Bethesda, Maryland). This study was also supported in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health (Bethesda, Maryland). NR 23 TC 13 Z9 13 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 1 PY 2010 VL 105 IS 9 BP 1348 EP 1352 DI 10.1016/j.amjcard.2009.12.054 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 594ZF UT WOS:000277579600025 PM 20403491 ER PT J AU Dwyer, J Donoghue, MD AF Dwyer, Johanna Donoghue, Maria DeTolve TI Is risk of Alzheimer disease a reason to use dietary supplements? SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; BASE-LINE DATA; COGNITIVE FUNCTION; GINKGO EVALUATION; OLDER-PEOPLE; FOLIC-ACID; DEMENTIA; PREVENTION; VITAMIN-B-12; BILOBA C1 [Dwyer, Johanna] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Dwyer, Johanna] Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer USDA, Boston, MA 02111 USA. [Donoghue, Maria DeTolve] G&M Consulting Serv, Winnetka, IL USA. RP Dwyer, J (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01, Bethesda, MD 20892 USA. OI Dwyer, Johanna/0000-0002-0783-1769 NR 16 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAY 1 PY 2010 VL 91 IS 5 BP 1155 EP 1156 DI 10.3945/ajcn.2010.29498 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 585RD UT WOS:000276845100003 PM 20335540 ER PT J AU Pronk, A Ji, BT Shu, XO Xue, SZ Yang, G Li, HL Rothman, N Gao, YT Zheng, W Chow, WH AF Pronk, Anjoeka Ji, Bu-Tian Shu, Xiao-Ou Xue, Shouzheng Yang, Gong Li, Hong-Lan Rothman, Nathaniel Gao, Yu-Tang Zheng, Wei Chow, Wong-Ho TI Night-Shift Work and Breast Cancer Risk in a Cohort of Chinese Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast neoplasms; China; prospective studies; work schedule tolerance ID LIGHT; NURSES; HEALTH AB Shift work involving disruption of circadian rhythms has been classified as a probable cause of human cancer by the International Agency for Research on Cancer, based on limited epidemiologic evidence and abundant experimental evidence. The authors investigated this association in a population-based prospective cohort study of Chinese women. At baseline (1996-2000), information on lifetime occupational history was obtained from 73,049 women. Lifetime night-shift exposure indices were created using a job exposure matrix. During 2002-2004, self-reported data on frequency and duration of night-shift work were collected. Hazard ratios and 95% confidence intervals, adjusted for major breast cancer risk factors, were calculated. During follow-up through 2007, 717 incident cases of breast cancer were diagnosed. Breast cancer risk was not associated with ever working the night shift on the basis of the job exposure matrix (adjusted hazard ratio = 1.0, 95% confidence interval: 0.9, 1.2) or self-reported history of night-shift work (adjusted hazard ratio = 0.9, 95% confidence interval: 0.7, 1.1). Risk was also not associated with frequency, duration, or cumulative amount of night-shift work. There were no indications of effect modification. The lack of an association between night-shift work and breast cancer adds to the inconsistent epidemiologic evidence. It may be premature to consider shift work a cause of cancer. C1 [Pronk, Anjoeka; Ji, Bu-Tian; Xue, Shouzheng; Rothman, Nathaniel; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Shu, Xiao-Ou; Yang, Gong; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med,Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Li, Hong-Lan; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. RP Chow, WH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8111,MSC 7240, Bethesda, MD 20892 USA. EM choww@mail.nih.gov FU US National Institutes of Health [R01 CA70867]; National Institutes of Health [N02 CP1101066] FX This research was supported by the US National Institutes of Health (grant R01 CA70867) and the Intramural Research Program of the National Institutes of Health (contract N02 CP1101066). NR 21 TC 74 Z9 76 U1 6 U2 27 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 1 PY 2010 VL 171 IS 9 BP 953 EP 959 DI 10.1093/aje/kwq029 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 587NJ UT WOS:000276999100001 PM 20375193 ER PT J AU Kim, S Sandler, DP Galanko, J Martin, C Sandler, RS AF Kim, Sangmi Sandler, Dale P. Galanko, Joseph Martin, Christopher Sandler, Robert S. TI Intake of Polyunsaturated Fatty Acids and Distal Large Bowel Cancer Risk in Whites and African Americans SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE colorectal neoplasms; fatty acids; omega-3; fatty acids; unsaturated; intestine; large ID COLORECTAL-CANCER; COLON-CANCER; PROSPECTIVE COHORT; UNITED-STATES; N-3; OMEGA-3-FATTY-ACIDS; FISH; CARCINOMA; OMEGA-6; CHAIN AB Long-chain omega-3 polyunsaturated fatty acids (PUFAs) may have antineoplastic properties in the colon. The authors examined the association between intakes of different PUFAs and distal large bowel cancer in a population-based case-control study of 1,503 whites (716 cases; 787 controls) and 369 African Americans (213 cases; 156 controls) in North Carolina (2001-2006). Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals for distal large bowel cancer risk in relation to quartiles of PUFA intake. Increased consumption of long-chain omega-3 PUFAs was associated with reduced risk of distal large bowel cancer in whites (multivariable odds ratios = 0.88 (95% confidence interval (CI): 0.63, 1.22), 0.69 (95% CI: 0.49, 0.98), and 0.49 (95% CI: 0.34, 0.71) for second, third, and highest vs. lowest quartile) (P-trend < 0.01). Intake of individual eicosapentaenoic acids and docosahexaenoic acids was inversely related to distal large bowel cancer risk, whereas the ratio of omega-6 to long-chain omega-3 PUFAs was associated with increased risk of distal large bowel cancer in whites, but not among African Americans (P-interaction < 0.05). Study results support the hypothesis that long-chain omega-3 PUFAs have beneficial effects in colorectal carcinogenesis. Whether or not the possible benefit of long-chain omega-3 PUFAs varies by race warrants further evaluation. C1 [Kim, Sangmi; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Galanko, Joseph; Martin, Christopher; Sandler, Robert S.] Univ N Carolina, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC USA. RP Kim, S (reprint author), NIEHS, Epidemiol Branch, NIH, POB 12233,MD A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM kims3@niehs.nih.gov OI Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health [P30 DK34987, R01 CA66635]; National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES04400509] FX This research was supported, in part, by grants from the National Institutes of Health (P30 DK34987 and R01 CA66635) and by the Intramural Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES04400509). NR 47 TC 29 Z9 30 U1 0 U2 1 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 MAY 1 PY 2010 VL 171 IS 9 BP 969 EP 979 DI 10.1093/aje/kwq032 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 587NJ UT WOS:000276999100003 PM 20392864 ER PT J AU Windham, BG Griswold, ME Farasat, SM Ling, SM Carlson, O Egan, JM Ferrucci, L Najjar, SS AF Windham, B. Gwen Griswold, Michael E. Farasat, S. Morteza Ling, Shari M. Carlson, Olga Egan, Josephine M. Ferrucci, Luigi Najjar, Samer S. TI Influence of Leptin, Adiponectin, and Resistin on the Association Between Abdominal Adiposity and Arterial Stiffness SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE arteriosclerosis; blood pressure; elasticity; epidemiology; hypertension; obesity ID PULSE-WAVE VELOCITY; AORTIC STIFFNESS; CARDIOVASCULAR-DISEASE; HYPERTENSIVE PATIENTS; BLOOD-PRESSURE; OLDER-ADULTS; RISK; INFLAMMATION; OBESITY; WEIGHT AB BACKGROUND Adiposity is associated with arterial stiffness, and both adiposity and arterial stiffness independently predict morbidity and mortality. Because adipocytes account for most adipokine production, the objectives of this study were to examine the influence of adipokines such as leptin, adiponectin, and resistin on the relationship between abdominal adiposity and arterial stiffness. METHODS This is a cross-sectional analysis of data from the Baltimore Longitudinal Study of Aging (BLSA). Adiposity was measured as kilograms of abdominal adipose tissue using dual-energy X-ray absorptiometry (DXA). Arterial stiffness was assessed as carotid femoral pulse wave velocity (PWV). Leptin, adiponectin, and resistin were assayed in fasting serum samples. The influence of adipokines on the relationship between adiposity and arterial stiffness by adipokines was examined using standard mediation pathway analysis. RESULTS Among 749 participants ages 26-96 years (mean age 67,52% men, 27% black), abdominal adiposity was positively associated with PWV (relative ratio (RR) = 1.04, P = 0.02), after adjusting for potential confounders but was attenuated and no longer significant after adjusting for leptin (RR = 0.99, P = 0.77). The relationship between adiposity and PWV was not substantially influenced by adiponectin (RR = 1.03, P = 0.06) or resistin (RR = 1.05, P = 0.010). Leptin (RR = 1.02, P < 0.001), resistin (RR = 0.92, P < 0.0001), and adiponectin (RR = 0.97, P = 0.004), but not abdominal adiposity (RR = 1.00, P = 0.94), retained significant associations with PWV when adjusting for each other and confounders. CONCLUSIONS Our findings are consistent with the hypothesis that leptin explains, in part, the observed relationship between abdominal adiposity and arterial stiffness. Adiponectin, leptin, and resistin are independent correlates of PWV. C1 [Windham, B. Gwen] Univ Mississippi, Med Ctr, Dept Internal Med, Div Geriatr Med, Jackson, MS 39216 USA. [Griswold, Michael E.] Univ Mississippi, Med Ctr, Dept Biostat, Jackson, MS 39216 USA. [Farasat, S. Morteza] MedStar Res Inst, Baltimore, MD USA. [Ling, Shari M.; Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Carlson, Olga; Egan, Josephine M.] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Najjar, Samer S.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Windham, BG (reprint author), Univ Mississippi, Med Ctr, Dept Internal Med, Div Geriatr Med, Jackson, MS 39216 USA. EM gwindham@medicine.umsmed.edu FU National Institutes of Health, National Institute on Aging; MedStar Research Institute FX Acknowledgments:This study was supported in whole by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. A portion of that support was through an R&D contract with MedStar Research Institute. Data for these analyses were obtained from the Baltimore Longitudinal Study of Aging, a study conducted by the National Institute on Aging. NR 40 TC 41 Z9 42 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2010 VL 23 IS 5 BP 501 EP 507 DI 10.1038/ajh.2010.8 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 589OW UT WOS:000277162600014 PM 20150891 ER PT J AU Brinkley, TE Lovato, JF Arnold, AM Furberg, CD Kuller, LH Burke, GL Nahin, RL Lopez, OL Yasar, S Williamson, JD AF Brinkley, Tina E. Lovato, James F. Arnold, Alice M. Furberg, Curt D. Kuller, Lewis H. Burke, Gregory L. Nahin, Richard L. Lopez, Oscar L. Yasar, Sevil Williamson, Jeff D. CA GEM Study Investigators TI Effect of Ginkgo biloba on Blood Pressure and Incidence of Hypertension in Elderly Men and Women SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; elderly; Gingko biloba; hypertension ID DIETARY-SUPPLEMENTS; EXTRACT EGB-761; RATS; PREVENTION; MEDICINES; DRUGS; FLOW AB BACKGROUND Accumulating evidence suggests that Ginkgo biloba is cardioprotective, in part, through its vasodilatory and antihypertensive properties. However, definitive data on its blood pressure (BP)-lowering effects in humans is lacking. METHODS We determined the effects of G. biloba extract (240 mg/day) on BP and incident hypertension in 3,069 participants (mean age, 79 years; 46% female; 96% white) from the Ginkgo Evaluation of Memory (GEM) study. We also examined whether the treatment effects are modified by baseline hypertension status. RESULTS At baseline, 54% of the study participants were hypertensive, 28% were prehypertensive, and 17% were normotensive. Over a median follow-up of 6.1 years, there were similar changes in BP and pulse pressure (PP) in the G. biloba and placebo groups. Although baseline hypertension status did not modify the antihypertensive effects of G. biloba, it did influence the changes in BP variables observed during follow-up, with decreases in hypertensives, increases in normotensives, and no changes in prehypertensives. Among participants who were not on antihypertensive medications at baseline, there was no difference between treatment groups in medication use over time, as the odds ratio (95% confidence interval (CI)) for being a never-user in the G. biloba group was 0.75 (0.48-1.16). The rate of incident hypertension also did not differ between participants assigned to G. biloba vs. placebo (hazard ratio (HR), 0.99, 95% CI, 0.84-1.15). CONCLUSIONS Our data indicate that G. biloba does not reduce BP or the incidence of hypertension in elderly men and women. C1 [Brinkley, Tina E.; Lovato, James F.; Furberg, Curt D.; Burke, Gregory L.; Williamson, Jeff D.] Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Arnold, Alice M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Kuller, Lewis H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Nahin, Richard L.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Lopez, Oscar L.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Yasar, Sevil] Johns Hopkins Univ, Div Geriatr Med & Gerontol, Baltimore, MD USA. RP Brinkley, TE (reprint author), Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. EM tbrinkle@wfubmc.edu OI Nahin, Richard/0000-0002-3682-4816 FU National Center for Complementary and Alternative Medicine (NCCAM) [U01 AT000162]; Office of Dietary Supplements; National Institute on Aging, National Heart, Lung, and Blood Institute; University of Pittsburgh Alzheimer's Disease Research Center [P50 AG05133]; Roena Kulynych Center for Memory and Cognition Research; National Institute of Neurological Disorders and Stroke; GmbH & Co. KG, Karlsruhe, Germany FX This study was supported by U01 AT000162 from the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements, and also received support from the National Institute on Aging, National Heart, Lung, and Blood Institute, the University of Pittsburgh Alzheimer's Disease Research Center (P50 AG05133), the Roena Kulynych Center for Memory and Cognition Research, and the National Institute of Neurological Disorders and Stroke. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, or the National Institutes of Health. We are indebted to Stephen Straus, the late former director of NCCAM, who championed efforts to evaluate complementary and alternative therapies in rigorous scientific fashion. We gratefully acknowledge the contribution of Dr Schwabe, GmbH & Co. KG, Karlsruhe, Germany, for their donation of the G. biloba tablets and identical placebos, in blister packs, for the study. We are also grateful to our volunteers, whose faithful participation in this longitudinal study made it possible. NR 19 TC 14 Z9 16 U1 2 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2010 VL 23 IS 5 BP 528 EP 533 DI 10.1038/ajh.2010.14 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 589OW UT WOS:000277162600018 PM 20168306 ER PT J AU Montgomery, MP Kamel, F Hoppin, JA Freeman, LEB Alavanja, MCR Sandler, DP AF Montgomery, Martha P. Kamel, Freya Hoppin, Jane A. Freeman, Laura E. Beane Alavanja, Michael C. R. Sandler, Dale P. TI Effects of Self-Reported Health Conditions and Pesticide Exposures on Probability of Follow-Up in a Prospective Cohort Study SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE selection bias; follow-up studies; prospective studies; cohort studies; pesticides; agriculture ID AGRICULTURAL HEALTH; DEPRESSION; BIAS; PREVALENCE AB Background We investigated the potential for selection bias due to non-participation in the follow-up of a large prospective cohort study. Methods Licensed pesticide applicators (52,395 private; 4,916 commercial) in the Agricultural Health Study provided demographic, health, and pesticide exposure information at enrollment (1993-1997) and in a 5-year follow-up telephone interview Factors associated with non-participation in the follow-up were identified using multiple logistic regression. Potential for selection bias was evaluated by comparing exposure disease associations between the entire cohort and the follow-up subset. Results Sixty-six percent of private and 60% of commercial applicators completed the follow-up interview Private and commercial applicators who did not complete the follow-up reported at enrollment younger age, less education, lower body mass index, poorer health behaviors but fewer health conditions, and lower pesticide use. Estimates of exposure disease associations calculated with and without non-participants did not indicate strong selection bias. Conclusions Differences between non-participants and participants in the follow-up interview were generally small, and we did not find significant evidence of selection bias. However the extent of bias may depend on the specific exposure and outcome under study. Am. J. Ind. Med. 53:486-496, 2010. (C) 2009 Wiley-Liss, Inc. C1 [Montgomery, Martha P.; Kamel, Freya; Hoppin, Jane A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Freeman, Laura E. Beane; Alavanja, Michael C. R.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. RP Sandler, DP (reprint author), NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. EM sandler@niehs.nih.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Sandler, Dale/0000-0002-6776-0018 FU NIH, National Institute of Environmental Health Sciences [Z01-ES049030]; National Cancer Institute [Z01 CP010119] FX Contract grant sponsor: Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; Contract grant number: Z01-ES049030, Contract grant sponsor: National Cancer Institute; Contract grant number: Z01 CP010119. NR 10 TC 7 Z9 7 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD MAY PY 2010 VL 53 IS 5 BP 486 EP 496 DI 10.1002/ajim.20789 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 587HH UT WOS:000276980600003 PM 20017198 ER PT J AU Cohen, JS Biesecker, BB AF Cohen, Julie S. Biesecker, Barbara B. TI Quality of Life in Rare Genetic Conditions: A Systematic Review of the Literature SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Review DE quality of life; genetic diseases; genetic counseling; psychological adaptation ID MARIE-TOOTH-DISEASE; HEREDITARY HEMORRHAGIC TELANGIECTASIA; X-LINKED AGAMMAGLOBULINEMIA; SICKLE-CELL-DISEASE; CYSTIC-FIBROSIS; MUSCULAR-DYSTROPHY; NEUROFIBROMATOSIS TYPE-1; FOLLOW-UP; COAGULATION DISORDERS; HUNTINGTONS-DISEASE AB Quality of life (QoL) refers to an individual's sense of overall well-being encompassing physical, psychological, emotional, social, and spiritual dimensions. Although genetics healthcare providers strive to promote patient well-being, and the term QoL is often invoked to refer to this outcome, there is lack of clarity as to what actually constitutes QoL from the patient's perspective. This systematic literature review aims to summarize and integrate research findings to help elucidate how healthcare providers can more effectively enhance the QoL of patients affected with rare genetic conditions. Eligible studies were those that measured QoL as a primary outcome variable using a validated, multi-dimensional scale. Detailed criteria were used to rate quality of design, methodology, and analytic rigor. Fifty-eight studies were selected for inclusion in the review, and a narrative synthesis of the data was performed. A central theme emerging from the literature is that, although genetic conditions have the potential to have significant negative consequences for individuals' lives, having a genetic condition does not necessarily entail poor QoL. Evidence demonstrates that factors beyond the physical manifestations of the disease, such as psychological well-being, coping, and illness perceptions, influence QoL and may serve as potent targets for intervention. The field of research on QoL in rare genetic conditions will be advanced by uniting around a clear conceptualization of QoL and using more rigorous methodology with comprehensive measures of global QoL. Published 2010 Wiley-Liss, Inc. C1 [Cohen, Julie S.] Kennedy Krieger Inst, Baltimore, MD 21205 USA. [Biesecker, Barbara B.] NIH, Bethesda, MD 20892 USA. RP Cohen, JS (reprint author), Kennedy Krieger Inst, 801 N Broadway,5th Floor, Baltimore, MD 21205 USA. EM cohenju@kennedykrieger.org FU National Human Genome Research Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 84 TC 22 Z9 24 U1 2 U2 15 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAY PY 2010 VL 152A IS 5 BP 1136 EP 1156 DI 10.1002/ajmg.a.33380 PG 21 WC Genetics & Heredity SC Genetics & Heredity GA 597ES UT WOS:000277739800008 PM 20425818 ER PT J AU Levy, D Splansky, GL Strand, NK Atwood, LD Benjamin, EJ Blease, S Cupples, LA D'Agostino, RB Fox, CS Kelly-Hayes, M Koski, G Larson, MG Mutalik, KM Oberacker, E O'Donnell, CJ Sutherland, P Valentino, M Vasan, RS Wolf, PA Murabito, JM AF Levy, Daniel Splansky, Greta Lee Strand, Nicolle K. Atwood, Larry D. Benjamin, Emelia J. Blease, Susan Cupples, L. Adrienne D'Agostino, Ralph B., Sr. Fox, Caroline S. Kelly-Hayes, Margaret Koski, Greg Larson, Martin G. Mutalik, Karen M. Oberacker, Elizabeth O'Donnell, Christopher J. Sutherland, Patrice Valentino, Maureen Vasan, Ramachandran S. Wolf, Philip A. Murabito, Joanne M. TI Consent for Genetic Research in the Framingham Heart Study SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE epidemiology; genetics; genome-wide association; medical ethics; population study ID GENOME-WIDE ASSOCIATION; INFORMED-CONSENT; POPULATION; DISEASE; DESIGN; LOCI AB Extensive efforts have been aimed at understanding the genetic underpinnings of complex diseases that affect humans. Numerous genome-wide association studies have assessed the association of genes with human disease, including the Framingham Heart Study (FHS), which genotyped 550,000 SNPs in 9,000 participants. The success of such efforts requires high rates of consent by participants, which is dependent on ethical oversight, communications, and trust between research participants and investigators. To study this we calculated percentages of participants who consented to collection of DNA and to various uses of their genetic information in two FHS cohorts between 2002 and 2009. The data included rates of consent for providing a DNA sample, creating an immortalized cell line, conducting research on various genetic conditions including those that might be considered sensitive, and for notifying participants of clinically significant genetic findings were above 95%. Only with regard to granting permission to share DNA or genetic findings with for-profit companies was the consent rate below 95%. We concluded that the FHS has maintained high rates of retention and consent for genetic research that has provided the scientific freedom to establish collaborations and address a broad range of research questions. We speculate that our high rates of consent have been achieved by establishing frequent and open communications with participants that highlight extensive oversight procedures. Our approach to maintaining high consent rates via ethical oversight of genetic research and communication with study participants is summarized in this report and should be of help to other studies engaged in similar types of research. Published (C) 2010 Wiley-Liss, Inc. C1 [Levy, Daniel; Splansky, Greta Lee; Strand, Nicolle K.; Atwood, Larry D.; Benjamin, Emelia J.; Blease, Susan; Cupples, L. Adrienne; D'Agostino, Ralph B., Sr.; Fox, Caroline S.; Kelly-Hayes, Margaret; Larson, Martin G.; Mutalik, Karen M.; Oberacker, Elizabeth; O'Donnell, Christopher J.; Sutherland, Patrice; Valentino, Maureen; Vasan, Ramachandran S.; Wolf, Philip A.; Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Levy, Daniel; Strand, Nicolle K.; Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Levy, Daniel; Atwood, Larry D.; Benjamin, Emelia J.; Kelly-Hayes, Margaret; Vasan, Ramachandran S.; Wolf, Philip A.; Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Levy, Daniel; Atwood, Larry D.; Benjamin, Emelia J.; Kelly-Hayes, Margaret; Vasan, Ramachandran S.; Wolf, Philip A.; Murabito, Joanne M.] Boston Univ, Sch Med, Dept Cardiol, Boston, MA 02118 USA. [Levy, Daniel; Atwood, Larry D.; Benjamin, Emelia J.; Kelly-Hayes, Margaret; Vasan, Ramachandran S.; Wolf, Philip A.; Murabito, Joanne M.] Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. [Levy, Daniel; Atwood, Larry D.; Benjamin, Emelia J.; Kelly-Hayes, Margaret; Vasan, Ramachandran S.; Wolf, Philip A.; Murabito, Joanne M.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Levy, Daniel] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Cardiol, Boston, MA 02215 USA. [Koski, Greg] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Koski, Greg] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol, Boston, MA USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [D'Agostino, Ralph B., Sr.; Larson, Martin G.; Vasan, Ramachandran S.] Boston Univ, Dept Math, Boston, MA 02215 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM levyd@nih.gov OI Murabito, Joanne/0000-0002-0192-7516; Larson, Martin/0000-0002-9631-1254; Cupples, L. Adrienne/0000-0003-0273-7965; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NIH [N01-HC-25195] FX We would like to acknowledge the members of the Framingham Heart Study Ethics Advisory Board who volunteer their free time to make ours a better and more responsive study; the Framingham Heart Study participants who are the key to our past success and our future aspirations; and the Framingham Heart Study participant coordinators who administer our informed consent process. This study was supported by The Framingham Heart Study is funded by NIH (N01-HC-25195). NR 18 TC 12 Z9 12 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAY PY 2010 VL 152A IS 5 BP 1250 EP 1256 DI 10.1002/ajmg.a.33377 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 597ES UT WOS:000277739800020 PM 20425830 ER PT J AU Lima, FO Lev, MH Levy, RA Silva, GS Ebril, M de Camargo, EC Pomerantz, S Singhal, AB Greer, DM Ay, H Gonzalez, RG Koroshetz, WJ Smith, WS Furie, KL AF Lima, F. O. Lev, M. H. Levy, R. A. Silva, G. S. Ebril, M. de Camargo, E. C. Pomerantz, S. Singhal, A. B. Greer, D. M. Ay, H. Gonzalez, R. Gilberto Koroshetz, W. J. Smith, W. S. Furie, K. L. TI Functional Contrast-Enhanced CT for Evaluation of Acute Ischemic Stroke Does Not Increase the Risk of Contrast-Induced Nephropathy SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID PROGNOSTIC IMPLICATIONS; RENAL-INSUFFICIENCY; COMPUTED-TOMOGRAPHY; SERUM CREATININE; ANGIOGRAPHY; PERFUSION; NEPHROTOXICITY; ACCURACY; FAILURE; SAFETY AB BACKGROUND AND PURPOSE Concerns have recently grown regarding the safety of iodinated contrast agents used for CIA and CTP imaging We tested whether the incidence of AN, defined by a >= 25% increase in the post contrast scan creatinine level, was higher among patients with ischemic stroke who underwent a functional contrast-enhanced CT protocol compared with those who had no iodinated contrast administration MATERIALS AND METHODS The contrast-exposed group consisted of 575 patients with acute ischemic stroke who underwent CIA In = 313), CTA/CTP (n = 224), or CTA/CTP followed by conventional angiography In = 38) within 24 hours of stroke onset and were consecutively enrolled in a prospective cohort study The nonexposed group consisted of 343 patients with ischemic stroke, consecutively admitted to the same institution, who did not receive iodinated contrast material Patients were stratified by baseline eGFR In the primary analysis, the Fisher exact test was used to compare the incidence of AN between the contrast-exposed and the nonexposed patients at 24, 48, and 72 hours and on a cumulative basis A secondary analysis compared the incidence of AN in patients who underwent conventional angiography following CTA/CTP versus patients who underwent CTA/CTP only RESULTS: The incidence of AN was 5% in the exposed and 10% in the nonexposed group (P = 0031 Patients who underwent conventional angiography after contrast CT were at no greater risk of AN than patients who underwent CTA/CTP alone (26 patients, 5%, and 2 patients, 5%, respectively, P = 71 CONCLUSIONS Administration of a contrast-enhanced CT protocol involving CTA/CTP and conventional angiography in selected patients does not appear to increase the incidence of CIN C1 [Lima, F. O.] Massachusetts Gen Hosp, JP Kistler Stroke Res Ctr, Dept Neurol, Boston, MA 02114 USA. [Lev, M. H.; Pomerantz, S.; Gonzalez, R. Gilberto] Massachusetts Gen Hosp, Dept Radiol, Stroke Serv, Boston, MA 02114 USA. [Greer, D. M.] Massachusetts Gen Hosp, Dept Neurol, Neurocrit Care Serv, Boston, MA 02114 USA. [Levy, R. A.] Harvard Univ, Cambridge, MA 02138 USA. [Ebril, M.] Tufts Med Sch, Boston, MA USA. [Ay, H.] Martinos Ctr Biomed Imaging, Dept Radiol, Boston, MA USA. [Koroshetz, W. J.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Smith, W. S.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Lima, FO (reprint author), Massachusetts Gen Hosp, JP Kistler Stroke Res Ctr, Dept Neurol, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. RI Lima, Fabricio/E-6507-2015 OI Lima, Fabricio/0000-0002-0383-4145 FU NIH [1-R01-NS059710-01A2, R01-NS051412, P50 NS051343]; Agency for Healthcare Research and Quality [R01 HS011392]; American Heart Association-Bugher Foundation; Deane Institute for Integrative Research in Atrial Fibrillation and Stroke; Esther U Sharp Fund; Conway Fellowship Fund; Lakeside Fund; Levitt Fund FX Dr Ay receives grant support from the NIH grant 1-R01-NS059710-01A2 Dr Singhal receives grant support front the NIH giant R01-NS051412 This work was also supported by the Agency for Healthcare Research and Quality R01 HS011392, NIH P50 NS051343, the American Heart Association-Bugher Foundation, and the Deane Institute for Integrative Research in Atrial Fibrillation and Stroke We recognize the generous support of the Esther U Sharp Fund, the Conway Fellowship Fund, the Lakeside Fund, and the Levitt Fund NR 23 TC 32 Z9 32 U1 1 U2 3 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD MAY PY 2010 VL 31 IS 5 BP 817 EP 821 DI 10.3174/ajnr.A1927 PG 5 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 599MH UT WOS:000277916600006 PM 20044502 ER PT J AU Incerti, M Vink, J Roberson, R Benassou, I Abebe, D Spong, CY AF Incerti, Maddalena Vink, Joy Roberson, Robin Benassou, Ines Abebe, Daniel Spong, Catherine Y. TI Prevention of the alcohol-induced changes in brain-derived neurotrophic factor expression using neuroprotective peptides in a model of fetal alcohol syndrome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology DE brain-derived neurotrophic factor; fetal alcohol syndrome; mouse; NAPVSIPQ; SALLRSIPA ID VASOACTIVE-INTESTINAL-PEPTIDE; INDUCED LEARNING-DEFICITS; MOUSE MODEL; SPECTRUM DISORDER; GROWTH-FACTOR; EXPOSURE; PROTEIN; MICE; VIP AB OBJECTIVE: Our objective was to evaluate whether brain-derived neurotrophic factor (BDNF) expression is affected by prenatal alcohol exposure and whether the neuroprotective effects of the vasoactive intestinal peptide (VIP)-related peptides, NAPVSIPQ (NAP) and SALLRSIPA (SAL), are mediated through BDNF. STUDY DESIGN: Using a well-characterized fetal alcohol syndrome (FAS) model, timed pregnant C57BL6/J mice were treated on gestational day (E) 8 with alcohol (0.03 mL/g), placebo, or alcohol plus (NAP plus SAL). Embryos were harvested at 6 hours (E8), 24 hours (E9), and 10 days (E18) and pups at postnatal day 40. Calibrator-normalized relative real time polymerase chain reaction was performed to quantify BDNF with hypoxanthine phosphoribosyl transferase-1 standardization. RESULTS: BDNF expression was lower in the alcohol-exposed embryos than in controls at 6 hours and higher at 24 hours and 10 days (all P<.05). Pretreatment with NAP plus SAL prevented the alcohol-induced rise in BDNF expression (P<.05) at 24 hours and 10 days after alcohol exposure. We found no difference between alcohol and control in young-adults' brain (P>.05). CONCLUSION: NAP plus SAL treatment prevented alcohol-induced changes in BDNF expression 24 hours and 10 days after alcohol exposure in mouse embryos. This may explain, at least in part, the peptides' prevention of neurodevelopmental anomalies in FAS. C1 [Incerti, Maddalena; Vink, Joy; Roberson, Robin; Benassou, Ines; Abebe, Daniel; Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Perinatal & Dev Neurobiol, NIH, Bethesda, MD USA. [Vink, Joy] Columbia Univ, Div Maternal Fetal Med, Med Ctr, New York, NY USA. RP Incerti, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Perinatal & Dev Neurobiol, NIH, Bethesda, MD USA. FU Intramural NIH HHS NR 28 TC 1 Z9 1 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2010 VL 202 IS 5 AR 457.e1 DI 10.1016/j.ajog.2010.03.050 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 592TM UT WOS:000277403200017 PM 20452488 ER PT J AU Nhan-Chang, CL Romero, R Tarca, AL Mittal, P Kusanovic, JP Erez, O Mazaki-Tovi, S Chaiworapongsa, T Hotra, J Than, NG Kim, JS Hassan, SS Kim, CJ AF Nhan-Chang, Chia-Ling Romero, Roberto Tarca, Adi L. Mittal, Pooja Kusanovic, Juan Pedro Erez, Offer Mazaki-Tovi, Shali Chaiworapongsa, Tinnakorn Hotra, John Than, Nandor Gabor Kim, Jung-Sun Hassan, Sonia S. Kim, Chong Jai TI Characterization of the transcriptome of chorioamniotic membranes at the site of rupture in spontaneous labor at term SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology DE chorion; extracellular matrix; inflammation; labor; microarray; parturition; spontaneous rupture of membranes ID HUMAN FETAL MEMBRANES; AMNIOTIC-FLUID INTERLEUKIN-6; TUMOR-NECROSIS-FACTOR; BLOOD-CELL COUNT; ACTIVATING PEPTIDE-1 INTERLEUKIN-8; PRETERM PARTURITION SYNDROME; HIGH-DIMENSIONAL BIOLOGY; LOWER UTERINE POLE; PREMATURE RUPTURE; MICROBIAL INVASION AB OBJECTIVE: The purpose of this study was to compare the transcriptome between the site of membrane rupture and the chorioamniotic membranes away from the site of rupture. STUDY DESIGN: The transcriptome of amnion and chorion (n = 20 each) from and distal to the site of rupture from women with spontaneous labor and vaginal delivery at term after spontaneous rupture of membranes was profiled with Illumina HumanHT-12 microarrays. Selected genes were validated with the use of quantitative reverse transcription-polymerase chain reaction. RESULTS: Six hundred seventy-seven genes were differentially expressed in the chorion between the rupture and nonrupture sites (false discovery rate <0.1; fold change >1.5). Quantitative reverse transcription-polymerase chain reaction confirmed the differential expression in 10 of 14 genes. Enriched biological processes included anatomic structure development, cell adhesion and signal transduction. Extracellular matrix-receptor interaction was the most impacted signaling pathway. CONCLUSION: The transcriptome of fetal membranes after spontaneous rupture of membranes in term labor is characterized by region- and tissue-specific differential expression of genes that are involved in signature pathways, which include extracellular matrix-receptor interactions. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, NICHD,NIH,DHHS,Intramural Div, Perinatol Res Branch,Eunice Kennedy Shriver Natl, Detroit, MI 48201 USA. [Nhan-Chang, Chia-Ling; Romero, Roberto; Tarca, Adi L.; Mittal, Pooja; Kusanovic, Juan Pedro; Erez, Offer; Mazaki-Tovi, Shali; Chaiworapongsa, Tinnakorn; Hotra, John; Than, Nandor Gabor; Kim, Jung-Sun; Hassan, Sonia S.; Kim, Chong Jai] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Bethesda, MD USA. [Nhan-Chang, Chia-Ling; Romero, Roberto; Tarca, Adi L.; Mittal, Pooja; Kusanovic, Juan Pedro; Erez, Offer; Mazaki-Tovi, Shali; Chaiworapongsa, Tinnakorn; Hotra, John; Than, Nandor Gabor; Kim, Jung-Sun; Hassan, Sonia S.; Kim, Chong Jai] Hutzel Womens Hosp, Bethesda, MD USA. [Nhan-Chang, Chia-Ling; Mittal, Pooja; Kusanovic, Juan Pedro; Erez, Offer; Mazaki-Tovi, Shali; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] Wayne State Univ, Hutzel Womens Hosp, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto; Tarca, Adi L.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Tarca, Adi L.] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. [Kim, Jung-Sun; Kim, Chong Jai] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD,NIH,DHHS,Intramural Div, Perinatol Res Branch,Eunice Kennedy Shriver Natl, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu FU Intramural NIH HHS [Z01 HD002400-17, ZIA HD002400-19] NR 122 TC 12 Z9 12 U1 1 U2 12 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2010 VL 202 IS 5 AR 462.e1 DI 10.1016/j.ajog.2010.02.045 PG 41 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 592TM UT WOS:000277403200019 PM 20452490 ER PT J AU Romero, R Edwards, DRV Kusanovic, JP Hassan, SS Mazaki-Tovi, S Vaisbuch, E Kim, CJ Chaiworapongsa, T Pearce, BD Friel, LA Bartlett, J Anant, MK Salisbury, BA Vovis, GF Lee, MS Gomez, R Behnke, E Oyarzun, E Tromp, G Williams, SM Menon, R AF Romero, Roberto Edwards, Digna R. Velez Kusanovic, Juan Pedro Hassan, Sonia S. Mazaki-Tovi, Shali Vaisbuch, Edi Kim, Chong Jai Chaiworapongsa, Tinnakorn Pearce, Brad D. Friel, Lara A. Bartlett, Jacquelaine Anant, Madan Kumar Salisbury, Benjamin A. Vovis, Gerald F. Lee, Min Seob Gomez, Ricardo Behnke, Ernesto Oyarzun, Enrique Tromp, Gerard Williams, Scott M. Menon, Ramkumar TI Identification of fetal and maternal single nucleotide polymorphisms in candidate genes that predispose to spontaneous preterm labor with intact membranes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology DE chorioamnionitis; DNA variants; extracellular matrix; genetic association study; genotype; haplotype; IL-6; parturition; SNP ID TUMOR-NECROSIS-FACTOR; INTERLEUKIN-1 RECEPTOR ANTAGONIST; INFLAMMATORY RESPONSE SYNDROME; AMNIOTIC-FLUID INTERLEUKIN-6; FACTOR-ALPHA GENE; LOW-BIRTH-WEIGHT; PROINFLAMMATORY CYTOKINE POLYMORPHISMS; MULTIFACTOR-DIMENSIONALITY REDUCTION; HARDY-WEINBERG EQUILIBRIUM; ENDOTHELIAL GROWTH-FACTOR AB OBJECTIVE: The purpose of this study was to determine whether maternal/fetal single nucleotide polymorphisms (SNPs) in candidate genes are associated with spontaneous preterm labor/delivery. STUDY DESIGN: A genetic association study was conducted in 223 mothers and 179 fetuses (preterm labor with intact membranes who delivered <37 weeks of gestation [preterm birth (PTB)]), and 599 mothers and 628 fetuses (normal pregnancy); 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; the false discovery rate was used to correct for multiple testing. RESULTS: The strongest single locus associations with PTB were interleukin-6 receptor 1 (fetus; P = .000148) and tissue inhibitor of metalloproteinase 2 (mother; P = .000197), which remained significant after correction for multiple comparisons. Global haplotype analysis indicated an association between a fetal DNA variant in insulin-like growth factor F2 and maternal alpha 3 type IV collagen isoform 1 (global, P = .004 and .007, respectively). CONCLUSION: An SNP involved in controlling fetal inflammation (interleukin-6 receptor 1) and DNA variants in maternal genes encoding for proteins involved in extracellular matrix metabolism approximately doubled the risk of PTB. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, NICHD,NIH,DHHS, Perinatol Res Branch, Detroit, MI 48201 USA. [Romero, Roberto; Kusanovic, Juan Pedro; Hassan, Sonia S.; Mazaki-Tovi, Shali; Vaisbuch, Edi; Kim, Chong Jai; Chaiworapongsa, Tinnakorn; Friel, Lara A.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Tromp, Gerard] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Romero, Roberto; Kusanovic, Juan Pedro; Hassan, Sonia S.; Mazaki-Tovi, Shali; Vaisbuch, Edi; Chaiworapongsa, Tinnakorn; Friel, Lara A.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA. [Edwards, Digna R. Velez] Vanderbilt Univ, Dept Obstet & Gynecol, Inst Med & Publ Hlth, Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Pearce, Brad D.; Menon, Ramkumar] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Bartlett, Jacquelaine; Williams, Scott M.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN USA. [Williams, Scott M.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Anant, Madan Kumar; Salisbury, Benjamin A.] PGxHealth LLC, New Haven, CT USA. [Vovis, Gerald F.] Helix Therapeut LLC, New Haven, CT USA. [Lee, Min Seob] Genaissance Pharmaceut Inc, New Haven, CT USA. [Gomez, Ricardo; Behnke, Ernesto] Hosp Dr Sotero del Rio, Dept Obstet & Gynecol, Ctr Perinatal Diag & Res, Santiago, Chile. [Gomez, Ricardo; Oyarzun, Enrique] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD,NIH,DHHS, Perinatol Res Branch, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu RI Williams, Scott/B-9491-2012; Velez Edwards, Digna/C-1090-2012; Tromp, Gerard/B-2677-2017; OI Tromp, Gerard/0000-0002-7761-0806; Vaisbuch, Edi/0000-0002-8400-9031; Salisbury, Benjamin/0000-0003-0796-6492 FU Intramural NIH HHS [ZIA HD002400-20, Z01 HD002400-17] NR 198 TC 10 Z9 11 U1 2 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2010 VL 202 IS 5 AR 431.e1 DI 10.1016/j.ajog.2010.03.026 PG 34 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 592TM UT WOS:000277403200007 PM 20452482 ER PT J AU Vaisbuch, E Hassan, SS Mazaki-Tovi, S Nhan-Chang, CL Kusanovic, JP Chaiworapongsa, T Dong, Z Yeo, L Mittal, P Yoon, BH Romero, R AF Vaisbuch, Edi Hassan, Sonia S. Mazaki-Tovi, Shali Nhan-Chang, Chia-Ling Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Dong, Zhong Yeo, Lami Mittal, Pooja Yoon, Bo Hyun Romero, Roberto TI Patients with an asymptomatic short cervix (<= 15 mm) have a high rate of subclinical intraamniotic inflammation: implications for patient counseling SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology DE cervical length; intraamniotic inflammation; matrix metalloproteinase-8; MMP-8; pregnancy; prematurity; preterm delivery ID SPONTANEOUS PRETERM DELIVERY; POLYMERASE-CHAIN-REACTION; FLUID MATRIX METALLOPROTEINASE-8; HUMAN NEUTROPHIL COLLAGENASE; AMNIOTIC-FLUID; CLINICAL-SIGNIFICANCE; INTACT MEMBRANES; PREMATURE RUPTURE; TRANSVAGINAL ULTRASOUND; UREAPLASMA-UREALYTICUM AB OBJECTIVE: The objective of the study was to determine the frequency and clinical significance of intraamniotic inflammation in asymptomatic women with a sonographic short cervix (SCX) in the midtrimester. STUDY DESIGN: This cohort study included 47 asymptomatic women (14-24 weeks) with an SCX (<= 15 mm) who underwent amniocentesis. Women with multiple gestation, cerclage, or cervical dilatation greater than 2 cm were excluded. Intraamniotic inflammation was defined as an elevated amniotic fluid (AF) matrix metalloproteinase-8 concentration (>23 ng/mL). RESULTS: (1) intraamniotic infection was found in 4.3% of patients; (2) among patients with a negative AF culture, the prevalence of intraamniotic inflammation was 22.2%; and (3) patients with a negative AF culture, but with intraamniotic inflammation, had a higher rate of delivery within 7 days (40% vs 5.7%; P = .016) and a shorter median diagnosis-to-delivery interval than those without intraamniotic inflammation (18 vs 42 days; P = .01). CONCLUSION: Twenty-two percent of patients with a midtrimester SCX have intraamniotic inflammation. The risk of preterm delivery within 7 days for these patients is 40%. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, NICHHD, NIH,Dept Hlth & Human Serv,Perinatol Res Branch, Detroit, MI 48201 USA. [Vaisbuch, Edi; Hassan, Sonia S.; Mazaki-Tovi, Shali; Nhan-Chang, Chia-Ling; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Dong, Zhong; Yeo, Lami; Mittal, Pooja; Romero, Roberto] NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Vaisbuch, Edi; Hassan, Sonia S.; Mazaki-Tovi, Shali; Nhan-Chang, Chia-Ling; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Yeo, Lami; Mittal, Pooja] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Yoon, Bo Hyun] Seoul Natl Univ, Clin Res Inst, Lab Fetal Med Res, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHHD, NIH,Dept Hlth & Human Serv,Perinatol Res Branch, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu RI Yoon, Bo Hyun/H-6344-2011; OI Vaisbuch, Edi/0000-0002-8400-9031 FU Intramural NIH HHS [Z01 HD002400-17] NR 72 TC 10 Z9 10 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2010 VL 202 IS 5 AR 433.e1 DI 10.1016/j.ajog.2010.02.007 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 592TM UT WOS:000277403200008 PM 20452483 ER PT J AU Lee, PJ Liu, CJL Wojciechowski, R Bailey-Wilson, JE Cheng, CY AF Lee, Pei-Jung Liu, Catherine Jui-Ling Wojciechowski, Robert Bailey-Wilson, Joan E. Cheng, Ching-Yu TI Structure Function Correlations Using Scanning Laser Polarimetry in Primary Angle-Closure Glaucoma and Primary Open-Angle Glaucoma SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID NERVE-FIBER LAYER; VARIABLE CORNEAL COMPENSATION; OPTICAL COHERENCE TOMOGRAPHY; STANDARD AUTOMATED PERIMETRY; NORMAL-TENSION GLAUCOMA; VISUAL-FIELD; GDX-VCC; BIREFRINGENCE; THICKNESS; EYES AB PURPOSE: To assess the correlations between retinal nerve fiber layer (RNFL) thickness measured with scanning laser polarimetry and visual field (VF) sensitivity in primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). DESIGN: Prospective, comparative, observational cases series. METHODS: Fifty patients with POAG and 56 patients with PACG were examined using scanning laser polarimetry with variable corneal compensation (GDx VCC; Laser Diagnostic Technologies, Inc.) and Humphrey VF analyzer (Carl Zeiss Meditec, Inc.) between August 2005 and July 2006 at Taipei Veterans General Hospital. Correlations between RNFL thickness and VF sensitivity, expressed as mean sensitivity in both decibel and 1/Lambert scales, were estimated by the Spearman rank correlation coefficient (r(s)) and multivariate median regression models (pseudo R(2)). The correlations were determined globally and for 6 RNFL sectors and their corresponding VF regions. RESULTS: The correlation between RNFL thickness and mean sensitivity (in decibels) was weaker in the PACG group (r(s) = 0.38; P = .004; pseudo R(2) = 0.17) than in the POAG group (r(s) = 0.51; P < .001; pseudo R(2) =.31), but the difference in the magnitude of correlation was not significant (P = .42). With Bonferroni correction, the structure function correlation was significant in the superotemporal (r(s) = 0.62), superonasal (r(s) = 0.56), inferonasal (r(s) = 0.53), and inferotemporal (r(s) = 0.50) sectors in the POAG group (all P < .001), whereas it was significant only in the superotemporal (r(s) = 0.53) and inferotemporal (r(s) = 0.48) sectors in the PACG group (both P < .001). The results were similar when mean sensitivity was expressed as 1/Lambert scale. CONCLUSIONS: Both POAG and PACG eyes had moderate structure function correlations using scanning laser polarimetry. Compared with eyes with POAG, fewer RNFL sectors have significant structure function correlations in eyes with PACG. (Am J Ophthalmol 2010;149: 817-825. (C) 2010 by Elsevier Inc. All rights reserved.) C1 [Lee, Pei-Jung; Liu, Catherine Jui-Ling; Cheng, Ching-Yu] Taipei Vet Gen Hosp, Dept Ophthalmol, Taipei, Taiwan. [Liu, Catherine Jui-Ling; Cheng, Ching-Yu] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Wojciechowski, Robert; Bailey-Wilson, Joan E.; Cheng, Ching-Yu] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Cheng, Ching-Yu] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Cheng, CY (reprint author), Taipei Vet Gen Hosp, Dept Ophthalmol, 201 Shih Pai Rd,Sect 2, Taipei, Taiwan. EM cycheng@vghtpe.gov.tw RI Cheng, Ching-Yu/K-7017-2013; OI Cheng, Ching-Yu/0000-0003-0655-885X; Bailey-Wilson, Joan/0000-0002-9153-2920; Wojciechowski, Robert/0000-0002-9593-4652 FU Intramural NIH HHS [Z99 HG999999] NR 35 TC 11 Z9 12 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD MAY PY 2010 VL 149 IS 5 BP 817 EP 825 DI 10.1016/j.ajo.2009.12.007 PG 9 WC Ophthalmology SC Ophthalmology GA 593WT UT WOS:000277493800018 PM 20202618 ER PT J AU Naz, S Riazuddin, SA Li, L Shahid, M Kousar, S Sieving, PA Hejtmancik, JF Riazuddin, S AF Naz, Shagufta Riazuddin, S. Amer Li, Lin Shahid, Mariam Kousar, Samra Sieving, Paul A. Hejtmancik, J. Fielding Riazuddin, Sheikh TI A Novel Locus for Autosomal Recessive Retinitis Pigmentosa in a Consanguineous Pakistani Family Maps to Chromosome 2p SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID DYSTROPHIES; PROTEIN AB OBJECTIVE: To identify a disease locus for autosomal recessive retinitis pigmentosa in a consanguineous Pakistani family. DESIGN: Prospective linkage study. METHODS: Blood samples were collected and genomic DNA was extracted. A genome-wide scan was performed using 382 polymorphic microsatellite markers on genomic DNA from 4 affected and 5 unaffected family members, and logarithm of odds scores were calculated. RESULTS: A maximum 2-point logarithm of odds score of 3.14 at 0 = 0 was obtained for marker D2S165 during the genome-wide scan. Fine mapping markers identified a 20.92-cM (19.98-Mb) interval flanked by D2S149 and D2S367 that cosegregates with the disease phenotype. Haplotype analyses further refined the critical interval, distal to D2S220 in a 12.31-cM (13.35-Mb) region that does not harbor any genes that previously have been associated with retinitis pigmentosa. CONCLUSIONS: Linkage analysis identified a new locus for autosomal recessive retinitis pigmentosa that maps to chromosome 2p22.3-p24.1 in a consanguineous Pakistani family. (Am J Ophthalmol 2010;149:861-866. (C) 2010 by Elsevier Inc. All rights reserved.) C1 [Naz, Shagufta; Riazuddin, S. Amer; Shahid, Mariam; Kousar, Samra; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. [Li, Lin; Sieving, Paul A.; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Riazuddin, S (reprint author), Univ Punjab, Natl Ctr Excellence Mol Biol, 87 W Canal Bank Rd, Lahore 53700, Pakistan. EM riaz@aimrc.org FU HIGHER EDUCATION COMMISSION AND MINISTRY OF SCIENCE AND TECHNOLOGY, ISLAMABAD, Pakistan FX SUPPORTED IN PART BY THE HIGHER EDUCATION COMMISSION AND MINISTRY OF SCIENCE AND TECHNOLOGY, ISLAMABAD, Pakistan. The authors indicate no financial support or financial conflict of interest. Involved in design and conduct of study (S.N., S.A.R.); Data collection (S.N., L.L.); Statistical analysis (S.N., S.A.R., L.L.); Analysis and interpretation of data (S.N., S.A.R., L.L., M.S., S.K.); Preparation, review, and approval of manuscript (S.N., S.A.R., L.L., F.A.S., J.F.H., S.R.); Obtaining funding (J.F.H., SR.); and Administrative, technical, and logistic support (J.F.H., S.R.). Authors (S.N., S.A.R., J.F.H., SR.) contributed equally towards the study. Institutional review board approval was obtained for this study from the Centre of Excellence in Molecular Biology, Lahore, Pakistan, and the National Eye Institute, Bethesda, Maryland. The participating subjects gave informed consent consistent with the tenets of the Declaration of Helsinki. NR 14 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD MAY PY 2010 VL 149 IS 5 BP 861 EP 866 DI 10.1016/j.ajo.2009.12.034 PG 6 WC Ophthalmology SC Ophthalmology GA 593WT UT WOS:000277493800023 PM 20227676 ER PT J AU Yu, YL Merlino, G AF Yu, Yanlin Merlino, Glenn TI Roles for Aberrant CXCR3 Signaling in Basal Cell Carcinoma A Case for Dual Activity SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Editorial Material ID SONIC HEDGEHOG; BREAST-CANCER; RECEPTOR; EXPRESSION; CXCL10; METASTASIS; MELANOMA; VARIANT; MODEL C1 [Yu, Yanlin; Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Yu, YL (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bldg 37,Room 5002, Bethesda, MD 20892 USA. EM YuY@mail.nih.gov FU Intramural NIH HHS NR 20 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD MAY PY 2010 VL 176 IS 5 BP 2088 EP 2091 DI 10.2353/ajpath.2010.091284 PG 4 WC Pathology SC Pathology GA 627XV UT WOS:000280078600004 PM 20185576 ER PT J AU Xia, XJ Park, E Liu, BG Willette-Brown, J Gong, WH Wang, JM Mitchell, D Fischer, SM Hu, YL AF Xia, Xiaojun Park, Eunmi Liu, Bigang Willette-Brown, Jami Gong, Wanghua Wang, Jiming Mitchell, David Fischer, Susan M. Hu, Yinling TI Reduction of IKK alpha Expression Promotes Chronic Ultraviolet B Exposure-Induced Skin Inflammation and Carcinogenesis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID NF-KAPPA-B; SQUAMOUS-CELL CARCINOMAS; INDUCED P53 MUTATIONS; MOUSE SKIN; KINASE-ALPHA; CANCER DEVELOPMENT; UV CARCINOGENESIS; TUMOR PROGRESSION; INDUCED APOPTOSIS; HAIRLESS MICE AB Ultraviolet B light (UVB) is a common cause of human skin cancer. UVB irradiation induces mutations in the tumor suppressor p53 gene as well as chronic inflammation, which are both essential for UVB carcinogenesis. Inhibitor of nuclear factor kappa B kinase-alpha (IKK alpha) plays an important role in maintaining skin homeostasis, and expression of IKK alpha was found to be down-regulated in human and murine skin squamous cell carcinomas. However, the role of IKK alpha in UVB skin carcinogenesis has not been investigated. Thus, here we performed UVB carcinogenesis experiments on Ikk alpha(+/+) and Ikk alpha(+/-) mice. Ikk alpha(+/-) mice were found to develop a twofold greater number of skin tumors than Ikk alpha(+/+) mice after chronic UVB irradiation. In addition, tumor latency was significantly shorter and tumors were bigger in IKK alpha(+/-) than in Ikk alpha(+/+) mice. At an early stage of carcinogenesis, an increase in UVB-induced p53 mutations as well as macrophage recruitment and mitogenic activity, and a decrease in UVB-induced apoptosis, were detected in Ikk alpha(+/-) compared with those in Ikk alpha(+/+) skin. Also, reduction of IKK alpha levels in keratinocytes up-regulated the expression of monocyte chemoattractant protein-1 (MCP-1/CCL2), TNF alpha, IL-1, and IL-6, and elevated macrophage migration, which might promote macrophage recruitment and inflammation. Therefore, these findings suggest that reduction of IKK alpha expression orchestrates UVB carcinogen, accelerating tumorigenesis. (Am J Pathol 2010, 176:2500-2508; DOI: 10.2353/ajpath.2010.091041) C1 [Willette-Brown, Jami; Wang, Jiming; Hu, Yinling] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Xia, Xiaojun] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Park, Eunmi] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Liu, Bigang; Mitchell, David; Fischer, Susan M.] Univ Texas MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX USA. [Gong, Wanghua] Sci Applicat Int Corp, Basic Res Program, Frederick, MD USA. RP Hu, YL (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. EM huy2@mail.nih.gov FU National Cancer Institute [CA102510, CA117314, CA105345] FX Supported by National Cancer Institute grants CA102510, CA117314 (to Y.H.), and CA105345 (to S.M.F.). NR 49 TC 10 Z9 10 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD MAY PY 2010 VL 176 IS 5 BP 2500 EP 2508 DI 10.2353/ajpath.2010.091041 PG 9 WC Pathology SC Pathology GA 627XV UT WOS:000280078600044 PM 20304950 ER PT J AU Schlenz, H Kummer, W Jositsch, G Wess, J Krasteva, G AF Schlenz, Heike Kummer, Wolfgang Jositsch, Gitte Wess, Juergen Krasteva, Gabriela TI Muscarinic receptor-mediated bronchoconstriction is coupled to caveolae in murine airways SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE bronchus; caveolin; fluorescence resonance energy transfer; smooth muscle; muscarinic ID NITRIC-OXIDE SYNTHASE; SMOOTH-MUSCLE-CELLS; ACETYLCHOLINE-RECEPTOR; KNOCKOUT MICE; CARDIAC MYOCYTES; CHOLESTEROL DEPLETION; MEMBRANE CHOLESTEROL; INDUCED CONTRACTION; PERIPHERAL AIRWAYS; SKELETAL-MUSCLE AB Schlenz H, Kummer W, Jositsch G, Wess J, Krasteva G. Muscarinic receptor-mediated bronchoconstriction is coupled to caveolae in murine airways. Am J Physiol Lung Cell Mol Physiol 298: L626-L636, 2010. First published December 18, 2009; doi: 10.1152/ajplung.00261.2009.-Cholinergic bronchoconstriction is mediated by M(2) and M(3) muscarinic receptors (MR). In heart and urinary bladder, MR are linked to caveolin-1 or -3, the structural proteins of caveolae. Caveolae are cholesterol-rich, omega-shaped invaginations of the plasma membrane. They provide a scaffold for multiple G protein receptors and membrane-bound enzymes, thereby orchestrating signaling into the cell interior. Hence, we hypothesized that airway MR signaling pathways are coupled to caveolae as well. To address this issue, we determined the distribution of caveolin isoforms and MR subtype M2R in murine and human airways and investigated protein-protein associations by fluorescence resonance energy transfer (FRET)-confocal laser scanning microscopy (CLSM) analysis in immunolabeled murine tissue sections. Bronchoconstrictor responses of murine bronchi were recorded in lung-slice preparations before and after caveolae disruption by methyl-beta-cyclodextrin, with efficiency of this treatment being validated by electron microscopy. KCl-induced bronchoconstriction was unaffected after treatment, demonstrating functional integrity of the smooth muscle. Caveolae disruption decreased muscarine-induced bronchoconstriction in wild-type and abolished it in M2R(-/-) and M3R(-/-) mice. Thus M2R and M3R signaling pathways require intact caveolae. Furthermore, we identified a presumed skeletal and cardiac myocyte-specific caveolin isoform, caveolin-3, in human and murine bronchial smooth muscle and found it to be associated with M2R in situ. In contrast, M2R was not associated with caveolin-1, despite an in situ association of caveolin-1 and caveolin-3 that was detected. Here, we demonstrated that M2R- and M3R-mediated bronchoconstriction is caveolae-dependent. Since caveolin-3 is directly associated with M2R, we suggest caveolin-3 as novel regulator of M2R-mediated signaling. C1 [Schlenz, Heike; Kummer, Wolfgang; Jositsch, Gitte; Krasteva, Gabriela] Univ Giessen, Inst Anat & Cell Biol, Lung Ctr, Excellence Cluster Cardiopulm Syst, D-35385 Giessen, Germany. [Wess, Juergen] NIDDK, Bioorgan Chem Lab, US Dept HHS, Bethesda, MD 20892 USA. RP Krasteva, G (reprint author), Univ Giessen, Inst Anat & Cell Biol, Lung Ctr, Excellence Cluster Cardiopulm Syst, D-35385 Giessen, Germany. EM gabriela.krasteva@anatomie.med.uni-giessen.de RI Krasteva-Christ, Gabriela/K-7253-2015 OI Krasteva-Christ, Gabriela/0000-0002-0113-521X FU Excellence Cluster Cardio-Pulmonary System (ECCPS); Medical Faculty of the Justus-Liebig-University Giessen FX This study was supported by a postdoctoral stipend from the Excellence Cluster Cardio-Pulmonary System (ECCPS) and by a young scientist grant from the Medical Faculty of the Justus-Liebig-University Giessen to G. Krasteva. NR 45 TC 13 Z9 14 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD MAY PY 2010 VL 298 IS 5 BP L626 EP L636 DI 10.1152/ajplung.00261.2009 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 585GR UT WOS:000276813400003 PM 20023174 ER PT J AU Lee-Young, RS Ayala, JE Hunley, CF James, FD Bracy, DP Kang, L Wasserman, DH AF Lee-Young, Robert S. Ayala, Julio E. Hunley, Charles F. James, Freyja D. Bracy, Deanna P. Kang, Li Wasserman, David H. TI Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE mitochondria; oxidative phosphorylation; blood flow ID ACTIVATED PROTEIN-KINASE; ENOS-KNOCKOUT MICE; GLUCOSE-UPTAKE; MITOCHONDRIAL BIOGENESIS; BLOOD-FLOW; INSULIN-RESISTANCE; NO SYNTHASE; FATTY-ACID; AMP; TRANSPORT AB Lee-Young RS, Ayala JE, Hunley CF, James FD, Bracy DP, Kang L, Wasserman DH. Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo. Am J Physiol Regul Integr Comp Physiol 298: R1399-R1408, 2010. First published March 3, 2010; doi: 10.1152/ajpregu.00004.2010.-Endothelial nitric oxide synthase (eNOS) is associated with a number of physiological functions involved in the regulation of metabolism; however, the functional role of eNOS is poorly understood. We tested the hypothesis that eNOS is critical to muscle cell signaling and fuel usage during exercise in vivo, using 16-wk-old catheterized (carotid artery and jugular vein) C57BL/6J mice with wild-type (WT), partial (+/-), or no expression (-/-) of eNOS. Quantitative reductions in eNOS expression (similar to 40%) elicited many of the phenotypic effects observed in enos(-/-) mice under fasted, sedentary conditions, with expression of oxidative phosphorylation complexes I to V and ATP levels being decreased, and total NOS activity and Ca(2+)/CaM kinase II Thr(286) phosphorylation being increased in skeletal muscle. Despite these alterations, exercise tolerance was markedly impaired in enos(-/-) mice during an acute 30-min bout of exercise. An eNOS-dependent effect was observed with regard to AMP-activated protein kinase signaling and muscle perfusion. Muscle glucose and long-chain fatty acid uptake, and hepatic and skeletal muscle glycogenolysis during the exercise bout was markedly accelerated in enos(-/-) mice compared with enos(+/-) and WT mice. Correspondingly, enos(-/-) mice exhibited hypoglycemia during exercise. Thus, the ablation of eNOS alters a number of physiological processes that result in impaired exercise capacity in vivo. The finding that a partial reduction in eNOS expression is sufficient to induce many of the changes associated with ablation of eNOS has implications for chronic metabolic diseases, such as obesity and insulin resistance, which are associated with reduced eNOS expression. C1 [Lee-Young, Robert S.; Ayala, Julio E.; Hunley, Charles F.; James, Freyja D.; Bracy, Deanna P.; Kang, Li; Wasserman, David H.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Ayala, Julio E.; Wasserman, David H.] Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37212 USA. RP Lee-Young, RS (reprint author), 823 Light Hall,2200 Pierce Ave, Nashville, TN 37232 USA. EM robert.s.lee-young@vanderbilt.edu FU National Institutes of Health [U24 DK-59637, R01 DK-54902]; American Diabetes Association FX This work was supported by National Institutes of Health Grants U24 DK-59637 and R01 DK-54902 (DHW). Robert S. Lee-Young was supported by a Mentor-Based Fellowship from the American Diabetes Association. NR 51 TC 33 Z9 33 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD MAY PY 2010 VL 298 IS 5 BP R1399 EP R1408 DI 10.1152/ajpregu.00004.2010 PG 10 WC Physiology SC Physiology GA 588EZ UT WOS:000277051700027 PM 20200137 ER PT J AU Reedy, J Krebs-Smith, SM Bosire, C AF Reedy, Jill Krebs-Smith, Susan M. Bosire, Claire TI Evaluating the Food Environment Application of the Healthy Eating Index-2005 SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID PHYSICAL-ACTIVITY ENVIRONMENTS; RECOMMENDATIONS; PATTERNS AB Background: The Healthy Eating Index-2005 (HEI-2005), a tool designed to evaluate concordance with the 2005 Dietary Guidelines, has been used to monitor the quality of foods consumed by Americans. Because the HEI-2005 is not tied to individual requirements and is scored on a per 1000 kcal basis, it can be used to assess the overall quality of any mix of foods. Purpose: The goal of this paper is to examine whether the HET-2005 can be applied to the food environment. Methods: Two examples were selected to examine the application of the HEI-2005 to the food environment: the dollar menu displayed at a fast-food restaurant (coded and linked to the MyPyramid Equivalents Database and the Food and Nutrient Database for Dietary Studies) to represent the community level and the 2005 U.S. Food Supply (measured with food availability data, loss-adjusted food availability data, nutrient availability data, and Salt Institute data) to represent the macro level. Results: The dollar menu and the 2005 U.S. Food Supply received 43.4 and 54.9 points, respectively (100 possible points). According to the HEI-2005, for the offerings at a local fast-food restaurant and the U.S. Food Supply to align with national dietary guidance, substantial shifts would be necessary: a concomitant addition of fruit, dark-green vegetables, orange vegetables, legumes, and nonfat milk; replacement of refined grains with whole grains; and reduction in foods and food products containing sodium, solid fats, and added sugars. Conclusions: Because the HEI-2005 can be applied to both environmental- and individual-level data, it provides a useful metric for studies linking data across various levels of the socioecologic framework of dietary behavior. The present findings suggest that new dietary guidance could target not only individuals but also the architects of our food environment. (Am J Prey Med 2010;38(5):465-471) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Reedy, Jill; Krebs-Smith, Susan M.; Bosire, Claire] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Reedy, J (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM reedyj@mail.nih.gov NR 27 TC 31 Z9 31 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAY PY 2010 VL 38 IS 5 BP 465 EP 471 DI 10.1016/j.amepre.2010.01.015 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 590GP UT WOS:000277213500001 PM 20171823 ER PT J AU Krebs-Smith, SM Reedy, J Bosire, C AF Krebs-Smith, Susan M. Reedy, Jill Bosire, Claire TI Healthfulness of the US Food Supply Little Improvement Despite Decades of Dietary Guidance SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HEALTHY EATING INDEX-2005 AB Background: Every 5 years for the past several decades, the USDHHS and the U.S. Department of Agriculture have issued and updated the Dietary Guidelines for Americans, which form the basis of federal nutrition policy and have shown remarkable consistency across various editions among the major themes. Purpose: This paper examines whether the U.S. food supply is sufficiently balanced to provide the recommended proportions of various foods and nutrients per the amount of energy, whether this balance has shifted over time, and which areas of the food supply may have changed more than others. Methods: The Healthy Eating Index-2005 (HEI-2005) was used to measure the dietary quality of the U.S. food supply, from 1970 to 2007. Sources of data were the USDA's food availability data, loss-adjusted food availability data, and nutrient availability data, and the U.S. Salt Institute's data on salt sold for human consumption. Results: Total HEI-2005 scores improved by about 10 points between 1970 and 2007, but they never achieved even 60 points on a scale from 0 to 100. Although meats and total grains were supplied generally in recommended proportions, total vegetables, total fruit, whole fruit, and milk were supplied in suboptimal proportions that changed very little over time. Saturated fat, sodium, and calories from solid fat, alcoholic beverages, and added sugars were supplied in varying degrees of unhealthy abundance over the years. Supplies of dark-green/orange vegetables and legumes and whole grains were entirely insufficient relative to recommendations, with virtually no change over time. Conclusions: Deliberate efforts on the part of policymakers, the agriculture sector, and the food industry are necessary to provide a supply of foods consistent with nutrition recommendations and to make healthy choices available to all. (Am J Prev Med 2010;38(5):472-477) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Krebs-Smith, Susan M.; Reedy, Jill; Bosire, Claire] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Krebs-Smith, SM (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM krebssms@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 36 TC 34 Z9 34 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAY PY 2010 VL 38 IS 5 BP 472 EP 477 DI 10.1016/j.amepre.2010.01.016 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 590GP UT WOS:000277213500002 PM 20153133 ER PT J AU McBride, CM Bowen, D Brody, LC Condit, CM Croyle, RT Gwinn, M Khoury, MJ Koehly, LM Korf, BR Marteau, TM Mc Leroy, K Patrick, K Valente, TW AF McBride, Colleen M. Bowen, Deborah Brody, Lawrence C. Condit, Celeste M. Croyle, Robert T. Gwinn, Marta Khoury, Muin J. Koehly, Laura M. Korf, Bruce R. Marteau, Theresa M. Mc Leroy, Kenneth Patrick, Kevin Valente, Thomas W. TI Future Health Applications of Genomics Priorities for Communication, Behavioral, and Social Sciences Research SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID NONPOLYPOSIS COLORECTAL-CANCER; GENETIC RISK-ASSESSMENT; PUBLIC-HEALTH; TRANSLATION RESEARCH; WIDE ASSOCIATION; DISEASE; OBESITY; MEDICINE; PREVENTION; FAMILIES AB Despite the quickening momentum of genomic discovery, the communication, behavioral, and social sciences research needed for translating this discovery into public health applications has lagged behind. The National Human Genome Research Institute held a 2-day workshop in October 2008 convening an interdisciplinary group of scientists to recommend forward-looking priorities for translational research. This research agenda would be designed to redress the top three risk factors (tobacco use, poor diet, and physical inactivity) that contribute to the four major chronic diseases (heart disease, type 2 diabetes, lung disease, and many cancers) and account for half of all deaths worldwide. Three priority research areas were identified: (1) improving the public's genetic literacy in order to enhance consumer skills; (2) gauging whether genomic information improves risk communication and adoption of healthier behaviors more than current approaches; and (3) exploring whether genomic discovery in concert with emerging technologies can elucidate new behavioral intervention targets. Important crosscutting themes also were identified, including the need to: (1) anticipate directions of genomic discovery; (2) take an agnostic scientific perspective in framing research questions asking whether genomic discovery adds value to other health promotion efforts; and (3) consider multiple levels of influence and systems that contribute to important public health problems. The priorities and themes offer a framework for a variety of stakeholders, including those who develop priorities for research funding, interdisciplinary teams engaged in genomics research, and policymakers grappling with how to use the products born of genomics research to address public health challenges. (Am J Prey Med 2010;38(5):556 561) (C) 2010 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine. C1 [McBride, Colleen M.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Brody, Lawrence C.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Croyle, Robert T.] NCI, Div Canc Control Prevent & Screening, Bethesda, MD 20892 USA. [Bowen, Deborah] Boston Univ, Dept Social & Behav Sci, Boston, MA 02215 USA. [Condit, Celeste M.] Univ Georgia, Dept Speech Commun, Athens, GA 30602 USA. [Gwinn, Marta; Khoury, Muin J.] CDC, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Korf, Bruce R.] Univ Alabama, Dept Genet, Tuscaloosa, AL USA. [Marteau, Theresa M.] Kings Coll London, Dept Psychol, London WC2R 2LS, England. Texas A&M Hlth Sci Ctr, Dept Social & Behav Hlth, College Stn, TX USA. [Patrick, Kevin] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Valente, Thomas W.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. RP McBride, CM (reprint author), NHGRI, Social & Behav Res Branch, NIH, 31 Ctr Dr,Bldg 31,Room B1B54, Bethesda, MD 20892 USA. EM cmcbride@mail.nih.gov OI Marteau, Theresa/0000-0003-3025-1129 FU National Human Genome Research Institute FX Funding for the meeting was provided by the Intramural Research Program of the National Human Genome Research Institute. The authors gratefully acknowledge the scientists who attended the workshop and participated in the discussions. They include: Christine Bachrach, PhD; Andreas Baxevanis, PhD; Barbara Bernhardt, MS, CGC; Barbara Biesecker, MS; Leslie Biesecker, MD; Vence Bonham, Jr, JD; Joseph Cappella, PhD; Francis Collins, MD, PhD; William G. Feero, MD, PhD; Phyllis Frosst, PhD; Sarah Gehlert, PhD; Eric Green, MD, PhD; Lawrence Green, DrPH; Robert Green, MD, MPH; Alan Guttmacher, MD; Donald Hadley, MS, CGC; Kathy Hudson, PhD; Kimberly Kaphingst, ScD; Deborah Klein-Walker, EdD, Matthew Kreuter, PhD, MPH; Anne Madeo, MS; Brendan Maher; Cynthia Morton, PhD; Robert Nussbaum, MD; Eliseo Perez-Stable, MD; Susan Persky, PhD; Barbara K. Rimer, DrPH; Debra Roter, DrPH; Charles Rotimi, PhD; Kurt Stange, MD, PhD; Vish Vishwaneth, PhD; Nora Volkow, MD. Additional thanks go to Ms. Gillian Hooker, Ms. Sarah Knerr, Ms. Christina Lachance, Dr. Christopher Wade, and Ms. Laura Wagner for their assistance in documenting and facilitating the breakout sessions. NR 96 TC 77 Z9 77 U1 0 U2 24 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAY PY 2010 VL 38 IS 5 BP 556 EP 565 DI 10.1016/j.amepre.2010.01.027 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 590GP UT WOS:000277213500014 PM 20409503 ER PT J AU Ernst, M AF Ernst, Monique TI Conflict Adaptation in Generalized Anxiety Disorder: Small Paradigm Twist, Large Scientific Leap SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID COGNITIVE CONTROL C1 NIMH, Emot Dev & Affect Neurosci Branch EDAN, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, Emot Dev & Affect Neurosci Branch EDAN, Mood & Anxiety Disorders Program, NIH, 15K N Dr, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov FU Intramural NIH HHS NR 7 TC 4 Z9 4 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAY PY 2010 VL 167 IS 5 BP 489 EP 492 DI 10.1176/appi.ajp.2010.10010234 PG 4 WC Psychiatry SC Psychiatry GA 590OT UT WOS:000277237100002 PM 20439393 ER PT J AU Caspi, A Hariri, AR Holmes, A Uher, R Moffitt, TE AF Caspi, Avshalom Hariri, Ahmad R. Holmes, Andrew Uher, Rudolf Moffitt, Terrie E. TI Genetic Sensitivity to the Environment: The Case of the Serotonin Transporter Gene and Its Implications for Studying Complex Diseases and Traits SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID STRESSFUL LIFE EVENTS; BODY-MASS INDEX; REGION 5-HTTLPR POLYMORPHISM; 5-HT1A RECEPTOR-BINDING; LINKED PROMOTER REGION; FTO GENE; PHYSICAL-ACTIVITY; NEGATIVE AFFECTIVITY; MAJOR DEPRESSION; BIASED ATTENTION AB Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity in nonhuman primates; and 4) studies of stress sensitivity and genetically engineered 5-HTT mutations in rodents. The authors then dispel some misconceptions and offer recommendations for GxE research. The authors discuss how GxE interaction hypotheses can be tested with large and small samples, how GxE research can be carried out before as well as after replicated gene discovery, the uses of GxE research as a tool for gene discovery, the importance of construct validation in evaluating GxE research, and the contribution of GxE research to the public understanding of genetic science. C1 [Caspi, Avshalom] Duke Univ, Dept Psychol & Neurosci, Durham, NC 27708 USA. Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27708 USA. Duke Univ, Inst Genome Sci & Policy, Durham, NC 27708 USA. Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat, London, England. NIAAA, Sect Behav Sci & Genet, NIH, Bethesda, MD USA. RP Caspi, A (reprint author), Duke Univ, Dept Psychol & Neurosci, 2020 W Main St,Suite 201,Box 104410, Durham, NC 27708 USA. EM ac115@duke.edu RI caspi, avshalom/D-5294-2011; Hariri, Ahmad/D-5761-2011; Uher, Rudolf/A-5477-2008; Moffitt, Terrie/D-5295-2011 OI Uher, Rudolf/0000-0002-2998-0546; Moffitt, Terrie/0000-0002-8589-6760 FU U. K. Medical Research Council [G0100527, G0601483]; National Institute on Aging [AG032282]; NIMH [MH077874, MH072837]; NICHD [HD061298]; National Institute on Alcohol Abuse and Alcoholism; Royal Society-Wolfson FX Supported by grants from the U. K. Medical Research Council (G0100527, G0601483), National Institute on Aging (AG032282), NIMH (MH077874, MH072837), NICHD (HD061298), and Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism. Avshalom Caspi is a Royal Society-Wolfson Merit Award holder. NR 158 TC 651 Z9 663 U1 53 U2 324 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAY PY 2010 VL 167 IS 5 BP 509 EP 527 DI 10.1176/appi.ajp.2010.09101452 PG 19 WC Psychiatry SC Psychiatry GA 590OT UT WOS:000277237100009 PM 20231323 ER PT J AU Fee, E AF Fee, Elizabeth TI George E. Bolling (1876-1945): Founder of an Early Public Health Laboratory SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 [Fee, Elizabeth] NIH, Div Hist Med, Natl Lib Med, Bethesda, MD 20892 USA. RP Fee, E (reprint author), Care Of Chang BB, Natl Lib Med, Hist Med Div, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2010 VL 100 IS 5 BP 807 EP 807 DI 10.2105/AJPH.2009.185728 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 585ME UT WOS:000276828800011 PM 20299639 ER PT J AU Bu, LP Fee, E AF Bu, Liping Fee, Elizabeth TI Preventing High Blood Pressure and Promoting Longevity SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Bu, Liping] Alma Coll, Dept Hist, Alma, MI 48801 USA. [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Bu, LP (reprint author), Alma Coll, Dept Hist, 614 W Super St, Alma, MI 48801 USA. EM bulipi@alma.edu NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2010 VL 100 IS 5 BP 809 EP 810 DI 10.2105/AJPH.2009.179960 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 585ME UT WOS:000276828800013 PM 20299642 ER PT J AU Mazaki-Tovi, S Vaisbuch, E Romero, R Kusanovic, JP Chaiworapongsa, T Kim, SK Ogge, G Yoon, BH Dong, Z Gonzalez, JM Gervasi, MT Hassan, SS AF Mazaki-Tovi, Shali Vaisbuch, Edi Romero, Roberto Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Kim, Sun Kwon Ogge, Giovanna Yoon, Bo Hyun Dong, Zhong Gonzalez, Juan M. Gervasi, Maria Teresa Hassan, Sonia S. TI Hyperresistinemia - a Novel Feature in Systemic Infection During Human Pregnancy SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE Acute bacterial infection; adipokines; body mass index; cytokine; pyelonephritis; resistin; systemic inflammatory response syndrome; urinary tract infection ID MATERNAL SERUM ADIPONECTIN; GESTATIONAL DIABETES-MELLITUS; GLOMERULAR-FILTRATION-RATE; ACUTE PYELONEPHRITIS; INSULIN-RESISTANCE; ADIPOSE-TISSUE; PRETERM LABOR; AMNIOTIC-FLUID; SEPTIC SHOCK; BIRTH-WEIGHT AB Problem Resistin, originally described as an adipokine, has emerged as a potent pro-inflammatory protein associated with both acute and chronic inflammation. Moreover, resistin has been proposed as a powerful marker of sepsis severity, as well as a predictor of survival of critically ill non-pregnant patients. The aim of this study was to determine whether pyelonephritis during pregnancy is associated with changes in maternal plasma resistin concentrations. Methods of study This cross-sectional study included the following groups: (i) normal pregnant women (n = 85) and (ii) pregnant women with pyelonephritis (n = 40). Maternal plasma resistin concentrations were determined by ELISA. Non-parametric statistics was used for analyses. Results (i) The median maternal plasma resistin concentration was higher in patients with pyelonephritis than in those with a normal pregnancy (P < 0.001); (ii) among patients with pyelonephritis, the median maternal resistin concentration did not differ significantly between those with and without a positive blood culture (P = 0.3); (iii) among patients with pyelonephritis who were diagnosed with systemic inflammatory response syndrome (SIRS), those who fulfilled >= 3 criteria for SIRS had a significantly higher median maternal plasma resistin concentration than those who met only two criteria; and (iv) maternal WBC count positively correlated with circulating resistin concentration (r = 0.47, P = 0.02). Conclusion Hyperresistinemia is a feature of acute pyelonephritis during pregnancy. The results of this study support the role of resistin as an acute-phase protein in the presence of bacterial infection during pregnancy. C1 [Mazaki-Tovi, Shali; Vaisbuch, Edi; Romero, Roberto; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Kim, Sun Kwon; Ogge, Giovanna; Dong, Zhong; Gonzalez, Juan M.; Hassan, Sonia S.] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Mazaki-Tovi, Shali; Vaisbuch, Edi; Romero, Roberto; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Kim, Sun Kwon; Ogge, Giovanna; Dong, Zhong; Gonzalez, Juan M.; Hassan, Sonia S.] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Bethesda, MD USA. [Mazaki-Tovi, Shali; Vaisbuch, Edi; Romero, Roberto; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Gonzalez, Juan M.; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Hutzel Womens Hosp, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Yoon, Bo Hyun] Seoul Natl Univ, Dept Obstet & Gynecol, Seoul, South Korea. [Gervasi, Maria Teresa] Azienda Osped Padova, Dept Obstet & Gynecol, Padua, Italy. RP Romero, R (reprint author), Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Box 4,3990 John R, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu RI Yoon, Bo Hyun/H-6344-2011; OI Vaisbuch, Edi/0000-0002-8400-9031 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX Supported by the Perinatology Research Branch, Division of Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 99 TC 11 Z9 11 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD MAY PY 2010 VL 63 IS 5 BP 358 EP 369 DI 10.1111/j.1600-0897.2010.00809.x PG 12 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 581BQ UT WOS:000276496400003 PM 20178460 ER PT J AU Mansouri, B Kapoor, A Li, M Guion, P Beck, A Saxena, V Sharma, K Wood, B AF Mansouri, B. Kapoor, A. Li, M. Guion, P. Beck, A. Saxena, V. Sharma, K. Wood, B. TI Semiautomated Angle Selection Devices for Interventional Procedures SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Meeting Abstract CT 110th Annual Meeting of the American-Roentgen-Ray-Society CY MAY 02-07, 2010 CL San Diego, CA SP Amer Roentgen Ray Soc C1 [Mansouri, B.; Kapoor, A.; Li, M.; Guion, P.; Beck, A.; Saxena, V.; Sharma, K.; Wood, B.] NCI, NIH, Bethesda, MD 20892 USA. [Sharma, K.] Georgetown Univ Hosp, Washington, DC 20007 USA. EM bobbak.mansouri@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAY PY 2010 VL 194 IS 5 SU S MA E673 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 586RV UT WOS:000276931000914 ER PT J AU Beghi, E Logroscino, G Chio, A Hardiman, O Millul, A Mitchell, D Swingler, R Traynor, BJ AF Beghi, Ettore Logroscino, Giancarlo Chio, Adriano Hardiman, Orla Millul, Andrea Mitchell, Douglas Swingler, Robert Traynor, Bryan J. TI Amyotrophic lateral sclerosis, physical exercise, trauma and sports: Results of a population-based pilot case-control study SO AMYOTROPHIC LATERAL SCLEROSIS LA English DT Article ID ITALIAN SOCCER; ALS; PLAYERS; DISEASE; RISK AB Our objective was to investigate exposure to physical exercise and trauma in patients with amyotrophic lateral sclerosis (ALS) compared to the general population. Previous studies in this area have yielded conflicting results. Using population-based ALS registries from Italy, the UK and Ireland, newly diagnosed patients with definite, probable or possible ALS were enrolled in a case- control study with two age- and sex-matched controls for each patient. Source, intensity and duration of physical activity and history of trauma were recorded. We here present the results of a pilot investigation. We studied 61 patients and 112 controls. Forty-one per cent of cases and 17.0% of controls (p = 0.001) had blue-collar occupations; 13.1% versus 3.6% reported strenuous physical activity at work (p = 0.05). Compared with controls, ALS patients had a longer exposure to work-related (10.7 vs. 7.3 years; p = 0.02) and sport-related physical exercise (9.6 vs. 5.2 years; p = 0.005). Three patients (0 controls) reported professional sports (p = 0.04). Traumatic events were similar. Blue collar occupation (OR 4.27; 95% CI 1.68-10.88) and duration of sport-related physical exercise (OR 1.03; 95% CI 1.00-1.05) were independent variables in multivariate analysis. We concluded that ALS is associated with physical exercise but not with traumatic events. C1 [Beghi, Ettore; Millul, Andrea] Ist Ric Farmacol Mario Negri, I-20157 Milan, Italy. [Logroscino, Giancarlo] Univ Bari, Dept Neurol & Psychiat, I-70121 Bari, Italy. [Chio, Adriano] Univ Turin, Dept Neurosci, I-10124 Turin, Italy. [Hardiman, Orla] Beaumont Hosp, Dept Neurol, Dublin 9, Ireland. [Hardiman, Orla] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Mitchell, Douglas] Royal Preston Hosp, Preston MND Care & Res Ctr, Preston, Lancs, England. [Swingler, Robert] Univ Dundee, Ninewells Hosp & Med Sch, Dept Neurol, Dundee DD1 9SY, Scotland. [Traynor, Bryan J.] NIMH, Sect Dev Genet Epidemiol, NIH, Bethesda, MD 20892 USA. RP Beghi, E (reprint author), Ist Ric Farmacol Mario Negri, Via Eritrea 62, I-20157 Milan, Italy. EM beghi@marionegri.it RI Traynor, Bryan/G-5690-2010; LOGROSCINO, GIANCARLO/K-5148-2016; OI LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Chio, Adriano/0000-0001-9579-5341; Hardiman, Orla/0000-0003-2610-1291 FU Istituto Superiore di Sanita; American ALS Association (ALSA); National Institute on Aging FX The study was supported by a grant from the Istituto Superiore di Sanita, and American ALS Association (ALSA). The research was also supported (in part) by the Intramural Research Program of the National Institute on Aging. NR 17 TC 43 Z9 43 U1 0 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1748-2968 J9 AMYOTROPH LATERAL SC JI Amyotroph. Lateral. Scler. PD MAY PY 2010 VL 11 IS 3 BP 289 EP 292 DI 10.3109/17482960903384283 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 590KS UT WOS:000277225200006 PM 20433412 ER PT J AU Huey, ED Koppel, J Armstrong, N Grafman, J Floeter, MK AF Huey, Edward D. Koppel, Jeremy Armstrong, Nicole Grafman, Jordan Floeter, Mary Kay TI A pilot study of the prevalence of psychiatric disorders in PLS and ALS SO AMYOTROPHIC LATERAL SCLEROSIS LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; MOTOR-NEURON DISEASE; MINI-MENTAL-STATE; COGNITIVE IMPAIRMENT; DEPRESSIVE-DISORDERS; CRITERIA; SYMPTOMS; DEMENTIA; DIAGNOSIS; COMMUNITY AB The prevalence of psychiatric disorders in primary lateral sclerosis (PLS) is currently unknown. In the present study, we compared the prevalence of psychiatric illness in patients with PLS and amyotrophic lateral sclerosis (ALS). We hypothesized that if the psychosocial stress of motor neuron disease predisposes patients to depressive disorders, patients with ALS (with a poorer prognosis and more disability than patients with PLS) should have a higher prevalence of depressive disorders than patients with PLS. We administered the gold standard of psychiatric assessment, the SCID, to 19 PLS and 13 ALS patients. We found a prevalence of current depressive disorders in PLS patients that was, by a non-significant trend, lower than that of ALS patients. The prevalence of current depressive disorders in the ALS patients was higher than previously reported and similar to that observed in non-neurological medical disorders. Other psychiatric disorders were rare. In conclusion, depressive disorders were the most commonly observed psychiatric disorders in both PLS and ALS. By a non-significant trend, the PLS patients had a lower current prevalence of depressive disorders than the ALS patients. These data are consistent with the hypothesis that the psychosocial stress of MND is a risk factor for depression. C1 [Huey, Edward D.; Koppel, Jeremy; Armstrong, Nicole] N Shore Long Isl Jewish Healthcare Syst, Litwin Zucker Res Ctr Study Alzheimers Dis & Memo, Manhasset, NY 11030 USA. [Huey, Edward D.; Armstrong, Nicole; Grafman, Jordan] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, Med Neurol Branch, NIH, Bethesda, MD USA. [Floeter, Mary Kay] Natl Inst Neurol Disorders & Stroke, Human Spinal Physiol Unit, Med Neurol Branch, NIH, Bethesda, MD USA. RP Huey, ED (reprint author), N Shore Long Isl Jewish Healthcare Syst, Litwin Zucker Res Ctr Study Alzheimers Dis & Memo, 350 Community Dr, Manhasset, NY 11030 USA. EM EHuey@nshs.edu OI Grafman, Jordan H./0000-0001-8645-4457 FU National Institutes of Health/The National Institute of Neurological Disorders and Stroke; Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders FX We thank the staff of the Human Spinal Physiology Unit and the Clinical Center nurses for patient care, Tracy Peters for neuropsychological testing, and the patients and their families for their generous participation. This study was supported by the intramural program of The National Institutes of Health/The National Institute of Neurological Disorders and Stroke, an NIH/NINDS grant received by EDH, and the Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders. NR 44 TC 5 Z9 6 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1748-2968 J9 AMYOTROPH LATERAL SC JI Amyotroph. Lateral. Scler. PD MAY PY 2010 VL 11 IS 3 BP 293 EP 297 DI 10.3109/17482960903544576 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 590KS UT WOS:000277225200007 PM 20132085 ER PT J AU Karschner, EL Barnes, AJ Lowe, RH Scheidweiler, KB Huestis, MA AF Karschner, Erin L. Barnes, Allan J. Lowe, Ross H. Scheidweiler, Karl B. Huestis, Marilyn A. TI Validation of a two-dimensional gas chromatography mass spectrometry method for the simultaneous quantification of cannabidiol, Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC in plasma SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article; Proceedings Paper CT 36th Colloquium Spectroscopicum Internationale CY AUG 30-SEP 03, 2009 CL Eotvos Lorand Univ, Budapest, HUNGARY HO Eotvos Lorand Univ DE Delta(9)-Tetrahydrocannabinol; Cannabidiol; Sativex (R); Two-dimensional chromatography; Plasma ID SOLID-PHASE EXTRACTION; 11-NOR-DELTA(9)-TETRAHYDROCANNABINOL-9-CARBOXYLIC ACID; CHEMICAL-IONIZATION; ORAL FLUID; GC-MS; TETRAHYDROCANNABINOL; CANNABINOIDS; BLOOD; 11-NOR-9-CARBOXY-DELTA(9)-TETRAHYDROCANNABINOL; CONFIRMATION AB A sensitive analytical method for simultaneous quantification of sub-nanogram concentrations of cannabidiol (CBD), Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) in plasma is presented for monitoring cannabinoid pharmacotherapy and illicit cannabis use. Analytes were extracted from 1 mL plasma by solid-phase extraction, derivatized with N,O-bis(trimethylsilyl) trifluoroacetamide with 1% trimethylchlorosilane, and analyzed by two-dimensional gas chromatography mass spectrometry (2D-GCMS) with cryofocusing. The lower calibration curve was linear from 0.25-25 ng/mL for CBD and THC, 0.125-25 ng/mL for 11-OH-THC and 0.25-50 ng/mL for THCCOOH. A second higher linear range from 5-100 ng/mL, achieved through modification of injection parameters, was validated for THC, 11-OH-THC, and THCCOOH and was only implemented if concentrations exceeded the lower curve upper limit of linearity. This procedure prevented laborious re-extraction by allowing the same specimen to be re-injected for quantification on the high calibration curve. Intra-and inter-assay imprecision, determined at four quality control concentrations, were <= 7.8% CV. Analytical bias was within +/- 9.2% of target and extraction efficiencies were >= 72.9% for all analytes. Analytes were stable when stored at 22 degrees C for 16 h, 4 degrees C for 48 h, after three freeze-thaw cycles at -20 degrees C and when stored on the autosampler for 48 h. This sensitive and specific 2D-GCMS assay provides a new means of simultaneously quantifying CBD, THC and metabolite biomarkers in clinical medicine, forensic toxicology, workplace drug testing, and driving under the influence of drugs programs. C1 [Karschner, Erin L.; Barnes, Allan J.; Lowe, Ross H.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Intramural Res Program, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Intramural Res Program, NIH, Biomed Res Ctr, 251 Bayview Blvd,Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000507-01, Z01 DA000541-02, ZIA DA000541-03, ZIA DA000541-04] NR 28 TC 20 Z9 20 U1 5 U2 20 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD MAY PY 2010 VL 397 IS 2 BP 603 EP 611 DI 10.1007/s00216-010-3599-6 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 584QW UT WOS:000276768400023 PM 20306180 ER PT J AU Yang, MH Bruck, HA Kostov, Y Rasooly, A AF Yang, Minghui Bruck, Hugh Alan Kostov, Yordan Rasooly, Avraham TI Biological Semiconductor Based on Electrical Percolation SO ANALYTICAL CHEMISTRY LA English DT Article ID STAPHYLOCOCCAL-ENTEROTOXIN-B; CARBON NANOTUBES; ATOPIC-DERMATITIS; REAL-TIME; RHEUMATOID-ARTHRITIS; FOOD; BIOSENSOR; FUNCTIONALIZATION; SUPERANTIGENS; IMMUNOASSAY AB We have developed a novel biological semiconductor (BSC) based on electrical percolation through a multilayer three-dimensional carbon nanotube-antibody bionano-composite network, which can measure biological interactions directly and electronically. In electrical percolation, the passage of current through the conductive network is dependent upon the continuity of the network. Molecular interactions, such as binding of antigens to the antibodies, disrupt the network continuity causing increased resistance of the network. A BSC is fabricated by immobilizing a prefunctionalized single-walled carbon nanotubes (SWNTs)-antibody bionanocomposite directly on a poly(methyl methacrylate) (PMMA) surface (also known as plexiglass or acrylic). We used the BSC for direct (label-free) electronic measurements of antibody-antigen binding, showing that, at slightly above the electrical percolation threshold of the network, binding of a specific antigen dramatically increases the electrical resistance. Using anti-staphylococcal enterotoxin B (SEB) IgG as a "gate" and SEB as an "actuator", we demonstrated that the BSC was able to detect SEB at concentrations of 1 ng/mL. The new BSCs may permit assembly of multiple sensors on the same chip to create "biological central processing units (CPUs)" with multiple BSC elements, capable of processing and sorting out information on multiple analytes simultaneously. C1 [Rasooly, Avraham] US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Yang, Minghui; Kostov, Yordan] Univ Maryland Baltimore Cty, Ctr Adv Sensor Technol, Baltimore, MD 21250 USA. [Bruck, Hugh Alan] Univ Maryland, College Pk, MD 20742 USA. [Yang, Minghui] Univ Jinan, Sch Chem & Chem Engn, Jinan 250022, Peoples R China. [Rasooly, Avraham] NCI, Bethesda, MD 20892 USA. RP Rasooly, A (reprint author), US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. EM rasoolya@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 50 TC 8 Z9 8 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD MAY 1 PY 2010 VL 82 IS 9 BP 3567 EP 3572 DI 10.1021/ac902644z PG 6 WC Chemistry, Analytical SC Chemistry GA 590GO UT WOS:000277213400028 PM 20361741 ER PT J AU Stybayeva, G Mudanyali, O Seo, S Silangcruz, J Macal, M Ramanculov, E Dandekar, S Erlinger, A Ozcan, A Revzin, A AF Stybayeva, Gulnaz Mudanyali, Onur Seo, Sungkyu Silangcruz, Jaime Macal, Monica Ramanculov, Erlan Dandekar, Satya Erlinger, Anthony Ozcan, Aydogan Revzin, Alexander TI Lensfree Holographic Imaging of Antibody Microarrays for High-Throughput Detection of Leukocyte Numbers and Function SO ANALYTICAL CHEMISTRY LA English DT Article ID ON-CHIP; T-CELLS; BLOOD; INFECTION; LYMPHOCYTES; PROTECTION; DEPLETION; PLATFORM; SUBSETS; AIDS AB Characterization of leukocytes is an integral part of blood analysis and blood-based diagnostics. In the present paper, we combine lensless holographic imaging with antibody microarrays for rapid and multiparametric analysis of leukocytes from human blood. Monoclonal antibodies (Abs) specific for leukocyte surface antigens (CD4 and CD8) and cytokines (TNF-alpha, IFN-gamma, IL-2) were printed in an array so as to juxtapose cell capture and cytokine detection antibody (Ab) spots. Integration of Ab microarrays into a microfluidic flow chamber (4 mu L volume) followed by incubation with human blood resulted in capture of CD4 and CD8 T-cells on specific Ab spots. On-chip mitogenic activation of these cells induced release of cytokine molecules that were subsequently captured on neighboring anticytokine Ab spots. The binding of IL-2, TNF-alpha, and IFN-gamma molecules on their respective Ab spots was detected using horseradish peroxidase (HRP)-labeled anticytokine Abs and a visible color reagent. Lensfree holographic imaging was then used to rapidly (similar to 4 s) enumerate CD4 and CD8 T-lymphocytes captured on Ab spots and to quantify the cytokine signal emanating from IL-2, TNF-alpha, and IFN-gamma spots on the same chip. To demonstrate the utility of our approach for infectious disease monitoring, blood samples of healthy volunteers and human immunodeficiency virus (HIV)-infected patients were analyzed to determine the CD4/CD8 ratio, an important HIV/AIDS diagnostic marker. The ratio obtained by lensfree on-chip imaging of CD4 and CD8 T-cells captured on Ab spots was in close agreement with conventional microscopy-based cell counting. The present paper, describing tandem use of Ab microarrays and lensfree holographic imaging, paves the way for future development of miniature cytometry devices for multi-parametric blood analysis at the point of care or in a resource-limited setting. C1 [Mudanyali, Onur; Seo, Sungkyu; Silangcruz, Jaime; Erlinger, Anthony; Ozcan, Aydogan] Univ Calif Los Angeles, Dept Elect Engn, Los Angeles, CA 90095 USA. [Ozcan, Aydogan] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA. [Stybayeva, Gulnaz; Revzin, Alexander] Univ Calif Los Angeles, Dept Biomed Engn, Los Angeles, CA 90095 USA. [Macal, Monica; Dandekar, Satya] Univ Calif Los Angeles, Dept Med Microbiol & Immunol, Los Angeles, CA 90095 USA. [Seo, Sungkyu] Korea Univ, Elect & Informat Engn Dept, Seoul, South Korea. [Stybayeva, Gulnaz; Ramanculov, Erlan] Natl Biotechnol Ctr, Astana, Kazakhstan. RP Ozcan, A (reprint author), Univ Calif Los Angeles, Dept Elect Engn, Engn 4 Bldg, Los Angeles, CA 90095 USA. EM ozcan@ucla.edu; arevzin@ucdavis.edu RI Ramanculov, Erlan/E-2823-2013; Ozcan, Aydogan/I-2608-2013 OI Ozcan, Aydogan/0000-0002-0717-683X FU Okawa Foundation; Vodafone Americas Foundation; DARPA DSO [56556-MS-DRP]; NSF [0754880, 0930501]; NIH [1R21EB009222-01, DP20D006427]; AFOSR [08NE255]; ONR; Autism Research Institute; UC Davis Point-of-Care Technologies Center [NIBIB U54 EB007959] FX G.S. and O.M. contributed equally to this work. The Ozcan Research Group at UCLA acknowledges the support of the Okawa Foundation, Vodafone Americas Foundation, DARPA DSO (under 56556-MS-DRP), NSF BISH program (under Awards # 0754880 and 0930501), NIH (under 1R21EB009222-01 and the NIH Director's New Innovator Award, Award Number DP20D006427 from the Office of The Director, National Institutes of Health), AFOSR (under Project # 08NE255), and ONR (under Young Investigator Award 2009). Revzin group acknowledges financial support from NSF (EFRI Award), Autism Research Institute and UC Davis Point-of-Care Technologies Center grant (NIBIB U54 EB007959). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Biomedical Imaging and Bioengineering or the National Institutes of Health. NR 41 TC 55 Z9 56 U1 2 U2 35 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD MAY 1 PY 2010 VL 82 IS 9 BP 3736 EP 3744 DI 10.1021/ac100142a PG 9 WC Chemistry, Analytical SC Chemistry GA 590GO UT WOS:000277213400051 PM 20359168 ER PT J AU Chen, D Chittajallu, DR Passalis, G Kakadiaris, IA AF Chen, D. Chittajallu, D. R. Passalis, G. Kakadiaris, I. A. TI Computational Tools for Quantitative Breast Morphometry Based on 3D Scans SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Breast shape model; Breast plastic surgery; Computer-aided Surgery; Breast morphometry; Deformable model; Breast reconstruction; Surgical planning; Breast volume estimation ID SURGERY; SHAPE; PHOTOGRAPHY AB Quantitative analysis of breast morphometry is critical to breast plastic surgery. Recently, three-dimensional (3D) photography has emerged as a strong new alternative for breast morphometry analysis in comparison to other existing techniques. 3D photography enables the capture of the entire breast surface topology virtually in a single snapshot and without any direct contact with the patient, thus causing minimal discomfort. In this paper, we present a set of computational tools for the quantitative analysis of two key morphological properties of the breast that are of interest to breast plastic surgery based on 3D scans, namely breast shape and volume. The breast shape is modeled using a compact geometric model capable of capturing the global shape of the breast with very few parameters. Specifically, the shape model is deduced by applying a set of five global deformations to a geometric primitive. These deformations, defined using very intuitive parameters, closely model the key shape variables that surgeons inherently use to describe the overall shape of the breast. Patient-specific parameters of the breast shape model are automatically recovered by fitting a generic breast shape model to the 3D scan of the patient's breast using a physics-based deformable model framework. The mean error of fit between the automatically fitted shape model and the actual breast surface for 12 subjects varied between 0.9 and 2.6 mm. These results are very encouraging considering the fact that only 17 parameters are used to determine the shape of the breast. The breast volume is estimated automatically by first localizing the breast on a 3D scan of the patient's torso and then computing the volume enclosed between an interpolated breast-less torso surface and the actual breast. The volume estimated by the proposed method was found to be within the intra-operator variability among five segmentation trials performed manually by an expert on 3D torso scans of three subjects. C1 [Chittajallu, D. R.; Passalis, G.; Kakadiaris, I. A.] Univ Houston, Computat Biomed Lab, Houston, TX 77004 USA. [Chen, D.] Natl Lib Med, Off High Performance Comp & Commun, Bethesda, MD USA. RP Kakadiaris, IA (reprint author), Univ Houston, Computat Biomed Lab, Houston, TX 77004 USA. EM ioannisk@uh.edu OI Kakadiaris, Ioannis/0000-0002-0591-1079 FU NSF [BES-0402591] FX This study was supported in part by NSF BES-0402591. Any opinions, findings, conclusions, or recommendations expressed in this material are of the authors and may not reflect the views of the sponsors. We would like to thank Dr. M. Miller and Dr. C. Patrick from the Department of Plastic Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA, for providing us with the data and their invaluable advice. NR 24 TC 6 Z9 6 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD MAY PY 2010 VL 38 IS 5 BP 1703 EP 1718 DI 10.1007/s10439-010-9971-z PG 16 WC Engineering, Biomedical SC Engineering GA 577EK UT WOS:000276204600001 PM 20300850 ER PT J AU Hendrix, A Denys, H Braems, G Pauwels, P Van den Broecke, R Cocquyt, V Westbroek, W Bracke, M De Wever, O AF Hendrix, A. Denys, H. Braems, G. Pauwels, P. Van den Broecke, R. Cocquyt, V. Westbroek, W. Bracke, M. De Wever, O. TI THE SECRETORY GTPASE RAB27B DRIVES POOR PROGNOSIS IN ER alpha-POSITIVE BREAST CANCER SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT IMPAKT Breast Cancer Conference 2010 CY MAY 06-08, 2010 CL Brussels, BELGIUM SP European Soc Med Oncol C1 [Bracke, M.; De Wever, O.] Ghent Univ Hosp, Lab Expt Canc Res, Ghent, Belgium. [Westbroek, W.] NHGRI, NIH, Bethesda, MD 20892 USA. RI de wever, olivier/J-3094-2013 OI de wever, olivier/0000-0002-5453-760X NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAY PY 2010 VL 21 SU 4 MA 112P BP 53 EP 53 PG 1 WC Oncology SC Oncology GA 597BN UT WOS:000277730800105 ER PT J AU Moriyama, B Henning, SA Childs, R Holland, SM Anderson, VL Morris, JC Wilson, WH Drusano, GL Walsh, TJ AF Moriyama, Brad Henning, Stacey A. Childs, Richard Holland, Steven M. Anderson, Victoria L. Morris, John C. Wilson, Wyndham H. Drusano, George L. Walsh, Thomas J. TI High-Dose Continuous Infusion beta-Lactam Antibiotics for the Treatment of Resistant Pseudomonas aeruginosa Infections in Immunocompromised Patients SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE beta-lactam antibiotics; continuous infusion; immunocompromised; Pseudomonas aeruginosa; resistance ID RABBIT ENDOCARDITIS MODEL; CYSTIC-FIBROSIS PATIENTS; INTERMITTENT INFUSION; NEUTROPENIC PATIENTS; CEFTAZIDIME; COMBINATION; EFFICACY; PHARMACOKINETICS; NEUROTOXICITY; TOBRAMYCIN AB OBJECTIVE: To report a case series of high-dose continuous infusion beta-lactam antibiotics for the treatment of resistant Pseudomonas aeruginosa infections. CASE SUMMARY: Continuous infusion ceftazidime or aztreonam was administered to achieve target drug concentrations at or above the minimum inhibitory concentration, when possible, in 3 patients with P aeruginosa infections. The maximal calculated target drug concentration was 100 mg/L. In the first patient, with primary immunodeficiency, neutropenia, and aggressive cutaneous T-cell lymphoma/leukemia, continuous infusion ceftazidime (6.5-9.6 g/day) was used to successfully treat multidrug-resistant P aeruginosa bacteremia. In the second patient, with leukocyte adhesion deficiency type 1, continuous infusion aztreonam (8.4 g/day) was used to successfully treat multidrug-resistant P aeruginosa wound infections. In the third patient, with severe aplastic anemia, continuous infusion ceftazidime (7-16.8 g/day) was used to treat P aeruginosa pneumonia and bacteremia. In each patient, bacteremia cleared, infected wounds healed, and pneumonia improved in response to continuous infusion ceftazidime or aztreonam. DISCUSSION: Treatment strategies for multidrug-resistant P aeruginosa infections are limited. A novel treatment strategy, when no other options are available, is the continuous infusion of existing beta-lactam antibiotics to maximize their pharmacodynamic activity. High-dose continuous infusion ceftazidime or aztreonam was used for the successful treatment of resistant systemic P aeruginosa infections in 3 chronically immunocompromised patients. CONCLUSIONS: Continuous infusion beta-lactam antibiotics are a potentially useful treatment strategy for resistant P aeruginosa infections in immunocompromised patients. C1 [Moriyama, Brad; Henning, Stacey A.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Childs, Richard] NHLBI, Bethesda, MD 20892 USA. [Holland, Steven M.; Anderson, Victoria L.] NIAID, Bethesda, MD 20892 USA. [Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Drusano, George L.] Ordway Res Inst, Albany, NY USA. RP Moriyama, B (reprint author), NIH, Ctr Clin, Dept Pharm, 10 Ctr Dr, Bethesda, MD 20892 USA. EM bmoriyama@cc.nih.gov FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; National Cancer Institute of the National Institutes of Health FX This work was supported in part by the intramural research programs of the National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; and the National Cancer Institute of the National Institutes of Health. NR 32 TC 18 Z9 18 U1 0 U2 2 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD MAY PY 2010 VL 44 IS 5 BP 929 EP 935 DI 10.1345/aph.1M717 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 591JD UT WOS:000277295600020 PM 20371747 ER PT J AU Dookeran, KA Dignam, JJ Ferrer, K Sekosan, M McCaskill-Stevens, W Gehlert, S AF Dookeran, Keith A. Dignam, James J. Ferrer, Karen Sekosan, Marin McCaskill-Stevens, Worta Gehlert, Sarah TI p53 as a Marker of Prognosis in African-American Women with Breast Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID TRIPLE-NEGATIVE PHENOTYPE; GENE-EXPRESSION PATTERNS; MOLECULAR SUBTYPES; RACIAL-DIFFERENCES; SURVIVAL; CARCINOMA; WHITE; ASSOCIATION; MUTATIONS; PROTEIN AB p53 overexpression has been identified as a poor prognostic marker in breast cancer. We investigate the value of p53 status within the context of stage and intrinsic subtype classification (subtype), in a group of African-American (AA) women of lower socioeconomic status (SES) with primary breast cancer. Participants were 331 consecutive AA women treated at an urban hospital (median follow-up 41 months) with known subtype [luminal A = estrogen receptor (ER)+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (HER2)-; luminal B = ER+ and/or PR+, HER2+; HER2+ = ER-, PR-, HER2+; basal = ER-, PR-, HER2-, cytokeratin (CK)5/6+, and/or HER1+; and unclassified = negative for all five markers] and p53 (Pab1801 antibody) immunohistochemical status. Proportional hazards regression models were used to select and evaluate factors prognostic for all-cause mortality. p53+ status was associated with grade 3 tumors, ER/PR- status, and basal subtype. On univariate analysis, factors related to survival were stage, grade [(3/1) hazard ratio (HR) = 2.64; 95% confidence interval (CI), 1.15-6.07], subtype [(ex. basal/luminal A) HR = 2.15; 95% CI, 1.34-3.45], and p53 status [(+/-) HR = 1.77; 95% CI, 1.15-2.72]. Multivariable modeling indicated that p53+ status remained a negative prognostic factor (HR = 1.63; 95% CI, 1.01-2.59) after adjustment for effects of age, stage, grade, and subtype; 5-year adjusted survival was significantly greater for p53- (66.7%) than p53+ cases (54.7%). p53 status is an independent predictor of survival after consideration of other strong prognostic factors such as stage, tumor grade, and subtype, and thus may be useful in identifying AA women at high risk of breast cancer mortality. C1 [Dookeran, Keith A.] Canc Fdn Minor & Underserved Populat, Chicago, IL USA. [Dignam, James J.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Ferrer, Karen; Sekosan, Marin] John H Stroger Jr Hosp Cook Cty, Dept Pathol, Chicago, IL USA. [McCaskill-Stevens, Worta] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Gehlert, Sarah] Univ Chicago, Ctr Hlth Dispar Res, Chicago, IL 60637 USA. RP Dookeran, KA (reprint author), Canc Fdn Minor & Underserved Populat, Chicago, IL USA. EM keithdookeran@chicagobooth.edu OI Dookeran, Keith/0000-0003-3695-9873 FU CFMUP, Chicago, IL; Division of Cancer Prevention, NCI/NIH, Bethesda, MD FX The authors acknowledge the following sources of support: CFMUP, Chicago, IL and Division of Cancer Prevention, NCI/NIH, Bethesda, MD. NR 39 TC 16 Z9 24 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD MAY PY 2010 VL 17 IS 5 BP 1398 EP 1405 DI 10.1245/s10434-009-0889-3 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA 585ZE UT WOS:000276869000022 PM 20049641 ER PT J AU Louie, GH Ward, MM AF Louie, Grant H. Ward, Michael M. TI Changes in the rates of joint surgery among patients with rheumatoid arthritis in California, 1983-2007 SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID POPULATION-BASED ASSESSMENT; LONG-TERM OUTCOMES; ORTHOPEDIC-SURGERY; DISEASE; REPLACEMENT; REDUCTION; LIMBS AB Background Treatment of patients with rheumatoid arthritis (RA) has improved markedly over the past 25 years. Objective To investigate whether rates of joint surgery, a long-term consequence of poorly controlled RA, have changed over this period. Methods In this population-based, serial cross-sectional study of patients with RA aged >= 40 years in California, trends in annual rates of total knee arthroplasty, total hip arthroplasty, total ankle arthroplasty or arthrodesis and total wrist arthroplasty or arthrodesis from 1983 to 2007 were examined. Results Rates of joint surgery peaked in the 1990s and since have decreased. Among patients aged 40-59 years, rates of knee surgery in 2003-2007 were 19% lower than in 1983-1987 (adjusted rate ratio 0.81; 95% CI 0.74 to 0.87, p<0.0001), while rates of hip surgery in 2003-2007 were 40% lower (p<0.0001). Rates of knee and hip surgery did not decrease in patients aged >= 60 years but increased as observed in the general population. Compared with rates of ankle and wrist surgery in the mid-1980s, rates in the mid-2000s decreased significantly in both age groups. Conclusions Rates of joint surgery in RA peaked in the 1990s and have declined thereafter, suggesting that long-term outcomes of RA are improving. C1 [Louie, Grant H.; Ward, Michael M.] NIAMSD, Intramural Res Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Louie, GH (reprint author), NIAMS, NIH, IRP, Bldg 10,CRC Room 4-1339,10 Ctr Dr,MSC 1468, Bethesda, MD 20892 USA. EM grant.louie@nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. NR 15 TC 44 Z9 45 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAY PY 2010 VL 69 IS 5 BP 868 EP 871 DI 10.1136/ard.2009.112474 PG 4 WC Rheumatology SC Rheumatology GA 587HW UT WOS:000276982300017 PM 19581279 ER PT J AU Witkowski, B Lelievre, J Barragan, MJL Laurent, V Su, XZ Berry, A Benoit-Vical, F AF Witkowski, Benoit Lelievre, Joel Barragan, Maria Jose Lopez Laurent, Victor Su, Xin-zhuan Berry, Antoine Benoit-Vical, Francoise TI Increased Tolerance to Artemisinin in Plasmodium falciparum Is Mediated by a Quiescence Mechanism SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ERYTHROCYTIC STAGES; TARGETING MALARIA; RESISTANT MALARIA; SENSITIVITY; CULTURE; PROTEIN AB Artemisinin (ART)-based combination therapies (ACTs) are the first-line drugs-and often the last treatments-that can effectively cure Plasmodium falciparum infections. Unfortunately, the decreased clinical efficacy of artesunate, one of the major ART derivatives, was recently reported along the Thailand-Cambodia border. Through long-term artemisinin pressure in vitro, we have obtained an ART-tolerant strain that can survive extremely high doses of ART. We showed that drug pressure could induce a subpopulation of ring stages into developmental arrest, which can explain the ART tolerance in P. falciparum. We also observed interesting transcriptomic modifications possibly associated with the acquisition of ART tolerance. These modifications include the overexpression of heat shock and erythrocyte surface proteins and the downexpression of a cell cycle regulator and a DNA biosynthesis protein. This study highlights a new phenomenon in the Plasmodium response to ART that may explain the delayed clearance of parasites after artesunate treatment observed on the Thailand-Cambodia border and that provides important information for achieving a better understanding of the mechanisms of antimalarial resistance. C1 [Witkowski, Benoit; Lelievre, Joel; Laurent, Victor; Benoit-Vical, Francoise] CNRS, Chim Coordinat Lab, UPR8241, Toulouse, France. [Witkowski, Benoit; Lelievre, Joel; Laurent, Victor; Berry, Antoine; Benoit-Vical, Francoise] Univ Toulouse 3, Fac Med Rangueil, F-31062 Toulouse, France. [Witkowski, Benoit; Lelievre, Joel; Laurent, Victor; Berry, Antoine; Benoit-Vical, Francoise] Univ Toulouse, CHU Toulouse, Serv Parasitol Mycol, Toulouse, France. [Barragan, Maria Jose Lopez; Su, Xin-zhuan] NIAID, Malaria Funct Genom Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Berry, Antoine] Univ Toulouse 3, MD UM UPS UMR3, F-31062 Toulouse, France. RP Benoit-Vical, F (reprint author), Hop Rangueil, Serv Parasitol Mycol, TSA 50032, F-31059 Toulouse 9, France. EM Francoise.Vical@inserm.fr RI Berry, Antoine/J-9352-2014; Benoit-Vical, Francoise/E-3938-2016; OI Benoit-Vical, Francoise/0000-0002-9468-4823; Su, Xinzhuan/0000-0003-3246-3248 FU EU; Region Midi-Pyrenees; ANR [ANR-06-RIB-020]; Division of Intramural Research, NIAID, National Institutes of Health FX J. L. is indebted to the EU program for a Ph. D. fellowship, and B. W. received a Ph. D. grant from the Region Midi-Pyrenees. ANR (grant ANR-06-RIB-020) is acknowledged for financial support. This work was supported in part by the Intramural Research Program of the Division of Intramural Research, NIAID, National Institutes of Health. NR 28 TC 103 Z9 104 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAY PY 2010 VL 54 IS 5 BP 1872 EP 1877 DI 10.1128/AAC.01636-09 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 585DK UT WOS:000276804300030 PM 20160056 ER PT J AU Murray, PR Jain, A Uzel, G Ranken, R Ivy, C Blyn, LB Ecker, DJ Sampath, R Lee, CCR Turner, ML AF Murray, Patrick R. Jain, Ashish Uzel, Gulbu Ranken, Raymond Ivy, Cristina Blyn, Lawrence B. Ecker, David J. Sampath, Rangarajan Lee, Chyi-Chia Richard Turner, Maria L. TI Pyoderma Gangrenosum-Like Ulcer in a Patient With X-Linked Agammaglobulinemia Identification of Helicobacter bilis by Mass Spectrometry Analysis SO ARCHIVES OF DERMATOLOGY LA English DT Article ID HYPOGAMMAGLOBULINEMIA; BACTEREMIA; ORGANISM AB Background: Pyoderma gangrenosum-like ulcers and cellulitis of the lower extremities associated with recurrent fevers in patients with X-linked (Bruton) agammaglobulinemia have been reported to be caused by Helicobacter bilis (formerly classified as Flexispira rappini and then Helicobacter strain flexispira taxon 8). Consistent themes in these reports are the difficulty in recovering this organism in blood and wound cultures and in maintaining isolates in vitro. We confirmed the presence of this organism in a patient's culture by using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry. Observation: An adolescent boy with X-linked agammaglobulinemia presented with indurated plaques and a chronic leg ulcer whose origin was strongly suspected to be an H bilis organism. Histologic analysis demonstrated positive Warthin-Starry staining of curvilinear rods, which grew in culture but failed to grow when sub-cultured. They could not be identified by conventional techniques. A combination of gene amplification by polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry confirmed the identity of this organism. Conclusions: This novel technology was useful in the identification of a difficult-to-grow Helicobacter organism, the cause of pyoderma gangrenosum-like leg ulcers in patients with X-linked agammaglobulinemia. Correct identification of this organism as the cause of pyoderma gangrenosum-like ulcers in patients with X-linked agammaglobulinemia is of great importance for the early initiation of appropriate and curative antibiotic therapy. C1 [Turner, Maria L.] NIH, Dermatol Branch, Bethesda, MD 20892 USA. [Murray, Patrick R.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Jain, Ashish; Uzel, Gulbu] NIAID, Bethesda, MD 20892 USA. [Lee, Chyi-Chia Richard] NIH, Pathol Lab, Bethesda, MD 20892 USA. [Ranken, Raymond; Ivy, Cristina; Blyn, Lawrence B.; Ecker, David J.; Sampath, Rangarajan] Ibis Biosci, Des Plaines, IL USA. RP Turner, ML (reprint author), NIH, Dermatol Branch, Bldg 10,Room 12N 238, Bethesda, MD 20892 USA. EM mlturner@mail.nih.gov FU National Institute of Allergy and Infectious Diseases and Ibis Biosciences [06-I-0049] FX This study was supported in part by protocol 06-I-0049 of the National Institute of Allergy and Infectious Diseases and Ibis Biosciences (Abbott Laboratories), whose employees performed the spectrometric analysis of polymerase chain reaction products using the Ibis T5000 Biosensor System. NR 13 TC 11 Z9 11 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD MAY PY 2010 VL 146 IS 5 BP 523 EP 526 PG 4 WC Dermatology SC Dermatology GA 597QF UT WOS:000277773100010 PM 20479300 ER PT J AU Schneeweiss, S Patrick, AR Solomon, DH Mehta, J Dormuth, C Miller, M Lee, JC Wang, PS AF Schneeweiss, Sebastian Patrick, Amanda R. Solomon, Daniel H. Mehta, Jyotsna Dormuth, Colin Miller, Matthew Lee, Jennifer C. Wang, Philip S. TI Variation in the Risk of Suicide Attempts and Completed Suicides by Antidepressant Agent in Adults A Propensity Score-Adjusted Analysis of 9 Years' Data SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID SEROTONIN REUPTAKE INHIBITORS; RANDOMIZED CONTROLLED-TRIALS; SSRIS; METAANALYSIS; INDIVIDUALS; VENLAFAXINE; DEPRESSION; STRATEGIES; OUTCOMES; SWEDEN AB Context: A US Food and Drug Administration advisory has warned that antidepressants may be associated with an increased risk of suicidal thoughts and behaviors in adolescents. This prompted a meta-analysis of trials in adults that found no overall increase in risk, but individual agents could not be studied. Objective: To assess the risk of suicide and suicide attempts associated with individual antidepressant agents. Design: Cohort study of incident users of antidepressant agents. Setting: Population-based health care utilization data of all residents of British Columbia, Canada, aged 18 years and older between January 1, 1997, and December 31, 2005. Patients: British Columbia residents who had antidepressant therapy initiated and had a recorded diagnosis of depression. Intervention: Initiation of various antidepressant medications. Main Outcome Measures: Combined suicide death or hospitalization due to self-harm. Results: In a population of 287 543 adults aged 18 years and older with antidepressant therapy initiated, we ob-served outcome rates ranging from 4.41/1000 person-years to 9.09/1000 person-years. Most events occurred in the first 6 months after treatment initiation. After extensive propensity score adjustment, we found no clinically meaningful variation in the risk of suicide and suicide attempt between antidepressant agents compared with fluoxetine hydrochloride initiation: citalopram hydrobromide, hazard ratio=1.00 (95% confidence interval, 0.63-1.57); fluvoxamine maleate, hazard ratio=0.98 (95% confidence interval, 0.63-1.51); paroxetine hydrochloride, hazard ratio=1.02 (95% confidence interval, 0.77-1.35); and sertraline hydrochloride, hazard ratio=0.75 (95% confidence interval, 0.53-1.05). Compared with selective serotonin reuptake inhibitors as a drug class, other classes including serotonin-norepinephrine reuptake inhibitors, tricyclic agents, and other newer and atypical agents had a similar risk. Restriction to patients with no antidepressant use in the past 3 years further reduced apparent differences between groups. Conclusions: Our finding of equal event rates across antidepressant agents supports the US Food and Drug Administration's decision to treat all antidepressants alike in their advisory. Treatment decisions should be based on efficacy, and clinicians should be vigilant in monitoring after initiating therapy with any antidepressant agent. C1 [Schneeweiss, Sebastian; Patrick, Amanda R.; Solomon, Daniel H.; Mehta, Jyotsna; Lee, Jennifer C.; Wang, Philip S.] Harvard Univ, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med,Med Sch, Boston, MA 02120 USA. [Miller, Matthew] Harvard Univ, Sch Publ Hlth, Harvard Injury Control Res Ctr, Dept Hlth Policy & Management, Boston, MA 02120 USA. [Dormuth, Colin] Univ British Columbia, Therapeut Initiat, Dept Anesthesia Pharmacol & Therapeut, Vancouver, BC V5Z 1M9, Canada. [Miller, Matthew] NIMH, Bethesda, MD 20892 USA. RP Schneeweiss, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med,Med Sch, 1620 Tremont St,Ste 3030, Boston, MA 02120 USA. EM schneeweiss@post.harvard.edu RI miller, matthew/H-4624-2011; Schneeweiss, Sebastian/C-2125-2013 OI miller, matthew/0000-0002-3267-6510; FU National Institute of Mental Health [RO1-MH078708] FX This work was supported by grant RO1-MH078708 from the National Institute of Mental Health. NR 49 TC 35 Z9 35 U1 2 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD MAY PY 2010 VL 67 IS 5 BP 497 EP 506 PG 10 WC Psychiatry SC Psychiatry GA 590XH UT WOS:000277261200008 PM 20439831 ER PT J AU Gauerke, S Driscoll, JJ AF Gauerke, Steven Driscoll, James J. TI Hidradenocarcinomas A Brief Review and Future Directions SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Review ID SWEAT GLAND CARCINOMAS; MUCOEPIDERMOID CARCINOMA; METASTATIC HIDRADENOCARCINOMA; SALIVARY-GLAND; ADENOCARCINOMA; AXILLA; TUMORS AB Hidradenocarcinomas are rare, aggressive skin adnexal tumors of sweat gland origin that demonstrate a high potential for local recurrence, metastasis, and poor outcome. These neoplasms can derive from preexisting clear cell hidradenomas but more commonly appear de novo, with the molecular events responsible for the pathogenesis currently unknown. Historically, diagnosis has been difficult because of the few cases, inconsistent nomenclature, variable morphology of cells that compose the neoplasm, and confusion with other visceral metastatic tumors. Presentation is generally benign with an indolent clinical course that typically includes local and multiple recurrences. Despite wide-excision surgery, disease at regional lymph nodes and metastatic sites is common and linked to decreased survival. Currently, molecular markers of pathogenesis as well as effective forms of adjuvant chemotherapy are lacking. Future studies are required to identify the histopathologic and immunohistochemical features, which may facilitate diagnosis and foster development of molecularly targeted forms of adjuvant therapy. (Arch Pathol Lab Med. 2010;134:781-785) C1 [Driscoll, James J.] NCI, Dept Med Oncol, Bethesda, MD 20889 USA. [Gauerke, Steven] Natl Naval Med Ctr, Dept Anat Pathol, Bethesda, MD USA. [Gauerke, Steven] USN, Med Ctr, Dept Pathol, Portsmouth, VA USA. [Gauerke, Steven] Uniformed Serv Univ Hlth Sci, Dept Pathol, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. RP Driscoll, JJ (reprint author), NCI, Dept Med Oncol, Bldg 10,Rm 12N-226, Bethesda, MD 20889 USA. EM driscollj@mail.nih.gov NR 21 TC 11 Z9 11 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD MAY PY 2010 VL 134 IS 5 BP 781 EP 785 PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 591RI UT WOS:000277320200017 PM 20441512 ER PT J AU Gagarina, V Gabay, O Dvir-Ginzberg, M Lee, EJ Brady, JK Quon, MJ Hall, DJ AF Gagarina, Viktoria Gabay, Odile Dvir-Ginzberg, Mona Lee, Eun Jin Brady, Jillian K. Quon, Michael J. Hall, David J. TI SirT1 Enhances Survival of Human Osteoarthritic Chondrocytes by Repressing Protein Tyrosine Phosphatase 1B and Activating the Insulin-like Growth Factor Receptor Pathway SO ARTHRITIS AND RHEUMATISM LA English DT Article ID FOXO TRANSCRIPTION FACTORS; HUMAN ARTICULAR-CARTILAGE; RAT ADIPOSE-CELLS; STIMULATED TRANSLOCATION; MMP-13 EXPRESSION; FACTOR-I; APOPTOSIS; DEACETYLASE; DEATH; P53 AB Objective. The protein deacetylase SirT1 inhibits apoptosis in a variety of cell systems by distinct mechanisms, yet its role in chondrocyte death has not been explored. We undertook the present study to assess the role of SirT1 in the survival of osteoarthritic (OA) chondrocytes in humans. Methods. SirT1, protein tyrosine phosphatase 1B (PTP1B), and PTP1B mutant expression plasmids as well as SirT1 small interfering RNA (siRNA) and PTP1B siRNA were transfected into primary human chondrocytes. Levels of apoptosis were determined using flow cytometry, and activation of components of the insulin-like growth factor receptor (IGFR)/Akt pathway was assessed using immunoblotting. OA and normal knee cartilage samples were subjected to immunohistochemical analysis. Results. Expression of SirT1 in chondrocytes led to increased chondrocyte survival in either the presence or the absence of tumor necrosis factor alpha/actinomycin D, while a reduction of SirT1 by siRNA led to increased chondrocyte apoptosis. Expression of SirT1 in chondrocytes led to activation of IGFR and the downstream kinases phosphatidylinositol 3-kinase, phosphoinosite-dependent protein kinase 1, mTOR, and Akt, which in turn phosphorylated MDM2, inhibited p53, and blocked apoptosis. Activation of IGFR occurs at least in part via SirT1-mediated repression of PTP1B. Expression of PTP1B in chondrocytes increased apoptosis and reduced IGFR phosphorylation, while down-regulation of PTP1B by siRNA significantly decreased apoptosis. Examination of cartilage from normal donors and OA patients revealed that PTP1B levels are elevated in OA cartilage in which SirT1 levels are decreased. Conclusion. For the first time, it has been demonstrated that SirT1 is a mediator of human chondrocyte survival via down-regulation of PTP1B, a potent proapoptotic protein that is elevated in OA cartilage. C1 [Hall, David J.] NIAMSD, Cartilage Mol Genet Grp, Cartilage Biol & Orthoped Branch, NIH, Bethesda, MD 20892 USA. [Quon, Michael J.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Hall, DJ (reprint author), NIAMSD, Cartilage Mol Genet Grp, Cartilage Biol & Orthoped Branch, NIH, 50 South Dr,Room 1524, Bethesda, MD 20892 USA. EM halld@mail.nih.gov OI Dvir-Ginzberg, Mona/0000-0003-3089-6875; Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH; National Center for Complementary and Alternative Medicine, NIH FX Supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, and the National Center for Complementary and Alternative Medicine, NIH. NR 43 TC 62 Z9 69 U1 3 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD MAY PY 2010 VL 62 IS 5 BP 1383 EP 1392 DI 10.1002/art.27369 PG 10 WC Rheumatology SC Rheumatology GA 619LT UT WOS:000279432400021 PM 20131294 ER PT J AU Borenstein, D Altman, R Bello, A Chatham, W Clauw, D Crofford, L Croft, J Hassett, A Kozin, F Pisetsky, D Rich-Ardson, J Schanberg, L Starz, T Witter, J AF Borenstein, David Altman, Roy Bello, Alfonso Chatham, Winn Clauw, Daniel Crofford, Leslie Croft, Joseph Hassett, Afton Kozin, Franklin Pisetsky, David Rich-ardson, Jan Schanberg, Laura Starz, Terence Witter, James TI Report of the American College of Rheumatology Pain Management Task Force AMERICAN COLLEGE OF RHEUMATOLOGY PAIN MANAGEMENT TASK FORCE SO ARTHRITIS CARE & RESEARCH LA English DT Article ID LOW-BACK-PAIN; PSYCHOLOGICAL INTERVENTIONS; METHYLTRANSFERASE GENE; OPIOID THERAPY; CLINICAL PAIN; ARTHRITIS; FIBROMYALGIA; MECHANISMS; RESPONSES; CHILDREN C1 [Borenstein, David] Arthrit & Rheumatism Associates, Washington, DC USA. [Altman, Roy] Univ Calif Los Angeles, Los Angeles, CA USA. [Bello, Alfonso] Illinois Bone & Joint Inst, Glenview, IL USA. [Chatham, Winn] Univ Alabama, Birmingham, AL USA. [Clauw, Daniel] Univ Michigan, Ann Arbor, MI 48109 USA. [Crofford, Leslie] Univ Kentucky, Lexington, KY 40506 USA. [Hassett, Afton] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Kozin, Franklin] Scripps Clin, Med Grp, La Jolla, CA 92037 USA. [Pisetsky, David] Durham VA Hosp, Durham, NC USA. [Rich-ardson, Jan; Schanberg, Laura] Duke Univ, Durham, NC USA. [Starz, Terence] Arthrit & Internal Med Associates, Pittsburgh, PA USA. [Witter, James] NIH, Bethesda, MD 20892 USA. RP Borenstein, D (reprint author), 2021 K St NW,Suite 300, Washington, DC 20006 USA. EM DBorenstein715@aol.com RI Crofford, Leslie/J-8010-2013 NR 60 TC 13 Z9 13 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD MAY PY 2010 VL 62 IS 5 BP 590 EP 599 DI 10.1002/acr.20005 PG 10 WC Rheumatology SC Rheumatology GA 639MT UT WOS:000280979600003 ER PT J AU Volcik, KA Campbell, S Chambless, LE Coresh, J Folsom, AR Mosley, TH Ni, HY Wagenknecht, LE Wasserman, BA Boerwinkle, E AF Volcik, Kelly A. Campbell, Stephen Chambless, Lloyd E. Coresh, Josef Folsom, Aaron R. Mosley, Thomas H. Ni, Hanyu Wagenknecht, Lynne E. Wasserman, Bruce A. Boerwinkle, Eric TI MMP2 genetic variation is associated with measures of fibrous cap thickness: The Atherosclerosis Risk in Communities Carotid MRI Study SO ATHEROSCLEROSIS LA English DT Article DE Atherosclerosis; Carotid MRI; Vulnerable Plaque; MMP; Genetics ID PROMOTER 5A/6A POLYMORPHISM; ACUTE MYOCARDIAL-INFARCTION; MATRIX METALLOPROTEINASES; CORONARY-ARTERY; PLAQUE RUPTURE; INCREASED EXPRESSION; IN-VITRO; SUSCEPTIBILITY; IDENTIFICATION; REGIONS AB Objective: Genetic variation in matrix metalloproteinase(MMP) promoter regions alter the transcriptional activity of MMPs and has been consistently associated with CHD, presumably through plaque degradation and remodeling. We examined the association of MMP promoter variation with multiple plaque characteristics measured by gadolinium-enhanced MRI among 1700 participants in the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study. Methods: For the analyses presented here, 1700 participants of the biracial ARIC Carotid MRI Study (similar to 1000 participants with thick carotid artery walls and similar to 700 randomly sampled participants) were evaluated for associations of MMP genetic variation with multiple plaque characteristics, including carotid artery wall thickness, lipid core and fibrous cap measures. MRI studies were performed on a 1.5T scanner equipped with a bilateral 4-element phased array carotid coil. Results: Fifty-one percent of the participants were female, 77% white, 23% African American, and the mean age was 70 years. MMP2 C-1306T variant genotypes (CT + TT) were significantly associated with higher cap thickness measures, but not with wall thickness or lipid core measures. Individuals with the CC genotype had approximately 0.1 mm thinner cap thickness compared to those carrying a T allele (P = 0.02). Conclusion: Genetic variation within the MMP2 promoter region was associated with cap thickness and therefore may influence the role of MMP2 in plaque vulnerability. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Volcik, Kelly A.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Campbell, Stephen; Chambless, Lloyd E.] Univ N Carolina, Collaborat Studies Coordinating Ctr, Chapel Hill, NC 27514 USA. [Coresh, Josef] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Ni, Hanyu] NHLBI, NIH, Bethesda, MD 20892 USA. [Wagenknecht, Lynne E.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Wasserman, Bruce A.] Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. RP Volcik, KA (reprint author), Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, 1200 Hermann Pressler, Houston, TX 77030 USA. EM Kelly.A.Volcik@uth.tmc.edu FU National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022] FX The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the ARIC study for their important contributions. NR 43 TC 12 Z9 13 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAY PY 2010 VL 210 IS 1 BP 188 EP 193 DI 10.1016/j.atherosclerosis.2009.12.006 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 588PR UT WOS:000277085300030 PM 20064641 ER PT J AU Pessina, A Bonomi, A Cavicchini, L Albella, B Cerrato, L Parent-Massin, D Sibiril, Y Parchment, R Behrsing, H Verderio, P Pizzamiglio, S Giangreco, M Baglio, C Cocce, V Sisto, F Gribaldo, L AF Pessina, Augusto Bonomi, Arianna Cavicchini, Loredana Albella, Beatriz Cerrato, Laura Parent-Massin, Dominique Sibiril, Yann Parchment, Ralph Behrsing, Holger Verderio, Paolo Pizzamiglio, Sara Giangreco, Manuela Baglio, Carolina Cocce, Valentina Sisto, Francesca Gribaldo, Laura TI Prevalidation of the Rat CFU-GM Assay for In Vitro Toxicology Applications SO ATLA-ALTERNATIVES TO LABORATORY ANIMALS LA English DT Article DE in vitro toxicity; myelotoxicity; rat CFU-GM; prevalidation ID VALIDATION; TOXICITY; CELLS; RECOMMENDATIONS; NEUTROPENIA; SYSTEMS; TRIAL; TESTS; MODEL AB In vitro haematotoxicity assays are thought to have the potential to significantly reduce and refine the use of animals for haematotoxicity testing. These assays are used successfully in all types of studies however, their use is not so common in human toxicology studies in the preclinical setting, as they are not required for regulatory testing in this case. Furthermore, these assays could play a key role in bridging the gap between preclinical toxicology studies in animal models and clinical investigations. In previous studies, the Colony Forming Unit-Granulocyte Macrophage (CFU-GM) assay has been validated for testing drug haematotoxicity (with both mouse bone-marrow and human cord blood) and for predicting the in vivo human maximal tolerated dose (MTD) by adjusting in vivo data on mouse toxicity. Recently, a Colony Forming Unit-Megakaryocyte (CFU-MK) assay has also been prevalidated for testing drug toxicity toward megakaryocytes. The rat CFU-GM assay has been used by many researchers for its ability to evaluate in vitro haematotoxicity. Although it is not yet available, a standardised procedure for data comparison could be very important, since the rat is the most widely-used species for the in vivo testing of toxicants. This report presents the results of the prevalidation study developed to analyse the intra-laboratory and inter-laboratory variability of a standardised operating procedure for this assay and its performance for the in vitro determination of the inhibitory concentration (IC) values of drugs on rat myeloid progenitors (CFU-GM). The results demonstrate that the CFU-GM assay can be performed with cryopreserved rat bone-marrow cells (rBMC). The assay represents a useful tool for evaluating the toxicity of a compound, in terms of both relative toxicity (when different molecules are compared) and the prediction of the degree of in vivo toxicity. The use of this assay could greatly reduce the number of rats used in experimental procedures, and could also contribute to the accumulation of more toxicity data on compounds to be registered according to the criteria established by the European Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) programme. C1 [Pessina, Augusto; Bonomi, Arianna; Cavicchini, Loredana; Baglio, Carolina; Cocce, Valentina; Sisto, Francesca] Univ Milan, Dept Publ Hlth, I-20133 Milan, Italy. [Albella, Beatriz; Cerrato, Laura] CIEMAT, Unit Haematotox, E-28040 Madrid, Spain. [Parent-Massin, Dominique; Sibiril, Yann] ESMISAB UBO, Lab Food Toxicol, Plouzane, France. [Parchment, Ralph; Behrsing, Holger] NCI, Predict Toxicol Sect, Lab Human Toxicol & Pharmacol, Frederick, MD 21701 USA. [Verderio, Paolo; Pizzamiglio, Sara; Giangreco, Manuela] Fdn IRCCS Ist Nazl Tumori, Unit Med Stat & Biometry, Milan, Italy. [Gribaldo, Laura] Commiss European Communities, Joint Res Ctr, Inst Hlth Consumer Protect, I-21020 Ispra, Varese, Italy. RP Pessina, A (reprint author), Univ Milan, Dept Publ Hlth, Via Pascal 36, I-20133 Milan, Italy. EM augusto.pessina@unimi.it RI Giangreco, Manuela/R-7555-2016; Verderio, Paolo/B-5034-2017; Pizzamiglio, Sara/C-1061-2017 OI Giangreco, Manuela/0000-0002-4479-3087; Verderio, Paolo/0000-0002-9231-1281; Pizzamiglio, Sara/0000-0002-7759-0550 FU European Commission [CCR.IHCP.C432759.X0] FX Financial support for this study was provided by the European Commission (ECVAM, IHCP, Joint Research Centre), under the terms of Contract CCR.IHCP.C432759.X0, assigned to Consorzio Milano Ricerche (Italy). NR 32 TC 6 Z9 7 U1 0 U2 2 PU FRAME PI NOTTINGHAM PA RUSSELL & BURCH HOUSE 96-98 NORTH SHERWOOD ST, NOTTINGHAM NG1 4EE, NOTTS, ENGLAND SN 0261-1929 J9 ATLA-ALTERN LAB ANIM JI ATLA-Altern. Lab. Anim. PD MAY PY 2010 VL 38 IS 2 BP 105 EP 117 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 605MG UT WOS:000278351100010 PM 20507183 ER PT J AU Turbyville, JC Rao, VK AF Turbyville, Joseph C. Rao, V. Koneti TI The autoimmune lymphoproliferative syndrome: A rare disorder providing clues about normal tolerance SO AUTOIMMUNITY REVIEWS LA English DT Article DE ALPS; Autoimmune cytopenia; Double negative T cells; Endothelium; Fas ID FAS GENE-MUTATIONS; SYNDROME ALPS; T-CELLS; IMMUNOLOGICAL THROMBOCYTOPENIA; LYMPHOCYTE APOPTOSIS; IMMUNE CYTOPENIAS; MOLECULAR MIMICRY; DISEASE; LYMPHADENOPATHY; DEFECTS AB The autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic, non-malignant lymphoproliferation, autoimmunity often manifesting as multilineage cytopenias, and an increased risk of lymphoma. While considered a rare disease, there are currently over 250 patients with ALPS being followed at the National Institutes of Health in Bethesda, Maryland. Most of these patients have a mutation in the gene for the TNF receptor-family member Fas (CD 95, Apo-1), and about one-third have an unknown defect or mutations affecting function of other signaling proteins involved in the apoptotic pathway. While ALPS is one of the few autoimmune diseases with a known genetic defect, there remain unanswered questions regarding how a defect in apoptosis results in the observed phenotype. In addition to shedding light on the pathophysiology of this rare and fascinating condition, studying ALPS may improve our understanding of normal tolerance and more common, sporadic autoimmune disorders. Published by Elsevier B.V. C1 [Turbyville, Joseph C.] Walter Reed Army Med Ctr, Dept Allergy Immunol, Washington, DC 20307 USA. [Rao, V. Koneti] NIAID, ALPS Unit, LCID, NIH, Bethesda, MD 20892 USA. RP Turbyville, JC (reprint author), Walter Reed Army Med Ctr, Dept Allergy Immunol, 6900 Georgia Ave NW, Washington, DC 20307 USA. EM joseph.c.turbyville@us.army.mil FU NIH, NIAID, Bethesda, MD FX This research was supported by the Intramural Research Program of the NIH, NIAID, Bethesda, MD 20892. NR 40 TC 25 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD MAY PY 2010 VL 9 IS 7 SI SI BP 488 EP 493 DI 10.1016/j.autrev.2010.02.007 PG 6 WC Immunology SC Immunology GA 609QZ UT WOS:000278673500005 PM 20170754 ER PT J AU Elliott, CA Tanofsky-Kraff, M Shomaker, LB Columbo, KM Wolkoff, LE Ranzenhofer, LM Yanovski, JA AF Elliott, Camden A. Tanofsky-Kraff, Marian Shomaker, Lauren B. Columbo, Kelli M. Wolkoff, Laura E. Ranzenhofer, Lisa M. Yanovski, Jack A. TI An examination of the interpersonal model of loss of control eating in children and adolescents SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE Interpersonal model; Binge eating disorder; Loss of control eating; Children; Adolescents ID PUBERTAL CHANGES; WEIGHT-GAIN; DISORDER; OVERWEIGHT; BEHAVIORS; GIRLS; PSYCHOPATHOLOGY; PSYCHOTHERAPY; PERCEPTIONS; PATTERN AB The interpersonal model of binge eating disorder proposes that social problems lead to negative affect which, in turn, precipitates binge eating episodes. However, no study to date has examined this model among youth who report loss of control (LOC) eating. Participants were 219 non-treatment-seeking children and adolescent volunteers, age 8-17 years (13.1 +/- 2.8y; 50% female). Children's social problems were assessed by parent report. Youth completed self-report questionnaires of negative affect that assessed depressive symptoms and anxiety. Participants were interviewed to determine the presence or absence of LOC eating in the month prior to assessment. Structural equation modeling analyses found that social problems were positively related to LOC eating presence (p = .02). Negative affect mediated the relationship between social problems and LOC eating (95% CI Product = .00247, .01336). These preliminary results suggest that the interpersonal model of binge eating may describe one possible pathway for the development of LOC eating among non-treatment-seeking youth. Published by Elsevier Ltd. C1 [Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Elliott, Camden A.; Tanofsky-Kraff, Marian; Shomaker, Lauren B.; Columbo, Kelli M.; Wolkoff, Laura E.; Ranzenhofer, Lisa M.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD USA. RP Tanofsky-Kraff, M (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM mtanofsky@usuhs.mil OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD000641]; NIDDK NIH HHS [R01 DK080906-01A1, 1R01DK080906-01A1, R01 DK080906, R01 DK080906-01A1S1, R01 DK080906-02] NR 49 TC 26 Z9 29 U1 4 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 J9 BEHAV RES THER JI Behav. Res. Ther. PD MAY PY 2010 VL 48 IS 5 BP 424 EP 428 DI 10.1016/j.brat.2009.12.012 PG 5 WC Psychology, Clinical SC Psychology GA 602VW UT WOS:000278168000010 PM 20074702 ER PT J AU Li, SM Collins, GT Paul, NM Grundt, P Newman, AH Xu, M Grandy, DK Woods, JH Katz, JL AF Li, Su-Min Collins, Gregory T. Paul, Noel M. Grundt, Peter Newman, Amy H. Xu, Ming Grandy, David K. Woods, James H. Katz, Jonathan L. TI Yawning and locomotor behavior induced by dopamine receptor agonists in mice and rats SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE BP 897; dopamine agonist; dopamine D2/D3 receptor; knockout mouse; L-741626; PD 128907; PG01037; 7-OH-DPAT; quinpirole; U-91356A ID D3 RECEPTOR; THERAPEUTIC AGENTS; D-3 RECEPTORS; KNOCK-OUT; 7-OH-DPAT; ANTAGONISTS; QUINPIROLE; ANALOGS AB Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and low doses of several DA agonists decrease locomotor activity, an effect attributed to presynaptic D2 receptors. Effects of several DA agonists on yawning and locomotor activity were examined in rats and mice. Yawning was reliably produced in rats, and by the cholinergic agonist, physostigmine, in both the species. However, DA agonists were ineffective in producing yawning in Swiss-Webster or DA D2R and DA D3R knockout or wild-type mice. The drugs significantly decreased locomotor activity in rats at one or two low doses, with activity returning to control levels at higher doses. In mice, the drugs decreased locomotion across a 1000-10 000-fold range of doses, with activity at control levels (U-91356A) or above control levels [(+/-)-7-hydroxy-2-dipropylaminotetralin HBr, quinpirole] at the highest doses. Low doses of agonists decreased locomotion in all mice except the DA D2R knockout mice, but were not antagonized by DA D2R or D3R antagonists (L-741 626, BP 897, or PG01037). Yawning does not provide a selective in-vivo indicator of DA D3R agonist activity in mice. Decreases in mouse locomotor activity by the DA agonists seem to be mediated by D2 DA receptors. Behavioural Pharmacology 21: 171 -181 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Li, Su-Min; Katz, Jonathan L.] NIDA, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Paul, Noel M.; Grundt, Peter; Newman, Amy H.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Collins, Gregory T.; Woods, James H.] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Xu, Ming] Univ Chicago, Med Ctr, Dept Anesthesia & Crit Care, Chicago, IL 60637 USA. [Grandy, David K.] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Intramural Res Program, NIH, POB 5180, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov RI Collins, Gregory/K-3125-2012; OI Paul, Noel/0000-0002-4980-9383; Katz, Jonathan/0000-0002-1068-1159 FU National Institute on Drug Abuse; USPHS NIDA [DA 020669, DA17323, F 013771] FX The authors thank Patty Ballerstadt for administrative assistance. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, and USPHS NIDA grants DA 020669 (J.H.W., Principal Investigator), DA17323 (M. X, Principal Investigator), and F 013771 (J.H.W., Principal Investigator). Some of the data were reported at the Annual Meeting of the Society for Neuroscience, Atlanta, Georgia, USA (October, 2006). NR 29 TC 19 Z9 19 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD MAY PY 2010 VL 21 IS 3 BP 171 EP 181 DI 10.1097/FBP.0b013e32833a5c68 PG 11 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 601YZ UT WOS:000278105500002 PM 20463460 ER PT J AU Kohut, SJ Riley, AL AF Kohut, Stephen J. Riley, Anthony L. TI The effects of home-cage access to a sweet solution on the discriminative stimulus effects of cocaine SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE cocaine discriminative stimulus; drug discrimination; enrichment; Long-Evans; rat; sweet solution ID DOPAMINE TRANSPORTER; FOS EXPRESSION; RATS; ACQUISITION; ADDICTION; DECREASES; REWARD; RISK; DRUG AB This study assessed whether access to a sweet solution in the home cage could change sensitivity to cocaine, using a drug discrimination procedure. Rats were trained to discriminate 10 mg/kg cocaine from saline. After acquisition, rats were tested with a cumulative dose-response procedure (0-18 mg/kg) for 12 consecutive days. The 12 test days consisted of three 4-day cycles. The first cycle obtained a baseline of responding. During the second cycle, rats were given access to a bottle containing either a glucose/saccharin solution (G + S) or distilled water (dH(2)O) in addition to having free access to water in their home cage. During the final cycle, the G + S or dH(2)O bottle was removed. Discriminative control in the first cycle did not differ between pre-G + S and pre-dH(2)O. When the second bottle was presented, median effective dose values (ED(50)s) for cocaine in animals with access to G + S were higher than baseline, whereas the ED(50)s for cocaine in animals that received dH(2)O remained unchanged. During the final cycle when G + S was removed, ED(50) values again did not differ after dH(2)O but remained increased for the rats with previous access to the G + S solution. Our data suggest that rats were less sensitive to the cocaine cue when a sweet solution was available in the home cage. Behavioural Pharmacology 21: 241-245 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Kohut, Stephen J.; Riley, Anthony L.] American Univ, Psychopharmacol Lab, Washington, DC 20016 USA. RP Kohut, SJ (reprint author), NIDA, Psychobiol Sect, NIH, US Dept HHS, 251 Bayview Blvd,Room 06A711-03,Biomed Res Ctr, Baltimore, MD 21224 USA. EM steve.kohut@gmail.com FU Mellon Foundation FX This study was supported by a grant from the Mellon Foundation to Anthony L. Riley. There is no conflict of interest associated with this study. NR 18 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD MAY PY 2010 VL 21 IS 3 BP 241 EP 245 DI 10.1097/FBP.0b013e32833a5bdf PG 5 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 601YZ UT WOS:000278105500008 PM 20445440 ER PT J AU Cole, AA Dosemeci, A Reese, TS AF Cole, Andy A. Dosemeci, Ayse Reese, Thomas S. TI Co-segregation of AMPA receptors with G(M1) ganglioside in synaptosomal membrane subtractions SO BIOCHEMICAL JOURNAL LA English DT Article DE detergent-free; detergent-resistant; electron microscopy; lipid raft; negative stain; postsynaptic density ID PROTEIN-KINASE-II; LIPID RAFTS; POSTSYNAPTIC DENSITY; LOCALIZATION; DOMAINS AB Biochemical studies have suggested that certain synaptic proteins associate with lipid rafts to perform key functions within the synapse. However, variability in biochemical preparations raises questions as to which synaptic proteins actually associate with lipid rafts. In the present study, we use both electron microscopy and biochemistry to investigate AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor localization in synaptic membrane subfractions prepared in two different ways, by Triton X-100 detergent treatment or without detergent by sonication at high pH. Immunogold electron microscopy shows that a detergent-resistant synaptosomal membrane subfraction consists of empty vesicles 0.1-1.0 mu m in diameter. A subpopulation of these vesicles labelled for glycosphingolipid G(M1) ganglioside, a marker of lipid rafts, and 46% of the labelled vesicles also labelled for the AMPA receptor subunit GluR2. This co-segregation into specific vesicles does not depend on effects of detergent because a similar distribution of label was found in vesicles isolated without the use of detergent. Our results suggest that AMPA receptors localize within specific regions of synaptic membranes rich in G(M1) ganglioside. C1 [Cole, Andy A.; Dosemeci, Ayse; Reese, Thomas S.] NINDS, Neurobiol Lab, Struct Cell Biol Sect, NIH, Bethesda, MD 20892 USA. RP Cole, AA (reprint author), NINDS, Neurobiol Lab, Struct Cell Biol Sect, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM cole.andy.a@u.northwestern.edu OI Cole, Andy/0000-0002-3271-0774 FU National Institutes of Health, National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 20 TC 9 Z9 10 U1 0 U2 0 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 MAY 1 PY 2010 VL 427 BP 535 EP 540 DI 10.1042/BJ20091344 PN 3 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 597ZT UT WOS:000277801900019 PM 20148761 ER PT J AU Miller, SC Huang, RL Sakamuru, S Shukla, SJ Attene-Ramos, MS Shinn, P Van Leer, D Leister, W Austin, CP Xia, MH AF Miller, Susanne C. Huang, Ruili Sakamuru, Srilatha Shukla, Sunita J. Attene-Ramos, Matias S. Shinn, Paul Van Leer, Danielle Leister, William Austin, Christopher P. Xia, Menghang TI Identification of known drugs that act as inhibitors of NF-kappa B signaling and their mechanism of action SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Caspase 3/7; Cervical cancer; I kappa B alpha phosphorylation; NCGC Pharmaceutical Collection; NF-kappa B signaling ID CARDIAC-GLYCOSIDES; IN-VITRO; CELLS; ASSAYS; MELANOMA; LEUKEMIA; DISEASE; DIGOXIN; GROWTH; DNA AB Nuclear factor-kappa B (NF-kappa B) is a transcription factor that plays a critical role across many cellular processes including embryonic and neuronal development, cell proliferation, apoptosis, and immune responses to infection and inflammation. Dysregulation of NF-kappa B signaling is associated with inflammatory diseases and certain cancers. Constitutive activation of NF-kappa B signaling has been found in some types of tumors including breast, colon, prostate, skin and lymphoid, hence therapeutic blockade of NF-kappa B signaling in cancer cells provides an attractive strategy for the development of anticancer drugs. To identify small molecule inhibitors of NF-kappa B signaling, we screened approximately 2800 clinically approved drugs and bioactive compounds from the NIH Chemical Genomics Center Pharmaceutical Collection (NPC) in a NF-kappa B mediated P-lactamase reporter gene assay. Each compound was tested at fifteen different concentrations in a quantitative high throughput screening format. We identified nineteen drugs that inhibited NF-kappa B signaling, with potencies as low as 20 nM. Many of these drugs, including emetine, fluorosalan, sunitinib malate, bithionol, narasin, tribromsalan, and lestaurtinib, inhibited NF-kappa B signaling via inhibition of I kappa B alpha phosphorylation. Others, such as ectinascidin 743, chromomycin A3 and bortezomib utilized other mechanisms. Furthermore, many of these drugs induced caspase 3/7 activity and had an inhibitory effect on cervical cancer cell growth. Our results indicate that many currently approved pharmaceuticals have previously unappreciated effects on NF-kappa B signaling, which may contribute to anticancer therapeutic effects. Comprehensive profiling of approved drugs provides insight into their molecular mechanisms, thus providing a basis for drug repurposing. Published by Elsevier Inc. C1 [Miller, Susanne C.; Huang, Ruili; Sakamuru, Srilatha; Shukla, Sunita J.; Attene-Ramos, Matias S.; Shinn, Paul; Van Leer, Danielle; Leister, William; Austin, Christopher P.; Xia, Menghang] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Xia, MH (reprint author), NHGRI, NIH, Chem Genom Ctr, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM mxia@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health FX We thank Darryl Leja for illustrations. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 37 TC 82 Z9 87 U1 2 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 1 PY 2010 VL 79 IS 9 BP 1272 EP 1280 DI 10.1016/j.bcp.2009.12.021 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 570MH UT WOS:000275681900007 PM 20067776 ER PT J AU Balasubramanian, R de Azua, IR Wess, J Jacobson, KA AF Balasubramanian, Ramachandran de Azua, Inigo Ruiz Wess, Juergen Jacobson, Kenneth A. TI Activation of distinct P2Y receptor subtypes stimulates insulin secretion in MIN6 mouse pancreatic beta cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Nucleotides; G protein-coupled receptors; Phospholipase C; Radioligand binding ID PROTEIN-COUPLED RECEPTORS; ALPHA-INDUCED APOPTOSIS; NUCLEOTIDE RECEPTORS; IN-VITRO; ANTAGONISTS; AGONISTS; MODULATION; RELEASE; ANALOGS; ISLETS AB Extracellular nucleotides and their receptor antagonists have therapeutic potential in disorders such as inflammation, brain disorders, and cardiovascular diseases. Pancreatic beta cells express several purinergic receptors, and reported nucleotide effects on insulin secretion are contradictory. We studied the effect of P2Y receptors on insulin secretion and cell death in MIN6, mouse pancreatic beta cells. Expression of P2Y(1) and P2Y(6) receptors was revealed by total mRNA analysis using RT-PCR. MIN6 cells were stimulated in the presence of 16.7 mM glucose with or without P2Y(1) and P2Y(6) agonists, 2-MeSADP and UPA respectively. Both the agonists increased insulin secretion with EC(50) values of 44.6 +/- 7.0 nM and 30.7 +/- 12.7 nM respectively. The insulin secretion by P2Y(1) and P2Y(6) agonists was blocked by their selective antagonists MRS2179 and MRS2578, respectively. Binding of the selective P2Y(1) receptor antagonist radioligand [(125)I]MRS2500 in MIN6 cell membranes was saturable (K(D) 4.74 +/- 0.47 nM), and known P2Y, ligands competed with high affinities. Inflammation and glucose toxicity lead to pancreatic beta cell death in diabetes. Flow cytometric analysis revealed that Up(3)U but not 2-MeSADP protected MIN6 cells against TNF-alpha induced apoptosis. Overall, the results demonstrate that selective stimulation of P2Y(1) and P2Y(6) receptors increases insulin secretion that accompanies intracellular calcium release, suggesting potential application of P2Y receptor ligands in the treatment of diabetes. Published by Elsevier Inc. C1 [Balasubramanian, Ramachandran; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [de Azua, Inigo Ruiz; Wess, Juergen] NIDDKD, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural Research Program of NIDDK; National Institutes of Health, Bethesda, MD, USA FX This work was supported in part by the Intramural Research Program of NIDDK, National Institutes of Health, Bethesda, MD, USA. We thank Dr. Takami Oka (Wakunaga Pharmaceutical Co., Tokyo, Japan) and Dr. Masahiro Ohtani (Dept. of Pharmacology, Osaka Dental University, Osaka, Japan) and Prof.T.K. Harden(Umv. of North Carolina School of Medicine, Chapel Hill, NQ for helpful discussions. We thank Garth Brown (PerkinElmer, Boston, MA) for radiochemical synthesis. NR 49 TC 20 Z9 20 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 1 PY 2010 VL 79 IS 9 BP 1317 EP 1326 DI 10.1016/j.bcp.2009.12.026 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 570MH UT WOS:000275681900012 PM 20067775 ER PT J AU Bayfield, MA Yang, RQ Maraia, RJ AF Bayfield, Mark A. Yang, Ruiqing Maraia, Richard J. TI Conserved and divergent features of the structure and function of La and La-related proteins (LARPs) SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE La protein; La-related protein (LARP); Ribonucleoprotein (RNP); La motif; RNA recognition motif (RRM); 3 ' end binding; RNA processing ID RNA-POLYMERASE-III; SITE-MEDIATED TRANSLATION; PRECURSOR TRANSFER-RNAS; EPSTEIN-BARR-VIRUS; METHYLPHOSPHATE CAP STRUCTURE; SYSTEMIC LUPUS-ERYTHEMATOSUS; METHIONYL-TRANSFER-RNA; SS-B AUTOANTIGEN; 5S RIBOSOMAL-RNA; MESSENGER-RNA AB Genuine La proteins contain two RNA binding motifs, a La motif (LAM) followed by a RNA recognition motif (RRM), arranged in a unique way to bind RNA. These proteins interact with an extensive variety of cellular RNAs and exhibit activities in two broad categories: i) to promote the metabolism of nascent pol III transcripts, including precursor-tRNAs, by binding to their common, UUU-3'OH containing ends, and ii) to modulate the translation of certain mRNAs involving an unknown binding mechanism. Characterization of several La-RNA crystal structures as well as biochemical studies reveal insight into their unique two-motif domain architecture and how the LAM recognizes UUU-3'OH while the RRM binds other parts of a pre-tRNA. Recent studies of members of distinct families of conserved La-related proteins (LARPs) indicate that some of these harbor activity related to genuine La proteins, suggesting that their UUU-3'OH binding mode has been appropriated for the assembly and regulation of a specific snRNP (e.g., 7SK snRNP assembly by hLARP7/PIP7S). Analyses of other LARP family members suggest more diverged RNA binding modes and specialization for cytoplasmic mRNA-related functions. Thus it appears that while genuine La proteins exhibit broad general involvement in both snRNA-related and mRNA-related functions, different LARP families may have evolved specialized activities in either snRNA or mRNA-related functions. In this review, we summarize recent progress that has led to greater understanding of the structure and function of La proteins and their roles in tRNA processing and RNP assembly dynamics, as well as progress on the different LARPs. (C) 2010 Elsevier B.V. All rights reserved. C1 [Bayfield, Mark A.] York Univ, Dept Biol, Toronto, ON M3J 1P3, Canada. [Yang, Ruiqing; Maraia, Richard J.] NICHD, Intramural Res Program, NIH, Bethesda, MD USA. RP Bayfield, MA (reprint author), York Univ, Dept Biol, 4700 Keele St,Lumbers Bldg Room 219, Toronto, ON M3J 1P3, Canada. EM bayfield@yorku.ca FU National Science and Engineering Council of Canada; NICHD, NIH FX We are grateful to Sasi Conte, Stephen Curry, Cecile Bousquet-Antonelli and Ying Huang for critical comments and discussion, and to Qiang Zhou and Cecile Bousquet-Antonelli for sharing data prior to publication. This work was supported by the National Science and Engineering Council of Canada (M.B.) and the Intramural Research Program of the NICHD, NIH (R.M and R.Y.) NR 160 TC 68 Z9 71 U1 3 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD MAY-JUN PY 2010 VL 1799 IS 5-6 BP 365 EP 378 DI 10.1016/j.bbagrm.2010.01.011 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 605BD UT WOS:000278321400002 PM 20138158 ER PT J AU Kireeva, M Kashlev, M Burton, ZF AF Kireeva, Maria Kashlev, Mikhail Burton, Zachary F. TI Translocation by multi-subunit RNA polymerases SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE RNA polymerase; Elongation; Translocation; Pyrophosphate release; Allostery; NTP-driven translocation ID STATE KINETIC-ANALYSIS; II ELONGATION COMPLEX; HIV-1 REVERSE-TRANSCRIPTASE; NTP-DRIVEN TRANSLOCATION; 3.3 ANGSTROM RESOLUTION; DNA-BINDING PROTEIN; STRUCTURAL BASIS; ESCHERICHIA-COLI; NUCLEOSIDE TRIPHOSPHATES; SINGLE-MOLECULE AB DNA template and RNA/DNA hybrid movement through RNA polymerase (RNAP) is referred to as "translocation". Because nucleic acid movement is coupled to NTP loading, pyrophosphate release, and conformational changes, the precise ordering of events during bond addition is consequential. Moreover, based on several lines of experimental evidence, translocation, pyrophosphate release or an associated conformational change may determine the transcription elongation rate. In this review we discuss various models of translocation, the data supporting the hypothesis that translocation rate determines transcription elongation rate and also data that may be inconsistent with this point of view. A model of the nucleotide addition cycle accommodating available experimental data is proposed. On the basis of this model, the molecular mechanisms regulating translocation and potential routes for NIP entry are discussed. (C) 2010 Elsevier B.V. All rights reserved. C1 [Burton, Zachary F.] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. [Kireeva, Maria; Kashlev, Mikhail] Natl Canc Inst Frederick, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Burton, ZF (reprint author), Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. EM burton@cns.msu.edu FU Michigan State University; College of Osteopathic Medicine FX We thank Adam Parks for helpful discussions, and the anonymous reviewers for their insightful comments. The contents of this publication do not necessarily reveal the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial product, or organizations imply endorsement by the U.S. Government. ZFB has support from Michigan State University, The College of Osteopathic Medicine, Michigan State University, and the Initiative in Gene Expression in Development and Disease, Michigan State University. NR 100 TC 25 Z9 25 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD MAY-JUN PY 2010 VL 1799 IS 5-6 BP 389 EP 401 DI 10.1016/j.bbagrm.2010.01.007 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 605BD UT WOS:000278321400004 PM 20097318 ER PT J AU Sato, H Tsai-Morris, CH Dufau, ML AF Sato, Hisashi Tsai-Morris, Chon-Hwa Dufau, Maria L. TI Relevance of gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) in the structural integrity of the chromatoid body during spermatogenesis SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE GRTH/DDX25; DEAD-box RNA helicase; Chromatoid body; Round spermatid; GRTH-mRNP; Nuclear export; Spermatogenesis ID MALE GERM-CELLS; PROCESSING BODIES; MESSENGER-RNAS; GENE; EXPRESSION; PROTEIN; HOMOLOG; PIWI; MIWI; SPERMIOGENESIS AB Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), a multifunctional protein and a component of ribonucleoprotein complexes, is essential for the completion of spermatogenesis. We investigated the nuclear/cytoplasmic shuttling of GRTH in germ cells and its impact on the chromatoid body (CB)-a perinuclear organelle viewed as a storage/processing site of mRNAs. GRTH resides in the nucleus, cytoplasm and CB of round spermatids. Treatment of these cells with inhibitors of nuclear export or RNA synthesis caused nuclear retention of GRTH and its absence in the cytoplasm and CB. The nuclear levels of GRTH bound RNA messages were significantly enhanced and major reduction was,observed in the cytoplasm. This indicated GRTH main transport function of mRNAs to the cytoplasm and CB. MVH, a germ cell helicase, and MIWI, a component of the RNA-induced-silencing complex (RISC), confined to the CB/cytoplasm, were absent in the CB and accumulated in the cytoplasm upon treatment. This also occurred in spermatids of GRTH-KO mice. The CB changed from lobular-filamentous to a small condensed structure after treatment resembling the CB of GRTH-KO. No interaction of GRTH with MVH or RISC members in both protein and RNA were observed. Besides of participating in the transport of messages of relevant spermatogenic genes, GRTH was found to transport its own message to cytoplasmic sites. Our studies suggest that GRTH through its export/transport function as a component of mRNP is essential to govern the CB structure in spermatids and to maintain systems that may participate in mRNA storage and their processing during spermatogenesis. (C) 2010 Elsevier B.V. All rights reserved. C1 [Sato, Hisashi; Tsai-Morris, Chon-Hwa; Dufau, Maria L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Endocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Endocrinol, Program Dev Endocrinol & Genet, NIH, Bldg 49,Rm 6A-36, Bethesda, MD 20892 USA. EM dufaum@mail.nih.gov FU NICHD, National Institutes of Health FX This work was supported by the Intramural Research Program of the NICHD, National Institutes of Health. NR 25 TC 15 Z9 15 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD MAY PY 2010 VL 1803 IS 5 BP 534 EP 543 DI 10.1016/j.bbamcr.2010.02.004 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 597GC UT WOS:000277743600002 PM 20176059 ER PT J AU Gotte, M Rausch, JW Marchand, B Sarafianos, S Le Grice, SFJ AF Goette, Matthias Rausch, Jason W. Marchand, Bruno Sarafianos, Stefan Le Grice, Stuart F. J. TI Reverse transcriptase in motion: Conformational dynamics of enzyme-substrate interactions SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Review DE Retrovirus; Reverse transcriptase; Ribonuclease H; Translocational equilibrium; Single molecule spectroscopy ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; STRAND DNA-SYNTHESIS; SEQUENCE FEATURES IMPORTANT; POLYPURINE TRACT SELECTION; RNASE-H ACTIVITIES; ANGSTROM RESOLUTION; POLYMERASE TRANSLOCATION; CRYSTAL-STRUCTURE; RNA/DNA HYBRIDS AB Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RI) catalyzes synthesis of integration-competent, double-stranded DNA from the single-stranded viral RNA genome, combining both polymerizing and hydrolytic functions to synthesize approximately 20,000 phosphodiester bonds. Despite a wealth of biochemical studies, the manner whereby the enzyme adopts different orientations to coordinate its DNA polymerase and ribonuclease (RNase) H activities has remained elusive. Likewise, the lower processivity of HIV-1 RT raises the issue of polymerization site targeting, should the enzyme re-engage its nucleic acid substrate several hundred nucleotides from the primer terminus. Although X-ray crystallography has clearly contributed to our understanding of RT-containing nucleoprotein complexes, it provides a static picture, revealing few details regarding motion of the enzyme on the substrate. Recent development of site-specific footprinting and the application of single molecule spectroscopy have allowed us to follow individual steps in the reverse transcription process with significantly greater precision. Progress in these areas and the implications for investigational and established inhibitors that interfere with RI motion on nucleic acid is reviewed here. Published by Elsevier B.V. C1 [Rausch, Jason W.; Le Grice, Stuart F. J.] NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Goette, Matthias] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada. [Marchand, Bruno; Sarafianos, Stefan] Univ Missouri, Sch Med, Christopher Bond Life Sci Ctr, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. RP Le Grice, SFJ (reprint author), NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM legrices@mail.nih.gov OI Sarafianos, Stefan G/0000-0002-5840-154X FU National Cancer Institute, National Institutes of Health; Canadian Institutes of Health Research (CIHR); NIH [AI076119, AI079801, AI074389]; AmfAR Mathilde Krim Fellowship FX S.L.G. is supported by the Intramural Research Program (IRP) of the National Cancer Institute, National Institutes of Health. M.G. is recipient of a National Career Award from, and supported by, the Canadian Institutes of Health Research (CIHR). S.G.S. acknowledges support by NIH (grants AI076119, AI079801, and AI074389). B.M. is supported by an AmfAR Mathilde Krim Fellowship. NR 98 TC 18 Z9 18 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD MAY PY 2010 VL 1804 IS 5 SI SI BP 1202 EP 1212 DI 10.1016/j.bbapap.2009.07.020 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 584YB UT WOS:000276789300015 PM 19665597 ER PT J AU Ogawa, M Regino, CAS Marcelino, B Williams, M Kosaka, N Bryant, LH Choyke, PL Kobayashi, H AF Ogawa, Mikako Regino, Celeste A. S. Marcelino, Bernardo Williams, Mark Kosaka, Nobuyuki Bryant, L. Henry, Jr. Choyke, Peter L. Kobayashi, Hisataka TI New Nanosized Biocompatible MR Contrast Agents Based on Lysine-Dendri-Graft Macromolecules SO BIOCONJUGATE CHEMISTRY LA English DT Article ID RENAL UPTAKE; POLYAMIDOAMINE AB Paramagnetic nanomaterials for use as magnetic resonance imaging (MRI) contrast agents have higher relaxivity than conventional low molecular weight MRI agents. However, the biocompatibility and pharmacokinetics of such nanomaterials will strongly affect the likelihood of clinical approval. We synthesized MRI contrast agents based on biocompatible lysine-dendri-grafts: Gd-BzDTPA-lysineG2 and Gd-BzDTPA-lysineG3. The relaxivity of Gd-BzDTPA-lysineG2 and Gd-BzDTPA-lysineG3 increased with sample temperature, while the relaxivity of Gd-BzDTPA-PAMAMG4 decreased with increasing sample temperature. The increase in relaxivity with increasing temperature may be attributed to accessibility of water to the internal Gd chelates with lysine-dendri-grafts, which does not occur with PAMAM dendrimers. Gd-BzDTPA-lysineG3 had a long intravascular half-life but were largely excreted by the kidneys. Therefore, Gd-BzDTPA-lysineG3 enhanced the blood vessels for longer periods than Gd-BzDTPA-PAMAMG4, but was still excreted through the kidney. Because of their biocompatibility, desirable magneto-physical characteristics and favorable pharmacokinetics, which are derived from different interior structures rather than the physical size, lysine-dendri-graft MRI contrast agents may be feasible for clinical use. C1 [Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Res Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. NIH, Lab Diagnost Radiol Res Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room 1B40,MSC 1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 15 TC 27 Z9 27 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD MAY PY 2010 VL 21 IS 5 BP 955 EP 960 DI 10.1021/bc9005442 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 596KI UT WOS:000277683300021 PM 20235572 ER PT J AU Trembley, JH Chen, Z Unger, G Slaton, J Kren, BT Van Waes, C Ahmed, K AF Trembley, Janeen H. Chen, Zhong Unger, Gretchen Slaton, Joel Kren, Betsy T. Van Waes, Carter Ahmed, Khalil TI Emergence of protein kinase CK2 as a key target in cancer therapy SO BIOFACTORS LA English DT Article DE protein kinase CK2; casein kinase 2; signaling; cancer; NF-kappa B; nanocapsule; nanoparticle; tenfibgen; tenascin; antisense; siRNA ID FACTOR-KAPPA-B; SQUAMOUS-CELL CARCINOMA; HUMAN PROSTATE-CANCER; INDUCED APOPTOSIS; NUCLEAR-MATRIX; PHARMACOLOGICAL INHIBITION; ANDROGENIC REGULATION; MEDIATED DEGRADATION; CATALYTIC SUBUNITS; DOWN-REGULATION AB Protein kinase CK2, a protein serine/threonine kinase, plays a global role in activities related to cell growth, cell death, and cell survival. CK2 has a large number of potential substrates localized in diverse locations in the cell including, for example, NF-kappa B as an important downstream target of the kinase. In addition to its involvement in cell growth and proliferation it is also a potent suppressor of apoptosis, raising its key importance in cancer cell phenotype. CK2 interacts with diverse pathways which illustrates the breadth of its impact on the cellular machinery of both cell growth and cell death giving it the status of a "master regulator" in the cell. With respect to cancer, CK2 has been found to be dysregulated in all cancers examined demonstrating increased protein expression levels and nuclear localization in cancer cells compared with their normal counterparts. We originally proposed CK2 as a potentially important target for cancer therapy. Given the ubiquitous and essential for cell survival nature of the kinase, an important consideration would be to target it specifically in cancer cells while sparing normal cells. Towards that end, our design of a tenascin based sub-50 nm (i.e., less than 50 nm size) nanocapsule in which an anti-CK2 therapeutic agent can be packaged is highly promising because this formulation can specifically deliver the cargo intracellularly to the cancer cells in vivo. Thus, appropriate strategies to target CK2 especially by molecular approaches may lead to a highly feasible and effective approach to eradication of a given cancer. (C) 2010 International Union of Biochemistry and Molecular Biology, Inc. Volume 36, Number 3, May/June 2010, Pages 187-195 . E-mail: ahmedk@umn.edu C1 [Trembley, Janeen H.; Slaton, Joel; Kren, Betsy T.; Ahmed, Khalil] Univ Minnesota, Minneapolis VA Med Ctr, Cellular & Mol Biochem Res Lab, Res Serv, Minneapolis, MN 55417 USA. [Ahmed, Khalil] Univ Minnesota, VA Med Ctr, Res Serv 151, Dept Lab Med & Pathol, Minneapolis, MN 55417 USA. [Chen, Zhong; Van Waes, Carter] Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Bethesda, MD USA. [Unger, Gretchen] GeneSegues Inc, Chaska, MN USA. [Slaton, Joel; Ahmed, Khalil] Univ Minnesota, Dept Urol, Minneapolis, MN 55417 USA. [Slaton, Joel; Ahmed, Khalil] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55417 USA. [Kren, Betsy T.] Univ Minnesota, Dept Med, Minneapolis, MN 55417 USA. [Ahmed, Khalil] Univ Minnesota, Dept Otolaryngol, Minneapolis, MN 55417 USA. RP Ahmed, K (reprint author), Univ Minnesota, VA Med Ctr, Res Serv 151, Dept Lab Med & Pathol, 1 Vet Dr, Minneapolis, MN 55417 USA. EM ahmedk@umn.edu FU Department of Veterans Affairs Research Funds; National Cancer Institute (NIH) [U01-CA151362, R01-DK067436]; DOD [W81XWH-05-C-0084, ZIA-DC-00016] FX This work was supported by Department of Veterans Affairs Research Funds and National Cancer Institute (NIH) grant U01-CA151362 (K.A.), NIH grant R01-DK067436 (B.T.K), DOD Contract W81XWH-05-C-0084 (G.U.), and ZIA-DC-00016 (C.V.W., Z.C.). NR 98 TC 81 Z9 85 U1 0 U2 8 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0951-6433 J9 BIOFACTORS JI Biofactors PD MAY-JUN PY 2010 VL 36 IS 3 BP 187 EP 195 DI 10.1002/biof.96 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 613FP UT WOS:000278964700004 PM 20533398 ER PT J AU Lipska, BK AF Lipska, Barbara K. TI Genetic Regulation of Human Cortical Gene Expression Across the Lifespan SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Lipska, Barbara K.] NIMH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 16 BP 5S EP 5S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200017 ER PT J AU Siever, LJ Hodgkinson, CA Weinstein, S Shen, PH New, AS Goldman, D AF Siever, Larry J. Hodgkinson, Colin A. Weinstein, Shauna Shen, Pei-Hong New, Antonia S. Goldman, David TI Opioids and Oxytocin: Genotypes and Phenotypes in BPD SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Siever, Larry J.; Weinstein, Shauna; New, Antonia S.] Mt Sinai Sch Med, New York, NY USA. [Hodgkinson, Colin A.; Shen, Pei-Hong; Goldman, David] NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 19 BP 6S EP 6S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200020 ER PT J AU Chen, G AF Chen, Guang TI Roles of Bcl-2 Family Proteins and Mood Stabilizer-Induced Changes in Hippocampal Synapses in the Behavioral Regulation Related to Mood Disorders SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Chen, Guang] NIMH, Natl Inst Hlth, Bethesda, MD USA. RI Chen, Guang/A-2570-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 28 BP 9S EP 9S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200029 ER PT J AU Suomi, SJ AF Suomi, Stephen J. TI GxE Interactions Influence Attachment in Non-Human Primates SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Suomi, Stephen J.] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 29 BP 9S EP 9S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200030 ER PT J AU Bertolino, A Taurisano, P Pisciotta, NM Blasi, G Fazio, L Romano, R Gelao, B Lobianco, L Lozupone, M Di Giorgio, A Caforio, G Sambataro, F Niccoli-Asabella, A Papp, A Ursini, G Sinibaldi, L Popolizio, T Sadee, W Rubini, G AF Bertolino, Alessandro Taurisano, Paolo Pisciotta, Nicola M. Blasi, Giuseppe Fazio, Leonardo Romano, Raffaella Gelao, Barbara Lobianco, Luciana Lozupone, Madia Di Giorgio, Annabella Caforio, Grazia Sambataro, Fabio Niccoli-Asabella, Artor Papp, Audrey Ursini, Gianluca Sinibaldi, Lorenzo Popolizio, Teresa Sadee, Wolfgang Rubini, Giuseppe TI Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity During Working Memory SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Bertolino, Alessandro; Taurisano, Paolo; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Lobianco, Luciana; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Ursini, Gianluca] Univ Bari, Dept Neurol & Psychiat, Bari, Italy. [Pisciotta, Nicola M.; Niccoli-Asabella, Artor; Rubini, Giuseppe] Univ Bari, Dept Internal Med & Publ Med, Bari, Italy. [Sambataro, Fabio] NIMH, NIH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Papp, Audrey; Sadee, Wolfgang] Ohio State Univ, Dept Pharmacol, Columbus, OH 43210 USA. [Sinibaldi, Lorenzo] IRCCS Casa Sollievo Sofferenza, Mendel Inst, Rome, Italy. [Popolizio, Teresa] IRCCS Casa Sollievo Sofferenza, Dept Radiol, San Giovanni Rotondo, Italy. RI Fazio, Leonardo/J-4570-2012; Sambataro, Fabio/E-3426-2010 OI Fazio, Leonardo/0000-0003-4000-974X; Sambataro, Fabio/0000-0003-2102-416X NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 37 BP 12S EP 12S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200038 ER PT J AU Raznahan, A Lee, Y Greenstein, D Addington, A Long, R Clasen, L Giedd, J Rapoport, J Gogtay, N AF Raznahan, Armin Lee, Yohan Greenstein, Dede Addington, Ajene Long, Robert Clasen, Liv Giedd, Jay Rapoport, Judith Gogtay, Nitin TI A Longitudinal Imaging-Genetics Study of Catechol-O-Methyltransferase Val158Met Genotype and Cortical Maturation in Youth with Childhood-Onset Psychosis, Their Non-Psychotic Siblings and Typically Developing Controls SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Raznahan, Armin; Lee, Yohan; Greenstein, Dede; Addington, Ajene; Long, Robert; Clasen, Liv; Giedd, Jay; Rapoport, Judith; Gogtay, Nitin] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RI Giedd, Jay/A-3080-2008; Gogtay, Nitin/A-3035-2008; Raznahan, Armin/F-4534-2012; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 40 BP 13S EP 13S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200041 ER PT J AU Enoch, MA Hodgkinson, CA Gorodetsky, E Yuan, QP Goldman, D Roy, A AF Enoch, Mary-Anne Hodgkinson, Colin A. Gorodetsky, Elena Yuan, Qiaoping Goldman, David Roy, Alec TI Childhood Trauma and Variation in GABAergic and Serotonergic Genes Predict Alcohol, Heroin and Cocaine Dependence SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Enoch, Mary-Anne; Hodgkinson, Colin A.; Yuan, Qiaoping; Goldman, David] NIAAA, NIH, LNG, Bethesda, MD USA. [Roy, Alec] NJ VA Healthcare Syst, DVA, E Orange, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 50 BP 16S EP 16S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200050 ER PT J AU Srivastava, V Hong, LE Buzas, B Momenan, R Hodgkinson, CA Enoch, MA Hommer, DW Stein, EA Goldman, D AF Srivastava, Vibhuti Hong, L. Elliot Buzas, Beata Momenan, Reza Hodgkinson, Colin A. Enoch, Mary-Anne Hommer, Daniel W. Stein, Elliot A. Goldman, David TI Association of Common Genetic Variants with Structural and Functional Brain Alterations in Alcohol and Nicotine Dependent Individuals SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Srivastava, Vibhuti; Buzas, Beata; Momenan, Reza; Hodgkinson, Colin A.; Enoch, Mary-Anne; Hommer, Daniel W.; Goldman, David] NIAAA, NIH, Rockville, MD 20852 USA. [Hong, L. Elliot] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA. [Stein, Elliot A.] NIDA, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 51 BP 16S EP 16S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200051 ER PT J AU Guang, C AF Guang Chen TI Roles of Selected miRNAs in Stress Coping and Behavioral Regulation Related to Mania SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Guang Chen] NIMH, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 69 BP 22S EP 22S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200069 ER PT J AU Hardy, N Jimenez, D Martinowich, K Schloesser, RJ AF Hardy, Nicholas Jimenez, Dennisse Martinowich, Keri Schloesser, Robert J. TI Neurogenesis Dependent Modulations of Neuroplasticity in Cornu Ammonis Regions of the Adult Hippocampus SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Hardy, Nicholas; Jimenez, Dennisse; Martinowich, Keri; Schloesser, Robert J.] NIMH, LMP, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 82 BP 25S EP 26S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200082 ER PT J AU Martinowich, K Cardinale, K Schloesser, RJ Greig, NH Manji, HK AF Martinowich, Keri Cardinale, Kathleen Schloesser, Robert J. Greig, Nigel H. Manji, Husseini K. TI Acetylcholinesterase Inhibition Ameliorates Deficits in Motivational Drive and Apathetic Behavior SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Martinowich, Keri; Cardinale, Kathleen; Schloesser, Robert J.; Manji, Husseini K.] NIMH, LMP, MAP, Bethesda, MD 20892 USA. [Greig, Nigel H.] NIA, Neurosci Lab, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 91 BP 28S EP 29S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200091 ER PT J AU Arkin, NE Overstreet, CM Grillon, C Cornwell, BR AF Arkin, Nicole E. Overstreet, Cassie M. Grillon, Christian Cornwell, Brian R. TI Brain Correlates of Escape from Shock in Virtual Reality SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Arkin, Nicole E.; Overstreet, Cassie M.; Grillon, Christian; Cornwell, Brian R.] NIMH, MAP UAP, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 107 BP 34S EP 34S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200107 ER PT J AU Graybeal, C Feyder, M Saksida, L Bussey, T Holmes, A AF Graybeal, Carolyn Feyder, Michael Saksida, Lisa Bussey, Timothy Holmes, Andrew TI Stress Facilitates the Acquisition of Well-Learned Operant Behavior in a Mouse Reversal Task SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Graybeal, Carolyn; Feyder, Michael; Holmes, Andrew] NIAAA, NIH, Rockville, MD 20852 USA. [Saksida, Lisa; Bussey, Timothy] Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 111 BP 35S EP 35S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200111 ER PT J AU Letkiewicz, A Lissek, S Bradford, D Charney, D Barrios, M Grillon, C AF Letkiewicz, Allison Lissek, Shmuel Bradford, Daniel Charney, Danielle Barrios, Monique Grillon, Christian TI The Temporal Course of Conditioned Fear-Generalization in Healthy Subjects SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Letkiewicz, Allison; Lissek, Shmuel; Bradford, Daniel; Charney, Danielle; Barrios, Monique; Grillon, Christian] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 113 BP 35S EP 36S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200113 ER PT J AU Overstreet, C Arkin, N Grillon, C Cornwell, BR AF Overstreet, Cassie Arkin, Nicole Grillon, Christian Cornwell, Brian R. TI Anxiety Modulates Hippocampal Activity during Virtual Navigation SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Overstreet, Cassie; Arkin, Nicole; Grillon, Christian; Cornwell, Brian R.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 114 BP 36S EP 36S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200114 ER PT J AU Mueller, SC Maheu, FS Dozier, M Peloso, E Pine, DS Ernst, M AF Mueller, Sven C. Maheu, Francoise S. Dozier, Mary Peloso, Elizabeth Pine, Daniel S. Ernst, Monique TI Early Life Stress Due to Maltreatment in Childhood Modulates Reward Processing During an Inhibitory Control Task: An Antisaccade Study SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Mueller, Sven C.; Pine, Daniel S.; Ernst, Monique] NIMH, NIH, Bethesda, MD 20892 USA. [Maheu, Francoise S.] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada. [Dozier, Mary; Peloso, Elizabeth] Univ Delaware, Dept Psychol, Newark, DE USA. NR 0 TC 0 Z9 0 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 123 BP 38S EP 39S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200123 ER PT J AU Gilliam, MC Stockman, M Lalonde, F Rapoport, J Shaw, P AF Gilliam, Mary C. Stockman, Michael Lalonde, Francois Rapoport, Judith Shaw, Philip TI An Initial Delineation of Growth Rates of the Corpus Callosum in Attention-Deficit/Hyperactivity Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Gilliam, Mary C.; Stockman, Michael; Lalonde, Francois; Rapoport, Judith; Shaw, Philip] NIH, Child Psychiat Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 129 BP 40S EP 40S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200129 ER PT J AU Mueller, SC Merke, DP Leschek, EW Fromm, S VanRyzin, C Ernst, M AF Mueller, Sven C. Merke, Deborah P. Leschek, Ellen W. Fromm, Stephen VanRyzin, Carol Ernst, Monique TI Grey Matter Volume Correlates with Performance in a Virtual Water Maze Task: A Study Boys with Androgen Excess SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Mueller, Sven C.; Fromm, Stephen; Ernst, Monique] NIMH, NIH, Bethesda, MD 20892 USA. [Merke, Deborah P.; VanRyzin, Carol] NICHD, NIH, Ctr Clin, Bethesda, MD USA. [Leschek, Ellen W.] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 139 BP 43S EP 43S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200139 ER PT J AU Bevilacqua, L Yuan, QP Tikkanen, R Zhou, ZF Hodgkinson, CA Paunio, T Coccaro, E Virkkunen, M Goldman, D AF Bevilacqua, Laura Yuan, Qiaoping Tikkanen, Roope Zhou, Zhifeng Hodgkinson, Colin A. Paunio, Tiina Coccaro, Emil Virkkunen, Matti Goldman, David TI A Common, Population-Specific Stop Codon in HTR2B Co-Segregates with Severe Impulsivity SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Bevilacqua, Laura; Yuan, Qiaoping; Zhou, Zhifeng; Hodgkinson, Colin A.; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Tikkanen, Roope; Virkkunen, Matti] Univ Helsinki, Sch Med, Dept Psychiat, Helsinki, Finland. [Paunio, Tiina] Natl Publ Hlth Inst, Dept Mol Med & Mental Hlth, Helsinki, Finland. [Coccaro, Emil] Univ Chicago, Pritzker Sch Med, Dept Psychiat, Chicago, IL 60637 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 151 BP 47S EP 47S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200151 ER PT J AU Hunsberger, J Machado-Vieira, R Austin, D Zarate, C Chuang, DM Reed, J Chen, G Manji, H AF Hunsberger, Joshua Machado-Vieira, Rodrigo Austin, Daniel Zarate, Carlos Chuang, De-Maw Reed, John Chen, Guang Manji, Husseini TI Possible Involvement of Bax Inhibitor 1 (BI-1), A Modulator for Endoplasmic Reticulum (ER) Cellular Stress, in Affective Resilience SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Hunsberger, Joshua; Machado-Vieira, Rodrigo; Austin, Daniel; Zarate, Carlos; Chuang, De-Maw; Chen, Guang; Manji, Husseini] NIMH, NIH, Bethesda, MD 20892 USA. [Reed, John] Burnham Inst Med Res, Program Apoptosis & Cell Death Res, La Jolla, CA USA. RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; Chen, Guang/A-2570-2017 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 159 BP 49S EP 50S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200159 ER PT J AU Kiselycznyk, CL Holmes, A AF Kiselycznyk, Carly L. Holmes, Andrew TI Role of the NMDA Receptor NR2B Subunit in Mediating Anxiety- and Depression-Like Behaviors SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Kiselycznyk, Carly L.; Holmes, Andrew] NIAAA, Sect Behav Sci & Genet, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 161 BP 50S EP 50S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200161 ER PT J AU Guitart, X Yuan, PX Tragon, T Manji, H Chen, G AF Guitart, Xavier Yuan, Peixiong Tragon, Tyson Manji, Husseini Chen, Guang TI Levels of Several ERK Pathway Proteins and PDE4 are Altered in Postmortem Frontal Cortex of Individuals with Mood Disorders SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Guitart, Xavier; Yuan, Peixiong; Tragon, Tyson; Chen, Guang] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Manji, Husseini] Johnson & Johnson, New Brunswick, NJ USA. RI Chen, Guang/A-2570-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 172 BP 53S EP 53S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200172 ER PT J AU Wheeler-Castillo, C Khairova, R Wang, Y Yang, F Yuan, PX Wei, YL Machado-Vieira, R Zarate, C Manji, H Du, J AF Wheeler-Castillo, Cristina Khairova, Rushaniya Wang, Yun Yang, Feng Yuan, Peixiong Wei, Yanling Machado-Vieira, Rodrigo Zarate, Carlos Manji, Husseini Du, J. TI Tumor Necrosis Factor-alpha Enhanced AMPA-Containing Synaptogenesis In The Central Nervous System SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Wheeler-Castillo, Cristina; Zarate, Carlos] NIMH, Mol Pathophysiol Lab, Sect Expt Therapeut, NIH, Bethesda, MD 20892 USA. [Yang, Feng] NIMH, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. [Yuan, Peixiong] NIMH, Biomarker Lab, NIH, Bethesda, MD 20892 USA. [Manji, Husseini] Johnson & Johnson LLC, Pharmaceut & Res Dev, Raritan, NJ USA. RI Yang, Feng/C-9530-2011; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 183 BP 57S EP 57S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200183 ER PT J AU Schaefer, KL Luckenbaugh, DA Baumann, JC Zarate, CA AF Schaefer, Kathryn L. Luckenbaugh, David A. Baumann, Jacqueline C. Zarate, Carlos A. TI Face Emotion in Adult Bipolar and Unipolar Depression and Controls SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Schaefer, Kathryn L.; Luckenbaugh, David A.; Baumann, Jacqueline C.; Zarate, Carlos A.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 193 BP 60S EP 60S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200193 ER PT J AU Cole, VT Weinberger, DR Dickinson, D AF Cole, Veronica T. Weinberger, Daniel R. Dickinson, Dwight TI Intra-Individual Variability Across Neuropsychological Tasks in Schizophrenia: Its Relationship to Disease Status and Functioning SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Cole, Veronica T.; Weinberger, Daniel R.; Dickinson, Dwight] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Dickinson, Dwight] Univ Maryland, Dept Psychiat, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 261 BP 81S EP 82S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200260 ER PT J AU Cadet, JL Krasnova, I Ladenheim, B Hodges, A AF Cadet, Jean Lud Krasnova, Irina Ladenheim, Bruce Hodges, Amber TI Chronic Methamphetamine Administration Causes Differential Regulation of Dopaminergic Transcription Factors in the Rat Ventral Midbrain SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Cadet, Jean Lud; Krasnova, Irina; Ladenheim, Bruce; Hodges, Amber] Natl Inst Drug Abuse, Mol Neuropsychiat Res Branch, NIH, DHHS, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 282 BP 88S EP 88S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200281 ER PT J AU Schuebel, KE AF Schuebel, Kornel E. TI Epigenetics of Fetal Alcohol Syndrome SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Schuebel, Kornel E.] NIH, NIAAA, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 283 BP 88S EP 88S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200282 ER PT J AU Szabo, ST Patkar, A Magnum, B Beyer, WF McClernon, J Burnett, BK Gorelick, DH Lee, TH AF Szabo, Steven T. Patkar, Ashwin Magnum, Barry Beyer, Wayne F. McClernon, Joseph Burnett, Bruce K. Gorelick, David H. Lee, Tong H. TI Translational Development of Novel Pharmacotherapeutic Strategies for Psychostimulant Dependence SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Magnum, Barry] Duke Univ, Duke Clin Res Unit, Durham, NC USA. [Beyer, Wayne F.] Duke Univ, Translat Res Inst, Durham, NC USA. [Burnett, Bruce K.] Duke Univ, Duke Translat Med Inst, Durham, NC USA. [Gorelick, David H.] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 284 BP 88S EP 88S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200283 ER PT J AU Enoch, MA Gorodetsky, E Hodgkinson, C Goldman, D Roy, A AF Enoch, Mary-Anne Gorodetsky, Elena Hodgkinson, Colin Goldman, David Roy, Alec TI Functional Genetic Variants that Increase Synaptic Serotonin and 5-HT3 Receptor Sensitivity Additively Predict Alcohol and Drug Dependence SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Enoch, Mary-Anne; Gorodetsky, Elena; Hodgkinson, Colin; Goldman, David] NIAAA, NIH, LNG, Bethesda, MD USA. [Roy, Alec] NJ VA Healthcare Syst, DVA, Psychiat Serv, E Orange, NJ USA. RI Hodgkinson, Colin/F-9899-2010 NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 292 BP 91S EP 91S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200291 ER PT J AU Goldman, D AF Goldman, David TI The Genomics of Addiction SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Goldman, David] NIH, NIAAA, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 324 BP 93S EP 93S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200296 ER PT J AU Volkow, ND AF Volkow, Nora D. TI Addiction: Conflict Between Brain Circuits SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 327 BP 93S EP 94S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200299 ER PT J AU Cadet, JL AF Cadet, Jean Lud TI Molecular and Neurobiological Mechanisms of Methamphetamine Abuse SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Cadet, Jean Lud] Natl Inst Drug Abuse, NIH, Mol Neuropsychiat Branch, DHHS, Baltimore, MD USA. [Cadet, Jean Lud] NIDA, NIH, Molecular Neuropsychiat Branch, Intramural Res Program, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 328 BP 94S EP 94S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200300 ER PT J AU Fowler, JS Wang, GJ Volkow, ND AF Fowler, Joanna S. Wang, Gene-Jack Volkow, Nora D. TI PET Imaging of Methamphetamine Distribution and Kinetics in Humans SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Fowler, Joanna S.; Wang, Gene-Jack] Brookhaven Natl Lab, Upton, NY 11973 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 329 BP 94S EP 94S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200301 ER PT J AU Krasnova, IN AF Krasnova, Irina N. TI Methamphetamine Self-Administration in Rats as a Model for Persistent Neuroadaptations in the Brains of Chronic Methamphetamine Abusers SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 Natl Inst Drug Abuse, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 330 BP 94S EP 94S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200302 ER PT J AU Weinberger, D Savostyanova, AA Geramita, M Stern, A Callicott, JH Shen, J Straub, RE Marenco, S AF Weinberger, Daniel Savostyanova, Antonina A. Geramita, Matthew Stern, Alexa Callicott, Joseph H. Shen, Jun Straub, Richard E. Marenco, Stefano TI Genetic Regulation of GABA Activity and Risk for Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Weinberger, Daniel; Savostyanova, Antonina A.; Geramita, Matthew; Stern, Alexa; Callicott, Joseph H.; Shen, Jun; Straub, Richard E.; Marenco, Stefano] NIMH, Genes Cognit & Psychosis Program, NIH, IRP, Bethesda, MD 20892 USA. RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 333 BP 95S EP 95S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200305 ER PT J AU Volkow, ND Wang, GJ Kollins, S Wigal, T Newcorn, J Telang, F Fowler, J Swanson, J AF Volkow, Nora D. Wang, Gene-Jack Kollins, Scott Wigal, Tim Newcorn, Jeffrey Telang, Frank Fowler, Joanna Swanson, James TI Dopamine's Role in ADHD Symptoms: Beyond an Attention Deficit SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 11973 USA. [Wang, Gene-Jack; Fowler, Joanna] Brookhaven Natl Lab, Upton, NY USA. [Kollins, Scott] Duke Univ, Med Ctr, Durham, NC USA. [Wigal, Tim; Swanson, James] Univ Calif Irvine, Irvine, CA 10029 USA. [Newcorn, Jeffrey] Mt Sinai Med Ctr, New York, NY USA. [Telang, Frank] NIAAA, Bethesda, MD USA. RI Kollins, Scott/G-2965-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 336 BP 96S EP 96S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200308 ER PT J AU Buonanno, A AF Buonanno, Andres TI Physiological, Neurochemical and Behavioral Analyses of the Neuregulin Signaling Pathway in Wild-Type and Mutant Mice: Implications for Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Buonanno, Andres] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 344 BP 99S EP 99S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200316 ER PT J AU Drevets, WC Martin-Soelch, C AF Drevets, Wayne C. Martin-Soelch, Chantal TI Diminished Dopamine Release in Response to Unpredicted Monetary Reward in Major Depressive Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Drevets, Wayne C.] NIMH, Bethesda, MD USA. [Martin-Soelch, Chantal] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 353 BP 102S EP 102S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200325 ER PT J AU Laje, G AF Laje, Gonzalo TI Is Serotonin Transporter Expression Regulated by the Same HTR2A Variants Associated with Citalopram Response? SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Laje, Gonzalo] NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 356 BP 103S EP 103S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200328 ER PT J AU Tan, HY Chen, Q Browne, L Chen, AG Kolachana, B Apud, J Mattay, VS Callicott, JH Weinberger, DR AF Tan, Hao-Yang Chen, Qiang Browne, Lauren Chen, Anthony G. Kolachana, Bhaskar Apud, Jose Mattay, Venkata S. Callicott, Joseph H. Weinberger, Daniel R. TI Epistasis in Brain Imaging with AKT1 and Pharmacogenetics of Cognition in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Tan, Hao-Yang; Chen, Qiang; Browne, Lauren; Chen, Anthony G.; Kolachana, Bhaskar; Apud, Jose; Mattay, Venkata S.; Callicott, Joseph H.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 358 BP 103S EP 103S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200330 ER PT J AU Shaw, P AF Shaw, Philip TI The Structural Development of the Limbic System in Healthy Children and Adolescents SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Shaw, Philip] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 376 BP 106S EP 106S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200340 ER PT J AU Chen, G AF Chen, Guang TI BAG1 and Behavioral Endophenotype Related to Mood Disorder Vulnerability SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Chen, Guang] NIMH, NIH, Mol Pathophysiol Lab, Bethesda, MD USA. RI Chen, Guang/A-2570-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 382 BP 108S EP 108S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200346 ER PT J AU Du, J Wei, YL Blumenthal, R Karatsoreos, I McEwen, B Manji, H AF Du, Jing Wei, Yanling Blumenthal, Rayah Karatsoreos, Ilia McEwen, Bruce Manji, Husseini TI Bcl-2 Associated Athanogene (BAG-1) Regulates Glucocorticoid Receptor Trafficking to the Mitochondria: Physiology and Pathophysiology SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Du, Jing; Wei, Yanling; Blumenthal, Rayah] NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Karatsoreos, Ilia; McEwen, Bruce] Rockefeller Univ, Neuroendocrinol Lab, New York, NY 10021 USA. [Manji, Husseini] Johnson &Johnson Pharmaceut LLC, Res & Dev, Raritan, NJ USA. RI Karatsoreos, Ilia/B-4947-2012 OI Karatsoreos, Ilia/0000-0001-5605-4962 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 381 BP 108S EP 108S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200345 ER PT J AU Cuthbert, B AF Cuthbert, Bruce TI The NIMH Perspective on Translational Cognitive Neuroscience SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Cuthbert, Bruce] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 388 BP 110S EP 110S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200352 ER PT J AU Chavez, M Insel, T Zalcman, S AF Chavez, Mark Insel, Thomas Zalcman, Steven TI NIMH Funding: Priorities, Opportunities, and Strategies SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Chavez, Mark; Insel, Thomas; Zalcman, Steven] NIMH, Res Training & Career Dev Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 404 BP 113S EP 113S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200360 ER PT J AU Cummins, AC Chisholm, K Delaney, D Noble, PL Johnson, E Miller, AH Winslow, JT AF Cummins, Alex C. Chisholm, Kelly Delaney, Deborah Noble, Pamela L. Johnson, Emily Miller, Andrew H. Winslow, James T. TI Interferon-Alpha Treatment In Rhesus Macque; The Behavioral, Biochemical and Hematological Effects of Four Weeks of Daily Treatments SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Cummins, Alex C.; Chisholm, Kelly; Delaney, Deborah; Noble, Pamela L.; Johnson, Emily; Winslow, James T.] NIMH, Primate Res Core Facilty, IRP, Bethesda, MD 20892 USA. [Miller, Andrew H.] Emory Univ, Dept Psychiat & Behav Sci, Sch Med, Winship Canc Ctr, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 436 BP 123S EP 123S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200392 ER PT J AU Salvadore, G Viale, CI Zanatto, VC Cereser, VC Portela, LW Souza, DO Zarate, CA Machado-Vieira, R AF Salvadore, Giacomo Viale, Carlos I. Zanatto, Vanessa C. Cereser, Victor C., Jr. Portela, Luiz W. Souza, Diogo O. Zarate, Carlos A., Jr. Machado-Vieira, Rodrigo TI Increased Uric Acid Levels in Drug-Naive Subjects with Bipolar Disorder during First Manic Episode SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Salvadore, Giacomo; Zarate, Carlos A., Jr.; Machado-Vieira, Rodrigo] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Viale, Carlos I.; Zanatto, Vanessa C.; Cereser, Victor C., Jr.; Portela, Luiz W.; Souza, Diogo O.] Univ Fed Rio Grande do Sul, Dept Biochem, Porto Alegre, RS, Brazil. RI Souza, Diogo/J-8894-2014; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI Souza, Diogo/0000-0002-4322-0404; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 467 BP 133S EP 133S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200423 ER PT J AU Latov, DR Salvadore, G Grillon, C Cornwell, BR Zarate, CA AF Latov, David R. Salvadore, Giacomo Grillon, Christian Cornwell, Brian R. Zarate, Carlos A. TI Abnormal Hippocampal Theta Activity During Spatial Navigation in Bipolar Depression: A Magnetoencephalography Study SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Latov, David R.; Salvadore, Giacomo; Grillon, Christian; Cornwell, Brian R.; Zarate, Carlos A.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 494 BP 142S EP 142S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200450 ER PT J AU Mickey, BJ Zhou, Z Hsu, DT Langenecker, SA Love, TM Pecina, M Shafir, T Hodgkinson, CA Goldman, D Zubieta, JK AF Mickey, Brian J. Zhou, Zhifeng Hsu, David T. Langenecker, Scott A. Love, Tiffany M. Pecina, Marta Shafir, Tal Hodgkinson, Colin A. Goldman, David Zubieta, Jon-Kar TI Neural Responses to Affective Stimuli are Modulated by NPY Genotype SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Mickey, Brian J.; Hsu, David T.; Langenecker, Scott A.; Love, Tiffany M.; Pecina, Marta; Shafir, Tal; Zubieta, Jon-Kar] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Zhou, Zhifeng; Hodgkinson, Colin A.; Goldman, David] NIAAA, NIH, Bethesda, MD USA. RI Langenecker, Scott/F-3548-2012 OI Langenecker, Scott/0000-0002-7932-5494 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 500 BP 143S EP 144S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200456 ER PT J AU Pecina, M Mickey, B Hsu, D Shafir, T Shen, PH Hodgkinson, C Wright, S Scott, L Goldman, D Zubieta, JK AF Pecina, Marta Mickey, Brian Hsu, David Shafir, Tal Shen, Pei-Hong Hodgkinson, Colin Wright, Sara Scott, Langenecker Goldman, David Zubieta, Jon Kar TI D2/D3 Receptor Polymorphisms Predict Amygdala and Subgenual Cingulate Reactivity to Positive and Negative Emotional Stimuli SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Pecina, Marta; Mickey, Brian; Hsu, David; Shafir, Tal; Wright, Sara; Scott, Langenecker; Zubieta, Jon Kar] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Shen, Pei-Hong; Goldman, David] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. [Hodgkinson, Colin] NIAAA, Neurogenet Lab, Rockville, MI USA. RI Hodgkinson, Colin/F-9899-2010 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 499 BP 143S EP 143S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200455 ER PT J AU Martinowich, K Jimenez, D Schloesser, R Lu, B AF Martinowich, Keri Jimenez, Denisse Schloesser, Robert Lu, Bai TI Behavioral Characterization of Mice in Which BDNF Promoter-IV Driven Transcription is Impaired SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Martinowich, Keri; Lu, Bai] NIMH, GCAP, Bethesda, MD 20892 USA. [Jimenez, Denisse; Schloesser, Robert] NIMH, MAP, Bethesda, MD 20892 USA. RI Lu, Bai/A-4018-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 554 BP 161S EP 161S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200509 ER PT J AU Zhang, FY Chen, Q Ye, TZ Lipska, BK Hyde, TM Kleinman, JE Weinberger, DR AF Zhang, Fengyu Chen, Qiang Ye, Tianzhang Lipska, Barbara K. Hyde, Thomas M. Kleinman, Joel E. Weinberger, Daniel R. TI Sex-Sepcific Association of ZNF804A with Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Zhang, Fengyu; Chen, Qiang; Ye, Tianzhang; Lipska, Barbara K.; Hyde, Thomas M.; Kleinman, Joel E.; Weinberger, Daniel R.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 572 BP 166S EP 167S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200527 ER PT J AU Blair, J AF Blair, James TI Impairment in the Functional and Structural Connections between the Amygdala and Orbital Frontal Cortex in Conduct Disordered Youth with Callous and Unemotional Traits SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Blair, James] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 648 BP 182S EP 182S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200578 ER PT J AU Frascella, J AF Frascella, Joseph TI Desire Disorders: "Dirty Deeds" of a Highly Evolved Brain? SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Frascella, Joseph] Natl Inst Drug Abuse, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 653 BP 184S EP 184S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200583 ER PT J AU Wang, GJ Volkow, ND Fowler, JS AF Wang, Gene-Jack Volkow, Nora D. Fowler, Joanna S. TI Drug Addiction and Obesity: Results of Maladaptation to Modern Environment? SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Wang, Gene-Jack; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 654 BP 184S EP 184S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200584 ER PT J AU Insel, T AF Insel, Thomas TI From Prevention to Preemption SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Insel, Thomas] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 665 BP 188S EP 188S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200595 ER PT J AU McMahon, FJ AF McMahon, Francis J. TI Models that Incorporate Genetic and Clinical Variables Improve Prediction of Antidepressant Outcome SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [McMahon, Francis J.] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 687 BP 194S EP 194S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200617 ER PT J AU Marsh, AA Yu, HH Pine, DS Blair, RJR AF Marsh, Abigail A. Yu, Henry H. Pine, Daniel S. Blair, R. J. R. TI Intranasal Oxytocin Improves Specific Recognition of Positive Facial Expressions SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Marsh, Abigail A.] Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. [Yu, Henry H.; Pine, Daniel S.; Blair, R. J. R.] NIH, Mood & Anxiety Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 718 BP 204S EP 204S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200648 ER PT J AU Killgore, WDS Price, LM Britton, JC Simon, NM Pollack, MH Schwab, ZJ Weiner, MR Rosso, IM Rauch, SL AF Killgore, William D. S. Price, Lauren M. Britton, Jennifer C. Simon, Naomi M. Pollack, Mark H. Schwab, Zachary J. Weiner, Melissa R. Rosso, Isabelle M. Rauch, Scott L. TI Paralimbic Responses to Masked Emotional Faces in PTSD: Disorder and Valence Specificity SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Killgore, William D. S.; Price, Lauren M.; Schwab, Zachary J.; Weiner, Melissa R.; Rosso, Isabelle M.; Rauch, Scott L.] McLean Hosp, Belmont, MA 02178 USA. [Killgore, William D. S.; Simon, Naomi M.; Pollack, Mark H.; Rosso, Isabelle M.; Rauch, Scott L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Britton, Jennifer C.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Simon, Naomi M.; Pollack, Mark H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Britton, Jennifer/J-4501-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 732 BP 209S EP 209S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200662 ER PT J AU Schmitz, A Grillon, C Merikangas, KR AF Schmitz, Anja Grillon, Christian Merikangas, Kathleen R. TI Gender Differences in the Anxious Response to Predictable and Unpredictable Aversive Events in Children and Adults SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Schmitz, Anja; Grillon, Christian; Merikangas, Kathleen R.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 746 BP 213S EP 214S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200676 ER PT J AU Hirschhorn, E Charney, D Vythilingam, M Pine, DS Grillon, C AF Hirschhorn, Elizabeth Charney, Danielle Vythilingam, Meena Pine, Daniel S. Grillon, Christian TI Acute Hydrocortisone Increases Anxiety but not Fear in Healthy Humans SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Hirschhorn, Elizabeth; Charney, Danielle; Vythilingam, Meena; Pine, Daniel S.; Grillon, Christian] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 747 BP 214S EP 214S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200677 ER PT J AU Hirschhorn, EW Lissek, S Letkiewicz, A Luckenbaugh, D Geraci, M Pine, D Grillon, C AF Hirschhorn, Elizabeth W. Lissek, Shmuel Letkiewicz, Allison Luckenbaugh, David Geraci, Marilla Pine, Daniel Grillon, Christian TI Examining Generalization of Conditioned Fear Across Generalized Anxiety Disorder, Social Anxiety Disorder, and Panic Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Hirschhorn, Elizabeth W.; Lissek, Shmuel; Letkiewicz, Allison; Grillon, Christian] NIMH, Unit Affect Psychophysiol, Bethesda, MD 20892 USA. [Luckenbaugh, David; Geraci, Marilla] NIMH, NIH, Bethesda, MD 20892 USA. [Pine, Daniel] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 750 BP 215S EP 215S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200680 ER PT J AU Ibrahim, L Wheeler-Castillo, C Diazgranados, N Machado-Vieira, R Brutsche, N Luckenbaugh, D Zarate, C AF Ibrahim, Lobna Wheeler-Castillo, Cristina Diazgranados, Nancy Machado-Vieira, Rodrigo Brutsche, Nancy Luckenbaugh, David Zarate, Carlos TI Initial Antidepressant Response to an N-methyl-D-aspartate Antagonist in ECT-Resistant Major Depression SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Ibrahim, Lobna; Wheeler-Castillo, Cristina; Diazgranados, Nancy; Machado-Vieira, Rodrigo; Brutsche, Nancy; Luckenbaugh, David; Zarate, Carlos] NIMH, Mol Pathophysiol Lab, Sect Expt Therapeut, NIH, Bethesda, MD 20892 USA. RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 808 BP 233S EP 233S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200738 ER PT J AU Mallinger, AG Ibrahim, LA Ellen, F Thase, ME Luckenbaugh, D Kupfer, DJ AF Mallinger, Alan G. Ibrahim, Lobna A. Ellen, Frank Thase, Michael E. Luckenbaugh, David Kupfer, David J. TI Instability of Serum Lithium Level/Dose Ratio Predicts Affective Episode Recurrence in Bipolar I Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Mallinger, Alan G.; Ibrahim, Lobna A.; Luckenbaugh, David] NIMH, Bethesda, MD 20892 USA. [Ellen, Frank; Thase, Michael E.; Kupfer, David J.] Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 809 BP 233S EP 233S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200739 ER PT J AU Austin, DR Malkesman, O Tragon, T Wang, G Manji, HK Chen, GA AF Austin, Daniel R. Malkesman, Oz Tragon, Tyson Wang, Gang Manji, Husseini K. Chen, Guang TI Dynamic Alteration of Anhedonia-Related Behavior and Hippocampal Synaptosome N-Methyl-D-Aspartate Receptor Subunits Following Serotonin Depletion and Ketamine Treatment SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Austin, Daniel R.; Malkesman, Oz; Tragon, Tyson; Wang, Gang; Manji, Husseini K.; Chen, Guang] Inst Mental Hlth, NIH, Bethesda, MD USA. [Manji, Husseini K.] Johnson & Johnson Consumer Prod Inc, Neurosci Pharmaceut Res & Dev, Titusville, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 815 BP 235S EP 235S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200745 ER PT J AU Tragon, T AF Tragon, Tyson TI Roles of Voltage-Dependent L-Type Calcium Channels in Behavioral Regulation Related to Bipolar Mood Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Tragon, Tyson] NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 828 BP 239S EP 239S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200758 ER PT J AU Tost, H Braus, DF Hakimi, S Hohn, F Meyer-Lindenberg, A AF Tost, Heike Braus, Dieter F. Hakimi, Shabnam Hohn, Fabian Meyer-Lindenberg, Andreas TI A Rapid, Reversible Neural Plasticity Mechanism in Humans Predicts Acute Extrapyramidal Side Effects SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Tost, Heike; Hakimi, Shabnam] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Braus, Dieter F.; Hohn, Fabian; Meyer-Lindenberg, Andreas] Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, D-6800 Mannheim, Germany. RI Meyer-Lindenberg, Andreas/H-1076-2011 OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 840 BP 243S EP 244S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200770 ER PT J AU Perez-Rodriguez, MM Weinstein, S New, AS Bevilacqua, L Yuan, QP Zhou, ZF Hodgkinson, C Goodman, M Koenigsberg, HW Goldman, D Siever, LJ AF Perez-Rodriguez, M. Mercedes Weinstein, Shauna New, Antonia S. Bevilacqua, Laura Yuan, Qiaoping Zhou, Zhifeng Hodgkinson, Colin Goodman, Marianne Koenigsberg, Harold W. Goldman, David Siever, Larry J. TI Tryptophan Hydroxylase 2 Haplotype in Predicting Borderline Personality Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Perez-Rodriguez, M. Mercedes; Weinstein, Shauna; New, Antonia S.; Goodman, Marianne; Koenigsberg, Harold W.; Siever, Larry J.] Mt Sinai Sch Med, New York, NY USA. [New, Antonia S.; Goodman, Marianne; Koenigsberg, Harold W.; Siever, Larry J.] James J Peters Vet Affairs Med Ctr, Mental Hlth Patient Care Ctr, New York, NY USA. [Bevilacqua, Laura; Yuan, Qiaoping; Zhou, Zhifeng; Hodgkinson, Colin; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RI Hodgkinson, Colin/F-9899-2010; Perez Rodriguez, Maria/B-9410-2013 OI Perez Rodriguez, Maria/0000-0001-5137-1993 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 847 BP 246S EP 246S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200777 ER PT J AU Bakalar, JL Greenstein, D Chavez, A Miller, R Tossell, JW Clasen, L Rapoport, JL Gogtay, N AF Bakalar, Jennifer L. Greenstein, Deanna Chavez, Alex Miller, Rachel Tossell, Julia W. Clasen, Liv Rapoport, Judith L. Gogtay, Nitin TI Comparative Analysis of Cortical Thickness Differentiates Children with Atypical Psychosis from Childhood-Onset Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Bakalar, Jennifer L.; Greenstein, Deanna; Chavez, Alex; Miller, Rachel; Tossell, Julia W.; Clasen, Liv; Rapoport, Judith L.; Gogtay, Nitin] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 856 BP 249S EP 249S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200786 ER PT J AU Benferhat, A Czarapata, JB Dickinson, D Wei, SM Ianni, AM Weinberger, DR Berman, KF AF Benferhat, Anees Czarapata, Jasmin B. Dickinson, Dwight Wei, Shau-Ming Ianni, Angela M. Weinberger, Daniel R. Berman, Karen F. TI The Resting rCBF Profile as a Predictor of Neuropsychological Performance SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Benferhat, Anees; Czarapata, Jasmin B.; Wei, Shau-Ming; Ianni, Angela M.; Berman, Karen F.] NIMH, Sect Integrat Neuroimaging, Bethesda, MD 20892 USA. [Benferhat, Anees; Czarapata, Jasmin B.; Dickinson, Dwight; Wei, Shau-Ming; Ianni, Angela M.; Weinberger, Daniel R.; Berman, Karen F.] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 859 BP 250S EP 250S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200789 ER PT J AU Mattai, A Greenstein, D Clasen, L Weisinger, B Tossell, J Miller, R Rapoport, J Gogtay, N AF Mattai, Anand Greenstein, Deanna Clasen, Liv Weisinger, Brian Tossell, Julia Miller, Rachel Rapoport, Judith Gogtay, Nitin TI Normalization of Gray Matter Deficits in Nonpsychotic Siblings of Patients with Childhood-Onset Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Mattai, Anand; Greenstein, Deanna; Clasen, Liv; Weisinger, Brian; Tossell, Julia; Miller, Rachel; Rapoport, Judith; Gogtay, Nitin] NIMH, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 872 BP 254S EP 254S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200802 ER PT J AU Sambataro, F Mattay, VS Thurin, K Safrin, M Blasi, G Wabnitz, A Callicott, JH Weinberger, DR AF Sambataro, Fabio Mattay, Venkata S. Thurin, Kristina Safrin, Martin Blasi, Giuseppe Wabnitz, Ashley Callicott, Joseph H. Weinberger, Daniel R. TI Abnormal Cognitive Control Processing in Unaffected Siblings of Patients with Schizophrenia: An fMRI Intermediate Phenotype for Schizophrenia? SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Sambataro, Fabio; Mattay, Venkata S.; Thurin, Kristina; Safrin, Martin; Blasi, Giuseppe; Wabnitz, Ashley; Callicott, Joseph H.; Weinberger, Daniel R.] NIMH, GCAP, NIH, Bethesda, MD 20892 USA. [Blasi, Giuseppe] Univ Bari, Dept Neurol & Psychiat Sci, Bari, Italy. RI Sambataro, Fabio/E-3426-2010 OI Sambataro, Fabio/0000-0003-2102-416X NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 879 BP 256S EP 257S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200809 ER PT J AU Stidd, R Lee, S Chavez, A Hua, X Clasen, L Giedd, J Rapoport, J Thompson, P Gogtay, N AF Stidd, Reva Lee, Suh Chavez, Alex Hua, Xue Clasen, Liv Giedd, Jay Rapoport, Judith Thompson, Paul Gogtay, Nitin TI White Matter Development in Siblings of Patients with Childhood-Onset Schizophrenia Visualized Using Tensor-Based Morphometry SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Stidd, Reva; Chavez, Alex; Clasen, Liv; Giedd, Jay; Rapoport, Judith; Gogtay, Nitin] NIMH, Bethesda, MD 20892 USA. [Lee, Suh; Hua, Xue; Thompson, Paul] Univ Calif Los Angeles, Sch Med, Lab Neuro Imaging, Los Angeles, CA USA. RI Giedd, Jay/A-3080-2008; Gogtay, Nitin/A-3035-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 883 BP 258S EP 258S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200813 ER PT J AU Weisinger, B Mattai, A Greenstein, D Lalonde, F Rapoport, J Gogtay, N AF Weisinger, Brian Mattai, Anand Greenstein, Dede Lalonde, Francois Rapoport, Judith Gogtay, Nitin TI Comparison of Progressive Hippocampal Volume Change in Childhood-Onset Schizophrenia and Their Nonpsychotic Siblings SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Weisinger, Brian; Mattai, Anand; Greenstein, Dede; Lalonde, Francois; Rapoport, Judith; Gogtay, Nitin] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 886 BP 259S EP 259S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200816 ER PT J AU Bigos, KL Bies, RR Pollock, BG Lowy, J Weinberger, DR AF Bigos, Kristin L. Bies, Robert R. Pollock, Bruce G. Lowy, Joshua Weinberger, Daniel R. TI Genetic Variation in CYP3A43 Explains Racial Difference in Olanzapine Clearance SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 65th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 20-22, 2010 CL New Orleans, LA SP Soc Biol Psychiat C1 [Bigos, Kristin L.; Lowy, Joshua; Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Bies, Robert R.] Indiana Univ Sch Med, Div Clin Pharmacol, Indianapolis, IN USA. [Pollock, Bruce G.] Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON, Canada. RI Bigos, Kristin/E-9768-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 SU S MA 898 BP 262S EP 263S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IX UT WOS:000277064200828 ER PT J AU Cippitelli, A Damadzic, R Frankola, K Goldstein, A Thorsell, A Singley, E Eskay, RL Heilig, M AF Cippitelli, Andrea Damadzic, Ruslan Frankola, Kate Goldstein, Andrea Thorsell, Annika Singley, Erick Eskay, Robert L. Heilig, Markus TI Alcohol-Induced Neurodegeneration, Suppression of Transforming Growth Factor-beta, and Cognitive Impairment in Rats: Prevention by Group II Metabotropic Glutamate Receptor Activation SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Alcohol; entorhinal cortex; FJ-B; mGlu(2/3); neurodegeneration; TGF-beta ID BINGE ETHANOL EXPOSURE; CENTRAL-NERVOUS-SYSTEM; MORRIS WATER MAZE; NEURONAL DEGENERATION; SPATIAL MEMORY; BRAIN-DAMAGE; ADULT RATS; IN-VIVO; ENTORHINAL CORTEX; MESSENGER-RNA AB Background: Glutamatergic neurotransmission has been implicated in mechanisms of alcohol-induced neurodegeneration and cognitive impairment, but the underlying mechanism remains unknown. Here, we examined whether the group II metabotropic glutamate receptor agonist LY379268 prevents neuronal death and learning deficits in a rat model of binge-like exposure to alcohol. Methods: Following 4-day binge alcohol exposure concurrent with LY379268 or vehicle treatment, Fluoro-Jade B and transforming growth factor-beta (TGF-beta) staining were carried out, and reversal learning in the Morris water maze was assessed. Results: Fluoro-Jade B staining indicating neurodegeneration was most extensive in the ventral hippocampus and the entorhinal cortex (EC). LY379268 was potently neuroprotective in the EC but not in the dentate gyrus of the hippocampus. In parallel, binge alcohol exposure suppressed TGF-beta expression in both the EC and dentate gyrus, whereas LY379268 increased TGF-beta in the EC only. Finally, neuroprotective effects of LY379268 were accompanied by prevention of deficits in spatial reversal learning. Conclusions: Our data support a neuroprotective role for group II metabotropic glutamate receptor agonists and TGF-beta in alcohol-induced neurodegeneration. C1 [Cippitelli, Andrea; Damadzic, Ruslan; Frankola, Kate; Goldstein, Andrea; Thorsell, Annika; Singley, Erick; Eskay, Robert L.; Heilig, Markus] NIAAA, LCTS, NIH, Bethesda, MD 20892 USA. RP Heilig, M (reprint author), NIAAA, LCTS, NIH, 10 Ctr Dr,1-5330, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov RI Shipper, Andrea/G-7407-2014; OI Shipper, Andrea/0000-0003-2819-4276; Thorsell, Annika/0000-0003-3535-3845 FU National Institute on Alcohol Abuse and Alcoholism-Intramural Research Program FX This work was supported by the National Institute on Alcohol Abuse and Alcoholism-Intramural Research Program. NR 50 TC 29 Z9 29 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 BP 823 EP 830 DI 10.1016/j.biopsych.2009.12.018 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IW UT WOS:000277064100005 PM 20132926 ER PT J AU Malkesman, O Scattoni, ML Paredes, D Tragon, T Pearson, B Shaltiel, G Chen, G Crawley, JN Manji, HK AF Malkesman, Oz Scattoni, Maria Luisa Paredes, Daniel Tragon, Tyson Pearson, Brandon Shaltiel, Galit Chen, Guang Crawley, Jacqueline N. Manji, Husseini K. TI The Female Urine Sniffing Test: A Novel Approach for Assessing Reward-Seeking Behavior in Rodents SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Behavior; microdialysis; odor; reward-seeking; rodents; sex ID CHRONIC MILD STRESS; ULTRASONIC VOCALIZATIONS; SEXUAL-BEHAVIOR; KNOCKOUT MICE; ANIMAL-MODELS; OLFACTORY DISCRIMINATION; NUCLEUS-ACCUMBENS; INDUCED ANHEDONIA; MOUSE MODEL; HOUSE MICE AB Background: Abnormal hedonic behavior is a key feature of many psychiatric disorders. Several paradigms measure reward-seeking behavior in rodents, but each has limitations. We describe a novel approach for monitoring reward-seeking behavior in rodents: sniffing of estrus female urine by male mice, along with number of ultrasonic vocalizations (USVs) emitted during the test. Methods: The female urine sniffing test (FUST) was designed to monitor reward-seeking activity in rodents together with tests of helplessness and sweet solution preference. USVs and dopamine release from the nucleus accumbens (NAc) were recorded. Sniffing activity was measured in 1) manipulation-naive C57BL/6J and 129S1/SVImJ mice and Wistar-Kyoto rats; 2) stressed mice; 3) two groups of mice that underwent the learned helplessness paradigm one untreated, and one treated with the SSRI citalopram; and 4) GluR6 knockout mice, known to display lithium-responsive, mania-related behaviors. Results: Males from all three strains spent significantly longer sniffing female urine than sniffing water. Males emitted USVs and showed significantly elevated NAc dopamine levels while sniffing urine. Foot-shock stress significantly reduced female urine sniffing time. Compared with mice that did not undergo the LH paradigm, LH males spent less time sniffing female urine, and citalopram treatment alleviated this reduction. Compared with their wildtype littermates, GluR6KO males sniffed female urine longer and showed enhanced saccharin preference. Conclusions: In rodents, sniffing female urine is a preferred activity accompanied by biological changes previously linked to reward-seeking activities. The FUST is sensitive to behavioral and genetic manipulation and to relevant drug treatment. C1 [Malkesman, Oz; Tragon, Tyson; Pearson, Brandon; Shaltiel, Galit; Chen, Guang; Manji, Husseini K.] NIMH, Mol Pathophysiol Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Malkesman, Oz; Tragon, Tyson; Pearson, Brandon; Shaltiel, Galit; Chen, Guang; Manji, Husseini K.] NIMH, Mood & Anxiety Disorders Res Program, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Scattoni, Maria Luisa] Inst Super Sanita, Sect Neurotoxicol & Neuroendocrinol, Dept Cell Biol & Neurosci, Rome, Italy. [Scattoni, Maria Luisa; Crawley, Jacqueline N.] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. [Paredes, Daniel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurobiol Sect, NIH, Bethesda, MD USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, Intramural Res Program, NIH, Bldg 35,1C912, Bethesda, MD 20892 USA. EM manji@nih.gov RI Paredes , Daniel/L-6610-2013; Chen, Guang/A-2570-2017; OI Pearson, Brandon/0000-0003-4807-137X FU National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services FX This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services. NR 57 TC 56 Z9 57 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2010 VL 67 IS 9 BP 864 EP 871 DI 10.1016/j.biopsych.2009.10.018 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 588IW UT WOS:000277064100010 PM 20034613 ER PT J AU Sutin, AR Terracciano, A Deiana, B Uda, M Schlessinger, D Lakatta, EG Costa, PT AF Sutin, Angelina R. Terracciano, Antonio Deiana, Barbara Uda, Manuela Schlessinger, David Lakatta, Edward G. Costa, Paul T., Jr. TI Cholesterol, triglycerides, and the Five-Factor Model of personality SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Personality; Depression; Impulsivity; Cholesterol; Triglycerides ID CORONARY-HEART-DISEASE; NEO-PI-R; MIDDLE-AGED MEN; DEPRESSIVE SYMPTOMS; METABOLIC SYNDROME; YOUNG-ADULTS; A-BEHAVIOR; SERUM-CHOLESTEROL; HEALTH-STATUS; HOSTILITY AB Unhealthy lipid levels are among the leading controllable risk factors for coronary heart disease. To identify the psychological factors associated with dyslipidemia, this study investigates the personality correlates of cholesterol (total, LDL, and HDL) and triglycerides. A community-based sample (N = 5532) from Sardinia, Italy, had their cholesterol and triglyceride levels assessed and completed a comprehensive personality questionnaire, the NEO-PI-R. All analyses controlled for age, sex, BMI, smoking, drinking, hypertension, and diabetes. Low Conscientiousness and traits related to impulsivity were associated with lower HDL cholesterol and higher triglycerides. Compared to the lowest 10%, those who scored in top 10% on Impulsivity had a 2.5 times greater risk of exceeding the clinical threshold for elevated triglycerides (OR = 2.51, CI = 1.56-4.07). In addition, sex moderated the association between trait depression (a component of Neuroticism) and HDL cholesterol, such that trait depression was associated with lower levels of HDL cholesterol in women but not men. When considering the connection between personality and health, unhealthy lipid profiles may be one intermediate biomarker between personality and morbidity and mortality. Published by Elsevier B.V. C1 [Sutin, Angelina R.] NIA, Lab Personal & Cognit, NIH, DHHS, Baltimore, MD 21224 USA. RP Sutin, AR (reprint author), NIA, Lab Personal & Cognit, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sutina@mail.nih.gov RI terracciano, antonio/B-1884-2008; OI Costa, Paul/0000-0003-4375-1712 FU NIH; National Institute on Aging FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Paul Costa receives royalties from the Revised NEO Personality Inventory. NR 60 TC 35 Z9 35 U1 4 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD MAY PY 2010 VL 84 IS 2 BP 186 EP 191 DI 10.1016/j.biopsycho.2010.01.012 PG 6 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 616GQ UT WOS:000279197500004 PM 20109519 ER PT J AU Bishop, MR Alyea, EP Cairo, MS Falkenburg, JHF June, CH Kroger, N Little, RF Miller, JS Pavletic, SZ Porter, D Riddell, SR van Besien, K Wayne, AS Weisdorf, DJ Wu, R Giralt, S AF Bishop, Michael R. Alyea, Edwin P., III Cairo, Mitchell S. Falkenburg, J. H. Frederik June, Carl H. Kroeger, Nicolaus Little, Richard F. Miller, Jeffrey S. Pavletic, Steven Z. Porter, David Riddell, Stanley R. van Besien, Koen Wayne, Alan S. Weisdorf, Daniel J. Wu, Roy Giralt, Sergio TI Introduction to the Reports from the National Cancer Institute First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Editorial Material ID BONE-MARROW-TRANSPLANTATION; DONOR LYMPHOCYTE INFUSIONS; LEUKEMIA; LONG; EBMT C1 [Bishop, Michael R.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Alyea, Edwin P., III] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Cairo, Mitchell S.] Columbia Univ, Dept Pediat, Morgan Stanley Childrens Hosp New York Presbyteri, New York, NY 10027 USA. [Falkenburg, J. H. Frederik] Leiden Univ, Med Ctr, Dept Hematol, Leiden, Netherlands. [June, Carl H.; Porter, David] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Kroeger, Nicolaus] Univ Hosp Hamburg Eppendorf, Ctr Stem Cell Transplantat, Hamburg, Germany. [Little, Richard F.; Wu, Roy] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Miller, Jeffrey S.; Weisdorf, Daniel J.] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Riddell, Stanley R.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [van Besien, Koen] Univ Chicago, Sch Med, Dept Med, Chicago, IL 60637 USA. [Wayne, Alan S.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Giralt, Sergio] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat, Houston, TX 77030 USA. [Bishop, Michael R.; Alyea, Edwin P., III; Cairo, Mitchell S.; Falkenburg, J. H. Frederik; June, Carl H.; Kroeger, Nicolaus; Little, Richard F.; Miller, Jeffrey S.; Pavletic, Steven Z.; Porter, David; Riddell, Stanley R.; van Besien, Koen; Wayne, Alan S.; Weisdorf, Daniel J.; Wu, Roy; Giralt, Sergio] Natl Canc Inst First Int Workshop Biol Prevent &, Organizing Comm, Bethesda, MD USA. RP Bishop, MR (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, 10 Ctr Dr,CRC Room 4-3152, Bethesda, MD 20892 USA. EM mbishop@mail.nih.gov RI van Besien, Koen/G-4221-2012; OI van Besien, Koen/0000-0002-8164-6211; Miller, Jeffrey S/0000-0002-0339-4944 FU Intramural NIH HHS [ZIA BC011239-01]; NCI NIH HHS [R01 CA136551] NR 16 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAY PY 2010 VL 16 IS 5 BP 563 EP 564 DI 10.1016/j.bbmt.2010.02.025 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 589QR UT WOS:000277168200001 PM 20202482 ER PT J AU Miller, JS Warren, EH van den Brink, MRM Ritz, J Shlomchik, WD Murphy, WJ Barrett, AJ Kolb, HJ Giralt, S Bishop, MR Blazar, BR Falkenburg, JHF AF Miller, Jeffrey S. Warren, Edus H. van den Brink, Marcel R. M. Ritz, Jerome Shlomchik, Warren D. Murphy, William J. Barrett, A. John Kolb, Hans Jochem Giralt, Sergio Bishop, Michael R. Blazar, Bruce R. Falkenburg, J. H. Frederik TI NCI First International Workshop on The Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on the Biology Underlying Recurrence of Malignant Disease following Allogeneic HSCT: Graft-versus-Tumor/Leukemia Reaction SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE HCT; relapse; Graft-versus-host disease; Immune modulation; Graft-versus-leukemia reaction ID MINOR HISTOCOMPATIBILITY ANTIGEN; CD8(+) T-CELLS; NATURAL-KILLER-CELLS; DONOR LYMPHOCYTE INFUSION; CHRONIC MYELOGENOUS LEUKEMIA; KIR LIGAND INCOMPATIBILITY; ACUTE MYELOID-LEUKEMIA; MHC CLASS-I; ACUTE LYMPHOBLASTIC-LEUKEMIA; SUPERIOR ANTITUMOR IMMUNITY AB The success of allogeneic hematopoietic stem cell transplantation (HSCT) depends on the infusion of benign stem cells as well as lymphocytes capable of participating in a graft-versus-tumor/leukemia (GVL) reaction. Clinical proof of concept is derived from studies showing increased relapse after the infusion of lymphocyte depleted hematopoietic grafts as well as the therapeutic efficacy of donor lymphocyte infusions without chemotherapy to treat relapse in some diseases. Despite this knowledge, relapse after allogeneic HSCT is common with rates approaching 40% in those with high-risk disease. In this review, we cover the basic biology and potential application to exploit adaptive T cell responses, minor histocompatibility antigens, contraction and suppression mechanisms that hinder immune responses, adaptive B cell responses and innate NK cell responses, all orchestrated in a GVL reaction. Optimal strategies to precisely balance immune responses to favor GVL without harmful graft-versus-host disease (GVHD) are needed to protect against relapse, treat persistent disease and improve disease-free survival after HSCT. C1 [Miller, Jeffrey S.; Blazar, Bruce R.] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN 55455 USA. [Warren, Edus H.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Dept Immunol, New York, NY 10021 USA. [Ritz, Jerome] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Shlomchik, Warren D.] Yale Univ, Sch Med, Ctr Canc, Sect Med Oncol, New Haven, CT USA. [Murphy, William J.] Univ Calif, Davis Med Ctr, Sacramento, CA USA. [Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Kolb, Hans Jochem] Univ Munich, Dept Med 3, Munich, Germany. [Giralt, Sergio] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat, Houston, TX 77030 USA. [Bishop, Michael R.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Falkenburg, J. H. Frederik] Leiden Univ, Dept Hematol, Med Ctr, Leiden, Netherlands. RP Miller, JS (reprint author), Univ Minnesota, Blood & Marrow Transplant Program, 420 Delaware St,SE,MMC 806, Minneapolis, MN 55455 USA. EM mille011@umn.edu OI Miller, Jeffrey S/0000-0002-0339-4944 FU NCI NIH HHS [P01 CA065493, P01 CA142106, P01 CA111412-05, P01 CA111412] NR 183 TC 61 Z9 61 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAY PY 2010 VL 16 IS 5 BP 565 EP 586 DI 10.1016/j.bbmt.2010.02.005 PG 22 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 589QR UT WOS:000277168200002 PM 20152921 ER PT J AU Jessmon, P Kilburn, BA Romero, R Leach, RE Armant, DR AF Jessmon, Philip Kilburn, Brian A. Romero, Roberto Leach, Richard E. Armant, D. Randall TI Function-Specific Intracellular Signaling Pathways Downstream of Heparin-Binding EGF-Like Growth Factor Utilized by Human Trophoblasts SO BIOLOGY OF REPRODUCTION LA English DT Article DE AKT; apoptosis; cell differentiation; cell migration; mitogen-activated protein kinases; phosphoinositide-3-kinase; pregnancy; signal transduction; trophoblast ID ACTIVATED PROTEIN-KINASE; TUMOR-SUPPRESSOR GENE; FACTOR HB-EGF; HUMAN ENDOMETRIUM; CELL-LINE; INDUCED APOPTOSIS; OXIDATIVE STRESS; HUMAN PLACENTA; MESSENGER-RNA; IMMUNOHISTOCHEMICAL LOCALIZATION AB Heparin-binding EGF-like growth factor (HBEGF) is expressed by trophoblast cells throughout gestation. First-trimester cytotrophoblast cells are protected from hypoxia-induced apoptosis because of the accumulation of HBEGF through a posttranscriptional autocrine mechanism. Exogenous application of HBEGF is cytoprotective in a hypoxia/reoxygenation (H/R) injury model and initiates trophoblast extravillous differentiation to an invasive phenotype. The downstream signaling pathways induced by HBEGF that mediate these various cellular activities were identified using two human first-trimester cytotrophoblast cell lines, HTR-8/SVneo and SW. 71, with similar results. Recombinant HBEGF (1 nM) induced transient phosphorylation of MAPK3/1 (ERK), MAPK14 (p38), and AKT within 15 min and JNK after 1-2 h. To determine which downstream pathways regulate the various functions of HBEGF, cells were treated with specific inhibitors of the ERK upstream regulator MEK (U0126), the AKT upstream regulator phosphoinositide-3 (PI3)-kinase (LY294002), MAPK14 (SB203580), and JNK (SP600125), as well as with inactive structural analogues. Only SB203580 specifically prevented HBEGF-mediated rescue during H/R, while each inhibitor attenuated HBEGF-stimulated cell migration. Accumulation of HBEGF at reduced oxygen was blocked only by a combination of U0126, SB203580, and SP600125. We conclude that HBEGF advances trophoblast extravillous differentiation through coordinate activation of PI3 kinase, ERK, MAPK14, and JNK, while only MAPK14 is required for its antiapoptotic activity. Additionally, hypoxia induces an autocrine increase in HBEGF protein levels through MAPK14, JNK or ERK. These experiments reveal a complexity of the intracellular signaling circuitry that regulates trophoblast functions critical for implantation and placentation. C1 [Armant, D. Randall] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, CS Mott Ctr Human Growth & Dev, Detroit, MI 48201 USA. [Jessmon, Philip; Armant, D. Randall] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Jessmon, Philip; Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Leach, Richard E.] Michigan State Univ, Dept Obstet Gynecol & Reprod Biol, Grand Rapids, MI USA. RP Armant, DR (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, CS Mott Ctr Human Growth & Dev, 275 E Hancock Ave, Detroit, MI 48201 USA. EM D.Armant@Wayne.edu OI Armant, D. Randall/0000-0001-5904-9325 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health, NIH [R01HD045966]; DHHS; NICHD [U54 HD40093] FX Supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS and NIH grant R01HD045966, as well as through NICHD cooperative agreement U54 HD40093 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research. NR 77 TC 19 Z9 19 U1 0 U2 2 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD MAY PY 2010 VL 82 IS 5 BP 921 EP 929 DI 10.1095/biolreprod.109.082305 PG 9 WC Reproductive Biology SC Reproductive Biology GA 585YV UT WOS:000276867800014 PM 20130271 ER PT J AU Andreani, A Burnelli, S Granaiola, M Leoni, A Locatelli, A Morigi, R Rambaldi, M Varoli, L Landi, L Prata, C Dalla Sega, FV Caliceti, C Shoemaker, RH AF Andreani, Aldo Burnelli, Silvia Granaiola, Massimiliano Leoni, Alberto Locatelli, Alessandra Morigi, Rita Rambaldi, Mirella Varoli, Lucilla Landi, Laura Prata, Cecilia Dalla Sega, Francesco Vieceli Caliceti, Cristiana Shoemaker, Robert H. TI Antitumor activity and COMPARE analysis of bis-indole derivatives SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Indole; Pyridine; Antitumor; Hollow fiber assay; COMPARE; NQO1 ID TUMOR-CELL-LINES; INHIBITORS; INDUCERS; NAD(P)H AB This paper reports the synthesis of new derivatives (formed by two indole systems separated by a central moiety) analogous of potent antitumor agents previously described. The activity of the bis-indoles bearing a pyridine core confirms the good result described in the previous paper and compound 4c was chosen for the first in vivo experiment (Hollow Fiber Assay). COMPARE analysis and structure-activity relationships were also considered. Contrary to data reported by other Authors, no correlations were found between antitumor activity and NQO1 induction. (c) 2010 Elsevier Ltd. All rights reserved. C1 [Andreani, Aldo; Burnelli, Silvia; Granaiola, Massimiliano; Leoni, Alberto; Locatelli, Alessandra; Morigi, Rita; Rambaldi, Mirella; Varoli, Lucilla] Univ Bologna, Dipartimento Sci Farmaceut, I-40126 Bologna, Italy. [Landi, Laura; Prata, Cecilia; Dalla Sega, Francesco Vieceli; Caliceti, Cristiana] Univ Bologna, Dipartimento Biochim G Moruzzi, I-40126 Bologna, Italy. [Shoemaker, Robert H.] NCI, Div Canc Treatment & Diag, Screening Technol Branch, Dev Therapeut Program, Frederick, MD 21702 USA. RP Andreani, A (reprint author), Univ Bologna, Dipartimento Sci Farmaceut, Via Belmeloro 6, I-40126 Bologna, Italy. EM aldo.andreani@unibo.it OI LEONI, ALBERTO/0000-0001-8528-8207; caliceti, cristiana/0000-0002-6740-5331 NR 26 TC 13 Z9 13 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAY 1 PY 2010 VL 18 IS 9 BP 3004 EP 3011 DI 10.1016/j.bmc.2010.03.063 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 588PB UT WOS:000277083400002 PM 20395150 ER PT J AU Zhang, P Zou, MF Rodriguez, AL Conn, PJ Newman, AH AF Zhang, Peng Zou, Mu-Fa Rodriguez, Alice L. Conn, P. Jeffrey Newman, Amy Hauck TI Structure-activity relationships in a novel series of 7-substituted-aryl quinolines and 5-substituted-aryl benzothiazoles at the metabotropic glutamate receptor subtype 5 SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Metabotropic glutamate receptor subtype 5; mGluR5; MPEP; MTEP; Drug abuse ID PROTEIN-COUPLED RECEPTORS; SQUIRREL-MONKEYS; ANTAGONISTS; MGLUR5; POTENT; PHARMACOLOGY; DISCOVERY; COCAINE; DESIGN; SAR AB The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in numerous neuropsychiatric disorders including addiction. We have discovered that the rigid diaryl alkyne template, derived from the potent and selective noncompetitive mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP), can serve to guide the design of novel quinoline analogues and pharmacophore optimization has resulted in potent mGluR5 noncompetitive antagonists (EC(50) range 60-100 nM) in the quinoline series. Published by Elsevier Ltd. C1 [Zhang, Peng; Zou, Mu-Fa; Newman, Amy Hauck] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Rodriguez, Alice L.; Conn, P. Jeffrey] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov RI Conn, Peter/D-7848-2012 FU NINDS [F32 NS049865]; NIMH PDSP [NO1MH32004] FX This work was funded by the NIDA-Intramural Research Program and an NRSA Fellowship F32 NS049865 awarded by NINDS to A.L.R. mGluR5 binding data, and a functional screens across all mGluRs were provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract no. NO1MH32004 (NIMH PDSP). The NIDA Addiction Treatment Discovery Program provided the computational toxicology data, thanks to Dr. Rik Kline. NR 27 TC 11 Z9 11 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAY 1 PY 2010 VL 18 IS 9 BP 3026 EP 3035 DI 10.1016/j.bmc.2010.03.053 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 588PB UT WOS:000277083400005 PM 20382541 ER PT J AU Romagnoli, R Baraldi, PG Cruz-Lopez, O Cara, CL Carrion, MD Balzarini, J Hamel, E Basso, G Bortolozzi, R Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Cruz-Lopez, Olga Cara, Carlota Lopez Carrion, Maria Dora Balzarini, Jan Hamel, Ernest Basso, Giuseppe Bortolozzi, Roberta Viola, Giampietro TI Symmetrical alpha-bromoacryloylamido diaryldienone derivatives as a novel series of antiproliferative agents. Design, synthesis and biological evaluation SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Antiproliferative activity; Apoptosis; Antitumor agents; Hybrid compounds ID PROGRAMMED CELL-DEATH; ALPHA,BETA-UNSATURATED KETONES; ACRIDINE-ORANGE; DRUG DESIGN; APOPTOSIS; MITOCHONDRIA; ASSAY; BIOACTIVITIES; BROSTALLICIN; CARDIOLIPIN AB In a continuing study of hybrid compounds containing the alpha-bromoacryloyl moiety as potential anticancer drugs, we synthesized a novel series of hybrids 4a-h, in which this moiety was linked to a 1,5-diaryl-1,4-pentadien-3-one system. Many of the conjugates prepared (4b, 4c, 4e and 4g) demonstrated pronounced, submicromolar antiproliferative activity against four cancer cell lines. Moreover, compound 4b induced apoptosis through the mitochondrial pathway and activated caspase-3 in a concentration-dependent manner. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Cruz-Lopez, Olga; Cara, Carlota Lopez; Carrion, Maria Dora] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Balzarini, Jan] Katholieke Univ Leuven, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Basso, Giuseppe; Bortolozzi, Roberta; Viola, Giampietro] Univ Padua, Dipartimento Pediat, Lab Oncoematol, I-35131 Padua, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. EM rmr@unife.it; baraldi@unife.it RI Viola, Giampietro/I-4095-2012; Bortolozzi, Roberta/D-4950-2015; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Carrion, M. Dora/G-8638-2015; Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017; Cruz-Lopez, Olga /F-3060-2017; OI Viola, Giampietro/0000-0001-9329-165X; Bortolozzi, Roberta/0000-0002-3357-4815; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; Carrion, M. Dora/0000-0002-6794-3949; BASSO, GIUSEPPE/0000-0002-2634-9302 FU K.U. Leuven [05/19] FX Financial support was provided by GOA (Krediet No. 05/19) of the K.U. Leuven. The technical assistance of Mrs. Lizette van Berckelaer and Alberto Casolari is gratefully acknowledged. NR 36 TC 2 Z9 2 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAY 1 PY 2010 VL 20 IS 9 BP 2733 EP 2739 DI 10.1016/j.bmcl.2010.03.075 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 585HT UT WOS:000276816600008 PM 20378350 ER PT J AU Liu, F Hakami, RM Dyas, B Bahta, M Lountos, GT Waugh, DS Ulrich, RG Burke, TR AF Liu, Fa Hakami, Ramin Mollaaghababa Dyas, Beverly Bahta, Medhanit Lountos, George T. Waugh, David S. Ulrich, Robert G. Burke, Terrence R., Jr. TI A rapid oxime linker-based library approach to identification of bivalent inhibitors of the Yersinia pestis protein-tyrosine phosphatase, YopH SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Protein-tyrosine phosphatase; Yersinia pestis; YopH; Inhibitor ID DRUG DISCOVERY; CANCER; ACIDS AB A bivalent tethered approach toward YopH inhibitor development is presented that joins aldehydes with mixtures of bis-aminooxy-containing linkers using oxime coupling. The methodology is characterized by its facility and ease of use and its ability to rapidly identify low micromolar affinity inhibitors. The generality of the approach may potentially make it amenable to the development of bivalent inhibitors directed against other phosphatases. Published by Elsevier Ltd. C1 [Liu, Fa; Bahta, Medhanit; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Hakami, Ramin Mollaaghababa] Oak Ridge Associated Univ, Fac Res Participat Program, Belcamp, MD 21017 USA. [Hakami, Ramin Mollaaghababa; Dyas, Beverly; Ulrich, Robert G.] USA, Med Res Inst Infect Dis, Lab Mol Immunol, Frederick, MD 21702 USA. [Lountos, George T.; Waugh, David S.] NCI, Macromol Crystallog Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Liu, F (reprint author), Lilly Res Labs, Indianapolis, IN 46285 USA. EM tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014; Lountos, George/B-3983-2015 FU NIH, Center for Cancer Research, NCI-Frederick; National Cancer Institute, National Institutes of Health and the Joint Science and Technology Office of the Department of Defense FX Appreciation is expressed to Afroz Sultana (LMI) for technical support. This work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick and the National Cancer Institute, National Institutes of Health and the Joint Science and Technology Office of the Department of Defense. 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. Appreciation is expressed to Afroz Sultana (LMI), Scott Cherry and Joe Tropea (MCL) for technical support. NR 30 TC 15 Z9 15 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAY 1 PY 2010 VL 20 IS 9 BP 2813 EP 2816 DI 10.1016/j.bmcl.2010.03.058 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 585HT UT WOS:000276816600024 PM 20350805 ER PT J AU Attri, AK Fernandez, C Minton, AP AF Attri, Arun K. Fernandez, Cristina Minton, Allen P. TI Self-association of Zn-insulin at neutral pH: Investigation by concentration gradient-static and dynamic light scattering SO BIOPHYSICAL CHEMISTRY LA English DT Article DE Zn-insulin; Self-association equilibria; Static light scattering; Dynamic light scattering ID QUANTITATIVE CHARACTERIZATION; FIBRILLATION AB Equilibrium self-association of Zn-insulin at pH 7.0 was characterized over the range 0.3-5 mg/mL by simultaneous measurement of static and dynamic light scattering. Analysis of static light scattering yielded a concentration-dependent weight-average molecular weight, and analysis of dynamic light scattering yielded a concentration-dependent intensity-average diffusion coefficient. The concentration dependence of both quantities may be accounted for to within experimental precision by a simple model, according to which the basic structural unit of Zn-insulin at concentrations exceeding 0.3 mg/mL is a hexamer H. With increasing total protein concentration, hexameric protomers may self-associate in accordance with an isodesmic scheme in which a protomer may add to any prexisting oligomer H(n) to form H(n + 1) with an invariant stepwise equilibrium association constant. Published by Elsevier B.V. C1 [Attri, Arun K.; Fernandez, Cristina; Minton, Allen P.] NIDDK, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Attri, Arun K.] Jawaharlal Nehru Univ, Sch Environm Sci, New Delhi 110067, India. RP Minton, AP (reprint author), NIDDK, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM attri@mail.jnu.ac.in; minton@helix.nih.gov RI Fernandez, Cristina/G-2269-2015; OI Fernandez, Cristina/0000-0003-3792-4015; Minton, Allen/0000-0001-8459-1247 FU National Institute of Diabetes and Digestive and Kidney Diseases FX The authors thank Peter McPhie (NIH) for helpful comments and for a critical review of the initial draft of this report. A.K.A. thanks the NIH for hospitality during his sabbatical year. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 15 TC 16 Z9 16 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD MAY PY 2010 VL 148 IS 1-3 BP 23 EP 27 DI 10.1016/j.bpc.2010.02.001 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 597GF UT WOS:000277743900003 PM 20202736 ER PT J AU Attri, AK Fernandez, C Minton, AP AF Attri, Arun K. Fernandez, Cristina Minton, Allen P. TI pH-dependent self-association of zinc-free insulin characterized by concentration-gradient static light scattering SO BIOPHYSICAL CHEMISTRY LA English DT Article DE Insulin; Static light scattering; Self-association equilibria ID FREE BOVINE INSULIN; QUANTITATIVE CHARACTERIZATION; PROTEIN INTERACTIONS; FIBRIL FORMATION; IONIC-STRENGTH; 2D NMR; AGGREGATION; MODEL; PROINSULIN; KINETICS AB Insulin self-association at pH 1.85, 1.95, 3.0, 7.2, 8.0 and 10 was studied via composition gradient light scattering (CG-SLS). At pH 1.95 in acetic acid, insulin was found to exist as a monomer, and in pH 1.85 HCl as a dimer. At pH values of 3.0-8.0, the dependence of scattering intensity upon total insulin concentration at concentrations of up to 1.5 mg/mL may be quantitatively accounted for by a simple isodesmic association equilibrium scheme requiring only a single association constant for addition of monomer to monomer or any oligomer. At pH 10, the association constant for addition of monomer to monomer was found to be smaller than the association constant for addition of monomer to all higher oligomers by a factor of approximately five. The isodesmic association scheme was also found to quantitatively account for the concentration dependence of the weight-average molecular weight derived from previously published sedimentation equilibrium measurements made at pH 7.0, and the best-fit value of the stepwise equilibrium constant obtained therefrom was in excellent agreement with that obtained from analysis of the light scattering data obtained at pH 7.2. Published by Elsevier B.V. C1 [Attri, Arun K.; Fernandez, Cristina; Minton, Allen P.] NIDDK, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Attri, Arun K.] Jawaharlal Nehru Univ, Sch Environm Sci, New Delhi 110067, India. RP Minton, AP (reprint author), NIDDK, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM attri@mail.jnu.ac.in; minton@helix.nih.gov RI Fernandez, Cristina/G-2269-2015; OI Fernandez, Cristina/0000-0003-3792-4015; Minton, Allen/0000-0001-8459-1247 FU National Institute of Diabetes and Digestive and Kidney Diseases FX The authors thank Dr. Peter McPhie (NIH) for helpful comments on the draft of this report. A.K.A. thanks the NIH for hospitality extended during his sabbatical stay. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 31 TC 18 Z9 18 U1 2 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD MAY PY 2010 VL 148 IS 1-3 BP 28 EP 33 DI 10.1016/j.bpc.2010.02.002 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 597GF UT WOS:000277743900004 PM 20202737 ER PT J AU Foster, PMD AF Foster, P. M. D. TI The Cons of the Extended One - Generation Study Protocol SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Foster, P. M. D.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2010 VL 88 IS 5 BP 325 EP 325 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 605AV UT WOS:000278320600005 ER PT J AU Mills, JL AF Mills, J. L. TI Vitamin B-12 Deficiency and NTDs: Is There a Causal Relationship? SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Mills, J. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2010 VL 88 IS 5 BP 328 EP 328 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 605AV UT WOS:000278320600009 ER PT J AU Lakind, JS Youngstrom, E Goodman, M Squibb, K Lipkin, PH Anthony, LG Kenworthy, L Mattison, DR AF Lakind, J. S. Youngstrom, E. Goodman, M. Squibb, K. Lipkin, P. H. Anthony, L. G. Kenworthy, L. Mattison, D. R. TI A Multidisciplinary Approach to Advancing the Science of Neurodevelopmental Testing in Cohorts of Infants and Young Children SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Lakind, J. S.] LaKind Associates LLC, Catonsville, MD USA. [Lakind, J. S.; Squibb, K.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Penn State Coll Med, Hershey, PA USA. [Youngstrom, E.] Univ N Carolina, Chapel Hill, NC USA. [Goodman, M.] Emory Univ, Sch Publ Hlth, Atlanta, GA 30322 USA. [Lipkin, P. H.] Johns Hopkins Univ, Sch Med, Kennedy Krieger Inst, Baltimore, MD USA. [Anthony, L. G.; Kenworthy, L.] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Rockville, MD USA. [Mattison, D. R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hu, Natl Inst Hlth, HHS, Bethesda, MD USA. RI Mattison, Donald/C-2015-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2010 VL 88 IS 5 BP 337 EP 337 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 605AV UT WOS:000278320600027 ER PT J AU Anthony, LG Youngstrom, EA Kenworthy, LE Lakind, JS Goodman, M Squibb, KS Lipkin, PH Mattison, DR AF Anthony, L. G. Youngstrom, E. A. Kenworthy, L. E. Lakind, J. S. Goodman, M. Squibb, K. S. Lipkin, P. H. Mattison, D. R. TI Threats to Study Validity: The Flynn Effect, Examiner Drift, Confounders, Lost in Translation. and Other Important Considerations SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Anthony, L. G.] GWU, Childrens Natl Med Ctr, Rockville, MD USA. [Youngstrom, E. A.] Univ N Carolina, Chapel Hill, NC USA. [Lakind, J. S.] LaKind Associates LLC, Catonsville, MD USA. [Goodman, M.] Emory Univ, Sch Publ Hlth, Atlanta, GA 30322 USA. [Squibb, K. S.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Lipkin, P. H.] Johns Hopkins Univ, Sch Med, Kennedy Krieger Inst, Baltimore, MD USA. [Mattison, D. R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Washington, DC USA. RI Mattison, Donald/C-2015-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2010 VL 88 IS 5 BP 338 EP 338 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 605AV UT WOS:000278320600029 ER PT J AU Kenworthy, L Anthony, LG Goodman, M Lakind, JS Lipkin, PH Mattison, DR Squibb, K Youngstrom, E AF Kenworthy, L. Anthony, L. G. Goodman, M. Lakind, J. S. Lipkin, P. H. Mattison, D. R. Squibb, K. Youngstrom, E. TI Getting the Biggest Bang for Your Buck: Choosing Neurodevelopmental Tests That Maximize Power SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Kenworthy, L.; Anthony, L. G.] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Washington, DC 20010 USA. [Kenworthy, L.; Anthony, L. G.] George Washington Univ, Sch Med, Dept Pediat, Washington, DC 20052 USA. [Kenworthy, L.; Anthony, L. G.] George Washington Univ, Sch Med, Dept Psychiat, Washington, DC USA. [Goodman, M.] Emory Univ, Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Squibb, K.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Youngstrom, E.] Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. [Youngstrom, E.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Lipkin, P. H.] Johns Hopkins Univ, Sch Med, Ctr Dev & Learning, Kennedy Kreiger Inst,Dept Pediat, Baltimore, MD USA. [Mattison, D. R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Lakind, J. S.] LaKind Associates LLC, Catonsville, MD USA. [Lakind, J. S.] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RI Mattison, Donald/C-2015-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2010 VL 88 IS 5 BP 338 EP 338 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 605AV UT WOS:000278320600028 ER PT J AU Goodman, M Lakind, J Squibb, K Youngstrom, E Anthony, L Kenworthy, L Lipkin, P Mattison, D AF Goodman, M. Lakind, J. Squibb, K. Youngstrom, E. Anthony, L. Kenworthy, L. Lipkin, P. Mattison, D. TI Weight-of-the-Evidence Assessment in Neurodevelopmental Epidemiology: A Plea for Consistency SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Goodman, M.] Emory Univ, Atlanta, GA 30322 USA. [Lakind, J.] LaKind Associates LLC, Catonsville, MD USA. [Lakind, J.; Squibb, K.] Univ Maryland, Baltimore, MD 21201 USA. [Youngstrom, E.] Univ N Carolina, Chapel Hill, NC USA. [Anthony, L.; Kenworthy, L.] Childrens Natl Med Ctr, Rockville, MD USA. [Lipkin, P.] Johns Hopkins Univ, Baltimore, MD USA. [Mattison, D.] NICHHD, NIH, Bethesda, MD 20892 USA. RI Mattison, Donald/C-2015-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2010 VL 88 IS 5 BP 339 EP 339 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 605AV UT WOS:000278320600030 ER PT J AU Rinderknecht, AL Menjoge, AR Kannan, RM Kim, CJ Romero, R Faridnia, M Miller, RK AF Rinderknecht, A. L. Menjoge, A. R. Kannan, R. M. Kim, C. J. Romero, R. Faridnia, M. Miller, R. K. TI Transfer of Dendrimers in the Perfused Human Placental Lobule In Vitro: Prospects for Use as Drug Carriers during Pregnancy SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Rinderknecht, A. L.; Faridnia, M.; Miller, R. K.] Univ Rochester, Rochester, NY USA. [Menjoge, A. R.; Kannan, R. M.] Wayne State Univ, Detroit, MI USA. [Menjoge, A. R.; Kannan, R. M.; Kim, C. J.; Romero, R.] NICHHD, Detroit, MI USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2010 VL 88 IS 5 BP 351 EP 351 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 605AV UT WOS:000278320600049 ER PT J AU Tyl, RW Seely, JC Marr, MC Myers, CB Youn, VY Browning, DB Bishop, JB AF Tyl, R. W. Seely, J. C. Marr, M. C. Myers, C. B. Youn, V. Y. Browning, D. B. Bishop, J. B. TI Gonadal Responses to Vinclozolin Administered Orally to Han Wistar Rats SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Tyl, R. W.; Marr, M. C.; Myers, C. B.; Youn, V. Y.; Browning, D. B.] RTI Int, Res Triangle Pk, NC USA. [Seely, J. C.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Bishop, J. B.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2010 VL 88 IS 5 BP 358 EP 358 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 605AV UT WOS:000278320600063 ER PT J AU Fenton, SC Rudel, RA Euling, SY Makris, SL AF Fenton, S. E. Rudel, R. A. Euling, S. Y. Makris, S. L. TI Mammary Gland Development As a Sensitive Indicator of Early Life Exposures: Recommendations from an Interdisciplinary Workshop SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Fenton, S. E.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Rudel, R. A.] Silent Spring Inst, Newton, MA USA. [Euling, S. Y.; Makris, S. L.] NCEA, US EPA, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2010 VL 88 IS 5 BP 359 EP 359 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 605AV UT WOS:000278320600065 ER PT J AU Carter, TC Olney, RS Mitchell, AA Romitti, PA Bell, EM Druschel, CM AF Carter, T. C. Olney, R. S. Mitchell, A. A. Romitti, P. A. Bell, E. M. Druschel, C. M. TI Genital Tract Infections during Pregnancy and the Risk of Selected Birth Defects SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Carter, T. C.] NICHHD, NIH, Bethesda, MD 20892 USA. [Olney, R. S.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Mitchell, A. A.] Boston Univ, Slone Epidemiol Unit, Boston, MA 02215 USA. [Romitti, P. A.] Univ Iowa, Iowa City, IA USA. [Bell, E. M.] SUNY Albany, Albany, NY 12222 USA. [Druschel, C. M.] New York State Dept Hlth, Albany, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2010 VL 88 IS 5 BP 367 EP 367 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 605AV UT WOS:000278320600080 ER PT J AU Arbyn, M Martin-Hirsch, P Wentzensen, N AF Arbyn, M. Martin-Hirsch, P. Wentzensen, N. TI Human papillomavirus-based triage of women showing a cervical cytology result of borderline or mild dyskaryosis SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Editorial Material ID ATYPICAL SQUAMOUS-CELLS; INTRAEPITHELIAL NEOPLASIA; UNDETERMINED SIGNIFICANCE; NATURAL-HISTORY; METAANALYSIS; MANAGEMENT; SMEARS; RISK AB Please cite this paper as: Arbyn M, Martin-Hirsch P, Wentzensen N. HPV-based triage of women showing a cervical cytology result of borderline or mild dyskaryosis. BJOG 2010; DOI: 10.1111/j.1471-0528.2010.02521.x. C1 [Arbyn, M.] Sci Inst Publ Hlth, Canc Epidemiol Unit, B-1050 Brussels, Belgium. [Martin-Hirsch, P.] Cent Lancashire Teaching Hosp, Dept Obstet & Gynaecol, Preston, Lancs, England. [Wentzensen, N.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Arbyn, M (reprint author), Sci Inst Publ Hlth, Canc Epidemiol Unit, J Wytsmanst 14, B-1050 Brussels, Belgium. EM marc.arbyn@iph.fgov.be NR 12 TC 5 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1470-0328 J9 BJOG-INT J OBSTET GY JI BJOG PD MAY PY 2010 VL 117 IS 6 BP 641 EP 644 DI 10.1111/j.1471-0528.2010.02521.x PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 581GH UT WOS:000276509100001 PM 20383875 ER PT J AU Shimamura, A Alter, BP AF Shimamura, Akiko Alter, Blanche P. TI Pathophysiology and management of inherited bone marrow failure syndromes SO BLOOD REVIEWS LA English DT Review DE Aplastic anemia; Fanconi; Dyskeratosis congenita; Diamond-Blackfan anemia; Shwachman-Diamond syndrome; Inherited bone marrow failure syndromes ID SHWACHMAN-DIAMOND-SYNDROME; SEVERE CONGENITAL NEUTROPENIA; STEM-CELL TRANSPLANTATION; TELOMERASE REVERSE-TRANSCRIPTASE; COLONY-STIMULATING FACTOR; UNFOLDED PROTEIN RESPONSE; FANCONI-ANEMIA PATIENTS; DNA-DAMAGE RESPONSE; IDIOPATHIC PULMONARY-FIBROSIS; ACQUIRED APLASTIC-ANEMIA AB The inherited marrow failure syndromes are a diverse set of genetic disorders characterized by hematopoietic aplasia and cancer predisposition. The clinical phenotypes are highly variable and much broader than previously recognized. The medical management of the inherited marrow failure syndromes differs from that of acquired aplastic anemia or malignancies arising in the general population. Diagnostic workup, molecular pathogenesis, and clinical treatment are reviewed. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Shimamura, Akiko] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Shimamura, Akiko] Seattle Childrens Hosp, Seattle, WA USA. [Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Shimamura, A (reprint author), Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. EM shima2@u.washington.edu FU National Institutes of Health; National Cancer Institute; National Heart Lung and Blood Institute of the National Institutes of Health FX This work was supported in part by the Intramural Program of the National Institutes of Health and the National Cancer Institute (B.P.A.) and a grant from the National Heart Lung and Blood Institute of the National Institutes of Health (A.S.). NR 155 TC 121 Z9 121 U1 1 U2 11 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0268-960X J9 BLOOD REV JI Blood Rev. PD MAY PY 2010 VL 24 IS 3 BP 101 EP 122 DI 10.1016/j.blre.2010.03.002 PG 22 WC Hematology SC Hematology GA 605BF UT WOS:000278321600002 PM 20417588 ER PT J AU Lui, JCK Andrade, AC Forcinito, P Hegde, A Chen, WP Baron, J Nilsson, O AF Lui, Julian C. K. Andrade, Anenisia C. Forcinito, Patricia Hegde, Anita Chen, WeiPing Baron, Jeffrey Nilsson, Ola TI Spatial and temporal regulation of gene expression in the mammalian growth plate SO BONE LA English DT Article DE Growth plate; Chondrocytes; Gene expression; Longitudinal bone growth; Differentiation; Senescence ID MESSENGER-RNA LEVELS; CHONDROCYTE DIFFERENTIATION; CARTILAGE DEVELOPMENT; SKELETAL DEVELOPMENT; ZONE CHONDROCYTES; EPIPHYSEAL FUSION; BONE-DEVELOPMENT; NUCLEAR FACTOR; RESTING ZONE; FACTOR-BETA AB Growth plates are spatially polarized and structured into three histologically and functionally distinct layers the resting zone (RZ), proliferative zone (PZ), and hypertrophic zone (HZ). With age, growth plates undergo functional and structural senescent changes including declines of growth rate, proliferation rate, growth plate height and cell number. To explore the mechanisms responsible for spatially-associated differentiation and temporally-associated senescence of growth plate in an unbiased manner, we used microdissection to collect individual growth plate zones from proximal tibiae of 1-week rats and the PZ and early hypertrophic zones of growth plates from 3-, 6-, 9-, and 12-week rats and analyzed gene expression using microarray. We then used bioinformatic approaches to identify significant changes in biological functions, molecular pathways, transcription factors and also to identify specific gene products that can be used as molecular markers for individual zones or for temporal development. (C) 2010 Elsevier Inc. All rights reserved. C1 [Andrade, Anenisia C.; Nilsson, Ola] Karolinska Inst, Ctr Mol Med, SE-17176 Stockholm, Sweden. [Andrade, Anenisia C.; Nilsson, Ola] Karolinska Inst, Pediat Endocrinol Unit, Dept Woman & Child Hlth, SE-17176 Stockholm, Sweden. [Andrade, Anenisia C.; Nilsson, Ola] Karolinska Univ Hosp, SE-17176 Stockholm, Sweden. [Lui, Julian C. K.; Forcinito, Patricia; Hegde, Anita; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Chen, WeiPing] NIDDK, Genom Core Lab, NIH, Bethesda, MD 20892 USA. RP Nilsson, O (reprint author), Karolinska Inst, Ctr Mol Med, Q2 08, SE-17176 Stockholm, Sweden. EM Ola.Nilsson@ki.se RI Lui, Chun Kin Julian/E-2253-2012; OI Nilsson, Ola/0000-0002-9986-8138 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; Swedish Research Council [K2007-52X-20316-01-4]; Swedish Society of Medicine; Swedish Society of Medical Research; HKH kronprinsessan Lovisas Forening for Barnasjukvard; Sallskapet Barnavard; Stiftelsen Frimurare Barnhuset i Stockholm FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. Ola Nilsson was supported by grants from the Swedish Research Council (K2007-52X-20316-01-4), the Swedish Society of Medicine, the Swedish Society of Medical Research, HKH kronprinsessan Lovisas Forening for Barnasjukvard, Sallskapet Barnavard, and Stiftelsen Frimurare Barnhuset i Stockholm. NR 65 TC 34 Z9 34 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD MAY PY 2010 VL 46 IS 5 BP 1380 EP 1390 DI 10.1016/j.bone.2010.01.373 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 586VC UT WOS:000276941000022 PM 20096814 ER PT J AU Moeller, SJ Maloney, T Parvaz, MA Alia-Klein, N Woicik, PA Telang, F Wang, GJ Volkow, ND Goldstein, RZ AF Moeller, Scott J. Maloney, Thomas Parvaz, Muhammad A. Alia-Klein, Nelly Woicik, Patricia A. Telang, Frank Wang, Gene-Jack Volkow, Nora D. Goldstein, Rita Z. TI Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour SO BRAIN LA English DT Article DE cocaine addiction; insight; choice behaviour; neuropsychology; urine status ID MONETARY REWARD; AWARENESS; EMOTION; USERS; SENSITIVITY; OPPORTUNITY; PREDICTORS; ABSTINENCE; DEPENDENCE; RESPONSES AB Neuropsychiatric disorders are often characterized by impaired insight into behaviour. Such an insight deficit has been suggested, but never directly tested, in drug addiction. Here we tested for the first time this impaired insight hypothesis in drug addiction, and examined its potential association with drug-seeking behaviour. We also tested potential modulation of these effects by cocaine urine status, an individual difference known to impact underlying cognitive functions and prognosis. Sixteen cocaine addicted individuals testing positive for cocaine in urine, 26 cocaine addicted individuals testing negative for cocaine in urine, and 23 healthy controls completed a probabilistic choice task that assessed objective preference for viewing four types of pictures (pleasant, unpleasant, neutral and cocaine). This choice task concluded by asking subjects to report their most selected picture type; correspondence between subjects' self-reports with their objective choice behaviour provided our index of behavioural insight. Results showed that the urine positive cocaine subjects exhibited impaired insight into their own choice behaviour compared with healthy controls; this same study group also selected the most cocaine pictures (and fewest pleasant pictures) for viewing. Importantly, however, it was the urine negative cocaine subjects whose behaviour was most influenced by insight, such that impaired insight in this subgroup only was associated with higher cocaine-related choice on the task and more severe actual cocaine use. These findings suggest that interventions to enhance insight may decrease drug-seeking behaviour, especially in urine negative cocaine subjects, potentially to improve their longer-term clinical outcomes. C1 [Moeller, Scott J.; Maloney, Thomas; Parvaz, Muhammad A.; Alia-Klein, Nelly; Woicik, Patricia A.; Wang, Gene-Jack; Goldstein, Rita Z.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Moeller, Scott J.] Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. [Parvaz, Muhammad A.] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Telang, Frank] NIAAA, Intramural Program, Bethesda, MD 20892 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Directors Off, Bethesda, MD 20892 USA. RP Goldstein, RZ (reprint author), Brookhaven Natl Lab, Dept Med, 300 Bell Ave,Bldg 490, Upton, NY 11973 USA. EM rgoldstein@bnl.gov RI Moeller, Scott/L-5549-2016; OI Moeller, Scott/0000-0002-4449-0844; Parvaz, Muhammad/0000-0002-2671-2327 FU National Institute on Drug Abuse [1R01DA023579, R21DA02062]; General Clinical Research Center [5-MO1-RR-10710] FX National Institute on Drug Abuse (grants 1R01DA023579, R21DA02062 to R. Z. G.) and the General Clinical Research Center (5-MO1-RR-10710). NR 38 TC 35 Z9 35 U1 3 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 2010 VL 133 BP 1484 EP 1493 DI 10.1093/brain/awq066 PN 5 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 590KV UT WOS:000277225700026 PM 20395264 ER PT J AU Voon, V Brezing, C Gallea, C Ameli, R Roelofs, K LaFrance, WC Hallett, M AF Voon, Valerie Brezing, Christina Gallea, Cecile Ameli, Rezvan Roelofs, Karin LaFrance, W. Curt, Jr. Hallett, Mark TI Emotional stimuli and motor conversion disorder SO BRAIN LA English DT Article DE conversion disorder; arousal; amydala; affect; psychogenic movement disorder ID MEDICALLY UNEXPLAINED SYMPTOMS; PSYCHOGENIC NONEPILEPTIC SEIZURES; PREFRONTAL CORTEX; ANTIDEPRESSANT TREATMENT; MOVEMENT-DISORDERS; PROSPECTIVE COHORT; FACIAL EXPRESSION; AMYGDALA RESPONSE; PARALYSIS; TRAUMA AB Conversion disorder is characterized by neurological signs and symptoms related to an underlying psychological issue. Amygdala activity to affective stimuli is well characterized in healthy volunteers with greater amygdala activity to both negative and positive stimuli relative to neutral stimuli, and greater activity to negative relative to positive stimuli. We investigated the relationship between conversion disorder and affect by assessing amygdala activity to affective stimuli. We conducted a functional magnetic resonance imaging study using a block design incidental affective task with fearful, happy and neutral face stimuli and compared valence contrasts between 16 patients with conversion disorder and 16 age- and gender-matched healthy volunteers. The patients with conversion disorder had positive movements such as tremor, dystonia or gait abnormalities. We also assessed functional connectivity between the amygdala and regions associated with motor preparation. A group by affect valence interaction was observed. Post hoc analyses revealed that whereas healthy volunteers had greater right amygdala activity to fearful versus neutral compared with happy versus neutral as expected, there were no valence differences in patients with conversion disorder. There were no group differences observed. The time course analysis also revealed greater right amygdala activity in patients with conversion disorder for happy stimuli (t = 2.96, P = 0.006) (with a trend for fearful stimuli, t = 1.81, P = 0.08) compared with healthy volunteers, with a pattern suggestive of impaired amygdala habituation even when controlling for depressive and anxiety symptoms. Using psychophysiological interaction analysis, patients with conversion disorder had greater functional connectivity between the right amygdala and the right supplementary motor area during both fearful versus neutral, and happy versus neutral 'stimuli' compared with healthy volunteers. These results were confirmed with Granger Causality Modelling analysis indicating a directional influence from the right amygdala to the right supplementary motor area to happy stimuli (P < 0.05) with a similar trend observed to fearful stimuli (P = 0.07). Our data provide a potential neural mechanism that may explain why psychological or physiological stressors can trigger or exacerbate conversion disorder symptoms in some patients. Greater functional connectivity of limbic regions influencing motor preparatory regions during states of arousal may underlie the pathophysiology of motor conversion symptoms. C1 [Voon, Valerie; Brezing, Christina; Gallea, Cecile; Hallett, Mark] NINDS, NIH, Bethesda, MD 20892 USA. [Voon, Valerie] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Ameli, Rezvan] NIMH, NIH, Bethesda, MD 20892 USA. [Roelofs, Karin] Leiden Inst Brain & Cognit, NL-2333 AK Leiden, Netherlands. [Roelofs, Karin] Leiden Univ, Inst Psychol Res, Clin Psychol Unit, NL-2333 AK Leiden, Netherlands. [LaFrance, W. Curt, Jr.] Brown Univ, Rhode Isl Hosp, Providence, RI 02903 USA. RP Voon, V (reprint author), NINDS, NIH, 10 Ctr Dr,Bldg 10,Rm 7D37, Bethesda, MD 20892 USA. EM voonv@ninds.nih.gov RI Roelofs, Karin/D-6780-2012 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This study was funded by and conducted at the intramural National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 58 TC 101 Z9 101 U1 8 U2 41 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 2010 VL 133 BP 1526 EP 1536 DI 10.1093/brain/awq054 PN 5 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 590KV UT WOS:000277225700030 PM 20371508 ER PT J AU Dalakas, MC Rakocevic, G Schmidt, J McElroy, B Harris-Love, MO Shrader, JA Levy, EW Dambrosia, J AF Dalakas, Marinos C. Rakocevic, Goran Schmidt, Jens McElroy, Beverly Harris-Love, Michael O. Shrader, Joseph A. Levy, Ellen W. Dambrosia, James TI Reply: Comment on alemtuzumab and inclusion body myositis SO BRAIN LA English DT Letter C1 [Dalakas, Marinos C.; Rakocevic, Goran; Schmidt, Jens; McElroy, Beverly] NINDS, Neuromuscular Dis Sect, Bethesda, MD 20892 USA. [Harris-Love, Michael O.; Shrader, Joseph A.; Levy, Ellen W.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Dambrosia, James] NINDS, Biostat Branch, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), Univ London Imperial Coll Sci Technol & Med, Div Neurosci, Burlington Danes Bldg,Hammersmith Hosp Campus,Du, London W12 0NN, England. EM m.dalakos@imperial.ac.uk RI Schmidt, Jens/B-5791-2013 NR 4 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 2010 VL 133 AR e136 DI 10.1093/brain/awp276 PN 5 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 590KV UT WOS:000277225700002 ER PT J AU Hill, A Rother, RP Wang, XD Morris, SM Quinn-Senger, K Kelly, R Richards, SJ Bessler, M Bell, L Hillmen, P Gladwin, MT AF Hill, Anita Rother, Russell P. Wang, Xunde Morris, Sidney M., Jr. Quinn-Senger, Kerry Kelly, Richard Richards, Stephen J. Bessler, Monica Bell, Leonard Hillmen, Peter Gladwin, Mark T. TI Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE paroxysmal nocturnal haemoglobinuria; nitric oxide; complement; pulmonary hypertension; haemolysis ID SICKLE-CELL-DISEASE; BRAIN NATRIURETIC PEPTIDE; CROSS-LINKED HEMOGLOBIN; ISOLATED RAT LUNGS; COMPLEMENT INHIBITOR; ARGININE METABOLISM; ARGINASE ACTIVITY; NATURAL-HISTORY; S-NITROSATION; NT-PROBNP AB P>Pulmonary hypertension (PH) is a common complication of haemolytic anaemia. Intravascular haemolysis leads to nitric oxide (NO) depletion, endothelial and smooth muscle dysregulation, and vasculopathy, characterized by progressive hypertension. PH has been reported in patients with paroxysmal nocturnal haemoglobinuria (PNH), a life-threatening haemolytic disease. We explored the relationship between haemolysis, systemic NO, arginine catabolism and measures of PH in 73 PNH patients enrolled in the placebo-controlled TRIUMPH (Transfusion Reduction Efficacy and Safety Clinical Investigation Using Eculizumab in Paroxysmal Nocturnal Haemoglobinuria) study. At baseline, intravascular haemolysis was associated with elevated NO consumption (P < 0 center dot 0001) and arginase-1 release (P < 0 center dot 0001). Almost half of the patients in the trial had elevated levels (>= 160 pg/ml) of N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of pulmonary vascular resistance and right ventricular dysfunction previously shown to indicate PH. Eculizumab treatment significantly reduced haemolysis (P < 0 center dot 001), NO depletion (P < 0 center dot 001), vasomotor tone (P < 0 center dot 05), dyspnoea (P = 0 center dot 006) and resulted in a 50% reduction in the proportion of patients with elevated NT-proBNP (P < 0 center dot 001) within 2 weeks of treatment. Importantly, the significant improvements in dyspnoea and NT-proBNP levels occurred without significant changes in anaemia. These data demonstrated that intravascular haemolysis in PNH produces a state of NO catabolism leading to signs of PH, including elevated NT pro-BNP and dyspnoea that are significantly improved by treatment with eculizumab. C1 [Hill, Anita; Kelly, Richard; Richards, Stephen J.; Hillmen, Peter] St Jamess Inst Oncol, Dept Haematol, Leeds, W Yorkshire, England. [Hill, Anita] Bradford Teaching Hosp NHS Fdn Trust, Dept Haematol, Bradford BD9 6RJ, W Yorkshire, England. [Rother, Russell P.; Quinn-Senger, Kerry; Bell, Leonard] Alexion Pharmaceut Inc, Cheshire, CT USA. [Wang, Xunde] NHLBI, Pulm & Vasc Med Branch, Dept Crit Care Med, NIH, Bethesda, MD 20892 USA. [Morris, Sidney M., Jr.] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. [Bessler, Monica] Washington Univ, Sch Med, Div Hematol, St Louis, MO USA. [Gladwin, Mark T.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15260 USA. [Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15260 USA. RP Hill, A (reprint author), Bradford Teaching Hosp NHS Fdn Trust, Dept Haematol, Duckworth Lane, Bradford BD9 6RJ, W Yorkshire, England. EM anitahill@nhs.net RI Morris, Sidney/I-3440-2015 FU Alexion Pharmaceuticals; Intramural Research Division of the NHLBI, NIH; Institute of Transfusion Medicine and the Hemophilia Center of Western Pennsylvania, Pittsburgh, PA FX This study was funded by a research grant from Alexion Pharmaceuticals, Inc. Dr Gladwin's work was funded by the Intramural Research Division of the NHLBI, NIH and by the Institute of Transfusion Medicine and the Hemophilia Center of Western Pennsylvania, Pittsburgh, PA. NR 59 TC 50 Z9 54 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAY PY 2010 VL 149 IS 3 BP 414 EP 425 DI 10.1111/j.1365-2141.2010.08096.x PG 12 WC Hematology SC Hematology GA 582MO UT WOS:000276601900011 PM 20230403 ER PT J AU Barst, RJ Mubarak, KK Machado, RF Ataga, KI Benza, RL Castro, O Naeije, R Sood, N Swerdlow, PS Hildesheim, M Gladwin, MT AF Barst, Robyn J. Mubarak, Kamal K. Machado, Roberto F. Ataga, Kenneth I. Benza, Raymond L. Castro, Oswaldo Naeije, Robert Sood, Namita Swerdlow, Paul S. Hildesheim, Mariana Gladwin, Mark T. CA ASSET Study Grp TI Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE sickle cell anaemia; pulmonary hypertension; endothelin receptor antagonism; haemodynamics; exercise capacity ID ACUTE CHEST SYNDROME; PLASMA ENDOTHELIN-1; RISK-FACTOR; THERAPY; ANEMIA; DEATH; COMPLICATIONS; ERYTHROCYTES; CRISIS AB P>Doppler-defined pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with 40% mortality at 40 months. To assess the effect of bosentan in SCD-PH, two randomized, double-blind, placebo-controlled, 16-week studies were initiated. Safety concerns are particularly relevant in SCD due to comorbid conditions. ASSET-1 and -2 enrolled patients with pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PH), respectively. Haemodynamics and 6-min walk distance (6MWD) were obtained at baseline and week 16. The studies were terminated due to slow site initiation and patient enrolment (n = 26). Bosentan appeared to be well tolerated. Although sample sizes were limited, in ASSET-1 at baseline, 6MWD correlated with cardiac output (CO; P = 0 center dot 006) with non-significant inverse correlations between 6MWD and pulmonary vascular resistance (PVR; P = 0 center dot 07) and between 6MWD and right atrial pressure (P = 0 center dot 08). In ASSET-2 at baseline, there was a non-significant correlation between 6MWD and CO (P = 0 center dot 06). Due to limited sample sizes, efficacy endpoints were not analysed. However, in both studies, non-significant increases in CO were observed with bosentan compared to placebo. Similarly, non-significant decreases in PVR were observed with bosentan. Limited data in SCD-PH suggest that a low 6MWD predicts a low CO. Standard-dose bosentan appears to be well tolerated. Further investigation is warranted. Clinicaltrials.gov registration numbers NCT00310830, NCT00313196, NCT00360087. C1 [Barst, Robyn J.] Columbia Univ, Dept Pediat Cardiol, New York, NY 10027 USA. [Mubarak, Kamal K.] Univ Florida, Dept Med, Gainesville, FL USA. [Machado, Roberto F.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Ataga, Kenneth I.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Benza, Raymond L.] Allegheny Gen Hosp, Dept Med, Pittsburgh, PA 15212 USA. [Castro, Oswaldo] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Naeije, Robert] Erasme Univ Hosp, B-1070 Brussels, Belgium. [Sood, Namita] Ohio State Univ, Dept Med, Columbus, OH 43210 USA. [Swerdlow, Paul S.] Wayne State Univ, Dept Internal Med, Detroit, MI 48202 USA. [Hildesheim, Mariana] NIH, Bethesda, MD 20892 USA. [Gladwin, Mark T.] Univ Pittsburgh, Pittsburgh, PA USA. RP Barst, RJ (reprint author), Columbia Univ, Dept Pediat Cardiol, New York, NY 10027 USA. EM robyn.barst@gmail.com RI Sood, Namita/E-4124-2011 FU Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; National Heart, Lung and Blood Institutes; University of Pittsburgh; Institute of Transfusion Medicine and the Hemophilia Center of Western Pennsylvania FX Actelion Pharmaceuticals Ltd, Allschwil, Switzerland sponsored the studies. The statistical analyses were supported by the National Heart, Lung and Blood Institutes and the University of Pittsburgh (MT Gladwin Funding). MT Gladwin is funded by the Institute of Transfusion Medicine and the Hemophilia Center of Western Pennsylvania. NR 30 TC 56 Z9 57 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAY PY 2010 VL 149 IS 3 BP 426 EP 435 DI 10.1111/j.1365-2141.2010.08097.x PG 10 WC Hematology SC Hematology GA 582MO UT WOS:000276601900012 PM 20175775 ER PT J AU Zorca, S Freeman, L Hildesheim, M Allen, D Remaley, AT Taylor, JG Kato, GJ AF Zorca, Suzana Freeman, Lita Hildesheim, Mariana Allen, Darlene Remaley, Alan T. Taylor, James G. Kato, Gregory J. TI Lipid levels in sickle-cell disease associated with haemolytic severity, vascular dysfunction and pulmonary hypertension SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE sickle cell disease; pulmonary hypertension; triglycerides; cholesterol; haemolysis ID NITRIC-OXIDE BIOAVAILABILITY; SECRETORY PHOSPHOLIPASE A(2); FATTY-ACIDS; CARDIOVASCULAR-DISEASE; ARGININE METABOLISM; ORGAN DYSFUNCTION; PLASMA; ANEMIA; DEATH; INFLAMMATION AB P>Pulmonary hypertension (PH) in sickle cell disease (SCD) is an emerging and important clinical problem. In a single-institution adult cohort of 365 patients, we investigated lipid and lipoprotein levels and their relationship to markers of intravascular haemolysis, vascular dysfunction and PH. In agreement with prior studies, we confirm significantly decreased plasma levels of total cholesterol, high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) in SCD versus ethnically-matched healthy controls. Several cholesterol parameters correlated significantly with markers of anaemia, but not endothelial activation or PH. More importantly, serum triglyceride levels were significantly elevated in SCD compared to controls. Elevated triglyceride levels correlated significantly with markers of haemolysis (lactate dehydrogenase and arginase; both P < 0 center dot 0005), endothelial activation (soluble E-selectin, P < 0 center dot 0001; soluble P-selectin, P = 0 center dot 02; soluble vascular cell adhesion molecule-1, P = 0 center dot 01), inflammation (leucocyte count, P = 0 center dot 0004; erythrocyte sedimentation rate, P = 0 center dot 02) and PH (amino-terminal brain natriuretic peptide, P = 0 center dot 002; prevalence of elevated tricuspid regurgitant velocity (TRV), P < 0 center dot 001). In a multivariate analysis, triglyceride levels correlated independently with elevated TRV (P = 0 center dot 002). Finally, forearm blood flow studies in adult patients with SCD demonstrated a significant association between increased triglyceride/HDL-C ratio and endothelial dysfunction (P < 0 center dot 05). These results characterize elevated plasma triglyceride levels as a potential risk factor for PH in SCD. C1 [Zorca, Suzana; Freeman, Lita; Allen, Darlene; Remaley, Alan T.; Taylor, James G.; Kato, Gregory J.] NHLBI, Pulm & Vasc Med Branch, Bethesda, MD 20892 USA. [Hildesheim, Mariana; Kato, Gregory J.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kato, GJ (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,MSC 1476,Bldg 10 CRC,Room 5-5140, Bethesda, MD 20892 USA. EM gkato@mail.nih.gov RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Taylor, James/0000-0002-4421-1809 FU Intramural NIH HHS [ZIA HL006012-02, ZIA HL006012-01] NR 50 TC 21 Z9 21 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAY PY 2010 VL 149 IS 3 BP 436 EP 445 DI 10.1111/j.1365-2141.2010.08109.x PG 10 WC Hematology SC Hematology GA 582MO UT WOS:000276601900013 PM 20230401 ER PT J AU Yeh, S Weichel, ED Faia, LJ Albini, TA Wroblewski, KK Stetler-Stevenson, M Ruiz, P Sen, HN Chan, CC Nussenblatt, RB AF Yeh, Steven Weichel, Eric D. Faia, Lisa J. Albini, Thomas A. Wroblewski, Keith K. Stetler-Stevenson, Maryalice Ruiz, Phillip Sen, H. Nida Chan, Chi Chao Nussenblatt, Robert B. TI 25-Gauge transconjunctival sutureless vitrectomy for the diagnosis of intraocular lymphoma SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID POSTERIOR SEGMENT DISEASE; INTERLEUKIN-6 RATIO; GENE REARRANGEMENT; FLOW-CYTOMETRY; MANAGEMENT; UVEITIS; 20-GAUGE; BIOPSY AB Background/Aims Diagnostic pars plana vitrectomy is a useful technique in the diagnosis of intraocular lymphoma (IOL); however, the role of transconjunctival sutureless vitrectomy (TSV) has not been fully explored for this indication. The purpose of this study was to review our experience with 25-gauge TSV for the diagnosis of IOL. Methods Patients who underwent 25-gauge TSV for the diagnosis of IOL (primary, secondary or recurrent) from two tertiary referral centres were reviewed. Demographic data and underlying medical conditions were reviewed. Preoperative and postoperative visual acuities (VA) and ophthalmic examination data were assessed. Cytopathology, flow cytometry, cytokine and gene rearrangement studies were assessed. Results Twelve patients underwent 25-gauge diagnostic TSV with a median follow-up time of 37 weeks. B-cell or T-cell IOL was diagnosed based on cytology in 3/12 patients (25%, 95% CI 8.9 to 53.2%) and in eight patients (67%, 95% CI 39.1 to 86.1%) using adjunctive diagnostic testing. VA stabilised or improved in 11 eyes (92%). Mean VA improved from 20/95 to 20/66 (p=0.055, paired t test). Conclusions 25-Gauge TSV is safe and effective for obtaining vitreous specimens for the evaluation of IOL. The availability of expert ophthalmic pathological consultation, flow cytometry, cytokine evaluation and gene rearrangement studies were essential to the diagnosis. C1 [Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Weichel, Eric D.; Wroblewski, Keith K.] Walter Reed Army Med Ctr, Dept Ophthalmol, Washington, DC 20307 USA. [Albini, Thomas A.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Stetler-Stevenson, Maryalice] NCI, Flow Cytometry Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Ruiz, Phillip] Univ Miami, Miller Sch Med, Dept Surg, Miami, FL 33136 USA. [Ruiz, Phillip] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10,10N-112,10 Ctr Dr, Bethesda, MD 20892 USA. EM DrBob@nei.nih.gov OI Albini, Thomas/0000-0003-2199-9047 FU National Eye Institute, National Institutes of Health; Heed Ophthalmic Foundation; Ronald G. Michels Foundation FX Funding This research is supported by Intramural Research Program of the National Eye Institute, National Institutes of Health. SY has received support from the Heed Ophthalmic Foundation and the Ronald G. Michels Foundation. NR 25 TC 8 Z9 10 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD MAY PY 2010 VL 94 IS 5 BP 633 EP 638 DI 10.1136/bjo.2009.167940 PG 6 WC Ophthalmology SC Ophthalmology GA 592JH UT WOS:000277374500023 PM 20447965 ER PT J AU Behrsing, HP Furniss, MJ Robillard, KA Tomaszewski, JE Parchment, RE AF Behrsing, Holger Peter Furniss, Michael J. Robillard, Kristine A. Tomaszewski, Joseph E. Parchment, Ralph E. TI In vitro comparison of O4-benzylfolate modulated, BCNU-induced toxicity in human bone marrow using CFU-GM and tumor cell lines SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE CFU-GM; Human bone marrow; KB and HT29 tumor cells; Neutropenia; O4-benzylfolate ID O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ACTIVITY; HEMATOPOIETIC PROGENITOR CELLS; FOLATE RECEPTOR ISOFORMS; ALKYLATING-AGENTS; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; O-6-BENZYLGUANINE-MEDIATED ENHANCEMENT; DIFFERENTIAL TOXICITY; NITROSOUREA ACTIVITY; CLONOGENIC ASSAYS; MALIGNANT GLIOMA AB 2-Amino-O4-benzylpteridine derivatives inactivate the human DNA repair protein O6-alkylguanine-DNA alkyltransferase and have been tested as modulators of alkylating agent chemotherapy. Recently, the therapeutic potential of O4-benzylfolate (O4BF) in modulating bis-chloroethylnitrosourea (BCNU) toxicity was demonstrated in vitro using human HT29 and KB tumor lines. The current studies replicated the previous findings in HT29 and KB cells using ATP as an endpoint. However, the effective treatment conditions were severely toxic to human neutrophil progenitors called CFU-granulocyte/macrophage (CFU-GM), which could not tolerate a parts per thousand yen40 mu M BCNU at any O4BF concentration. A lower BCNU concentration (10 mu M) in combination with O4BF (2-100 mu M) was only moderately tumoricidal. To screen for conditions tolerated by CFU-GM, bone marrow (BM) cells were pre-incubated (5 h) with O4BF, co-treated with O4BF and BCNU (42 h), washed, and plated to quantify CFU-GM survival. O4BF at 2 or 5 mu M progressively lowered the inhibitory concentrations (ICs) for BCNU, but further increases in O4BF concentrations did not. Increasing O4BF concentrations with constant BCNU (10 mu M) under the same prolonged exposure as in the human marrow study achieved only modest tumoricidal effects. In summary, the unexpected finding that normal BM cells are impacted by an agent developed to target malignant tissue refutes speculation that normal beta-folate receptor expressing hematopoietic cells will be spared. Further, the validated IC(90) endpoint from the huCFU-GM assay has provided a reference point for judging the potential therapeutic effectiveness of this investigational combination in man using in vitro assays. C1 [Behrsing, Holger Peter; Furniss, Michael J.; Robillard, Kristine A.; Parchment, Ralph E.] NCI, Predict Toxicol Sect, Lab Human Toxicol & Pharmacol, Appl & Dev Res Directorate,SAIC Frederick Inc, Frederick, MD 21702 USA. [Tomaszewski, Joseph E.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Behrsing, HP (reprint author), NCI, Predict Toxicol Sect, Lab Human Toxicol & Pharmacol, Appl & Dev Res Directorate,SAIC Frederick Inc, Bldg 438, Frederick, MD 21702 USA. EM behrsingh@mail.nih.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400] FX The authors express their gratitude and thanks to Danielle Mesa, Ryan Richards, and John Hamre III for the excellent technical support. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reXect 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 Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 51 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD MAY PY 2010 VL 65 IS 6 BP 1083 EP 1091 DI 10.1007/s00280-009-1113-7 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 569WB UT WOS:000275632400009 PM 19727731 ER PT J AU Kapetanovic, IM Muzzio, M Hu, SC Crowell, JA Rajewski, RA Haslam, JL Jong, L McCormick, DL AF Kapetanovic, Izet M. Muzzio, Miguel Hu, Shu-Chieh Crowell, James A. Rajewski, Roger A. Haslam, John L. Jong, Ling McCormick, David L. TI Pharmacokinetics and enhanced bioavailability of candidate cancer preventative agent, SR13668 in dogs and monkeys SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Formulation; Pharmacokinetics; Absorption enhancer; Bioavailability; Chemoprevention; Liver function enzymes ID INDOLE-3-CARBINOL AB SR13668 (2,10-dicarbethoxy-6-methoxy-5,7-dihydro-indolo-(2,3-b)carbazole), is a new candidate cancer chemopreventive agent under development. It was designed using computational modeling based on a naturally occurring indole-3-carbinol and its in vivo condensation products. It showed promising anti-cancer activity and its preclinical toxicology profile (genotoxicity battery and subchronic rat and dog studies) was unremarkable. However, it exhibited a very poor oral bioavailability (< 1%) in both rats and dogs. Therefore, a study was initiated to develop and evaluate in dogs and non-human primates formulations with a more favorable oral bioavailability. Two formulations utilizing surfactant/emulsifiers, PEG400:Labrasol(A (R)) and Solutol(A (R)), were tested in dogs and monkeys. Levels of SR13668 were measured in plasma and blood using a high-performance liquid chromatograph-tandem mass spectrometer system. Non-compartmental analysis was used to derive pharmacokinetic parameters including the bioavailability. The Solutol(A (R)) formulation yielded better bioavailability reaching a maximum of about 14.6 and 7.3% in dogs and monkeys, respectively, following nominal oral dose of ca. 90 mg SR13668/m(2). Blood levels of SR13668 were consistently about threefold higher than those in plasma in both species. SR13668 did not cause untoward hematology, clinical chemistry, or coagulation effects in dogs or monkeys with the exception of a modest, reversible increase in liver function enzymes in monkeys. The lipid-based surfactant/emulsifiers, especially Solutol(A (R)), markedly enhanced the oral bioavailability of SR13668 over that previously seen in preclinical studies. These formulations are being evaluated in a Phase 0 clinical study prior to further clinical development of this drug. C1 [Kapetanovic, Izet M.; Crowell, James A.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Muzzio, Miguel; Hu, Shu-Chieh; McCormick, David L.] IIT, Res Inst, Life Sci Grp, Chicago, IL 60616 USA. [Rajewski, Roger A.; Haslam, John L.] Univ Kansas, Biotechnol Innovat & Optimizat Ctr, Lawrence, KS 66047 USA. [Jong, Ling] SRI Int, Biosci Div, Menlo Pk, CA 94087 USA. RP Kapetanovic, IM (reprint author), NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, 6130 Execut Blvd,Rm 2116, Bethesda, MD 20892 USA. EM kapetani@mail.nih.gov FU NCI [N01-CN-43304] FX This research was conducted under NCI contract N01-CN-43304. The authors wish to thank Dr. Paul J. Limburg, the Lead Investigator, and co-workers at the Cancer Prevention Network (CPN), Mayo Clinic, Rochester MN 55905 of the Early Phase Prevention Trial Consortia (NCI Contract N01-CN-35000) for their assistance and advice. NR 15 TC 8 Z9 9 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD MAY PY 2010 VL 65 IS 6 BP 1109 EP 1116 DI 10.1007/s00280-009-1116-4 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 569WB UT WOS:000275632400012 PM 19756605 ER PT J AU Chia, VM Quraishi, SM Devesa, SS Purdue, MP Cook, MB McGlynn, KA AF Chia, Victoria M. Quraishi, Sabah M. Devesa, Susan S. Purdue, Mark P. Cook, Michael B. McGlynn, Katherine A. TI International Trends in the Incidence of Testicular Cancer, 1973-2002 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GERM-CELL TUMORS; EPSTEIN-BARR-VIRUS; BODY-MASS INDEX; INCREASING INCIDENCE; BIRTH COHORT; RISK-FACTORS; EUROPEAN COUNTRIES; POLYCHLORINATED-BIPHENYLS; OCCUPATIONAL-EXPOSURE; MATERNAL SMOKING AB Background: Whereas testicular cancer incidence rates have been widely reported in populations of Northern European ancestry, rates in other populations have been less frequently examined. In a prior report, global testicular cancer incidence rates and trends for the years 1973 to 1997 were summarized. The current report extends these analyses with an additional 5 years of data from Cancer Incidence in Five Continents. Methods: Age-standardized incidence rates over successive 5-year time periods were obtained for populations in the Americas, Asia, Europe, and Oceania. Results: In general, testicular cancer incidence remained highest in Northern European populations (8.0-9.0 per 100,000) and lowest in Asian and African populations (<1 per 100,000). One notable exception to this pattern, however, was the very high rate reported by the Valdivia, Chile registry (8.8 per 100,000). In many populations, rates rose between 1973 and 2002, although the increases were strongest and most consistent among populations of European ancestry. In certain European populations, such as those of Denmark and of Geneva, Switzerland, some recent plateauing of rates was evident. There was little evidence of increase and possible evidence of a modest decline in rates among east Asian populations. Trends by histology (seminoma and nonseminoma) were generally similar to one another. Conclusions: Risk of testicular cancer remains relatively high in Northern European populations and low in Asian and African populations. Similar trends by histology suggest common risk factors. Effect: Reasons for increasing rates among Northern Europeans and stable or declining rates among East Asians are unexplained, supporting the need for future etiologic studies. Cancer Epidemiol Biomarkers Prev; 19(5); 1151-9. (C)2010 AACR. C1 [McGlynn, Katherine A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP McGlynn, KA (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, EPS Suite 550,6120 Execut Blvd, Bethesda, MD 20892 USA. EM mcglynnk@mail.nih.gov RI Cook, Michael/A-5641-2009; Purdue, Mark/C-9228-2016 OI Cook, Michael/0000-0002-0533-7302; Purdue, Mark/0000-0003-1177-3108 FU NIH, National Cancer Institute FX Grant Support; NIH Intramural Research Program, National Cancer Institute. NR 75 TC 116 Z9 117 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2010 VL 19 IS 5 BP 1151 EP 1159 DI 10.1158/1055-9965.EPI-10-0031 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607HI UT WOS:000278489800002 PM 20447912 ER PT J AU Sokoll, LJ Sanda, MG Feng, ZD Kagan, J Mizrahi, IA Broyles, DL Partin, AW Srivastava, S Thompson, IM Wei, JT Zhang, Z Chan, DW AF Sokoll, Lori J. Sanda, Martin G. Feng, Ziding Kagan, Jacob Mizrahi, Isaac A. Broyles, Dennis L. Partin, Alan W. Srivastava, Sudhir Thompson, Ian M. Wei, John T. Zhang, Zhen Chan, Daniel W. TI A Prospective, Multicenter, National Cancer Institute Early Detection Research Network Study of [-2]proPSA: Improving Prostate Cancer Detection and Correlating with Cancer Aggressiveness SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PROPROSTATE-SPECIFIC ANTIGEN; ARTIFICIAL NEURAL-NETWORK; CLINICAL-TRIAL; PRECURSOR FORM; -5,-7 PROPSA; BENIGN PSA; SERUM; NG/ML; MEN; COMPLEX AB Background: The free prostate-specific antigen (PSA) isoform, [-2]proPSA, has been shown to be associated with prostate cancer. The study objective was to characterize the clinical utility of serum [-2]proPSA for prostate cancer detection and assess its association with aggressive disease. Methods: From among 669 subjects in a prospective prostate cancer detection study at four National Cancer Institute Early Detection Research Network clinical validation centers, 566 were eligible. Serum PSA, free PSA, and [-2]proPSA were measured (Beckman Coulter Access 2 Analyzer). Results: Two hundred and forty-five (43%) of the 566 participants had prostate cancer on biopsy. At 70% specificity, the sensitivity of %[-2]proPSA ([-2]proPSA/fPSA) was 54% [95% confidence interval (CI), 48-61%; null hypothesis, 40%]. Including %[-2]proPSA in a multivariate prediction model incorporating PSA and % fPSA improved the performance (P < 0.01). In the 2 to 4 ng/mL PSA range, %[-2]proPSA outperformed % fPSA (receiver operator characteristic-areas under the curve, 0.73 versus 0.61; P = 0.01). At 80% sensitivity, %[-2]proPSA had significantly higher specificity (51.6%; 95% CI, 41.2-61.8%) than PSA (29.9%; 95% CI, 21.040.0%) and % fPSA (28.9%; 95% CI, 20.1-39.0%). In the 2 to 10 ng/mL PSA range, a multivariate model had significant improvement (area under the curve, 0.76) over individual PSA forms (P < 0.01 to < 0.0001). At 80% sensitivity, the specificity of %[-2]proPSA (44.9%; 95% CI, 38.4-51.5%) was significantly higher than PSA (30.8%; 95% CI, 24.9-37.1%) and relatively higher than % fPSA (34.6%; 95% CI, 28.5-41.4%). %[-2]proPSA increased with increasing Gleason score (P < 0.001) and was higher in aggressive cancers (P = 0.03). Conclusions: In this prospective study, %[-2]proPSA showed potential clinical utility for improving prostate cancer detection and was related to the risk of aggressive disease. Impact: The addition of %[-2]proPSA could affect the early detection of prostate cancer. Cancer Epidemiol Biomarkers Prev; 19(5); 1193-200. (C)2010 AACR. C1 [Sokoll, Lori J.; Partin, Alan W.; Zhang, Zhen; Chan, Daniel W.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. [Sokoll, Lori J.; Partin, Alan W.; Zhang, Zhen; Chan, Daniel W.] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21287 USA. [Sanda, Martin G.] Beth Israel Deaconess Med Ctr, Div Urol, Boston, MA 02215 USA. [Feng, Ziding] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Kagan, Jacob; Srivastava, Sudhir] NCI, Canc Prevent Div, Canc Biomarkers Res Grp, Rockville, MD USA. [Mizrahi, Isaac A.; Broyles, Dennis L.] Beckman Coulter Inc, San Diego, CA USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Wei, John T.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. RP Sokoll, LJ (reprint author), Johns Hopkins Med Inst, Dept Pathol, 600 N Wolfe St,Meyer B-125, Baltimore, MD 21287 USA. EM lsokoll@jhmi.edu RI Sanda, Martin/A-6202-2013; Sanda, Martin/B-2023-2015; Wei, John/E-8967-2012 FU National Cancer Institute [U24 CA115102, U01 CA86368, U01 CA86323, U01 CA113913, U01 CA86402]; Beckman Coulter, Inc. FX Grant Support; National Cancer Institute U24 CA115102 (D. W. Chan), U01 CA86368 (Z. Feng), U01 CA86323 (A. W. Partin), U01 CA113913 (M. G. Sanda), U01 CA86402 (I. M. Thompson), and Beckman Coulter, Inc. (reagent support). NR 34 TC 108 Z9 112 U1 0 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2010 VL 19 IS 5 BP 1193 EP 1200 DI 10.1158/1055-9965.EPI-10-0007 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607HI UT WOS:000278489800007 PM 20447916 ER PT J AU Quinlan, SC Morton, LM Pfeiffer, RM Anderson, LA Landgren, O Warren, JL Engels, EA AF Quinlan, Scott C. Morton, Lindsay M. Pfeiffer, Ruth M. Anderson, Lesley A. Landgren, Ola Warren, Joan L. Engels, Eric A. TI Increased Risk for Lymphoid and Myeloid Neoplasms in Elderly Solid-Organ Transplant Recipients SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS; NON-HODGKIN-LYMPHOMA; PRIMARY CNS LYMPHOMA; HEPATITIS-C VIRUS; EPIDEMIOLOGY CONSORTIUM; LIVER-TRANSPLANTATION; RENAL-TRANSPLANTATION; CANCER INCIDENCE; IMMUNOSUPPRESSION; DISEASE AB Background: By assessing the spectrum of hematologic malignancies associated with solid-organ transplantation in the elderly, we provide information on the pathogenesis of lymphoid and myeloid neoplasms and the clinical manifestations of immunosuppression. Methods: Using data from the U.S. Surveillance, Epidemiology, and End Results Medicare database, we identified 83,016 cases with a hematologic malignancy (age 66-99 years) and 166,057 population-based controls matched to cases by age, sex, and calendar year. Medicare claims were used to identify a history of solid-organ transplantation. We used polytomous logistic regression to calculate odds ratios (OR) comparing transplantation history among cases with various hematologic malignancy subtypes and controls, adjusting for the matching factors and race. Results: A prior solid-organ transplant was identified in 216 (0.26%) cases and 204 (0.12%) controls. Transplantation was associated with increased risk for non-Hodgkin lymphomas [OR, 2.13; 95% confidence interval (95% CI), 1.67-2.72], especially diffuse large B-cell lymphoma (OR, 3.29; 95% CI, 2.28-4.76), marginal zone lymphoma (OR, 2.48; 95% CI, 1.17-5.22), lymphoplasmacytic lymphoma (OR, 3.32; 95% CI, 1.41-7.81), and T-cell lymphoma (OR, 3.07; 95% CI, 1.56-6.06). Transplantation was also associated with elevated risk of Hodgkin lymphoma (OR, 2.53; 95% CI, 1.01-6.35) and plasma cell neoplasms (OR, 1.91; 95% CI, 1.24-2.93). Risks for myeloid neoplasms were also elevated (OR, 1.99; 95% CI, 1.41-2.81). Conclusion: Solid-organ transplantation is associated with a wide spectrum of hematologic malignancies in the elderly. Risk was increased for four specific non-Hodgkin lymphoma subtypes for which a viral agent has been implicated, supporting an added role for immunosuppression. Impact: Our results support monitoring for a wide spectrum of hematologic malignancies following solid-organ transplant. Cancer Epidemiol Biomarkers Prev; 19(5); 1229-37.(C)2010 AACR. C1 [Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Anderson, Lesley A.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Warren, Joan L.] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland. RP Engels, EA (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7076, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Morton, Lindsay/B-5234-2015; OI Morton, Lindsay/0000-0001-9767-2310; Anderson, Lesley/0000-0002-1000-3649 FU National Cancer Institute FX Grant Support; Intramural Research Program of the National Cancer Institute. NR 40 TC 21 Z9 23 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2010 VL 19 IS 5 BP 1229 EP 1237 DI 10.1158/1055-9965.EPI-09-1220 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607HI UT WOS:000278489800011 PM 20406959 ER PT J AU Wu, KN Sinha, R Holmes, MD Giovannucci, E Willett, W Cho, E AF Wu, Kana Sinha, Rashmi Holmes, Michelle D. Giovannucci, Edward Willett, Walter Cho, Eunyoung TI Meat Mutagens and Breast Cancer in Postmenopausal Women-A Cohort Analysis SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HETEROCYCLIC AROMATIC-AMINES; COOKED MEAT; GENETIC-POLYMORPHISM; PREMENOPAUSAL WOMEN; RISK; MUTAGENS/CARCINOGENS; CONSUMPTION; METABOLISM; CARCINOGEN; PHIP AB Background: Mutagenic compounds produced when meats are cooked at high temperatures have been hypothesized to increase risk of breast cancer. Methods: We examined the association between intakes of the heterocyclic amines (HCA) MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline), PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), DiMeIQx (2-amino-3,4,8-trimethylimidazo[4,5-f]), and meat-derived mutagenic (MDM) activity and risk of breast cancer using a cooking method questionnaire administered in 1996 in the Nurses' Health Study. Between 1996 and 2006, 2,317 breast cancer cases were diagnosed during 533,618 person-years. Results: Higher intake of HCAs or MDM was not associated with elevated risk of breast cancer [multivariate relative risk and 95% confidence interval for the highest versus lowest quintile: MeIQx: 0.90 (0.79-1.03); PhIP: 0.92 (0.80-1.05); DiMeIQx: 0.92 (0.80-1.05); and MDM: 0.98 (0.85-1.12)]. HCA or MDM was not associated with estrogen receptor-positive/progesterone receptor-positive breast cancer risk either. There was some suggestion of a decreased risk of estrogen receptor-negative/progesterone receptor-negative breast cancer with higher intakes of MeIQx, DiMeIQx, and PhIP, but none of the associations were statistically significant. There was little evidence for an interaction between intake of cruciferous vegetables and HCA or MDM intake and risk of breast cancer. Conclusion: Higher consumption of mutagens from meats cooked at higher temperature and longer duration was not associated with increased risk of postmenopausal breast cancer. Impact: Overall prospective data including results from our study do not provide support for a substantial increase in risk of breast cancer with higher intake of HCAs. Cancer Epidemiol Biomarkers Prev; 19(5); 1301-10. (C)2010 AACR. C1 [Wu, Kana; Giovannucci, Edward; Willett, Walter; Cho, Eunyoung] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward; Willett, Walter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Holmes, Michelle D.; Giovannucci, Edward; Willett, Walter; Cho, Eunyoung] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Wu, KN (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2, Boston, MA 02115 USA. EM kana.wu@channing.harvard.edu RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU American Institute for Cancer Research; National Cancer Institute, NIH [CA 55075] FX Grant Support; American Institute for Cancer Research and National Cancer Institute, NIH grant CA 55075. NR 45 TC 9 Z9 9 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2010 VL 19 IS 5 BP 1301 EP 1310 DI 10.1158/1055-9965.EPI-10-0002 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607HI UT WOS:000278489800018 PM 20447922 ER PT J AU Timpson, NJ Brennan, P Gaborieau, V Moore, L Zaridze, D Matveev, V Szeszenia-Dabrowska, N Lissowska, J Mates, D Bencko, V Foretova, L Janout, V Chow, WH Rothman, N Boffetta, P Harbord, RM Smith, GD AF Timpson, Nicholas J. Brennan, Paul Gaborieau, Valerie Moore, Lee Zaridze, David Matveev, Vsevolod Szeszenia-Dabrowska, Neonilia Lissowska, Jolanta Mates, Dana Bencko, Vladimir Foretova, Lenka Janout, Vladimir Chow, Wong-Ho Rothman, Nathaniel Boffetta, Paolo Harbord, Roger M. Smith, George Davey TI Can Lactase Persistence Genotype Be Used to Reassess the Relationship between Renal Cell Carcinoma and Milk Drinking? Potentials and Problems in the Application of Mendelian Randomization SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ADULT-TYPE HYPOLACTASIA; LACTOSE-INTOLERANCE; CALCIUM-ABSORPTION; BONE-FRACTURES; EPIDEMIOLOGY; OSTEOPOROSIS; METAANALYSIS; DEFICIENCY; SYMPTOMS; CANCER AB Background: Increased risk of renal cell carcinoma (RCC) with milk consumption has been reported from observational studies. Whether this represents a causal association or is a result of confounding or bias is unclear. We assessed the potential for using genetic variation in lactase persistence as a tool for the study of this relationship. Methods: Using a large, hospital-based case-control study, we used observational, phenotypic, and genetic data to determine whether the MCM6 -13910 C/T(rs4988235) variant may be used as a nonconfounded and unbiased marker for milk consumption. Results: Consumption of milk during adulthood was associated with increased risk of RCC [odds ratio (OR), 1.35; 95% confidence interval (95% CI), 1.03-1.76; P = 0.03]. Among controls, consumption of milk was associated with the lactase persistence genotype at rs4988235 (OR, 2.39; 95% CI, 1.81-3.15; P = 6.9 x 10-10); however, the same genotype was not associated with RCC (OR, 1.01; 95% CI, 0.83-1.22; P = 0.9). In controls, milk consumption was associated with confounding factors, including smoking and educational attainment, whereas genotypes at rs4988235 showed negligible association with confounding factors. Conclusion: The absence of an association between the MCM6 genotype and RCC suggests that observational associations between milk consumption and RCC may be due to confounding or bias. Impact: Although these data suggest that associations between milk consumption and RCC may be spurious, if the association between genotype and behavioral exposure is weak, then the power of this test may be low. The nature of intermediate risk factor instrumentation is an important consideration in the undertaking and interpretation of this type of causal analysis experiment. Cancer Epidemiol Biomarkers Prev; 19(5); 1341-8. (C)2010 AACR. C1 [Timpson, Nicholas J.; Smith, George Davey] Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Bristol BS8 2BN, Avon, England. [Harbord, Roger M.] Univ Bristol, Dept Social Med, Bristol BS8 2BN, Avon, England. [Brennan, Paul; Gaborieau, Valerie; Boffetta, Paolo] Int Agcy Res Canc, F-69372 Lyon 08, France. [Moore, Lee; Chow, Wong-Ho; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Zaridze, David; Matveev, Vsevolod] Russian NN Blokhin Canc Res Ctr, Dept Epidemiol & Prevent, Moscow, Russia. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. [Bencko, Vladimir] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague 2, Czech Republic. [Foretova, Lenka] Mazaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Janout, Vladimir] Palacky Univ, Fac Med, Dept Prevent Med, CR-77147 Olomouc, Czech Republic. RP Timpson, NJ (reprint author), Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Oakfield House, Bristol BS8 2BN, Avon, England. EM n.j.timpson@bris.ac.uk RI Harbord, Roger/A-8699-2008; Zaridze, David/K-5605-2013; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; Fox, Laura /C-6249-2016; Davey Smith, George/A-7407-2013; OI Harbord, Roger/0000-0002-2257-8271; Davey Smith, George/0000-0002-1407-8314; Monsalve, Beatriz Elena/0000-0002-5994-866X; mates, dana/0000-0002-6219-9807; Lissowska, Jolanta/0000-0003-2695-5799; Timpson, Nicholas/0000-0002-7141-9189 FU Medical Research Council (MRC) [G0601625, G0600705] FX Grant Support; Medical Research Council (MRC) grant G0601625 (R.M. Harbord). The MRC CAiTE Centre is supported by the MRC, grant reference G0600705. NR 30 TC 10 Z9 10 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2010 VL 19 IS 5 BP 1341 EP 1348 DI 10.1158/1055-9965.EPI-09-1019 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607HI UT WOS:000278489800022 PM 20447925 ER PT J AU Prokunina-Olsson, L Fu, YP Tang, W Jacobs, KB Hayes, RB Kraft, P Berndt, SI Wacholder, S Yu, K Hutchinson, A Feigelson, HS Thun, MJ Diver, WR Albanes, D Virtamo, J Weinstein, S Schumacher, FR Cancel-Tassin, G Cussenot, O Valeri, A Andriole, GL Crawford, ED Haiman, CA Henderson, BE Kolonel, L Le Marchand, L Siddiq, A Riboli, E Travis, R Kaaks, R Isaacs, WB Isaacs, SD Gronberg, H Wiklund, F Xu, JF Vatten, LJ Hveem, K Kumle, M Tucker, M Hoover, RN Fraumeni, JF Hunter, DJ Thomas, G Chatterjee, N Chanock, SJ Yeager, M AF Prokunina-Olsson, Ludmila Fu, Yi-Ping Tang, Wei Jacobs, Kevin B. Hayes, Richard B. Kraft, Peter Berndt, Sonja I. Wacholder, Sholom Yu, Kai Hutchinson, Amy Feigelson, Heather Spencer Thun, Michael J. Diver, W. Ryan Albanes, Demetrius Virtamo, Jarmo Weinstein, Stephanie Schumacher, Fredrick R. Cancel-Tassin, Geraldine Cussenot, Olivier Valeri, Antoine Andriole, Gerald L. Crawford, E. David Haiman, Christopher A. Henderson, Brian E. Kolonel, Laurence Le Marchand, Loic Siddiq, Afshan Riboli, Elio Travis, Ruth Kaaks, Rudolf Isaacs, William B. Isaacs, Sarah D. Gronberg, Henrik Wiklund, Fredrik Xu, Jianfeng Vatten, Lars J. Hveem, Kristian Kumle, Merethe Tucker, Margaret Hoover, Robert N. Fraumeni, Joseph F., Jr. Hunter, David J. Thomas, Gilles Chatterjee, Nilanjan Chanock, Stephen J. Yeager, Meredith TI Refining the Prostate Cancer Genetic Association within the JAZF1 Gene on Chromosome 7p15.2 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; RISK-ASSOCIATED LOCI; SUSCEPTIBILITY LOCI; MULTIETHNIC COHORT; DIABETES-MELLITUS; COMMON VARIANTS; METAANALYSIS; 8Q24; IDENTIFICATION; REPLICATION AB Background: Genome-wide association studies have identified multiple genetic variants associated with susceptibility to prostate cancer (PrCa). In the two-stage Cancer Genetic Markers of Susceptibility prostate cancer scan, a single-nucleotide polymorphism (SNP), rs10486567, located within intron 2 of JAZF1 gene on chromosome 7p15.2, showed a promising association with PrCa overall (P = 2.14 x 10(-6)), with a suggestion of stronger association with aggressive disease (P = 1.2 x 10(-7)). Methods: In the third stage of genome-wide association studies, we genotyped 106 JAZF1 SNPs in 10,286 PrCa cases and 9,135 controls of European ancestry. Results: The strongest association was observed with the initial marker rs10486567, which now achieves genome-wide significance [P = 7.79 x 10(-11); OR(HET), 1.19 (95% confidence interval, 1.12-1.27); OR(HOM), 1.37 (95% confidence interval, 1.20-1.56)]. We did not confirm a previous suggestion of a stronger association of rs10486567 with aggressive disease (P = 1.60 x 10(-4) for aggressive cancer, n = 4,597; P = 3.25 x 10(-8) for non-aggressive cancer, n = 4,514). Based on a multilocus model with adjustment for rs10486567, no additional independent signals were observed at chromosome 7p15.2. There was no association between PrCa risk and SNPs in JAZF1 previously associated with height (rs849140; P = 0.587), body stature (rs849141, tagged by rs849136; P = 0.171), and risk of type 2 diabetes and systemic lupus erythematosus (rs864745, tagged by rs849142; P = 0.657). Conclusion: rs10486567 remains the most significant marker for PrCa risk within JAZF1 in individuals of European ancestry. Impact: Future studies should identify all variants in high linkage disequilibrium with rs10486567 and evaluate their functional significance for PrCa. Cancer Epidemiol Biomarkers Prev; 19(5); 1349-55. (C)2010 AACR. C1 [Prokunina-Olsson, Ludmila; Fu, Yi-Ping; Tang, Wei; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Jacobs, Kevin B.; Hutchinson, Amy; Chanock, Stephen J.; Yeager, Meredith] NCI, Core Genotyping Facil, Adv Technol Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv, Gaithersburg, MD USA. [Hayes, Richard B.] NYU, Dept Environm Med, Sch Med, New York, NY 10016 USA. [Kraft, Peter; Schumacher, Fredrick R.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Cambridge, MA 02138 USA. [Schumacher, Fredrick R.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Cambridge, MA 02138 USA. [Hunter, David J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. [Feigelson, Heather Spencer; Thun, Michael J.; Diver, W. Ryan] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Cancel-Tassin, Geraldine; Cussenot, Olivier; Valeri, Antoine] Hop Tenon, AP HP, Ctr Rech Pathol Prostat, F-75970 Paris, France. [Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Crawford, E. David] Univ Colorado, Dept Surg, Denver, CO 80202 USA. [Crawford, E. David] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Kolonel, Laurence; Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Siddiq, Afshan; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, London, England. [Travis, Ruth] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Kaaks, Rudolf] German Canc Res Ctr, Div Clin Epidemiol, Heidelberg, Germany. [Isaacs, William B.; Isaacs, Sarah D.] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. [Gronberg, Henrik; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Xu, Jianfeng] Wake Forest Univ, Sch Med, Ctr Canc Genom, Winston Salem, NC 27109 USA. [Vatten, Lars J.; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth, N-7034 Trondheim, Norway. [Kumle, Merethe] Univ Tromso, Inst Community Med, Tromso, Norway. RP Prokunina-Olsson, L (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM prokuninal@mail.nih.gov RI Tucker, Margaret/B-4297-2015; Albanes, Demetrius/B-9749-2015; OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Hayes, Richard/0000-0002-0918-661X; Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU National Cancer Institute, NIH [HHSN261200800001E]; [UO1-CA98233]; [UO1-CA98710]; [UO1-CA98216]; [UO1-CA98758] FX Grant Support; Federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E, and grants to the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, UO1-CA98233, UO1-CA98710, UO1-CA98216, and UO1-CA98758. NR 34 TC 17 Z9 17 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2010 VL 19 IS 5 BP 1349 EP 1355 DI 10.1158/1055-9965.EPI-09-1181 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607HI UT WOS:000278489800023 PM 20406958 ER PT J AU Rajaraman, P Brenner, AV Neta, G Pfeiffer, R Wang, SS Yeager, M Thomas, G Fine, HA Linet, MS Rothman, N Chanock, SJ Inskip, PD AF Rajaraman, Preetha Brenner, Alina V. Neta, Gila Pfeiffer, Ruth Wang, Sophia S. Yeager, Meredith Thomas, Gilles Fine, Howard A. Linet, Martha S. Rothman, Nathaniel Chanock, Stephen J. Inskip, Peter D. TI Risk of Meningioma and Common Variation in Genes Related to Innate Immunity SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ADULT BRAIN-TUMORS; HODGKIN-LYMPHOMA; POLYMORPHISMS; GLIOMA; VARIANTS; DISEASE; NFKB1; SUSCEPTIBILITY; INFLAMMATION; METAANALYSIS AB Background: The etiology of meningioma, the second most common type of adult brain tumor in the United States, is largely unknown. Prior studies indicate that history of immune-related conditions may affect the risk of meningioma. Methods: To identify genetic markers for meningioma in genes involved with innate immunity, we conducted an exploratory association study of 101 meningioma cases and 330 frequency-matched controls of European ancestry using subjects from a hospital-based study conducted by the National Cancer Institute. We genotyped 1,407 "tag" single nucleotide polymorphisms (SNP) in 148 genetic regions chosen on the basis of an r(2) > 0.8 and minor allele frequency of >5% in Caucasians in HapMap1. Risk of meningioma was estimated by odds ratios and 95% confidence intervals. Results: Seventeen SNPs distributed across 12 genetic regions (NFKB1 (3), FCER1G (3), CCR6 (2), VCAM1, CD14, TNFRSF18, RAC2, XDH, C1D, TLR1/TLR10/TLR6, NOS1, and DEFA5) were associated with the risk of meningioma with P < 0.01. Although individual SNP tests were not significant after controlling for multiple comparisons, gene region-based tests were statistically significant (P < 0.05) for TNFRSF18, NFKB1, FCER1G, CD14, C1D, CCR6, and VCAM1. Conclusions and Impact: Our results indicate that common genetic polymorphisms in innate immunity genes may be associated with risk of meningioma. Given the small sample size, replication of these results in a larger study of meningioma is needed. Cancer Epidemiol Biomarkers Prev; 19(5); 1356-61. (C)2010 AACR. C1 [Rajaraman, Preetha] NCI, REB, NIH, Dept Hlth & Human Serv,Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fine, Howard A.] NCI, Neurooncol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Duarte, CA 91010 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Yeager, Meredith; Thomas, Gilles; Chanock, Stephen J.] NCI, Core Genotyping Facil, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Rajaraman, P (reprint author), NCI, REB, NIH, Dept Hlth & Human Serv,Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Room 7058, Bethesda, MD 20892 USA. EM rajarama@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 FU NCI, NIH, Department of Health and Human Services; NCI, NIH [N01-CO-12400] FX Grant Support; Grant Support: This research was supported by intramural funds from the NCI, NIH, Department of Health and Human Services, and has been funded in whole or in part with federal funds from the NCI, NIH, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 31 TC 19 Z9 19 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2010 VL 19 IS 5 BP 1356 EP 1361 DI 10.1158/1055-9965.EPI-09-1151 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607HI UT WOS:000278489800024 PM 20406964 ER PT J AU Gulley, JL Arlen, PM Madan, RA Tsang, KY Pazdur, MP Skarupa, L Jones, JL Poole, DJ Higgins, JP Hodge, JW Cereda, V Vergati, M Steinberg, SM Halabi, S Jones, E Chen, C Parnes, H Wright, JJ Dahut, WL Schlom, J AF Gulley, James L. Arlen, Philip M. Madan, Ravi A. Tsang, Kwong-Yok Pazdur, Mary P. Skarupa, Lisa Jones, Jacquin L. Poole, Diane J. Higgins, Jack P. Hodge, James W. Cereda, Vittore Vergati, Matteo Steinberg, Seth M. Halabi, Susan Jones, Elizabeth Chen, Clara Parnes, Howard Wright, John J. Dahut, William L. Schlom, Jeffrey TI Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 30-JUN 03, 2008 CL Chicago, IL SP Amer Soc Clin Oncol DE Cancer vaccine; Immunotherapy; Prostate cancer; Overall survival; PSA-TRICOM; PROSTVAC ID COLONY-STIMULATING FACTOR; RANDOMIZED PHASE-II; COMBINATION THERAPY; COSTIMULATORY MOLECULES; IMMUNE-RESPONSES; T-CELLS; ANTIGEN; TRIAL; ACTIVATION; INDUCTION AB A concurrent multicenter, randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of enhanced median overall survival (OS) (p = 0.0061) in patients with metastatic castrate-resistant prostate cancer (mCRPC). The study reported here employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. Thirty-two patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three costimulatory molecules. Patients received boosters with recombinant fowlpox containing the same four transgenes. Twelve of 32 patients showed declines in serum PSA post-vaccination and 2/12 showed decreases in index lesions. Median OS was 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). Patients with greater PSA-specific T-cell responses showed a trend (p = 0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF versus no GM-CSF. Patients with a Halabi predicted survival of < 18 months (median predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of a parts per thousand yen18 months (median predicted survival 20.9 months) will meet or exceed 37.3 months, with 12/15 patients living longer than predicted (p = 0.035). Treg suppressive function was shown to decrease following vaccine in patients surviving longer than predicted, and increase in patients surviving less than predicted. This hypothesis-generating study provides evidence that patients with more indolent mCRPC (Halabi predicted survival a parts per thousand yen18 months) may best benefit from vaccine therapy. C1 [Gulley, James L.; Arlen, Philip M.; Madan, Ravi A.; Tsang, Kwong-Yok; Pazdur, Mary P.; Skarupa, Lisa; Poole, Diane J.; Higgins, Jack P.; Hodge, James W.; Cereda, Vittore; Vergati, Matteo; Schlom, Jeffrey] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gulley, James L.; Arlen, Philip M.; Madan, Ravi A.; Jones, Jacquin L.; Dahut, William L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Rockville, MD 20852 USA. [Halabi, Susan] Duke Univ, Sch Med, Dept Biostat & Bioinformat, DUMC, Durham, NC 27710 USA. [Jones, Elizabeth] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Chen, Clara] NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. [Parnes, Howard] NCI, Canc Prevent Div, NIH, Rockville, MD 20852 USA. [Wright, John J.] NCI, Invest Drug Branch, Canc Therapy & Evaluat Program, NIH, Rockville, MD 20852 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS [Z01 BC010666-04] NR 33 TC 155 Z9 159 U1 2 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAY PY 2010 VL 59 IS 5 BP 663 EP 674 DI 10.1007/s00262-009-0782-8 PG 12 WC Oncology; Immunology SC Oncology; Immunology GA 563OJ UT WOS:000275141900003 PM 19890632 ER PT J AU Sarnovsky, R Tendler, T Makowski, M Kiley, M Antignani, A Traini, R Zhang, JL Hassan, R FitzGerald, DJ AF Sarnovsky, Robert Tendler, Tara Makowski, Matheusz Kiley, Maureen Antignani, Antonella Traini, Roberta Zhang, Jingli Hassan, Raffit FitzGerald, David J. TI Initial characterization of an immunotoxin constructed from domains II and III of cholera exotoxin SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Exotoxin; Cholix; Immunotoxin; Neutralization; Antibody ID SINGLE-CHAIN IMMUNOTOXIN; NON-HODGKINS-LYMPHOMA; HAIRY-CELL LEUKEMIA; PSEUDOMONAS EXOTOXIN; PHASE-I; RECOMBINANT IMMUNOTOXIN; MONOCLONAL-ANTIBODIES; VIBRIO-CHOLERAE; CANCER-THERAPY; SOLID TUMORS AB Immunotoxins are antibody-toxin fusion proteins under development as cancer therapeutics. In early clinical trials, immunotoxins constructed with domains II and III of Pseudomonas exotoxin (termed PE38), have produced a high rate of complete remissions in Hairy Cell Leukemia and objective responses in other malignancies. Cholera exotoxin (also known as cholix toxin) has a very similar three-dimensional structure to Pseudomonas exotoxin (PE) and when domains II and III of each are compared at the primary sequence level, they are 36% identical and 50% similar. Here we report on the construction and activity of an immunotoxin made with domains II and III of cholera exotoxin (here termed CET40). In cell viability assays, the CET40 immunotoxin was equipotent to tenfold less active compared to a PE-based immunotoxin made with the same single-chain Fv. A major limitation of toxin-based immunotoxins is the development of neutralizing antibodies to the toxin portion of the immunotoxin. Because of structure and sequence similarities, we evaluated a CET40 immunotoxin for the presence of PE-related epitopes. In western blots, three-of-three anti-PE antibody preparations failed to react with the CET40 immunotoxin. More importantly, in neutralization studies neither these antibodies nor those from patients with neutralizing titers to PE38, neutralized the CET40-immunotoxin. We propose that the use of modular components such as antibody Fvs and toxin domains will allow a greater flexibility in how these agents are designed and deployed including the sequential administration of a second immunotoxin after patients have developed neutralizing antibodies to the first. C1 [Sarnovsky, Robert; Tendler, Tara; Makowski, Matheusz; Kiley, Maureen; Antignani, Antonella; Traini, Roberta; Zhang, Jingli; Hassan, Raffit; FitzGerald, David J.] NCI, Mol Biol Lab, CCR, NIH,HHS, Bethesda, MD 20892 USA. RP FitzGerald, DJ (reprint author), NCI, Mol Biol Lab, CCR, NIH,HHS, 37 Convent Dr,Room 5124, Bethesda, MD 20892 USA. EM djpf@helix.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 41 TC 10 Z9 10 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAY PY 2010 VL 59 IS 5 BP 737 EP 746 DI 10.1007/s00262-009-0794-4 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA 563OJ UT WOS:000275141900010 PM 20091030 ER PT J AU Lipkin, SM Chao, EC Moreno, V Rozek, LS Rennert, H Pinchev, M Dizon, D Rennert, G Kopelovich, L Gruber, SB AF Lipkin, Steven M. Chao, Elizabeth C. Moreno, Victor Rozek, Laura S. Rennert, Hedy Pinchev, Mila Dizon, Diana Rennert, Gad Kopelovich, Levy Gruber, Stephen B. TI Genetic Variation in 3-Hydroxy-3-Methylglutaryl CoA Reductase Modifies the Chemopreventive Activity of Statins for Colorectal Cancer SO CANCER PREVENTION RESEARCH LA English DT Article ID COENZYME-A REDUCTASE; LIPOPROTEIN CHOLESTEROL RESPONSE; INDUCED APOPTOSIS; RISK; INHIBITOR; SIMVASTATIN; COMBINATION; PRAVASTATIN; CARCINOMA; EVENTS AB Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis, modifies the effect of statins on serum cholesterol levels. Long-term use of statins is associated with a reduced risk of colorectal cancer (CRC) in some, but not all, studies. We genotyped variants in 40 candidate genes important for cholesterol synthesis and metabolism in a population-based case-control study of CRC involving 2,138 incident cases and 2,049 population-based controls. We identified a single-nucleotide polymorphism in the HMGCR gene that significantly modified the protective association between statins and CRC risk. Compared with nonusers, the unadjusted odds ratio of CRC among statin users with the A/A genotype of rs12654264 in HMGCR was 0.3 (95% confidence interval, 0.18-0.51) and among statin users with the T/T genotype was 0.66 (95% confidence interval, 0.41-1.06; P-interaction = 0.0012). This genetic variant (A/A genotype of rs12654264) also was associated with lower serum levels of low-density lipoprotein among all cases and controls. In colon cancer cell lines, the reduction in cholesterol levels after statin treatment was substantially stronger in cells carrying the A/A genotype, and this difference was related to alternative splicing involving the HMGCR statin-binding domain. We anticipate that these data may advance the development of personalized statin use for reducing the risk of cancer as well as cardiovascular disease among the approximately 25 million people currently using statins worldwide. Cancer Prev Res; 3(5); 597-603. (C) 2010 AACR. C1 [Lipkin, Steven M.] Weill Cornell Sch Med, Dept Med, New York, NY USA. [Chao, Elizabeth C.; Dizon, Diana] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Moreno, Victor; Rozek, Laura S.; Gruber, Stephen B.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Moreno, Victor; Gruber, Stephen B.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Rozek, Laura S.] Univ Michigan, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Gruber, Stephen B.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Moreno, Victor] ICO, IDIBELL, Barcelona, Spain. [Moreno, Victor] Univ Barcelona, Barcelona, Spain. [Rennert, Hedy; Pinchev, Mila; Rennert, Gad] Technion Israel Inst Technol, Clalit Hlth Serv Natl Canc Control Ctr, Haifa, Israel. [Rennert, Hedy; Pinchev, Mila; Rennert, Gad] Technion Israel Inst Technol, Dept Community Med & Epidemiol, Carmel Med Ctr, Haifa, Israel. [Rennert, Hedy; Pinchev, Mila; Rennert, Gad] Technion Israel Inst Technol, Bruce Rappaport Fac Med, IL-31096 Haifa, Israel. [Kopelovich, Levy] NCI, Canc Prevent Div, Rockville, MD USA. RP Lipkin, SM (reprint author), Weill Cornell Med Coll, Room 718 HSS, New York, NY 10021 USA. EM stl2012@med.cornell.edu; sgruber@umich.edu RI Moreno, Victor/A-1697-2010 OI Moreno, Victor/0000-0002-2818-5487 FU National Cancer Institute [N01-CN43308, R01 CA81488]; University of Michigan Cancer Center [5 P30 CA46592]; Spanish Secretaria de Estado de Universidades e Investigacion [PR2006-0474]; Irving Weinstein and Ravitz Foundation FX National Cancer Institute grants N01-CN43308 (S. M. Lipkin) and R01 CA81488 (S. B. Gruber), University of Michigan Cancer Center Support Grant 5 P30 CA46592, Spanish Secretaria de Estado de Universidades e Investigacion grant PR2006-0474 (V. Moreno), and the Irving Weinstein and Ravitz Foundation (S. B. Gruber). NR 30 TC 42 Z9 43 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAY PY 2010 VL 3 IS 5 BP 597 EP 603 DI 10.1158/1940-6207.CAPR-10-0007 PG 7 WC Oncology SC Oncology GA 591IP UT WOS:000277294000005 PM 20403997 ER PT J AU Irons, R Tsuji, PA Carlson, BA Ouyang, P Yoo, MH Xu, XM Hatfield, DL Gladyshev, VN Davis, CD AF Irons, Robert Tsuji, Petra A. Carlson, Bradley A. Ouyang, Ping Yoo, Min-Hyuk Xu, Xue-Ming Hatfield, Dolph L. Gladyshev, Vadim N. Davis, Cindy D. TI Deficiency in the 15-kDa Selenoprotein Inhibits Tumorigenicity and Metastasis of Colon Cancer Cells SO CANCER PREVENTION RESEARCH LA English DT Article ID THIOREDOXIN REDUCTASE; SELENIUM; EXPRESSION; PROTEIN; TUMOR; CARCINOMA; GROWTH; ROLES; RISK; GENE AB Selenium has cancer-preventive activity that is mediated, in part, through selenoproteins. The role of the 15-kDa selenoprotein (Sep15) in colon cancer was assessed by preparing and using mouse colon CT26 cells stably transfected with short hairpin RNA constructs targeting Sep15. Metabolic (75)Se labeling and Northern and Western blot analyses revealed that >90% of Sep15 was downregulated. Growth of the resulting Sep15-deficient CT26 cells was reduced (P < 0.01), and cells formed significantly (P < 0.001) fewer colonies in soft agar compared with control CT26 cells. Whereas most (14 of 15) BALB/c mice injected with control cells developed tumors, few (3 of 30) mice injected with Sep15-deficient cells developed tumors (P < 0.0001). The ability to form pulmonary metastases had similar results. Mice injected with the plasmid-transfected control cells had >250 lung metastases per mouse; however, mice injected with cells with downregulation of Sep15 only had 7.8 +/- 5.4 metastases. To investigate molecular targets affected by Sep15 status, gene expression patterns between control and knockdown CT26 cells were compared. Ingenuity Pathways Analysis was used to analyze the 1,045 genes that were significantly (P < 0.001) affected by Sep15 deficiency. The highest-scored biological functions were cancer and cellular growth and proliferation. Consistent with these observations, subsequent analyses revealed a G(2)-M cell cycle arrest in cells with targeted downregulation of Sep15. In contrast to CT26 cells, Sep15-targeted downregulation in Lewis lung carcinoma (LLC1) cells did not affect anchorage-dependent or anchorage-independent cell growth. These data suggest tissue specificity in the cancer-protective effects of Sep15 downregulation, which are mediated, at least in part, by influencing the cell cycle. Cancer Prev Res; 3(5); 630-9. (C) 2010 AACR. C1 [Davis, Cindy D.] NCI, Nutr Sci Res Grp, Canc Prevent Div, Rockville, MD 20892 USA. [Tsuji, Petra A.] NCI, Canc Prevent Fellowship Program, Rockville, MD 20892 USA. [Irons, Robert; Tsuji, Petra A.; Carlson, Bradley A.; Ouyang, Ping; Yoo, Min-Hyuk; Xu, Xue-Ming; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Bethesda, MD 20892 USA. [Irons, Robert] VE Irons Inc, Kansas City, MO USA. [Gladyshev, Vadim N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Davis, CD (reprint author), NCI, Nutr Sci Res Grp, Canc Prevent Div, 6130 Execut Blvd,Suite 3159, Rockville, MD 20892 USA. EM davisci@mail.nih.gov RI Gladyshev, Vadim/A-9894-2013 FU National Cancer Institute; Cancer Prevention Fellowship Program; NIH [CA080946] FX National Cancer Institute Intramural support; Cancer Prevention Fellowship Program; Division of Cancer Prevention, National Cancer Institute; and NIH grant CA080946. NR 29 TC 33 Z9 34 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAY PY 2010 VL 3 IS 5 BP 630 EP 639 DI 10.1158/1940-6207.CAPR-10-0003 PG 10 WC Oncology SC Oncology GA 591IP UT WOS:000277294000009 PM 20388823 ER PT J AU Bender, AM Collier, LS Rodriguez, FJ Tieu, C Larson, JD Halder, C Mahlum, E Kollmeyer, TM Akagi, K Sarkar, G Largaespada, DA Jenkins, RB AF Bender, Aaron M. Collier, Lara S. Rodriguez, Fausto J. Tieu, Christina Larson, Jon D. Halder, Chandralekha Mahlum, Eric Kollmeyer, Thomas M. Akagi, Keiko Sarkar, Gobinda Largaespada, David A. Jenkins, Robert B. TI Sleeping Beauty-Mediated Somatic Mutagenesis Implicates CSF1 in the Formation of High-Grade Astrocytomas SO CANCER RESEARCH LA English DT Article ID COLONY-STIMULATING FACTOR; CANCER GENE DISCOVERY; FACTOR-I; TUMOR-CELLS; STEM-CELLS; EXPRESSION; MOUSE; MICE; RECEPTOR; GLIOMAS AB The Sleeping Beauty (SB) transposon system has been used as an insertional mutagenesis tool to identify novel cancer genes. To identify glioma-associated genes, we evaluated tumor formation in the brain tissue from 117 transgenic mice that had undergone constitutive SB-mediated transposition. Upon analysis, 21 samples (18%) contained neoplastic tissue with features of high-grade astrocytomas. These tumors expressed glial markers and were histologically similar to human glioma. Genomic DNA from SB-induced astrocytoma tissue was extracted and transposon insertion sites were identified. Insertions in the growth factor gene Csf1 were found in 13 of the 21 tumors (62%), clustered in introns 5 and 8. Using reverse transcription-PCR, we documented increased Csf1 RNAs in tumor versus adjacent normal tissue, with the identification of transposon-terminated Csf1 mRNAs in astrocytomas with SB insertions in intron 8. Analysis of human glioblastomas revealed increased levels of Csf1 RNA and protein. Together, these results indicate that SB-insertional mutagenesis can identify high-grade astrocytoma-associated genes and they imply an important role for CSF1 in the development of these tumors. Cancer Res; 70(9); 3557-65. (C) 2010 AACR. C1 [Bender, Aaron M.; Rodriguez, Fausto J.; Tieu, Christina; Halder, Chandralekha; Mahlum, Eric; Kollmeyer, Thomas M.; Sarkar, Gobinda; Jenkins, Robert B.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Collier, Lara S.] Univ Wisconsin, Sch Pharm, Div Pharmaceut Sci, Madison, WI 53706 USA. [Larson, Jon D.; Largaespada, David A.] Univ Minnesota, Arnold & Mabel Beckman Ctr Genome Engn, Minneapolis, MN USA. [Larson, Jon D.; Largaespada, David A.] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA. [Akagi, Keiko] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. [Akagi, Keiko] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Jenkins, RB (reprint author), Mayo Clin, Dept Lab Med & Pathol, Hilton 9-71,150 3rd St SW, Rochester, MN 55905 USA. EM rjenkins@mayo.edu RI Largaespada, David/C-9832-2014 FU Minnesota Partnership for Biotechnology and Medical Genomics [L6526214101]; NIH [R01CA113636, K01CA122183]; T32 National Research Service Award [PA-06-468]; American Cancer Society FX Grant Support; Minnesota Partnership for Biotechnology and Medical Genomics grant L6526214101 (D. A. Largaespada and R. B. Jenkins), an NIH R01CA113636 (D. A. Largaespada), a T32 National Research Service Award institutional training grant PA-06-468, an American Cancer Society predoctoral fellowship, and by NIH K01CA122183 (L. S. Collier). NR 46 TC 25 Z9 25 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2010 VL 70 IS 9 BP 3557 EP 3565 DI 10.1158/0008-5472.CAN-09-4674 PG 9 WC Oncology SC Oncology GA 607GD UT WOS:000278486200015 PM 20388773 ER PT J AU Strasak, AM Goebel, G Concin, H Pfeiffer, RM Brant, LJ Nagel, G Oberaigner, W Concin, N Diem, G Ruttmann, E Gruber-Moesenbacher, U Offner, F Pompella, A Pfeiffer, KP Ulmer, H AF Strasak, Alexander M. Goebel, Georg Concin, Hans Pfeiffer, Ruth M. Brant, Larry J. Nagel, Gabriele Oberaigner, Willi Concin, Nicole Diem, Guenter Ruttmann, Elfriede Gruber-Moesenbacher, Ulrike Offner, Felix Pompella, Alfonso Pfeiffer, Karl P. Ulmer, Hanno CA VHM&PP Study Grp TI Prospective Study of the Association of Serum gamma-Glutamyltransferase with Cervical Intraepithelial Neoplasia III and Invasive Cervical Cancer SO CANCER RESEARCH LA English DT Article ID HUMAN-PAPILLOMAVIRUS; DRUG-RESISTANCE; NATIONAL-HEALTH; TRANSPEPTIDASE; POPULATION; CELLS; WOMEN; MODULATION; PROGRAM; HISTORY AB Epidemiologic studies indicate that elevated levels of gamma-glutamyltransferase (GGT), a key enzyme of glutathione metabolism, might be associated with increased cancer risk. Furthermore, preclinical studies support a role for GGT in tumor invasion and progression. However, the relationship between GGT and risks of cervical intraepithelial neoplasia III (CIN-III) and invasive cervical cancer (ICC) have not been evaluated. We investigated the association of enzymatically determined GGT in blood serum with subsequent incidence of CIN-III and ICC in a prospective population-based cohort of 92,843 women ages 18 to 95, of whom 79% had at least one gynecologic examination including Pap smear testing during follow-up. Cox regression was used to compute adjusted hazard ratios (HR) with 95% confidence intervals for the association of GGT with CIN-III and ICC. During median follow-up of 13.8 years, 702 CIN-III and 117 ICC diagnoses were observed. Compared with normal low GGT (17.99 units/L), risk of ICC was significantly elevated for all other baseline GGT categories, with adjusted HRs of 2.31 (1.49-3.59) for normal high GGT (18.00-35.99 units/L), 2.76 (1.52-5.02) for elevated GGT (36.00-71.99 units/L), and 3.38 (1.63-7.00) for highly elevated GGT [>72.00 units/L; P trend < 0.0001, HR log unit increase 3.45 (1.92-6.19)]. In contrast, associations between GGT serum levels and CIN-III risk were not statistically significant in the main analysis. Exclusion of the first 2 or 5 years of follow-up did not change the results. Effects did not differ by age, body mass index, or socioeconomic status. Our findings implicate GGT in the progression of premalignant cervical lesions to invasive cancer. Cancer Res; 70(9); 3586-93. (C) 2010 AACR. C1 [Strasak, Alexander M.; Goebel, Georg; Pfeiffer, Karl P.; Ulmer, Hanno] Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, A-6020 Innsbruck, Austria. [Concin, Nicole] Innsbruck Med Univ, Dept Obstet & Gynaecol, A-6020 Innsbruck, Austria. [Ruttmann, Elfriede] Innsbruck Med Univ, Dept Cardiac Surg, A-6020 Innsbruck, Austria. [Concin, Hans; Diem, Guenter; Ulmer, Hanno] Agcy Prevent & Social Med, Bregenz, Austria. [Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Brant, Larry J.] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Nagel, Gabriele] Univ Ulm, Inst Epidemiol, Ulm, Germany. [Oberaigner, Willi] Tyrolean State Hosp Ltd, Dept Clin Epidemiol, Canc Registry Tyrol, Innsbruck, Austria. [Gruber-Moesenbacher, Ulrike; Offner, Felix] Acad Teaching Hosp, Dept Pathol, Feldkirch, Austria. [Pompella, Alfonso] Univ Pisa, Dept Expt Pathol, Sch Med, I-56100 Pisa, Italy. [Pompella, Alfonso] Univ Pisa, Sch Med, BMIE, I-56100 Pisa, Italy. RP Goebel, G (reprint author), Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, Schoepfstr 41, A-6020 Innsbruck, Austria. EM georg.goebel@i-med.ac.at RI vhmpp, aks/F-9756-2012; Pompella, Alfonso/G-6785-2012; Goebel, Georg/P-6909-2015; Ulmer, Hanno/C-3488-2011; Ruttmann, Elfriede/D-6501-2011; Pfeiffer, Ruth /F-4748-2011; Nagel, Gabriele/C-3635-2012 OI Pompella, Alfonso/0000-0002-6435-9325; Ulmer, Hanno/0000-0001-5911-1002; Nagel, Gabriele/0000-0001-6185-8535 FU Austrian National Bank [OENB-12737]; National Institute on Aging FX Grant Support; Austrian National Bank grant OENB-12737 (H. Ulmer) and National Institute on Aging Intramural Research Program (L.J. Brant). NR 30 TC 18 Z9 18 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2010 VL 70 IS 9 BP 3586 EP 3593 DI 10.1158/0008-5472.CAN-09-3197 PG 8 WC Oncology SC Oncology GA 607GD UT WOS:000278486200018 PM 20388786 ER PT J AU Yang, HP Bosquet, JG Li, QZ Platz, EA Brinton, LA Sherman, ME Lacey, JV Gaudet, MM Burdette, LA Figueroa, JD Ciampa, JG Lissowska, J Peplonska, B Chanock, SJ Garcia-Closas, M AF Yang, Hannah P. Gonzalez Bosquet, Jesus Li, Qizhai Platz, Elizabeth A. Brinton, Louise A. Sherman, Mark E. Lacey, James V., Jr. Gaudet, Mia M. Burdette, Laurie A. Figueroa, Jonine D. Ciampa, Julia G. Lissowska, Jolanta Peplonska, Beata Chanock, Stephen J. Garcia-Closas, Montserrat TI Common genetic variation in the sex hormone metabolic pathway and endometrial cancer risk: pathway-based evaluation of candidate genes SO CARCINOGENESIS LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; BINDING GLOBULIN GENE; POSTMENOPAUSAL WOMEN; ANDROGEN RECEPTOR; STEROID-HORMONES; FUNCTIONAL POLYMORPHISM; CYTOCHROME-P450 1A1; REPLACEMENT THERAPY; BIOSYNTHESIS GENES; UNITED-STATES AB Background. Estrogen plays a major role in endometrial carcinogenesis, suggesting that common variants of genes in the sex hormone metabolic pathway may be related to endometrial cancer risk. In support of this view, variants in CYP19A1 [cytochrome P450 (CYP), family 19, subfamily A, polypeptide 1] have been associated with both circulating estrogen levels and endometrial cancer risk. Associations with variants in other genes have been suggested, but findings have been inconsistent. Methods. We examined 36 sex hormone-related genes using a tagging approach in a population-based case-control study of 417 endometrial cancer cases and 407 controls conducted in Poland. We evaluated common variation in these genes in relation to endometrial cancer risk using sequential haplotype scan, variable-sized sliding window and adaptive rank-truncated product (ARTP) methods. Results. In our case-control study, the strongest association with endometrial cancer risk was for AR (androgen receptor; ARTP P = 0.006). Multilocus analyses also identified boundaries for a region of interest in AR and in CYP19A1 around a previously identified susceptibility loci. We did not find evidence for consistent associations between previously reported candidate single-nucleotide polymorphisms in this pathway and endometrial cancer risk. Discussion. In summary, we identified regions in AR and CYP19A1 that are of interest for further evaluation in relation to endometrial cancer risk in future haplotype and subsequent fine mapping studies in larger study populations. C1 [Yang, Hannah P.; Gonzalez Bosquet, Jesus; Li, Qizhai; Brinton, Louise A.; Sherman, Mark E.; Lacey, James V., Jr.; Burdette, Laurie A.; Figueroa, Jonine D.; Ciampa, Julia G.; Chanock, Stephen J.; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20852 USA. [Yang, Hannah P.; Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Gaudet, Mia M.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY 10461 USA. [Burdette, Laurie A.; Chanock, Stephen J.] NCI, Core Genotype Facil, Adv Technol Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Peplonska, Beata] Nofer Inst Occupat Med, Dept Occupat & Environm Epidemiol, Lodz, Poland. RP Yang, HP (reprint author), NCI, 6120 Execut Blvd,EPS 5034A, Rockville, MD 20852 USA. EM yanghan@mail.nih.gov RI Peplonska, Beata/F-6004-2010; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799 FU National Cancer Institute, National Institutes of Health FX Intramural program of the National Cancer Institute, National Institutes of Health. NR 72 TC 24 Z9 24 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 2010 VL 31 IS 5 BP 827 EP 833 DI 10.1093/carcin/bgp328 PG 7 WC Oncology SC Oncology GA 593IQ UT WOS:000277447600009 PM 20053928 ER PT J AU Park, SK Andreotti, G Rashid, A Chen, JB Rosenberg, PS Yu, K Olsen, J Gao, YT Deng, J Sakoda, LC Zhang, MD Shen, MC Wang, BS Han, TQ Zhang, BH Yeager, M Chanock, SJ Hsing, AW AF Park, Sue K. Andreotti, Gabriella Rashid, Asif Chen, Jinbo Rosenberg, Philip S. Yu, Kai Olsen, Jennifer Gao, Yu-Tang Deng, Jie Sakoda, Lori C. Zhang, Mingdong Shen, Ming-Chang Wang, Bing-Sheng Han, Tian-Quan Zhang, Bai-He Yeager, Meredith Chanock, Stephen J. Hsing, Ann W. TI Polymorphisms of estrogen receptors and risk of biliary tract cancers and gallstones: a population-based study in Shanghai, China SO CARCINOGENESIS LA English DT Article ID GALLBLADDER CANCER; GENE POLYMORPHISMS; ALPHA GENE; ASSOCIATION; STONES; PROGRESSION; FREQUENCIES; METABOLISM; MECHANISMS; EXPRESSION AB Biliary tract cancer encompasses tumors of the gallbladder, bile duct and ampulla of Vater. Gallbladder cancer is more common in women, whereas bile duct cancer is more common in men, suggesting that sex hormones may play a role in the etiology of these cancers. The intracellular action of estrogens is regulated by the estrogen receptor (ESR); thus, we examined the role of common genetic variants in ESR genes on the risk of biliary tract cancers and stones in a population-based case-control study in Shanghai, China (411 cancer cases, 895 stone cases and 786 controls). We genotyped six single-nucleotide polymorphisms (SNPs), four in ESR1 (rs2234693, rs3841686, rs2228480 and rs1801132) and two in ESR2 (rs1256049 and rs4986938). In all participants, the ESR1 rs1801132 (P325P) G allele was associated with excess risks of bile duct [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.1-2.8] and ampulla of Vater cancers (OR = 2.1, 95% CI 0.9-4.9) compared with the CC genotype. The association with bile duct cancer was apparent among men (OR = 2.8, 95% CI 1.4-5.7) but not among women (P-heterogeneity = 0.01). Also, the ESR2 rs4986938 (38 bp 3' of STP) GG genotype was associated with a higher risk of bile duct cancer (OR = 3.3, 95% CI 1.3-8.7) compared with the AA genotype, although this estimate was based on a small number of subjects. None of the other SNPs examined was associated with biliary tract cancers or stones. False discovery rate-adjusted P-values were not significant (P > 0.1). No association was found for ESR1 haplotype based on four SNPs. These preliminary results suggest that variants in ESR genes could play a role in the etiology of biliary tract cancers, especially bile duct cancer in men. C1 [Hsing, Ann W.] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Park, Sue K.] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. [Rashid, Asif] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Chen, Jinbo] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Olsen, Jennifer] George Washington Univ, Dept Epidemiol & Biostat, Sch Publ Hlth & Hlth Serv, Washington, DC 20037 USA. [Gao, Yu-Tang; Deng, Jie] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Sakoda, Lori C.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Zhang, Mingdong] Biosense Webster Inc, Diamond Bar, CA USA. [Shen, Ming-Chang] Fudan Univ, Shanghai Tumor Hosp, Shanghai 200433, Peoples R China. [Wang, Bing-Sheng] Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Han, Tian-Quan] Shanghai Med Univ 2, Ruijin Hosp, Shanghai, Peoples R China. [Zhang, Bai-He] Second Mil Med Univ, Inst Oriental Hepatobiliary Surg, Shanghai, Peoples R China. [Yeager, Meredith; Chanock, Stephen J.] NCI, Core Genotyping Facil, Rockville, MD 20877 USA. RP Hsing, AW (reprint author), NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 5024,MSC7234, Bethesda, MD 20892 USA. EM hsinga@mail.nih.gov RI Park, Sue Kyung/J-2757-2012 FU National Institutes of Health; National Cancer Institute [N01-CO-12400] FX Intramural Research Program of the National Institutes of Health; National Cancer Institute, under contract N01-CO-12400. NR 33 TC 17 Z9 18 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 2010 VL 31 IS 5 BP 842 EP 846 DI 10.1093/carcin/bgq038 PG 5 WC Oncology SC Oncology GA 593IQ UT WOS:000277447600011 PM 20172949 ER PT J AU Hosgood, HD Liu, CS Rothman, N Weinstein, SJ Bonner, MR Shen, M Lim, U Virtamo, J Cheng, WL Albanes, D Lan, Q AF Hosgood, H. Dean, III Liu, Chin-San Rothman, Nathaniel Weinstein, Stephanie J. Bonner, Matthew R. Shen, Min Lim, Unhee Virtamo, Jarmo Cheng, Wen-ling Albanes, Demetrius Lan, Qing TI Mitochondrial DNA copy number and lung cancer risk in a prospective cohort study SO CARCINOGENESIS LA English DT Article ID OXIDATIVE STRESS; CIGARETTE-SMOKING; HUMAN-LEUKOCYTES; HUMAN-CELLS; DAMAGE; INCREASE; SMOKERS; MASS AB Mitochondria are eukaryotic organelles responsible for energy production. Mitochondrial DNA (mtDNA) lack introns and protective histones, have limited DNA repair capacity and compensate for damage by increasing the number of mtDNA copies. As a consequence, mitochondria are more susceptible to reactive oxygen species, an important determinant of cancer risk, and it is hypothesized that increased mtDNA copy number may be associated with carcinogenesis. We assessed the association of mtDNA copy number and lung cancer risk in 227 prospectively collected cases and 227 matched controls from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age at randomization, smoking years and number of cigarettes smoked per day. There was suggestion of a dose-dependent relationship between mtDNA copy number and subsequent risk of lung cancer, with a prominent effect observed in the highest mtDNA copy number quartile [ORs (95% CI) by quartile: 1.0 (reference), 1.3 (0.7-2.5), 1.1 (0.6-2.2) and 2.4 (1.1-5.1); P-trend = 0.008]. This is the first report, to the best of our knowledge, to suggest that mtDNA copy number may be positively associated with subsequent risk of lung cancer in a prospective cohort study; however, replication is needed in other studies and populations. C1 [Hosgood, H. Dean, III; Rothman, Nathaniel; Weinstein, Stephanie J.; Shen, Min; Albanes, Demetrius; Lan, Qing] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Liu, Chin-San; Cheng, Wen-ling] Changhua Christian Hosp, Dept Neurol, Changhua 500, Taiwan. [Liu, Chin-San; Cheng, Wen-ling] Changhua Christian Hosp, Vasc & Genom Res Ctr, Changhua 500, Taiwan. [Bonner, Matthew R.] SUNY Buffalo, Dept Social & Preventat Med, Buffalo, NY 14226 USA. [Lim, Unhee] Canc Res Ctr Hawaii, Program Epidemiol, Honolulu, HI 96813 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki 00271, Finland. RP Hosgood, HD (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8118,MCS 7240, Bethesda, MD 20892 USA. EM hosgoodd@mail.nih.gov RI Albanes, Demetrius/B-9749-2015 FU National Cancer Institute FX This work was supported by intramural funds from the National Cancer Institute. NR 25 TC 78 Z9 79 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 2010 VL 31 IS 5 BP 847 EP 849 DI 10.1093/carcin/bgq045 PG 3 WC Oncology SC Oncology GA 593IQ UT WOS:000277447600012 PM 20176654 ER PT J AU Izzotti, A Larghero, P Cartiglia, C Longobardi, M Pfeffer, U Steele, VE De Flora, S AF Izzotti, Alberto Larghero, Patrizia Cartiglia, Cristina Longobardi, Mariagrazia Pfeffer, Ulrich Steele, Vernon E. De Flora, Silvio TI Modulation of microRNA expression by budesonide, phenethyl isothiocyanate and cigarette smoke in mouse liver and lung SO CARCINOGENESIS LA English DT Article ID CHEMOPREVENTIVE AGENTS; A/J MICE; PULMONARY CARCINOGENESIS; AEROSOLIZED BUDESONIDE; N-ACETYLCYSTEINE; CANCER; TUMORS; RATS; PROGRESSION; BIOMARKERS AB Although microRNAs (miRNA) have extensively been investigated in cancer research, less attention has been paid to their regulation by carcinogens and/or protective factors in early stages of the carcinogenesis process. The present study was designed to evaluate the modulation of mRNA expression as related to exposure of neonatal mice to environmental cigarette smoke (ECS) and to treatment with chemopreventive agents. Exposure to ECS started immediately after birth and for 2 weeks after weaning. Thereafter, groups of mice received daily either budesonide (BUD) or phenethyl isothiocyanate (PEITC) with the diet. The expression of 576 miRNAs was evaluated by miRNA microarray in liver and lung. In sham-exposed mice, the expression of miRNAs tended to be higher in liver than in lung. ECS downregulated the expression of a number of miRNAs in lung, whereas mixed alterations were observed in liver. PEITC and BUD did not substantially affect the physiological situation in lung, whereas both agents caused intense variations in liver, reflecting the occurrence of damage mechanisms, such as inflammation, DNA and protein damage, cellular stress, proliferation and apoptosis. PEITC and BUD protected the lung from ECS-induced alterations of miRNA expression but exhibited some adverse effects in liver. C1 [Izzotti, Alberto; Larghero, Patrizia; Cartiglia, Cristina; Longobardi, Mariagrazia; Steele, Vernon E.; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. [Pfeffer, Ulrich] Natl Canc Res Inst IST, Funct Genom Unit, I-16132 Genoa, Italy. NCI, Canc Prevent Div, Rockville, MD 20892 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM sdf@unige.it RI Pfeffer, Ulrich/J-7064-2016 OI izzotti, alberto/0000-0002-8588-0347; Pfeffer, Ulrich/0000-0003-0872-4671 FU National Cancer Institute [N01-CN 53301]; Associazione Italiana per la Ricerca sul Cancro [8909] FX National Cancer Institute (contract N01-CN 53301); Associazione Italiana per la Ricerca sul Cancro (contract 8909). NR 33 TC 51 Z9 54 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 2010 VL 31 IS 5 BP 894 EP 901 DI 10.1093/carcin/bgq037 PG 8 WC Oncology SC Oncology GA 593IQ UT WOS:000277447600019 PM 20145010 ER PT J AU Li, MM Huang, J AF Li, Mangmang Huang, Jing TI A new puzzling role of p53 in mouse embryonic stem cells SO CELL CYCLE LA English DT Editorial Material C1 [Li, Mangmang; Huang, Jing] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Huang, J (reprint author), NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. EM huangj3@mail.nih.gov RI Huang, Jing/A-2566-2009; LI, MANGMANG/J-1683-2015 OI Huang, Jing/0000-0002-7163-5156; FU Intramural NIH HHS [ZIA BC011260-01, ZIA BC011158-03, ZIA BC011158-01, ZIA BC011158-02, ZIA BC011260-02, Z99 CA999999] NR 5 TC 7 Z9 7 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY 1 PY 2010 VL 9 IS 9 BP 1669 EP 1670 PG 2 WC Cell Biology SC Cell Biology GA 592TC UT WOS:000277402200005 PM 20404507 ER PT J AU Panicker, J Li, ZJ McMahon, C Sizer, C Steadman, K Piekarz, R Bates, SE Thiele, CJ AF Panicker, Jyoti Li, Zhijie McMahon, Christine Sizer, Caroline Steadman, Kenneth Piekarz, Richard Bates, Susan E. Thiele, Carol J. TI Romidepsin (FK228/depsipeptide) controls growth and induces apoptosis in neuroblastoma tumor cells SO CELL CYCLE LA English DT Article DE romidepsin; FK228; depsipeptide; neuroblastoma; apoptosis; HDAC inhibitor ID HISTONE DEACETYLASE INHIBITOR; SUBEROYLANILIDE HYDROXAMIC ACID; REFRACTORY SOLID TUMORS; ACUTE MYELOID-LEUKEMIA; HUMAN NEURO-BLASTOMA; IN-VIVO; PHASE-I; DEPSIPEPTIDE FR901228; ANTITUMOR EFFICACY; CANCER-THERAPY AB As histone deacetylase inhibitors such as romidepsin (depsipeptide, FK228) complete successful phase I clinical trials in pediatric solid tumors, it is important that their mechanisms of action are delineated in order to inform the development of subsequent clinical trials as single agents or in combination therapies. In this study, we evaluate the effect of romidepsin as a single agent on a number of different neuroblastoma (NB) cell lines. We find that the growth of 6/6 human NB tumor cell lines but not an immortalized fibroblast cell line (NIH3T3) is inhibited by romidepsin (IC(50) = 1-6.5 ng/ml) after 72 h of treatment. Romidepsin shows selective dose-dependent cytotoxicity in both single copy and N-myc amplified NB cell lines, in cell lines with wild type or mutant p53 and those containing Alk mutations. the decrease in cell proliferation is accompanied by caspase-dependent apoptosis as shown by PARP cleavage, an accumulation of cells in the sub-G(1) phase of the cell cycle and the ability of a pan-caspase inhibitor to reduce cell death. Romidepsin inhibits the growth of subcutaneous NB xenografts in a dose dependent manner in immunocompromised mice. Furthermore, romidepsin induces expression of genes such as p21 and expression of p75 and NTRK (TrkA) which are more highly expressed in the tumors from NB patients that have a good prognosis. these studies support continued investigations into the therapeutic activity of romidepsin in NB. C1 [Panicker, Jyoti; Li, Zhijie; McMahon, Christine; Sizer, Caroline; Thiele, Carol J.] NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Steadman, Kenneth; Piekarz, Richard; Bates, Susan E.] NCI, Dev Therapeut Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Piekarz, Richard] NCI, Canc Therapy Evaluat Program, DCTD, NIH, Bethesda, MD 20892 USA. [Panicker, Jyoti] Childrens Natl Med Ctr, Pediat Hematol Oncol Dept, Washington, DC 20010 USA. RP Thiele, CJ (reprint author), NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM ct47a@nih.gov RI Steadman, Kenneth/J-3883-2013 FU NIH; National Cancer Institute; Center for Cancer Research FX We are thankful to Robert Robey in the Cancer Therapeutics Branch, NCI for his insightful help. We are grateful to Kelly Martin, Reema Wahdan and other members of our lab, as well as the Cell and Molecular Biology Section for their immense help. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 53 TC 8 Z9 10 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY 1 PY 2010 VL 9 IS 9 BP 1830 EP 1838 PG 9 WC Cell Biology SC Cell Biology GA 592TC UT WOS:000277402200036 PM 20404560 ER PT J AU Patterson, AD Gonzalez, FJ Idle, JR AF Patterson, Andrew D. Gonzalez, Frank J. Idle, Jeffrey R. TI Xenobiotic Metabolism: A View through the Metabolometer SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Review ID FLIGHT MASS-SPECTROMETRY; MULTIVARIATE STATISTICAL-ANALYSIS; AMINOFLAVONE NSC-686288; HETEROCYCLIC AMINES; ANTITUMOR AGENT; HUMAN PLASMA; NSC 686288; IN-VITRO; MELATONIN; MOUSE AB The combination of advanced ultraperformance liquid chromatography coupled with mass spectrometry, chemometrics, and genetically modified mice provide an attractive raft of technologies with which to examine the metabolism of xenobiotics. Here, a reexamination of the metabolism of the food mutagen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), the suspect carcinogen areca alkaloids (arecoline, arecaidine, and arecoline 1-oxide), the hormone supplement melatonin, and the metabolism of the experimental cancer therapeutic agent aminoflavone is presented. In all cases, the metabolic maps of the xenobiotics were considerably enlarged, providing new insights into their toxicology. The inclusion of transgenic mice permitted unequivocal attribution of individual and often novel metabolic pathways to particular enzymes. Last, a future perspective for xenobiotic metabolomics is discussed and its impact on the metabolome is described. The studies reviewed here are not specific to the mouse and can be adapted to study xenobiotic metabolism in any animal species, including humans. The view through the metabolometer is unique and visualizes a metabolic space that contains both established and unknown metabolites of a xenobiotic, thereby enhancing knowledge of their modes of toxic action. C1 [Idle, Jeffrey R.] Charles Univ Prague, Fac Med 1, Inst Pharmacol, Prague 12800 2, Czech Republic. [Patterson, Andrew D.; Gonzalez, Frank J.; Idle, Jeffrey R.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Idle, JR (reprint author), Charles Univ Prague, Fac Med 1, Inst Pharmacol, Albertov 4, Prague 12800 2, Czech Republic. EM jidle@lf1.cuni.cz RI yang, min/G-3030-2011; Patterson, Andrew/G-3852-2012 OI Idle, Jeff/0000-0002-6143-1520; Patterson, Andrew/0000-0003-2073-0070 FU National Cancer Institute, Intramural Research Program, Center for Cancer Research; National Institute of General Medical Sciences; U.S. Smokeless Tobacco Company FX We thank Drs. Chi Chen, Sarbani Gin, and Xiaochao Ma for their extensive contributions to the xenobiotic metabolomics paradigm. This work was funded by the National Cancer Institute, Intramural Research Program, Center for Cancer Research. A.D.P. was supported by a Pharmacology Research Associate in Training Fellowship from the National Institute of General Medical Sciences. J.R.I. is grateful to U.S. Smokeless Tobacco Company for a grant for collaborative research. NR 61 TC 25 Z9 25 U1 2 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAY PY 2010 VL 23 IS 5 BP 851 EP 860 DI 10.1021/tx100020p PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 595FZ UT WOS:000277597400005 PM 20232918 ER PT J AU Siraki, AG Jiang, JJ Mason, RP AF Siraki, Arno G. Jiang, JinJie Mason, Ronald P. TI Investigating the Mechanisms of Aromatic Amine-Induced Protein Free Radical Formation by Quantitative Structure-Activity Relationships: Implications for Drug-Induced Agranulocytosis SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID REACTIVE METABOLITES; POTENTIAL MECHANISM; NITROXIDE RADICALS; RESONANCE-SPECTRA; MYELOPEROXIDASE; NUCLEAR; ACETYLPROCAINAMIDE; PROCAINAMIDE; PATHOGENESIS; ANTIBODIES AB Aromatic amine drugs have been associated with agranulocytosis (neutrophil depletion) for which the mechanism is unknown. We have previously shown that the metabolism of two aromatic amine drugs by human myeloperoxidase (MPO) results in phenyl radical metabolite formation and also in protein free radical formation on MPO. Because the concentration of drug required to produce a maximum signal for MPO protein free radical (MPO(center dot)) detection was different for each drug, this prompted us to consider that other aromatic amines may also show varying degrees of ability to induce MPO(center dot) formation. Immunoassay experiments using the immuno-spin-trapping technique were performed, which evaluated the potency of different aromatic amines containing the aniline substructure to generate the MPO(center dot). Each reaction contained equal amounts of H(2)O(2), 5,5-dimethyl-1-pyrroline-N-oxide, MPO, and variable concentrations of aniline derivatives. Several physicochemical parameters for aniline derivatives were used to derive quantitative structure-activity relationship equations, which showed that the Hammett constant (sigma) best correlated with the MPO(center dot) formation for all aniline derivatives. More statistically robust equations were derived if the anilines were separated into mono- and disubstituted groups. However, some aniline derivatives did not induce MPO(center dot) formation. Using electron spin resonance spectroscopy, we evaluated the ability of all aniline derivatives tested to produce phenyl radical metabolites, as previously shown by spin trapping for the aromatic amine drugs. Interestingly, we found that only those aniline derivatives that produced a phenyl radical also formed MPO(center dot). We propose that the phenyl radical is the reactive free radical metabolite responsible for generating the MPO(center dot). C1 [Siraki, Arno G.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Dent Pharm Ctr 3133, Edmonton, AB T6G 2N8, Canada. [Jiang, JinJie; Mason, Ronald P.] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Siraki, AG (reprint author), Univ Alberta, Fac Pharm & Pharmaceut Sci, Dent Pharm Ctr 3133, Edmonton, AB T6G 2N8, Canada. EM siraki@ualberta.ca FU NIH; NIH/NIEHS; University of Alberta FX The authors thank Ms. Jean Corbett (NIEHS) for purification of DMPO, Ms. Mary Jane Mason for her careful review of the manuscript, and the internal reviewer for her valuable critique. This research was supported by the Intramural Research Program of the NIH, and NIH/NIEHS, as well as the University of Alberta Startup Fund. NR 35 TC 8 Z9 8 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAY PY 2010 VL 23 IS 5 BP 880 EP 887 DI 10.1021/tx900432d PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 595FZ UT WOS:000277597400009 PM 20199096 ER PT J AU Kobayashi, H Ogawa, M Alford, R Choyke, PL Urano, Y AF Kobayashi, Hisataka Ogawa, Mikako Alford, Raphael Choyke, Peter L. Urano, Yasuteru TI New Strategies for Fluorescent Probe Design in Medical Diagnostic Imaging SO CHEMICAL REVIEWS LA English DT Review ID GROWTH-FACTOR RECEPTOR; LABELED MONOCLONAL-ANTIBODIES; DIFFUSE OPTICAL TOMOGRAPHY; OVARIAN-CANCER METASTASES; IN-VIVO; BREAST-CANCER; QUANTUM DOTS; LIVING CELLS; NITRIC-OXIDE; RATIONAL DESIGN C1 [Kobayashi, Hisataka; Ogawa, Mikako; Alford, Raphael; Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Urano, Yasuteru] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov RI Urano, Yasuteru/H-1380-2012 FU Center for Cancer Research, National Cancer Institute, NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 168 TC 719 Z9 725 U1 53 U2 412 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 J9 CHEM REV JI Chem. Rev. PD MAY PY 2010 VL 110 IS 5 BP 2620 EP 2640 DI 10.1021/cr900263j PG 21 WC Chemistry, Multidisciplinary SC Chemistry GA 598CW UT WOS:000277811600003 PM 20000749 ER PT J AU Villaraza, AJL Bumb, A Brechbiel, MW AF Villaraza, Aaron Joseph L. Bumb, Ambika Brechbiel, Martin W. TI Macromolecules, Dendrimers, and Nanomaterials in Magnetic Resonance Imaging: The Interplay between Size, Function, and Pharmacokinetics SO CHEMICAL REVIEWS LA English DT Review ID MRI CONTRAST AGENTS; SUPERPARAMAGNETIC IRON-OXIDE; NEPHROGENIC SYSTEMIC FIBROSIS; HUMAN SERUM-ALBUMIN; POLY(PROPYLENE IMINE) DENDRIMERS; ACUTE MYOCARDIAL-ISCHEMIA; NUCLEAR-SPIN RELAXATION; GADOLINIUM-LABELED LIPOSOMES; EXCHANGE SATURATION-TRANSFER; LOW-MOLECULAR-WEIGHT C1 [Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bldg 10,Room 1B53,10 Ctr Dr, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 481 TC 279 Z9 287 U1 15 U2 145 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD MAY PY 2010 VL 110 IS 5 BP 2921 EP 2959 DI 10.1021/cr900232t PG 39 WC Chemistry, Multidisciplinary SC Chemistry GA 598CW UT WOS:000277811600014 PM 20067234 ER PT J AU Lee, S Xie, J Chen, XY AF Lee, Seulki Xie, Jin Chen, Xiaoyuan TI Peptides and Peptide Hormones for Molecular Imaging and Disease Diagnosis SO CHEMICAL REVIEWS LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; INTEGRIN ALPHA(V)BETA(3) EXPRESSION; SEMICONDUCTOR QUANTUM DOTS; IRON-OXIDE NANOPARTICLES; RECEPTOR-POSITIVE TUMORS; IN-VIVO EVALUATION; ACTIVITY-BASED PROBES; DUCTAL PANCREATIC ADENOCARCINOMA; RGD-BOMBESIN HETERODIMER; CORE-SHELL NANOCRYSTALS C1 [Lee, Seulki; Xie, Jin; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed, NIH, 31 Ctr Dr,Suite 1C14, Bethesda, MD 20892 USA. EM Shawn.Chen@nih.gov RI Xie, Jin/E-8193-2010 FU NIBIB, NIH FX This project was supported, in part, by the Intramural Research Program, NIBIB, NIH. We thank Dr. Henry S. Eden for English editing and proofreading of the manuscript. NR 272 TC 155 Z9 159 U1 12 U2 93 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD MAY PY 2010 VL 110 IS 5 BP 3087 EP 3111 DI 10.1021/cr900361p PG 25 WC Chemistry, Multidisciplinary SC Chemistry GA 598CW UT WOS:000277811600019 PM 20225899 ER PT J AU Boxer, MB Quinn, AM Shen, M Jadhav, A Leister, W Simeonov, A Auld, DS Thomas, CJ AF Boxer, Matthew B. Quinn, Amy M. Shen, Min Jadhav, Ajit Leister, William Simeonov, Anton Auld, Douglas S. Thomas, Craig J. TI A Highly Potent and Selective Caspase 1 Inhibitor that Utilizes a Key 3-Cyanopropanoic Acid Moiety SO CHEMMEDCHEM LA English DT Article DE caspases; covalent modifiers; cysteine proteases; inhibitors; VRT-043198; VX-765 ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; CYSTEINE PROTEASES; INFLAMMATORY CASPASES; IMMUNE-RESPONSES; MECHANISM; TETRAZOLES; NITRILES; TARGETS; TBCATB; VX-765 AB Herein, we examine the potential of a nitrile-containing propionic acid moiety as an electrophile for covalent attack by the active-site cysteine residue of caspase 1. The syntheses of several cyanopropanate-containing small molecules based on the, optimized peptidic scaffold of prodrug VX-765 were accomplished. These compounds were found to be potent inhibitors of caspase 1 (IC(50) values <= 1 nM). Examination of these novel small molecules against a caspase panel demonstrated an impressive degree of selectivity for caspase 1 inhibition over other caspase isozymes. Assessment of hydrolytic stability and selected ADME properties highlighted these agents as potentially useful tools for studying caspase 1 down-regulation in various settings, including in vivo analyses. C1 [Boxer, Matthew B.; Quinn, Amy M.; Shen, Min; Jadhav, Ajit; Leister, William; Simeonov, Anton; Auld, Douglas S.; Thomas, Craig J.] NHGRI, NIH, NIH Chem Genom Ctr, Rockville, MD 20850 USA. RP Thomas, CJ (reprint author), NHGRI, NIH, NIH Chem Genom Ctr, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM craigt@mail.nih.gov FU Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; National Human Genome Research Institute, National Institutes of Health FX We thank Ms. Allison Mandich for critical reading of this manuscript and Mr. Paul Shinn for assistance with compound management. This research was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 32 TC 14 Z9 14 U1 1 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1860-7179 J9 CHEMMEDCHEM JI ChemMedChem PD MAY PY 2010 VL 5 IS 5 BP 730 EP 738 DI 10.1002/cmdc.200900531 PG 9 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 596ZP UT WOS:000277725100012 PM 20229566 ER PT J AU Bornstein, MH Mash, C AF Bornstein, Marc H. Mash, Clay TI Experience-Based and On-Line Categorization of Objects in Early Infancy SO CHILD DEVELOPMENT LA English DT Article ID SHAPE SIMILARITY; YOUNG INFANTS; CATEGORICAL REPRESENTATION; INDUCTIVE INFERENCES; 3-MONTH-OLD INFANTS; MEMORY RETRIEVAL; CONTEXT THEORY; SHARED LABELS; BASIC-LEVEL; CLASSIFICATION AB What processes do infants employ in categorizing? Infants might categorize on line as they encounter category-related entities; alternatively, infants might depend on prior experience with entities in formulating categories. These alternatives were tested in forty-four 5-month-olds. Infants who were familiarized in the laboratory with a category of never-before-seen objects subsequently treated novel objects of the same category as familiar-they categorized on line-just as did infants who were exposed to objects from the same category at home for 2 months leading to their laboratory assessment of object categorization. Infants with home experience also recognized novel category objects as familiar from the outset-that is, prior experience with category exemplars was brought to bear in laboratory tasks. C1 [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov FU Intramural NIH HHS [ZIA HD001119-22] NR 98 TC 11 Z9 11 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD MAY-JUN PY 2010 VL 81 IS 3 BP 884 EP 897 PG 14 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 596NF UT WOS:000277691200015 PM 20573111 ER PT J AU Costanzi, S AF Costanzi, Stefano TI Modelling G protein-coupled receptors A concrete possibility SO CHIMICA OGGI-CHEMISTRY TODAY LA English DT Article ID CRYSTAL-STRUCTURE; BETA(2)-ADRENERGIC RECEPTOR; HOMOLOGY MODELS; RHODOPSIN; DISCOVERY; ANTAGONISTS; LIGANDS; SEQUENCE AB G protein-coupled receptors (GPCRs) are a large superfamily of membrane-bound signalling proteins that are involved in the regulation of a wide range of physiological functions and constitute the most common target for therapeutic intervention Due to the paucity of crystal structures, homology modelling has become a widespread technique for the construction of GPCR models, which have been applied to the study of their structure-function relationships and to the identification of lead ligands through virtual screening Rhodopsin has been for years the only available template However, recent breakthroughs in GPCR crystallography have led to the solution of the structures of a few additional receptors In light of these newly elucidated crystal structures, we have been able to produce a substantial amount of data to demonstrate that accurate models of GPCRs in complex with their ligands can be constructed through homology modelling followed by fully flexible molecular docking These results have been confirmed by our success in the first blind assessment of GPCR modelling and docking, organized in coordination with the solution of the X-ray structure of the adenosine A(2A) receptor Taken together, these data indicate that a) the transmembrane helical bundle can be modelled with considerable accuracy, b) predicting the binding mode of a ligand, although doable, is challenging, c) modelling of the extracellular and intracellular loops is still problematic C1 NIDDKD, NIH, DHHS, Lab Biol Modeling, Bethesda, MD 20892 USA. RP Costanzi, S (reprint author), NIDDKD, NIH, DHHS, Lab Biol Modeling, 12A South Dr,Rm 4003,MSC 5621, Bethesda, MD 20892 USA. RI Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332 FU NIH, NIDDK FX This research was supported by the Intramural Research Program Of the NIH, NIDDK NR 30 TC 11 Z9 11 U1 0 U2 2 PU TEKNOSCIENZE PUBL PI MILANO PA VIALE BRIANZA 22, 20127 MILANO, ITALY SN 1973-8250 J9 CHIM OGGI JI Chim. Oggi-Chem. Today PD MAY-JUN PY 2010 VL 28 IS 3 BP 26 EP 30 PG 5 WC Biotechnology & Applied Microbiology; Chemistry, Multidisciplinary SC Biotechnology & Applied Microbiology; Chemistry GA 632IM UT WOS:000280415900017 PM 21253444 ER PT J AU Velagaleti, RS Gona, P Chuang, ML Salton, CJ Fox, CS Blease, SJ Yeon, SB Manning, WJ O'Donnell, CJ AF Velagaleti, Raghava S. Gona, Philimon Chuang, Michael L. Salton, Carol J. Fox, Caroline S. Blease, Susan J. Yeon, Susan B. Manning, Warren J. O'Donnell, Christopher J. TI Relations of Insulin Resistance and Glycemic Abnormalities to Cardiovascular Magnetic Resonance Measures of Cardiac Structure and Function The Framingham Heart Study SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE insulin resistance; diabetes; left ventricular mass; left ventricular remodeling; cardiovascular MRI; glycemia ID LEFT-VENTRICULAR MASS; TYPE-2 DIABETES-MELLITUS; SEX-RELATED DIFFERENCES; ESSENTIAL-HYPERTENSION; GLUCOSE-METABOLISM; SYSTOLIC FUNCTION; RISK-FACTORS; DB/DB MOUSE; ELDERLY-MEN; HYPERTROPHY AB Background-Data regarding the relationships of diabetes, insulin resistance, and subclinical hyperinsulinemia/hyperglycemia with cardiac structure and function are conflicting. We sought to apply volumetric cardiovascular magnetic resonance (CMR) in a free-living cohort to potentially clarify these associations. Methods and Results-A total of 1603 Framingham Heart Study Offspring participants (age, 64 +/- 9 years; 55% women) underwent CMR to determine left ventricular mass (LVM), LVM to end-diastolic volume ratio (LVM/LVEDV), relative wall thickness (RWT), ejection fraction, cardiac output, and left atrial size. Data regarding insulin resistance (homeostasis model, HOMA-IR) and glycemia categories (normal, impaired insulinemia or glycemia, prediabetes, and diabetes) were determined. In a subgroup (253 men, 290 women) that underwent oral glucose tolerance testing, we related 2-hour insulin and glucose with CMR measures. In both men and women, all age-adjusted CMR measures increased across HOMA-IR quartiles, but multivariable-adjusted trends were significant only for LVM/ht(2.7) and LVM/LVEDV. LVM/LVEDV and RWT were higher in participants with prediabetes and diabetes (in both sexes) in age-adjusted models, but these associations remained significant after multivariable adjustment only in men. LVM/LVEDV was significantly associated with 2-hour insulin in men only, and RWT was significantly associated with 2-hour glucose in women only. In multivariable stepwise selection analyses, the inclusion of body mass index led to a loss in statistical significance. Conclusions-Although insulin and glucose indices are associated with abnormalities in cardiac structure, insulin resistance and worsening glycemia are consistently and independently associated with LVM/LVEDV. These data implicate hyperglycemia and insulin resistance in concentric LV remodeling. (Circ Cardiovasc Imaging. 2010; 3: 257-263.) C1 [Velagaleti, Raghava S.; Gona, Philimon; Fox, Caroline S.; Blease, Susan J.; O'Donnell, Christopher J.] NHLBI Framingham Heart Study, Framingham, MA 01702 USA. [Chuang, Michael L.; Salton, Carol J.; Yeon, Susan B.; Manning, Warren J.; O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Div,Dept Med, Boston, MA USA. [Manning, Warren J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP O'Donnell, CJ (reprint author), NHLBI Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM codonnell@nih.gov FU National Heart, Lung, and Blood Institute [NO1-HC-25193, RO1-HL70279] FX This study was supported by National Heart, Lung, and Blood Institute contract No. NO1-HC-25193 and grant RO1-HL70279. NR 38 TC 41 Z9 43 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAY PY 2010 VL 3 IS 3 BP 257 EP U60 DI 10.1161/CIRCIMAGING.109.911438 PG 16 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 597RU UT WOS:000277779300006 PM 20208015 ER PT J AU Jain, A Shehata, ML Stuber, M Berkowitz, SJ Calkins, H Lima, JAC Bluemke, DA Tandri, H AF Jain, Aditya Shehata, Monda L. Stuber, Matthias Berkowitz, Seth J. Calkins, Hugh Lima, Joao A. C. Bluemke, David A. Tandri, Harikrishna TI Prevalence of Left Ventricular Regional Dysfunction in Arrhythmogenic Right Ventricular Dysplasia A Tagged MRI Study SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE ARVD; LV involvement; MRI tagging; regional strain ID MYOCARDIAL-FUNCTION; HARP-MRI; DYSPLASIA/CARDIOMYOPATHY; INVOLVEMENT; CARDIOMYOPATHY; MULTICENTER; IMAGES; MOTION; HEART AB Background-Although arrhythmogenic right ventricular dysplasia (ARVD) predominantly affects the right ventricle (RV), genetic/molecular and histological changes are biventricular. Regional left ventricular (LV) function has not been systematically studied in ARVD. Methods and Results-The study population included 21 patients with suspected ARVD who underwent evaluation with MRI including tagging. Eleven healthy volunteers served as control subjects. Peak systolic regional circumferential strain (Ecc, %) was calculated by harmonic phase from tagged MRI based on the 16-segment model. Patients who met ARVD Task Force criteria were classified as definite ARVD, whereas patients with a positive family history who had 1 additional minor criterion and patients without a family history with 1 major or 2 minor criteria were classified as probable ARVD. Of the 21 ARVD subjects, 11 had definite ARVD and 10 had probable ARVD. Compared with control subjects, probable ARVD patients had similar RV ejection fraction (58.9 +/- 6.2% versus 53.5 +/- 7.6%, P = 0.20), but definite ARVD patients had significantly reduced RV ejection fraction (58.9 +/- 6.2% versus 45.2 +/- 6.0%, P = 0.001). LV ejection fraction was similar in all 3 groups. Compared with control subjects, peak systolic Ecc was significantly less negative in 6 of 16 (37.5%) segments in definite ARVD and 3 of 16 segments (18.7%) in probable ARVD (all P < 0.05). Conclusions-ARVD is associated with regional LV dysfunction, which appears to parallel degree of RV dysfunction. Further large studies are needed to validate this finding and to better define implications of subclinical segmental LV dysfunction. (Circ Cardiovasc Imaging. 2010; 3: 290-297.) C1 [Jain, Aditya; Shehata, Monda L.; Stuber, Matthias; Berkowitz, Seth J.; Lima, Joao A. C.; Bluemke, David A.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Calkins, Hugh; Lima, Joao A. C.; Bluemke, David A.; Tandri, Harikrishna] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 21205 USA. [Bluemke, David A.] NIH, Baltimore, MD USA. RP Tandri, H (reprint author), Johns Hopkins Univ Hosp, Carnegie 565D,600 N Wolfe St, Baltimore, MD 21287 USA. EM htandri1@jhmi.edu RI Stuber, Matthias/B-2949-2010; OI Stuber, Matthias/0000-0001-9843-2028; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [K23HL093350]; St Jude Medical Foundation; Medtronic Inc; Boston Scientific Corp; Bogle Foundation; Healing Hearts Foundation; Campanella family; Wilmerding Endowments FX This study was supported by the National Heart, Lung, and Blood Institute (K23HL093350 to Dr Tandri) and the St Jude Medical Foundation, Medtronic Inc, and Boston Scientific Corp. The Johns Hopkins ARVD Program is supported by the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, and the Wilmerding Endowments. NR 23 TC 10 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAY PY 2010 VL 3 IS 3 BP 290 EP 297 DI 10.1161/CIRCIMAGING.109.911313 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 597RU UT WOS:000277779300010 PM 20197508 ER PT J AU Smith, SC Zheng, ZJ AF Smith, Sidney C., Jr. Zheng, Zhi-Jie TI The Impending Cardiovascular Pandemic in China SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Editorial Material DE Editorials; cardiovascular disease; China; epidemiology; prevention; risk model ID DISEASE; PREVENTION; HEART; ASSOCIATION; STATEMENT C1 [Smith, Sidney C., Jr.] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Zheng, Zhi-Jie] NHLBI, Div Applicat Res Discoveries, NIH, Bethesda, MD 20892 USA. RP Smith, SC (reprint author), Univ N Carolina, Sch Med, CB 7075,Bioinformat Bldg,160 Dent Cir, Chapel Hill, NC 27599 USA. NR 14 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD MAY PY 2010 VL 3 IS 3 BP 226 EP 227 DI 10.1161/CIRCOUTCOMES.110.957183 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 597RN UT WOS:000277778400003 PM 20442212 ER PT J AU Kolibab, K Yang, A Derrick, SC Waldmann, TA Perera, LP Morris, SL AF Kolibab, Kristopher Yang, Amy Derrick, Steven C. Waldmann, Thomas A. Perera, Liyanage P. Morris, Sheldon L. TI Highly Persistent and Effective Prime/Boost Regimens against Tuberculosis That Use a Multivalent Modified Vaccine Virus Ankara-Based Tuberculosis Vaccine with Interleukin-15 as a Molecular Adjuvant SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; IMMUNE-RESPONSES; T-CELLS; IMMUNODEFICIENCY VIRUS; PROTECTIVE IMMUNITY; CALMETTE-GUERIN; RHESUS MACAQUES; BCG; PRIME; EFFICACY AB Novel immunization strategies are needed to enhance the global control of tuberculosis (TB). In this study, we assessed the immunizing activity of a recombinant modified vaccinia Ankara (MVA) construct (MVA/IL-15/5Mtb) which overexpresses five Mycobacterium tuberculosis antigens (antigen 85A, antigen 85B, ESAT6, HSP60, and Mtb39), as well as the molecular adjuvant interleukin-15 (IL-15). Homologous prime/boost studies showed that the MVA/IL-15/5Mtb vaccine induced moderate but highly persistent protective immune responses for at least 16 months after the initial vaccination and that the interval between the prime and boost did not significantly alter vaccine-induced antituberculosis protective immunity. At 16 months, when the Mycobacterium bovis BCG and MVA/IL-15/5Mtb vaccine-induced protection was essentially equivalent, the protective responses after a tuberculous challenge were associated with elevated levels of gamma interferon (IFN-gamma), IL-17F, Cxcl9, and Cxcl10. To amplify the immunizing potential of the MVA/IL-15/5Mtb vaccine, a heterologous prime/boost regimen was tested using an ESAT6-antigen 85B (E6-85) fusion protein formulated in dimethyldiotacylammonium bromide/monophosphoryl lipid A (DDA/MPL) adjuvant as the priming vaccine and the MVA/IL-15/5Mtb recombinant virus as the boosting agent. When MVA/IL-15/5Mtb vaccine boosting was done at 2 or 6 months following the final fusion protein injections, the prime/boost regimen evoked protective responses against an aerogenic M. tuberculosis challenge which was equivalent to that induced by BCG immunization. Long-term memory after immunization with the E6-85-MVA/IL-15/5Mtb combination regimen was associated with the induction of monofunctional CD4 and CD8 IFN-gamma-producing T cells and multifunctional CD4 and CD8 T cells expressing IFN-gamma/tumor necrosis factor alpha (TNF-alpha), TNF-alpha/IL-2, and IFN-gamma/TNF-alpha/IL-2. In contrast, BCG-induced protection was characterized by fewer CD4 and CD8 monofunctional T cells expressing IFN-gamma and only IFN-gamma/TNF-alpha and IFN-gamma/TNF-alpha/IL-2 expressing multifunctional T (MFT) cells. Taken together, these results suggest that a heterologous prime/boost protocol using an MVA-based tuberculosis vaccines to boost after priming with TB protein/adjuvant preparations should be considered when designing long-lived TB immunization strategies. C1 [Kolibab, Kristopher; Yang, Amy; Derrick, Steven C.; Morris, Sheldon L.] US FDA, Lab Mycobacterial Dis & Cellular Immunol, CBER, Bethesda, MD 20892 USA. [Waldmann, Thomas A.; Perera, Liyanage P.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Morris, SL (reprint author), US FDA, Lab Mycobacterial Dis & Cellular Immunol, CBER, Bldg 29,Room 502,29 Lincoln Dr, Bethesda, MD 20892 USA. EM pereral@mail.nih.gov; sheldon.morris@fda.hhs.gov NR 29 TC 27 Z9 28 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD MAY PY 2010 VL 17 IS 5 BP 793 EP 801 DI 10.1128/CVI.00006-10 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 590QX UT WOS:000277243200014 PM 20357059 ER PT J AU Milosevic, D Lundquist, P Cradic, K Vidal-Folch, N Huynh, T Pacak, K Grebe, SKG AF Milosevic, Dragana Lundquist, Patrick Cradic, Kendall Vidal-Folch, Noemi Huynh, ThanhTruc Pacak, Karel Grebe, Stefan K. G. TI Development and validation of a comprehensive mutation and deletion detection assay for SDHB, SDHC, and SDHD SO CLINICAL BIOCHEMISTRY LA English DT Article DE SDHB; SDHC; SDHD; Paraganglioma; Pheochromocytoma; Genotyping; DNA sequencing; Deletion detection; MLPA ID PHEOCHROMOCYTOMA; PARAGANGLIOMA AB Background: Lack of sequencing validation and complexity of deletion testing hinder genetic diagnosis of SDH-associated paraganglioma/pheochromocytoma. Methods: We developed sequencing assays and multiplex ligation-dependent probe amplification (MLPA) deletion detection for SDHB. SDHC and SDHD. Clinical performance was validated on 141 blinded samples, previously tested at NIH. Results: Sequencing and deletion detection were highly reproducible and agreed with previous NIH results in 99.3% and 100%, respectively. Conclusions: DNA sequencing combined with MLPA allows reliable and simplified genotyping of SDHB, SDHC and SDHD. (C) 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. C1 [Milosevic, Dragana; Lundquist, Patrick; Cradic, Kendall; Vidal-Folch, Noemi; Grebe, Stefan K. G.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55902 USA. [Grebe, Stefan K. G.] Mayo Clin, Dept Med, Rochester, MN USA. [Huynh, ThanhTruc; Pacak, Karel] NICHD, Reprod & Adult Endocrinol Program, NIH, Bethesda, MD USA. RP Grebe, SKG (reprint author), Mayo Clin, Dept Lab Med & Pathol, 200 1st St SW, Rochester, MN 55902 USA. EM grebs@mayo.edu FU Intramural NIH HHS [ZIA HD008735-10] NR 9 TC 3 Z9 3 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 J9 CLIN BIOCHEM JI Clin. Biochem. PD MAY PY 2010 VL 43 IS 7-8 BP 700 EP 704 DI 10.1016/j.clinbiochem.2010.01.016 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 587JO UT WOS:000276988000015 PM 20153743 ER PT J AU Lovely, RS Kazmierczak, SC Massaro, JM D'Agostino, RB O'Donnell, CJ Farrell, DH AF Lovely, Rehana S. Kazmierczak, Steven C. Massaro, Joseph M. D'Agostino, Ralph B., Sr. O'Donnell, Christopher J. Farrell, David H. TI gamma ' Fibrinogen: Evaluation of a New Assay for Study of Associations with Cardiovascular Disease SO CLINICAL CHEMISTRY LA English DT Article ID INDIVIDUAL PARTICIPANT METAANALYSIS; SPLICE VARIANT; EXOSITE-II; CHAIN; THROMBIN; IDENTIFICATION; FIBRINOLYSIS; HEMOSTASIS; PEPTIDE; RISK AB BACKGROUND: Studies of disease associations with gamma' fibrinogen, a newly emerging risk factor for cardiovascular disease, have been hampered by the lack of a standardized and well-characterized assay. METHODS: We developed an immunometric technique to measure gamma' fibrinogen concentrations in plasma and studied the clinical utility of this test in samples from healthy individuals enrolled in the Framingham Off-spring Study and in a separate case/control study of coronary artery disease (CAD). Monoclonal antibody 2.G2.H9, specific for the unique carboxyl terminal peptide of the fibrinogen gamma' chain, was used as capture antibody. Sheep antihuman fibrinogen/horseradish peroxidase conjugate was used for detection, with 3,3',5,5'-tetramethylbenzidine as substrate. We evaluated the linearity, imprecision, analytical specificity, and lower limit of quantification of the assay. We determined the reference interval for gamma' fibrinogen in healthy individuals from the Framingham Offspring Study (n = 2879) and quantified associations between gamma' fibrinogen and cardiovascular disease risk factors. The sensitivity and specificity of gamma' fibrinogen in evaluating CAD patients (n = 133) was determined with ROC curve analysis. RESULTS: The gamma' fibrinogen ELISA had within-run CVs of 13.4% at 0.127 g/L and 4.8% at 0.416 g/L. The limit of quantification at an imprecision of 20% was 0.10 g/L. The reference interval for healthy individuals was 0.088-0.551 g/L. ROC curve analysis of results from patients with CAD yielded an area under the curve of 0.76, with a diagnostic accuracy of 0.78 at a decision threshold of 0.30 g/L. CONCLUSIONS: gamma' Fibrinogen shows excellent utility for cardiovascular risk analysis. (C) 2010 American Association for Clinical Chemistry C1 [Kazmierczak, Steven C.; Farrell, David H.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97239 USA. [Lovely, Rehana S.] SW Missouri State Univ, Dept Biomed Sci, Springfield, MO 65802 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Farrell, DH (reprint author), Oregon Hlth & Sci Univ, Dept Pathol, L113,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM farrelld@ohsu.edu OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Heart Association [0865486G]; National Heart, Lung, and Blood Institute of the NIH [R21-HL-75006, R21-HL-97298]; Office of Naval Research [N000140610411] FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract no. N01-HC-25195), by grant 0865486G from the American Heart Association (to R. S. Lovely), and by grants R21-HL-75006 and R21-HL-97298 from the National Heart, Lung, and Blood Institute of the NIH and N000140610411 from the Office of Naval Research (to D. H. Farrell). NR 28 TC 25 Z9 25 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD MAY PY 2010 VL 56 IS 5 BP 781 EP 788 DI 10.1373/clinchem.2009.138347 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 589OM UT WOS:000277160800020 PM 20348406 ER PT J AU Holmes, C Whittaker, N Heredia-Moya, J Goldstein, DS AF Holmes, Courtney Whittaker, Noel Heredia-Moya, Jorge Goldstein, David S. TI Contamination of the Norepinephrine Prodrug Droxidopa by Dihydroxyphenylacetaldehyde SO CLINICAL CHEMISTRY LA English DT Article ID PARKINSONS-DISEASE; 3,4-DIHYDROXYPHENYLACETALDEHYDE; DOPAMINE; METABOLITE; CELLS AB BACKGROUND: L-Threo-3,4-dihydroxyphenylserine (L-DOPS, droxidopa) is a norepinephrine (NE) prodrug under development to treat orthostatic hypotension. 3,4-Dihydroxyphenylacetaldehyde (DOPAL), an endogenous catecholaldehyde produced by enzymatic oxidative deamination of dopamine, is toxic to catecholaminergic neurons. Based on the observation of increasing plasma DOPAL after oral administration of L-DOPS to a patient, we examined whether other subjects also had DOPAL in their plasma after droxidopa administration, and whether droxidopa is contaminated with DOPAL. METHODS: Thirteen subjects took 400 mg droxidopa orally. We sampled venous blood at baseline and 1, 2, 3, 6, 24, and 48 h after drug administration and assayed L-DOPS, NE, and DOPAL by use of liquid chromatography with electrochemical detection (LC-ED). Droxidopa in acidic solution (20: 80 mixture of 0.04 mol/L phosphoric acid: 0.20 mol/L acetic acid) was vacuum centrifuged for 1 h at 30 degrees C and then assayed by LC-ED. RESULTS: Droxidopa contained 0.01% DOPAL. At 6 h after droxidopa, all subjects had detectable DOPAL in plasma (1.89 nmol/L, P = 0.0001). Across the sampling times, plasma DOPAL correlated with plasma L-DOPS (r = 0.996). The mean increment in plasma DOPAL was more than 4 times that in plasma NE (0.39 nmol/L). In 2 patients with Parkinson disease and orthostatic hypotension, DOPAL was detected in plasma at baseline (0.12 nmol/L) and increased by about 70-fold after droxidopa. Vacuum concentration of droxidopa in the acid solution converted L-DOPS to DOPAL completely. CONCLUSIONS: Droxidopa is contaminated with DOPAL. After oral droxidopa administration, DOPAL is detected in plasma of humans. Droxidopa is susceptible to extensive nonenzymatic conversion to DOPAL. (C) 2010 American Association for Clinical Chemistry C1 [Holmes, Courtney; Goldstein, David S.] NINDS, Clin Neurocardiol Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Whittaker, Noel; Heredia-Moya, Jorge] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, Div Intramural Res, NIH, 10 Ctr Dr,MSC-1620,Bldg 10,Room 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 13 TC 6 Z9 6 U1 1 U2 4 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD MAY PY 2010 VL 56 IS 5 BP 832 EP 838 DI 10.1373/clinchem.2009.139709 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 589OM UT WOS:000277160800026 PM 20207766 ER PT J AU Gray, TR Kelly, T LaGasse, LL Smith, LM Derauf, C Grant, P Shah, R Arria, A Haning, W Della Grotta, S Strauss, A Lester, BM Huestis, MA AF Gray, Teresa R. Kelly, Tamsin LaGasse, Linda L. Smith, Lynne M. Derauf, Chris Grant, Penny Shah, Rizwan Arria, Amelia Haning, William Della Grotta, Sheri Strauss, Arthur Lester, Barry M. Huestis, Marilyn A. TI New Meconium Biomarkers of Prenatal Methamphetamine Exposure Increase Identification of Affected Neonates SO CLINICAL CHEMISTRY LA English DT Article ID MASS-SPECTROMETRY METHOD; LIFE-STYLE IDEAL; INFANT DEVELOPMENT; ENVIRONMENT; METABOLITES; PREGNANCY; DRUGS; PHARMACOKINETICS; MOTHERS; ABUSE AB BACKGROUND: Prenatal methamphetamine (MAMP) exposure is poorly reflected in neonatal meconium. Often, maternal self-reported MAMP use is not corroborated by positive results in amphetamines immunoassays of meconium, and even if initial test results are positive, they frequently are not confirmed for MAMP or amphetamine (AMP) by chromatographic analysis. The presence of the MAMP metabolites p-hydroxymethamphetamine (pOHMAMP), p-hydroxyamphetamine (pOHAMP), and norephedrine (NOREPH) in meconium may improve the identification of MAMP- and AMP-exposed neonates. METHODS: Immunoassay-positive and -negative meconium samples were subjected to liquid chromatography tandem mass spectrometric reanalysis for these recently identified metabolites. RESULTS: pOHAMP and NOREPH were detected only when MAMP and/or AMP were present and thus do not appear to be promising biomarkers of prenatal MAMP exposure. pOHMAMP, in contrast, identified 6 additional neonates whose mothers reported MAMP exposure, yet had a meconium sample screened as negative; pOHMAMP was more likely to be present if maternal MAMP use continued into the third trimester. Although the pOHMAMP results for meconium samples corroborated the maternal self-reports, the confirmation rate for positive meconium screening results did not improve with the inclusion of these new biomarkers. CONCLUSIONS: pOHMAMP identified additional MAMP-exposed neonates; therefore, MAMP, AMP, and pOHMAMP should be included in meconium chromatographic analyses. Maximizing the identification of MAMP-exposed children requires improvement in immunoassay screening tests to reduce false-negative and false-positive results. Additional research will help clarify which AMP-related compounds, if any, contribute to unconfirmed positive results in screening tests. Furthermore, nonamphetamine compounds endogenous to the complex meconium matrix also may cross-react, making chromatographic confirmation of screening results essential. C1 [Gray, Teresa R.; Kelly, Tamsin; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Kelly, Tamsin] Univ Canberra, Fac Sci Appl, Canberra, ACT 2601, Australia. [LaGasse, Linda L.; Della Grotta, Sheri; Lester, Barry M.] Brown Univ, Warren Alpert Med Sch, Ctr Study Children Risk, Providence, RI 02912 USA. [Smith, Lynne M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Torrance, CA USA. [Derauf, Chris] Univ Hawaii, John A Burns Sch Med, Dept Pediat, Honolulu, HI 96822 USA. [Grant, Penny] Univ Oklahoma, Dept Pediat, Tulsa, OK USA. [Shah, Rizwan] Blank Childrens Hosp Iowa Hlth, Dept Pediat, Des Moines, IA USA. [Arria, Amelia] Univ Maryland, Ctr Subst Abuse Res, College Pk, MD 20742 USA. [Haning, William] Univ Hawaii, John A Burns Sch Med, Dept Psychiat, Honolulu, HI 96822 USA. [Strauss, Arthur] Long Beach Mem Med Ctr, Dept Pediat, Long Beach, CA USA. RP Huestis, MA (reprint author), 251 Bayview Blvd,Suite 200,Rm 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov RI Kelly, Tamsin/A-2456-2009; OI Kelly, Tamsin/0000-0002-8946-9686; Arria, Amelia/0000-0002-6360-9265 FU NIDA, NIH; NIDA [R01DA014948] FX W. Haning, National Institute on Drug Abuse (NIDA). This research was funded by the Intramural Research Program of NIDA, NIH, and NIDA grant R01DA014948. NR 20 TC 7 Z9 7 U1 1 U2 4 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD MAY PY 2010 VL 56 IS 5 BP 856 EP 860 DI 10.1373/clinchem.2009.139055 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 589OM UT WOS:000277160800029 PM 20185623 ER PT J AU Celi, FS Zemskova, M Linderman, JD Babar, NI Skarulis, MC Csako, G Wesley, R Costello, R Penzak, SR Pucino, F AF Celi, Francesco S. Zemskova, Marina Linderman, Joyce D. Babar, Nabeel I. Skarulis, Monica C. Csako, Gyorgy Wesley, Robert Costello, Rene Penzak, Scott R. Pucino, Frank TI The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross-over study in thyroidectomized patients SO CLINICAL ENDOCRINOLOGY LA English DT Article ID THYROXINE PLUS TRIIODOTHYRONINE; THYROID-HORMONE REPLACEMENT; CONTROLLED-TRIAL; PRIMARY HYPOTHYROIDISM; COMBINATION REGIMEN; THERAPY; 3,5,3'-TRIIODOTHYRONINE; TSH; T-4; EUTHYROIDISM AB P>Context The substitution of liothyronine (L-T3) for levothyroxine (L-T4) is commonly employed during thyroid hormone (TH) withdrawal in preparation for diagnostic and therapeutic interventions on thyroid cancer patients. Presently, only limited data are available on the L-T3 for L-T4 therapeutic substitution. Objective To characterize the pharmcodynamic equivalence of L-T3 and L-T4. Design Randomized, double-blind, cross-over intervention study. Setting NIH clinical center. Patients Ten thyroidectomized patients. Interventions Study participants were treated with L-T3 or L-T4 with a target TSH >= 0 center dot 5 < 1 center dot 5 mU/l for at least 30 days before undergoing inpatient testing. Following testing, subjects crossed-over according to the same scheme. Main outcome measures Area under the serum concentration-time curve of TSH from 0 to 60 min (AUC(0-60)) and peak TSH serum concentration (C(max)) following thyrotropin-releasing hormone (TRH) stimulation test, total L-T4 and L-T3 dose (mcg/kg), and L-T4/L-T3 ratio. Results No difference was observed for time 0 TSH values between L-T3 and L-T4 replacement phases (1 center dot 48 +/- 0 center dot 77 vs. 1 center dot 21 +/- 0 center dot 62 mU/l, P = 0 center dot 293) at average daily doses of 40 center dot 3 +/- 11 center dot 3 mcg L-T3 and 115 center dot 2 +/- 38 center dot 5 mcg L-T4, L-T3: L-T4 ratio 0 center dot 36 +/- 0 center dot 06. TRH stimulation test resulted in similar L-T3 vs. L-T4 TSH responses with AUC(0-60) of 326 center dot 1 (95% CI 232 center dot 6-457 center dot 1) and 247 center dot 1 (95% CI 153 center dot 8-397 center dot 1) mU* min/l (P = 0 center dot 285); and C(max) of 6 center dot 83 (95% CI 4 center dot 88-9 center dot 55) and 5 center dot 23 (95% CI 3 center dot 31-8 center dot 3) mU/l (P = 0 center dot 383). Conclusions This is the first study addressing the equivalency between L-T3 and L-T4 therapy measured by baseline and TRH-stimulated TSH. The therapeutic substitution of L-T3 for L-T4 was achieved at approximately 1:3 ratio. C1 [Celi, Francesco S.; Linderman, Joyce D.; Babar, Nabeel I.; Skarulis, Monica C.] NIDDKD, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Zemskova, Marina] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Reprod Endocrinol, NIH, Bethesda, MD USA. [Csako, Gyorgy; Costello, Rene] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Wesley, Robert] NIH, Hosp Epidemiol, Ctr Clin, Bethesda, MD 20892 USA. [Penzak, Scott R.; Pucino, Frank] NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. RP Celi, FS (reprint author), NIDDKD, Clin Endocrinol Branch, NIH, Bldg 10,CRC,RM 6-3940,10 Ctr Dr,MSC 1613, Bethesda, MD 20892 USA. EM fc93a@nih.gov FU NIDDK-NIH [Z01-DK047057-02]; NIH Clinical Center [NCT00106119] FX The authors gratefully acknowledge the help and professionalism of the nursing, laboratory, pharmacy (especially George Grimes Judy Starling), and ancillary personnel of the NIH Clinical Center. This research could have not been accomplished without the selflessness participation of the study participants. This study was supported by the Intramural Research Program of the NIDDK-NIH, program Z01-DK047057-02 and the Intramural Research Program of the NIH Clinical Center. ClinicalTrials.gov identifier: NCT00106119. NR 32 TC 16 Z9 18 U1 1 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD MAY PY 2010 VL 72 IS 5 BP 709 EP 715 DI 10.1111/j.1365-2265.2009.03700.x PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 574SI UT WOS:000276013000020 PM 20447070 ER PT J AU Gordon, RR La Merrill, M Hunter, KW Sorensen, P Threadgill, DW Pomp, D AF Gordon, Ryan R. La Merrill, Michele Hunter, Kent W. Sorensen, Peter Threadgill, David W. Pomp, Daniel TI Dietary fat-dependent transcriptional architecture and copy number alterations associated with modifiers of mammary cancer metastasis SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Article DE Breast cancer; Causality; eQTL; High-fat diet; Tumors ID BREAST-CANCER; GENE-EXPRESSION; MICE; DISEASE; TUMORS; MICROARRAY; MUTATIONS; BEHAVIOR; PLATFORM; OBESITY AB Breast cancer is a complex disease resulting from a combination of genetic and environmental factors. Among environmental factors, body composition and intake of specific dietary components like total fat are associated with increased incidence of breast cancer and metastasis. We previously showed that mice fed a high-fat diet have shorter mammary cancer latency, increased tumor growth and more pulmonary metastases than mice fed a standard diet. Subsequent genetic analysis identified several modifiers of metastatic mammary cancer along with widespread interactions between cancer modifiers and dietary fat. To elucidate diet-dependent genetic modifiers of mammary cancer and metastasis risk, global gene expression profiles and copy number alterations from mammary cancers were measured and expression quantitative trait loci (eQTL) identified. Functional candidate genes that colocalized with previously detected metastasis modifiers were identified. Additional analyses, such as eQTL by dietary fat interaction analysis, causality and database evaluations, helped to further refine the candidate loci to produce an enriched list of genes potentially involved in the pathogenesis of metastatic mammary cancer. C1 [Gordon, Ryan R.; Threadgill, David W.] N Carolina State Univ, Dept Genet, Raleigh, NC 27695 USA. [Gordon, Ryan R.; Pomp, Daniel] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Threadgill, David W.; Pomp, Daniel] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Pomp, Daniel] Univ N Carolina, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. [Threadgill, David W.; Pomp, Daniel] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [La Merrill, Michele] Mt Sinai Sch Med, Dept Prevent Med, New York, NY 10029 USA. [Hunter, Kent W.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Sorensen, Peter] Aarhus Univ, Dept Genet & Biotechnol, Fac Agr Sci, Aarhus, Denmark. RP Gordon, RR (reprint author), N Carolina State Univ, Dept Genet, 100 Derieux Pl,Gardner Hall 3510, Raleigh, NC 27695 USA. EM rrgordon@ncsu.edu RI Threadgill, David/N-4425-2013 OI Threadgill, David/0000-0003-3538-1635 FU NCI-MMHCC [U01CA105417]; NIDDK [DK076050]; NIH, National Cancer Institute, Center for Cancer Research FX This work was partially funded by grants from the NCI-MMHCC (U01CA105417) and NIDDK (DK076050), and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 30 TC 6 Z9 6 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD MAY PY 2010 VL 27 IS 5 BP 279 EP 293 DI 10.1007/s10585-010-9326-z PG 15 WC Oncology SC Oncology GA 602PX UT WOS:000278152400001 PM 20354763 ER PT J AU Agarwal, VK McHutchison, JG Hoofnagle, JH AF Agarwal, Vijay K. McHutchison, John G. Hoofnagle, Jay H. CA DILIN TI Important Elements for the Diagnosis of Drug-Induced Liver Injury SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Acute Liver Failure; Adverse Drug Reaction Reporting Systems; Case Reports; Hepatotoxicity; Standards ID AMOXICILLIN-CLAVULANIC ACID; PATIENT RECEIVING ROSIGLITAZONE; SEVERE CHOLESTATIC HEPATITIS; INDUCED FULMINANT-HEPATITIS; UNITED-STATES; HEPATOCELLULAR INJURY; PIOGLITAZONE THERAPY; TROGLITAZONE; HEPATOTOXICITY; FAILURE AB BACKGROUND & AIMS: Drug-induced liver disease is the leading cause of acute liver failure in the United States. Accurate reporting of drug-induced liver injury is essential for early detection of hepatoroxicity and for developing reliable, interpretable literature. We assessed the extent to which published case reports of drug-induced liver disease include sufficient clinical data for interpreting the cause of toxicity. METHODS: We developed a list of 42 predetermined, specific minimal elements necessary in evaluating causality of drug-induced liver injury. We then analyzed 97 published case reports or series studies of hepatotoxicity from 6 drugs (from 3 classes): amoxicillin/clavulanic acid (n = 35), troglitazone (n = 32), rosiglitazone (n = 10), pioglitazone (n = 8), zafirlukasr (n = 8), and montelukast (n = 4). RESULTS: Patient age, sex, primary disease, and drug name were reported in most, if not all, published case reports. However, many elements were underreported; some publications did not mention initial bilirubin levels (12%), many did not provide initial alkaline phosphatase levels (58%), and others provided vague descriptions of how certain diagnoses were excluded, that is, tests for hepatitis A, B, and C were negative. Data on abnormal results from serial liver tests frequently were absent. Exclusions of competing viral etiologies were reported in less than 50% of the studies. CONCLUSIONS: Reports of drug-induced liver diseases often do not provide the data needed to determine the causes of the adverse effects. Efforts to promote and include a list of essential diagnostic elements in research articles could increase the quality and clinical utility of published case reports of drug toxicity. C1 [McHutchison, John G.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27715 USA. [Hoofnagle, Jay H.] NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD USA. RP McHutchison, JG (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. EM mchut001@mc.duke.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238, 1U01DK065176] FX Funding for the Drug-Induced Liver Injury Network is provided by the National Institute of Diabetes and Digestive and Kidney Diseases under cooperative agreements: 1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238, and 1U01DK065176. NR 63 TC 56 Z9 59 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD MAY PY 2010 VL 8 IS 5 BP 463 EP 470 DI 10.1016/j.cgh.2010.02.008 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 593XQ UT WOS:000277496900017 PM 20170750 ER PT J AU Henderson, C Goldbach-Mansky, R AF Henderson, Cailin Goldbach-Mansky, Raphaela TI Monogenic IL-1 mediated autoinflammatory and immunodeficiency syndromes: Finding the right balance in response to danger signals SO CLINICAL IMMUNOLOGY LA English DT Review DE IL-1; Autoinflammatory diseases; NOMID/CINCA; DIRA; NLRP3; IL1RN; IL-1Ra; NOD like receptors; Anakinra; Neonatal disorder; Genetic disease ID FAMILIAL MEDITERRANEAN FEVER; MULTISYSTEM INFLAMMATORY DISEASE; MUCKLE-WELLS-SYNDROME; PYOGENIC BACTERIAL-INFECTIONS; ENCODING MEVALONATE KINASE; INNATE IMMUNE-RESPONSE; NF-KAPPA-B; NALP3 INFLAMMASOME; CASPASE-1 ACTIVATION; INTERLEUKIN-1-RECEPTOR ANTAGONIST AB Introduction: Interleukin-1 was the first cytokine identified and is a powerful inducer of fever and inflammation. The biologically active receptor for IL-1, shares signaling pathways with some pathogen recognition receptors, the Toll-like receptors (TLRs) which early on suggested an important role in innate immune function. Discussion: The discovery that some intracellular "danger receptors", the NOD like receptors (NLRs) can assemble to form multimolecular platforms, the inflammasomes, that not only sense intracellular danger but also activate IL-1 beta, has provided the molecular basis for the integration of IL-1 as an early response mediator in danger recognition. The critical role of balancing IL-1 production and signaling in human disease has recently been demonstrated in rare human monogenic diseases with mutations that affect the meticulous control of IL-1 production, release and signaling by leading to decreased or increased TLR/IL-1 signaling. In diseases of decreased TLR/IL-1 signaling (IRAK-4 and MyD88 deficiencies) patients are at risk for infections with gram positive organisms; and in diseases of increased signaling, patients develop systemic autoinflammatory diseases (cryopyrin-associated periodic syndromes (CAPS), and deficiency of the IL-1 receptor antagonist (DIRA)). Conclusion: Monogenic defects in a number of rare diseases that affect the balance of TLR/IL-1 signaling have provided us with opportunities to study the systemic effects of IL-1 in human diseases. The molecular defects in CAPS and DIRA provided a therapeutic rationale for targeting IL-1 and the impressive clinical results from IL-1 blocking therapies have undoubtedly confirmed the pivotal role of IL-1 in human disease and spurred the exploration of modifying IL-1 signaling in a number of genetically complex common human diseases. Published by Elsevier Inc. C1 [Henderson, Cailin; Goldbach-Mansky, Raphaela] NIAMSD, NIH, Translat Autoinflammatory Dis Sect, Bethesda, MD USA. RP Goldbach-Mansky, R (reprint author), NIAMS, NIH, Bldg 10,Rm 6D-478,10 Ctr Dr, Bethesda, MD 20892 USA. EM hendersoncc@mail.nih.gov; goldbacr@mail.nih.gov FU Intramural NIH HHS [Z01 AR041138-05] NR 103 TC 21 Z9 22 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2010 VL 135 IS 2 SI SI BP 210 EP 222 DI 10.1016/j.clim.2010.02.013 PG 13 WC Immunology SC Immunology GA 588ZH UT WOS:000277112900006 PM 20353899 ER PT J AU Niemela, J Lianghao, L Caminha, I Rao, V Davis, J Fleisher, T Oliveira, JB AF Niemela, J. Lianghao, L. Caminha, I. Rao, V. Davis, J. Fleisher, T. Oliveira, J. B. TI Gain-of-Function Somatic Kras Mutation Associated With A Syndrome of Autoimmunity, Lymphoproliferation And Recurrent Infections SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 1st North American Primary Immune Deficiency National Conference CY MAY 20-23, 2010 CL Philadelphia, PA C1 [Niemela, J.; Lianghao, L.; Caminha, I.; Rao, V.; Davis, J.; Fleisher, T.; Oliveira, J. B.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2010 VL 135 IS 2 SI SI MA 13 BP 289 EP 289 PG 1 WC Immunology SC Immunology GA 588ZH UT WOS:000277112900025 ER PT J AU Browne, SK Zaman, R Sampaio, EP Kristosturyan, E Holland, SM AF Browne, S. K. Zaman, R. Sampaio, E. P. Kristosturyan, E. Holland, S. M. TI Rituximab Impacts Anti-IFNG Autoantibodies in Humans SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 1st North American Primary Immune Deficiency National Conference CY MAY 20-23, 2010 CL Philadelphia, PA C1 [Browne, S. K.; Zaman, R.; Sampaio, E. P.; Kristosturyan, E.; Holland, S. M.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2010 VL 135 IS 2 SI SI MA 16 BP 290 EP 290 PG 1 WC Immunology SC Immunology GA 588ZH UT WOS:000277112900028 ER PT J AU Adriani, M Jones, K Kirby, M Anderson, S Silvin, C Wincowitch, S Candotti, F AF Adriani, M. Jones, K. Kirby, M. Anderson, S. Silvin, C. Wincowitch, S. Candotti, F. TI Natural and Induced Regulatory T Cells Are Defective in the Wiskott-Aldrich Syndrome SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 1st North American Primary Immune Deficiency National Conference CY MAY 20-23, 2010 CL Philadelphia, PA C1 [Adriani, M.; Jones, K.; Kirby, M.; Anderson, S.; Silvin, C.; Wincowitch, S.; Candotti, F.] NHGRI, NIH, GMBB, Bethesda, MD 20892 USA. RI Adriani, Marsilio/F-2553-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2010 VL 135 IS 2 SI SI MA 22 BP 292 EP 293 PG 2 WC Immunology SC Immunology GA 588ZH UT WOS:000277112900034 ER PT J AU Sokolic, R Kesserwan, C Candotti, F AF Sokolic, R. Kesserwan, C. Candotti, F. TI Myeloid Dysplasia and Dermatofibrosarcoma Protuberans: New Clinical Features of Adenosine Deaminase Deficiency SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 1st North American Primary Immune Deficiency National Conference CY MAY 20-23, 2010 CL Philadelphia, PA C1 [Sokolic, R.; Kesserwan, C.; Candotti, F.] NHGRI, NIH, Bethesda, MD 20892 USA. RI Sokolic, Robert/I-6072-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2010 VL 135 IS 2 SI SI MA 36 BP 298 EP 299 PG 2 WC Immunology SC Immunology GA 588ZH UT WOS:000277112900048 ER PT J AU Browne, SK Burbelo, PD Sampaio, EP Ching, KH Zaman, R Kristosturyan, E Rajan, A Giaccone, G Iadarola, MJ Holland, SM AF Browne, S. K. Burbelo, P. D. Sampaio, E. P. Ching, K. H. Zaman, R. Kristosturyan, E. Rajan, A. Giaccone, G. Iadarola, M. J. Holland, S. M. TI Anti-Cytokine Autoantibodies and Opportunistic Infections in Thymic Malignancies SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 1st North American Primary Immune Deficiency National Conference CY MAY 20-23, 2010 CL Philadelphia, PA C1 [Browne, S. K.; Burbelo, P. D.; Sampaio, E. P.; Ching, K. H.; Zaman, R.; Kristosturyan, E.; Rajan, A.; Giaccone, G.; Iadarola, M. J.; Holland, S. M.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2010 VL 135 IS 2 SI SI MA 57 BP 308 EP 308 PG 1 WC Immunology SC Immunology GA 588ZH UT WOS:000277112900069 ER PT J AU Heimall, J Milner, JD Kleiner, G Holland, SM Uzel, G Freeman, AF AF Heimall, J. Milner, J. D. Kleiner, G. Holland, S. M. Uzel, G. Freeman, A. F. TI Hypogammaglobulinemia Associated With Defective Class Switched Memory B Cells in Hyper IgE Syndrome SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 1st North American Primary Immune Deficiency National Conference CY MAY 20-23, 2010 CL Philadelphia, PA C1 NIAID, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Miami, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2010 VL 135 IS 2 SI SI MA 58 BP 308 EP 309 PG 2 WC Immunology SC Immunology GA 588ZH UT WOS:000277112900070 ER PT J AU Milner, JD Sack, MN Huang, R Holland, SM Freeman, AF AF Milner, J. D. Sack, M. N. Huang, R. Holland, S. M. Freeman, A. F. TI Effects of STAT3 Mutations on Atopy and Mast Cell Function SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 1st North American Primary Immune Deficiency National Conference CY MAY 20-23, 2010 CL Philadelphia, PA C1 [Milner, J. D.; Sack, M. N.; Huang, R.; Holland, S. M.; Freeman, A. F.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2010 VL 135 IS 2 SI SI MA 60 BP 309 EP 310 PG 2 WC Immunology SC Immunology GA 588ZH UT WOS:000277112900072 ER PT J AU Heimall, J Arora, M Holland, SM Heller, T Freeman, A AF Heimall, J. Arora, M. Holland, S. M. Heller, T. Freeman, A. TI Gastrointestinal Manifestations of Autosomal Dominant Hyper IgE Syndrome SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 1st North American Primary Immune Deficiency National Conference CY MAY 20-23, 2010 CL Philadelphia, PA C1 [Heimall, J.; Arora, M.; Holland, S. M.; Heller, T.; Freeman, A.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2010 VL 135 IS 2 SI SI MA 77 BP 317 EP 317 PG 1 WC Immunology SC Immunology GA 588ZH UT WOS:000277112900088 ER PT J AU Memoli, MJ Hrabal, RJ Hassantoufighi, A Eichelberger, MC Taubenberger, JK AF Memoli, Matthew J. Hrabal, Rachel J. Hassantoufighi, Arash Eichelberger, Maryna C. Taubenberger, Jeffery K. TI Rapid Selection of Oseltamivir- and Peramivir-Resistant Pandemic H1N1 Virus during Therapy in 2 Immunocompromised Hosts SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID INFLUENZA A/H3N2 VIRUS; SUSCEPTIBILITY; PROPHYLAXIS; INFECTION; ZANAMIVIR AB Pandemic 2009 H1N1 virus isolates containing the neuraminidase inhibitor resistance mutation H275Y have been reported. We describe rapid selection for the H275Y resistance mutation during therapy in 2 immunocompromised individuals at 9 and 14 days of therapy, as well as the first described case of clinically significant resistance to peramivir. C1 [Memoli, Matthew J.; Hrabal, Rachel J.; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Hassantoufighi, Arash; Eichelberger, Maryna C.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Memoli, MJ (reprint author), NIAID, Resp Virus Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, MSC 3203,33 N Dr, Bethesda, MD 20892 USA. EM memolim@niaid.nih.gov OI Hagey, Rachel/0000-0002-4368-3169 FU Intramural NIH HHS [Z99 AI999999] NR 15 TC 87 Z9 89 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 1 PY 2010 VL 50 IS 9 BP 1252 EP 1255 DI 10.1086/651605 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 577UA UT WOS:000276248300008 PM 20345239 ER PT J AU Holland, SM Reichenbach, J AF Holland, Steven M. Reichenbach, Janine TI Chronic Granulomatous Disease, Catalase, and Actinomyces Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID VIRULENCE C1 [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Reichenbach, Janine] Univ Childrens Hosp Zurich, Div Immunol Hematol & Bone Marrow Transplantat, Zurich, Switzerland. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, NIH, Bldg 10,CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM sholland@niaid.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 1 PY 2010 VL 50 IS 9 BP 1325 EP 1326 DI 10.1086/651691 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 577UA UT WOS:000276248300019 ER PT J AU Grunwald, JE Alexander, J Maguire, M Whittock, R Parker, C McWilliams, K Lo, JC Townsend, R Gadegbeku, CA Lash, JP Fink, JC Rahman, M Feldman, H Kusek, J Ojo, A AF Grunwald, Juan E. Alexander, Judith Maguire, Maureen Whittock, Revell Parker, Candace McWilliams, Kathleen Lo, Joan C. Townsend, Raymond Gadegbeku, Crystal A. Lash, James P. Fink, Jeffrey C. Rahman, Mahaboob Feldman, Harold Kusek, John Ojo, Akinlolu CA CRIC Study Grp TI Prevalence of Ocular Fundus Pathology in Patients with Chronic Kidney Disease SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC RENAL-INSUFFICIENCY; MACULAR DEGENERATION; CHOROIDAL NEOVASCULARIZATION; RETINOPATHY; ASSOCIATIONS; VERTEPORFIN; THERAPY; TRIAL; RISK AB Background and objectives: The objective of this study was to describe the prevalence of ocular fundus pathology in the Chronic Renal Insufficiency Cohort (CRIC) study, a multicenter, longitudinal study of individuals with varying stages of chronic kidney disease (CKD). Design, setting, participants, & measurements: In this cross-sectional study, 45 digital photos of the disc and macula in both eyes were obtained by nonophthalmologic personnel using a nonmydriatic Canon CR-DGI fundus camera in 1936 individuals who participated in the CRIC study. Photographs were assessed in a masked manner by graders and a retinal specialist at a central photograph reading center. The purpose of this review was to inform participants quickly of conditions that warranted a complete eye examination by an ophthalmologist. Results: Among the 1936 participants who were photographed, 1904 (98%) had assessable photographs in at least one eye. Eye pathologies that required a follow-up examination by an ophthalmologist were identified in 864 (45%) of these 1904 participants. These eye pathologies included, among others, retinopathy (diabetic and/or hypertensive), a finding that was observed in 482 (25%) of these 1904 participants. Three percent (65 participants) of the 1904 participants had serious eye conditions that required urgent follow-up and treatment. Lower estimated GFR and cardiovascular disease were associated with greater eye pathology. Estimated GFR <30 ml/min per 1.73 m(2) was associated with a three times higher risk for retinopathy. Conclusions: We found a high prevalence of fundus pathology in participants with CKD. This finding supports recommendations for regular complete eye examinations in the CKD population. Clin J Am Sac Nephrol 5: 867-873, 2010. doi: 10.2215/CJN.08271109 C1 [Grunwald, Juan E.; Alexander, Judith; Maguire, Maureen; Whittock, Revell; Parker, Candace; McWilliams, Kathleen] Univ Penn, Sch Med, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Townsend, Raymond; Feldman, Harold] Univ Penn, Sch Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Lo, Joan C.] Kaiser Permanente No Calif, Div Res, San Francisco, CA USA. [Gadegbeku, Crystal A.; Ojo, Akinlolu] Univ Michigan, Div Nephrol, Ann Arbor, MI 48109 USA. [Lash, James P.] Univ Illinois, Nephrol Sect, Chicago, IL USA. [Fink, Jeffrey C.] Univ Maryland, Div Nephrol, Baltimore, MD 21201 USA. [Rahman, Mahaboob] Case Western Univ, Dept Nephrol, Cleveland, OH USA. [Rahman, Mahaboob] Case Western Univ, Div Hypertens, Cleveland, OH USA. [Kusek, John] NIDDKD, Div Kidney & Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Grunwald, JE (reprint author), 51 N 39th St, Philadelphia, PA 19104 USA. EM juangrun@mail.med.upenn.edu OI Fink, Jeffrey/0000-0002-5622-5052 FU National Institutes of Health [R01 DK 74151, UL1 RR-024134, MO1 RR-16500, UL1 RR-024989, MO1 RR-000042, UL1 RR-024986, UL1 RR-029879, UL1 RR-024131]; Vivian S. Lasko Research Fund; Nina C. Mackall Trust; Research to Prevent Blindness FX This study was supported by National Institutes of Health grants R01 DK 74151, UL1 RR-024134, MO1 RR-16500, UL1 RR-024989, MO1 RR-000042, UL1 RR-024986, UL1 RR-029879, and UL1 RR-024131; Vivian S. Lasko Research Fund; Nina C. Mackall Trust; and Research to Prevent Blindness. NR 22 TC 22 Z9 22 U1 1 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAY PY 2010 VL 5 IS 5 BP 867 EP 873 DI 10.2215/CJN.08271109 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 593TJ UT WOS:000277483300020 PM 20299372 ER PT J AU Wagner, JA Prince, M Wright, EC Ennis, MM Kochan, J Nunez, DJR Schneider, B Wang, MD Chen, Y Ghosh, S Musser, BJ Vassileva, MT AF Wagner, J. A. Prince, M. Wright, E. C. Ennis, M. M. Kochan, J. Nunez, D. J. R. Schneider, B. Wang, M-D Chen, Y. Ghosh, S. Musser, B. J. Vassileva, M. T. TI The Biomarkers Consortium: Practice and Pitfalls of Open-Source Precompetitive Collaboration SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID DRUG DEVELOPMENT; INNOVATION AB Precompetitive collaboration is a growing driver for innovation and increased productivity in biomedical science and drug development. The Biomarkers Consortium, a public-private platform for precompetitive collaboration specific to biomarkers, demonstrated that adiponectin has potential utility as a predictor of metabolic responses to peroxisome proliferator-activated receptor (PPAR) agonists in individuals with type 2 diabetes. Despite the challenges overcome by this project, the most important lesson learned is that cross-company precompetitive collaboration is a feasible robust approach to biomarker qualification. C1 [Vassileva, M. T.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Wagner, J. A.; Chen, Y.; Musser, B. J.] Merck, Rahway, NJ USA. [Prince, M.; Wang, M-D] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Wright, E. C.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Ennis, M. M.] Quintiles Inc, Austin, TX USA. [Kochan, J.] Hoffmann La Roche, Nutley, NJ USA. [Nunez, D. J. R.] GlaxoSmithKline Inc, Metab Pathways Ctr Excellence Drug Discovery, Res Triangle Pk, NC USA. [Schneider, B.] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Ghosh, S.] N Carolina Cent Univ, Biomed Biotechnol Res Inst, Durham, NC USA. RP Vassileva, MT (reprint author), Fdn Natl Inst Hlth, Bethesda, MD USA. EM mvassileva@fnih.org OI GHOSH, SUJOY/0000-0002-7601-165X NR 10 TC 25 Z9 25 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAY PY 2010 VL 87 IS 5 BP 539 EP 542 DI 10.1038/clpt.2009.227 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 586ZT UT WOS:000276956300008 PM 20407460 ER PT J AU Gerondakis, S Siebenlist, U AF Gerondakis, Steve Siebenlist, Ulrich TI Roles of the NF-kappa B Pathway in Lymphocyte Development and Function SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID T-CELL DEVELOPMENT; CLASS-SWITCH RECOMBINATION; LYMPHOTOXIN-BETA-RECEPTOR; GERMINAL CENTER REACTIONS; THYMIC EPITHELIAL-CELLS; C-REL TRANSCRIPTION; FAS-MEDIATED APOPTOSIS; V-ALPHA-14I NKT CELLS; IMMUNE-RESPONSES; DISTINCT ROLES AB This article focuses on the functions of NF-kappa B that vitally impact lymphocytes and thus adaptive immunity. NF-kappa B has long been known to be essential for many of the responses of mature lymphocytes to invading pathogens. In addition, NF-kappa B has important functions in shaping the immune system so it is able to generate adaptive responses to pathogens. In both contexts, NF-kappa B executes critical cell-autonomous functions within lymphocytes as well as within supportive cells, such as antigen-presenting cells or epithelial cells. It is these aspects of NF-kappa B's physiologic impact that we address in this article. C1 [Gerondakis, Steve] Burnet Inst, Prahran, Vic 3004, Australia. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Gerondakis, S (reprint author), Burnet Inst, 85 Commercial Rd, Prahran, Vic 3004, Australia. EM gerondakis@burnet.edu.au; usiebenlist@niaid.nih.gov NR 230 TC 81 Z9 89 U1 0 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD MAY PY 2010 VL 2 IS 5 AR a000182 DI 10.1101/cshperspect.a000182 PG 29 WC Cell Biology SC Cell Biology GA 625GI UT WOS:000279882700001 PM 20452952 ER PT J AU Pedrosa, VA Paliwal, S Balasubramanian, S Nepal, D Davis, V Wild, J Ramanculov, E Simonian, A AF Pedrosa, Valber A. Paliwal, Sheetal Balasubramanian, Shankar Nepal, Dhriti Davis, Virginia Wild, James Ramanculov, Erlan Simonian, Aleksandr TI Enhanced stability of enzyme organophosphate hydrolase interfaced on the carbon nanotubes SO COLLOIDS AND SURFACES B-BIOINTERFACES LA English DT Article DE Carbon nanotubes; Covalent immobilization; Organophosphate ID NERVE AGENTS; PESTICIDES; BIOSENSOR; CHEMISTRY AB In this paper we demonstrate that SWNTs and a covalent immobilization strategy enable very sensitive sensors with excellent long term stability. Organophosphorus hydrolase (OPH) functionalized single and multi-walled carbon nanotube (CNT) conjugates were exploited for direct amperometric detection of paraoxon, a model organophosphate. The catalytic hydrolysis of paraoxon produces equimoles of p-nitrophenol; oxidation was monitored amperometrically in real time under flow-injection (FIA) mode. OPH covalently immobilized on single-walled carbon nanotubes (SWNTs) demonstrated much higher activity than OPH conjugated to multi-walled carbon nanotubes (MWNTs). The dynamic concentration range for SWNT-OPH was 0.5-8.5 mu mol L(-1) with a detection limit of 0.01 mu mol L(-1) (S/N = 3). In addition to this high sensitivity, the immobilized OPH retained a significant degree of enzymatic activity, and displayed remarkable stability with only 25% signal loss over 7 months. These results suggest that covalent immobilization of OPH on CNTs can be used for specific immobilization with advantages of long term stability, high sensitivity, and simplicity. Published by Elsevier B.V. C1 [Pedrosa, Valber A.; Paliwal, Sheetal; Balasubramanian, Shankar; Simonian, Aleksandr] Auburn Univ, Dept Mat Engn, Auburn, AL 36849 USA. [Nepal, Dhriti; Davis, Virginia] Auburn Univ, Dept Chem Engn, Auburn, AL 36849 USA. [Wild, James] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77840 USA. [Ramanculov, Erlan] Natl Ctr Biotechnol Republ Kazakhstan, Astana 010000, Kazakhstan. RP Simonian, A (reprint author), Auburn Univ, Dept Mat Engn, 274 Wilmore Labs, Auburn, AL 36849 USA. EM als@eng.auburn.edu RI Pedrosa, Valber/H-5822-2012; Ramanculov, Erlan/E-2823-2013; Balasubramanian, Shankar Ganesh/B-1048-2009 OI Balasubramanian, Shankar Ganesh/0000-0002-6149-6471 FU NSF [CTS-0330189]; USDA-CSREES [2006-34394-16953] FX This research was supported by NSF under the Grant CTS-0330189 and by the USDA-CSREES under grant 2006-34394-16953. We also acknowledge the Richard E. Smalley Institute for Nanoscale Science and Technology at Rice University for the SWNTs. Additionally, this material was based on work which supported ALS by the National Science Foundation, while working at the Foundation. Any opinion, finding, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. NR 21 TC 53 Z9 54 U1 1 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0927-7765 J9 COLLOID SURFACE B JI Colloid Surf. B-Biointerfaces PD MAY 1 PY 2010 VL 77 IS 1 BP 69 EP 74 DI 10.1016/j.colsurfb.2010.01.009 PG 6 WC Biophysics; Chemistry, Physical; Materials Science, Biomaterials SC Biophysics; Chemistry; Materials Science GA 578CX UT WOS:000276272100010 PM 20138483 ER PT J AU Moss, ML Rasmussen, FH Nudelman, R Dempsey, PJ Williams, J AF Moss, Marcia L. Rasmussen, Fred H. Nudelman, Raphael Dempsey, Peter J. Williams, Jason TI Fluorescent Substrates Useful as High Throughput Screening Tools for ADAM9 SO COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING LA English DT Article DE ADAM8; ADAM9; ADAM10; ADAM12; ADAM17; TACE; fluorescent; substrate; inhibitor; TMI-1; GI254023; GM6001; disintegrin; metalloproteinase; FRET; CD23; TGF-alpha ID ALPHA-CONVERTING-ENZYME; METALLOPROTEASE-DISINTEGRIN MDC9; RHEUMATOID-ARTHRITIS; INSULIN-RESISTANCE; CATALYTIC-ACTIVITY; RECEPTOR CD23; INHIBITOR; CANCER; FAMILY; MICE AB Fluorescence resonance energy transfer substrates were designed and tested as substrates for ADAM9. The donor/quencher pair used were 5-carboxyfluorescein (Fam) and 4-(4-dimethyl-aminophenylazo) benzoyl (Dabcyl) since they have been well studied sensitive fluorescent probes. The peptides based on precursor TNF-alpha, Dabcyl-Ser-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Lys(Fam)-NH(2) and Dabcyl-Leu-Ala-Gln-Ala-HomoPhe-Arg-Ser-Lys(Fam)-NH(2), and C-terminal TGF-alpha, Dabcyl-Glu-His-Ala-Asp-Leu-Leu-Ala-Val-Val-Ala-Ala-Lys(Fam)-NH(2) cleavage sites were effectively processed by ADAM9 with turnover numbers of 100 +/- 20 x 10(-2) min(-1), 20 +/- 10 x 10(-2) min(-1), and 10 +/- 3 x 10(-2) min(-1). In addition, a peptide based on the 33kDa cleavage site of the low affinity receptor for IgE, CD23, Dabcyl-Leu-Arg-Ala-Glu-Gln-Gln-Arg-Leu-Lys-Ser-Lys(Fam)- NH(2) was processed as well but with less efficiency. A more selective substrate for ADAM9 was found based on the betacellulin cleavage site. However, the valine containing precursor TNFalpha based substrate was used to measure IC(50) values of metalloproteinase inhibitors against ADAM9 since it was processed most efficiently. The tightest binding inhibitor was the Wyeth Aerst compound, TMI-1, with an IC(50) of 2.1 +/- 0.3 nM. In addition, GI254023, previously identified as a selective inhibitor of ADAM10, also inhibited ADAM9 with an IC(50) of 280 +/- 110 nM. These results demonstrate that sensitive substrates for ADAM9 can be developed that are useful in high throughput screening assays for ADAM9. C1 [Moss, Marcia L.; Rasmussen, Fred H.] BioZyme Inc, Apex, NC 27523 USA. [Nudelman, Raphael] TEVA Pharmaceut Ind Ltd, IL-49131 Petah Tiqwa, Israel. [Dempsey, Peter J.] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Williams, Jason] NIEHS, Res Triangle Pk, NC 27709 USA. RP Moss, ML (reprint author), BioZyme Inc, 1513 Old White Oak Church Rd, Apex, NC 27523 USA. EM mmoss@biozyme-inc.com NR 42 TC 15 Z9 15 U1 0 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1386-2073 J9 COMB CHEM HIGH T SCR JI Comb. Chem. High Throughput Screen PD MAY PY 2010 VL 13 IS 4 BP 358 EP 365 PG 8 WC Biochemical Research Methods; Chemistry, Applied; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA 588LX UT WOS:000277072800007 PM 20015014 ER PT J AU Ghosh, D Guha, R AF Ghosh, Debarchana Guha, Rajarshi TI Use of genetic algorithm and neural network approaches for risk factor selection: A case study of West Nile virus dynamics in an urban environment SO COMPUTERS ENVIRONMENT AND URBAN SYSTEMS LA English DT Article DE West Nile virus; Risk factors; Genetic algorithm; Variable selection; Neural network ID UNITED-STATES; LAND-COVER; INFECTION; SURVEILLANCE; TRANSMISSION; DISEASE; EPIDEMIC; PATTERNS; MODEL; AMPLIFICATION AB The West Nile virus (WNV) is an infectious disease spreading rapidly throughout the United States, causing illness among thousands of birds, animals, and humans. Yet, we only have a rudimentary understanding of how the mosquito-borne virus operates in complex avian-human environmental systems coupled with risk factors. The large array of multidimensional risk factors underlying WNV incidences is environmental, built-environment, socioeconomic, and existing mosquito abatement policies. Therefore it is essential to identify an optimal number of risk factors whose management would result in effective disease prevention and containment. Previous models built to select important risk factors assumed a priori that there is a linear relationship between these risk factors and disease incidences. However, it is difficult for linear models to incorporate the complexity of the WNV transmission network and hence identify an optimal number of risk factors objectively. There are two objectives of this paper, first, use combination of genetic algorithm (GA) and computational neural network (CNN) approaches to build a model incorporating the non-linearity between incidences and hypothesized risk factors. Here GA is used for risk factor (variable) selection and CNN for model building mainly because of their ability to capture complex relationships with higher accuracy than linear models. The second objective is to propose a method to measure the relative importance of the selected risk factors included in the model. The study is situated in the metropolitan area of Minnesota, which had experienced significant outbreaks from 2002 till present. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Ghosh, Debarchana] Kent State Univ, Dept Geog, Kent, OH 44240 USA. [Guha, Rajarshi] NIH, Chem Genom Ctr, Rockville, MD 20852 USA. RP Ghosh, D (reprint author), Kent State Univ, Dept Geog, 413 McGilvrey Hall, Kent, OH 44240 USA. EM dghosh@kent.edu; guhar@mail.nih.gov NR 50 TC 5 Z9 5 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0198-9715 J9 COMPUT ENVIRON URBAN JI Comput. Environ. Urban Syst. PD MAY PY 2010 VL 34 IS 3 BP 189 EP 203 DI 10.1016/j.compenvurbsys.2010.02.007 PG 15 WC Computer Science, Interdisciplinary Applications; Engineering, Environmental; Environmental Studies; Geography; Operations Research & Management Science SC Computer Science; Engineering; Environmental Sciences & Ecology; Geography; Operations Research & Management Science GA 604UU UT WOS:000278304800002 ER PT J AU Berger, VW AF Berger, Vance W. TI Randomization, permuted blocks, masking, allocation concealment, and selection bias in the Tobacco Quit Line Study SO CONTEMPORARY CLINICAL TRIALS LA English DT Letter DE Allocation concealment; Clinical trial; Masking; Permuted blocks; Restricted randomization; Selection bias ID CLINICAL-TRIALS C1 NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 6 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAY PY 2010 VL 31 IS 3 BP 201 EP 201 DI 10.1016/j.cct.2010.02.004 PG 1 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 598CT UT WOS:000277811300001 PM 20219696 ER PT J AU Winters, BD Eberlein, M Leung, J Needham, DM Pronovost, PJ Sevransky, JE AF Winters, Bradford D. Eberlein, Michael Leung, Janice Needham, Dale M. Pronovost, Peter J. Sevransky, Jonathan E. TI Long-term mortality and quality of life in sepsis: A systematic review SO CRITICAL CARE MEDICINE LA English DT Article DE sepsis; mortality; quality of life; long-term; follow-up ID RESPIRATORY-DISTRESS-SYNDROME; INTENSIVE-CARE-UNIT; ACUTE LUNG INJURY; POSTTRAUMATIC-STRESS-DISORDER; ONE-YEAR OUTCOMES; CRITICAL ILLNESS; SEPTIC SHOCK; FOLLOW-UP; MITOCHONDRIAL-DNA; SURVIVORS AB Background: Long-term outcomes from sepsis are poorly understood, and sepsis in patients may have different long-term effects on mortality and quality of life. Long-term outcome studies of other critical illnesses such as acute lung injury have demonstrated incremental health effects that persist after hospital discharge. Whether patients with sepsis have similar long-term mortality and quality-of-life effects is unclear. Objective: We performed a systematic review of studies reporting long-term mortality and quality-of-life data (> 3 months) in patients with sepsis, severe sepsis, and septic shock using defined search criteria. Design: Systematic review of the literature. Interventions: None. Main Results: Patients with sepsis showed ongoing mortality up to 2 yrs and beyond after the standard 28-day inhospital mortality end point. Patients with sepsis also had decrements in quality-of-life measures after hospital discharge. Results were consistent across varying severity of illness and different patient populations in different countries, including large and small studies. In addition, these results were consistent within observational and randomized, controlled trials. Study quality was limited by inadequate control groups and poor adjustment for confounding variables. Conclusions: Patients with sepsis have ongoing mortality beyond short-term end points, and survivors consistently demonstrate impaired quality of life. The use of 28-day mortality as an end point for clinical studies may lead to inaccurate inferences. Both observational and interventional future studies should include longer-term end points to better-understand the natural history of sepsis and the effect of interventions on patient morbidities. (Crit Care Med 2010; 38: 1276-1283) C1 [Winters, Bradford D.; Pronovost, Peter J.] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Winters, Bradford D.] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. [Eberlein, Michael; Leung, Janice] NIH, Bethesda, MD 20892 USA. [Needham, Dale M.] Johns Hopkins Univ, Crit Care Phys Med & Rehabil Program, Baltimore, MD USA. [Sevransky, Jonathan E.] Johns Hopkins Univ, Med Intens Care Unit, Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. RP Winters, BD (reprint author), Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. EM bwinters@jhmi.edu NR 56 TC 167 Z9 172 U1 1 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD MAY PY 2010 VL 38 IS 5 BP 1276 EP 1283 DI 10.1097/CCM.0b013e3181d8cc1d PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 593JD UT WOS:000277449100006 PM 20308885 ER PT J AU Velayati, A Yu, WH Sidransky, E AF Velayati, Arash Yu, W. Haung Sidransky, Ellen TI The Role of Glucocerebrosidase Mutations in Parkinson Disease and Lewy Body Disorders SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Parkinson disease; Gaucher disease; Alpha synuclein; Glucoceerebrosidase; Lew body disorders ID CHAPERONE-MEDIATED AUTOPHAGY; MULTIPLE SYSTEM ATROPHY; GAUCHER-DISEASE; ALPHA-SYNUCLEIN; GENE-MUTATIONS; EARLY-ONSET; RISK-FACTOR; BETA-GLUCOCEREBROSIDASE; DEGRADATION; ASSOCIATION AB Mutations in the gene encoding glucocerebrosidase (GBA), the enzyme deficient in the lysosomal storage disorder Gaucher disease, are associated with the development of Parkinson disease and other Lewy body disorders. In fact, GBA variants are currently the most common genetic risk factor associated with parkinsonism, and identified subjects with Parkinson disease are more than five times more likely to carry mutations in GBA. The mechanisms underlying this association are not known, but proposed theories include enhanced protein aggregation, alterations in lipid levels, and autophagy-lysosomal dysfunction promoting the retention of undegraded proteins. We review the genetic studies linking GBA to parkinsonism, as well as several of the mechanisms postulated to explain the association of GBA mutations and the synucleinopathies, which demonstrate how studies of a rare mendelian disease may provide insights into our understanding of a common complex disorder. C1 [Velayati, Arash; Sidransky, Ellen] NHGRI, Neurogenet Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Yu, W. Haung] Columbia Univ, Dept Pathol, Taub Inst Alzheimers Dis Res, New York, NY USA. RP Sidransky, E (reprint author), NHGRI, Neurogenet Sect, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU National Human Genome Research Institute; National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health. The authors thank Dr. Nahid Tayebi, Dr. Grisel Lopez, Dr. Ehud Goldin, Sarah Klontz, and Jae H. Choi for their critical reading of the manuscript. NR 80 TC 62 Z9 65 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD MAY PY 2010 VL 10 IS 3 BP 190 EP 198 DI 10.1007/s11910-010-0102-x PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 602AY UT WOS:000278111700005 PM 20425034 ER PT J AU Tanno, T Noel, P Miller, JL AF Tanno, Toshihiko Noel, Pierre Miller, Jeffery L. TI Growth differentiation factor 15 in erythroid health and disease SO CURRENT OPINION IN HEMATOLOGY LA English DT Article DE GDF15; ineffective erythropoiesis; iron regulation ID MACROPHAGE-INHIBITORY CYTOKINE-1; TGF-BETA SUPERFAMILY; PYRUVATE-KINASE DEFICIENCY; ANEMIA TYPE-I; PROSTATE-CANCER; IRON-METABOLISM; INEFFECTIVE ERYTHROPOIESIS; TRANSGENIC MICE; UP-REGULATION; WEIGHT-LOSS AB Purpose of review Growth differentiation factor 15 (GDF15) was identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. This review addresses the regulation, expression and potential functions of GDF15 in the context of erythroid biology. Recent findings GDF15 expression during late erythroid differentiation was discovered as part of an erythroblast transcriptome project. As GDF15 expression is associated with cellular stress or apoptosis, further investigation of the cytokine was focused upon its involvement in ineffective erythropoiesis. Remarkably high serum levels were detected in patients with thalassemia syndromes, congenital dyserythropoiesis and some acquired sideroblastic anemias. High-level GDF15 expression is not a feature of normal erythropoiesis, or erythroid recovery after bone-marrow transplantation. As GDF15 is a transforming growth factor-beta superfamily member, it was investigated as an effector of ineffective erythropoiesis that suppresses hepcidin expression despite iron overloading. Summary In contrast to the low levels of GDF15 expressed during normal erythropoiesis, ineffective erythropoiesis causes high-level expression of GDF15. In patients with thalassemia and related anemias, GDF15 expression may contribute to iron overloading or other features of the disease phenotype. C1 [Noel, Pierre] NIH, Dept Mol Med, Bethesda, MD 20892 USA. [Tanno, Toshihiko; Miller, Jeffery L.] NIDDK, Mol Med Branch, Bethesda, MD USA. RP Miller, JL (reprint author), NIH, Mol Med Branch, Bldg 10,Room9N311, Bethesda, MD 20892 USA. EM jm7f@nih.gov FU NIH, NIDDK FX We thank Colleen Byrnes and Y. Terry Lee for help in preparing this manuscript. This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 65 TC 65 Z9 75 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1065-6251 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD MAY PY 2010 VL 17 IS 3 BP 184 EP 190 DI 10.1097/MOH.0b013e328337b52f PG 7 WC Hematology SC Hematology GA 591NH UT WOS:000277307300005 PM 20182355 ER PT J AU Bouchelouche, K Capala, J AF Bouchelouche, Kirsten Capala, Jacek TI 'Image and treat': an individualized approach to urological tumors SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE carbonic anhydrase IX; G250; HER2 receptor; positron-emission tomography; prostate-specific membrane antigen; radioimmunotherapy ID RENAL-CELL CARCINOMA; CARBONIC-ANHYDRASE-IX; RESISTANT PROSTATE-CANCER; MONOCLONAL-ANTIBODY G250; POSITRON-EMISSION-TOMOGRAPHY; MEMBRANE ANTIGEN PSMA; BREAST-CANCER; AFFIBODY MOLECULE; EXTRACELLULAR DOMAIN; RADIONUCLIDE THERAPY AB Purpose of review The current treatment options for advanced urologic cancers demonstrate limited efficacy. To obtain optimal clinical results, there is a need for new, individualized, therapeutic strategies, which have only recently been applied to these malignancies. Nuclear medicine plays an important role in establishing imaging biomarkers necessary for personalized medicine. This review focuses on the current status of the 'image and treat' approach combining molecular imaging with targeted radionuclide therapy of urological malignancies Recent findings Tumor-specific targets in uro-oncology are showing promising results for development of personalized therapy using positron emission tomography/computed tomography (PET/CT) molecular imaging and radioimmunotherapy. The antibody cG250, which binds to carbonic anhydrase IX, is being evaluated as a radiolabeled imaging and therapeutic agent in clear-cell renal cell carcinoma. (124)I-cG250 PET/CT has demonstrated excellent targeting of clear-cell renal cell carcinoma. Prostate-specific membrane antigen is a promising target for both PET/CT and radioimmunotherapy of prostate cancer. HER2 may be another potential target in bladder and prostate cancer. Summary Tumor-specific targets and biomarkers are being studied for PET/CT and radioimmunotherapy. This may lead to development of new therapeutic strategies. However, considerable investment in new research will be required for personalized medicine to be routinely used in uro-oncology. C1 [Bouchelouche, Kirsten] Univ Copenhagen, PET Rigshosp 3982, PET & Cyclotron Unit, DK-2100 Copenhagen, Denmark. [Capala, Jacek] NCI, Mol Targeting Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Bouchelouche, K (reprint author), Univ Copenhagen, PET Rigshosp 3982, PET & Cyclotron Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. EM bouchelouche@mail.tele.dk FU Intramural NIH HHS [ZIA BC010727-04] NR 79 TC 13 Z9 13 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD MAY PY 2010 VL 22 IS 3 BP 274 EP 280 DI 10.1097/CCO.0b013e3283373d5c PG 7 WC Oncology SC Oncology GA 592LL UT WOS:000277380300018 PM 20150811 ER PT J AU Krishnadev, N Meleth, AD Chew, EY AF Krishnadev, Nupura Meleth, Annal D. Chew, Emily Y. TI Nutritional supplements for age-related macular degeneration SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article DE age-related macular degeneration; antioxidant vitamins; lutein; omega-3 fatty acids; zeaxanthin ID BLUE-MOUNTAINS-EYE; VITAMIN-C; PLASMA HOMOCYSTEINE; UNITED-STATES; FATTY-ACIDS; FOLIC-ACID; CAROTENOIDS; DISEASE; HEALTH; ANTIOXIDANTS AB Purpose of review Age-related macular degeneration (AMD), a leading cause of visual loss in older adults, has limited therapeutic options. This review describes the current literature on the role of nutritional supplementation in primary and secondary prevention of AMD. Recent findings Many observational studies have explored the association between diet, nutrient intake, and AMD. In particular, high dietary intakes of omega-3 fatty acids, and macular xanthophylls lutein and zeaxanthin have been associated with a lower risk of prevalent and incident AMD. However, the Age-Related Eye Disease study (AREDS) is the only large-scale randomized controlled clinical trial to show a 25% beneficial effect of nutritional supplementation in reducing the risk progression to advanced AMD in patients with intermediate AMD or with advanced AMD in one eye at 5 years of follow-up. On the basis of the results of AREDS, these patients are recommended to take AREDS formulation of vitamins C, E, beta-carotene, and zinc with copper. Summary At the present time, there is insufficient evidence in the literature to recommend routine nutritional supplementation in healthy adults for primary prevention of AMD. However, patients with intermediate risk of AMD or advanced AMD in one eye should consider taking AREDS-type supplements. Observational studies have also suggested benefit from increased dietary intake of macular xanthophylls and omega-3 fatty acids. These are currently being evaluated prospectively in a randomized controlled clinical trial, the AREDS2. C1 [Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, CRC, Bethesda, MD 20892 USA. RP Chew, EY (reprint author), NEI, Div Epidemiol & Clin Applicat, NIH, CRC, Bldg 10,Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU Intramural NIH HHS [Z99 EY999999, ZIE EY000487-01] NR 34 TC 48 Z9 49 U1 2 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8738 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD MAY PY 2010 VL 21 IS 3 BP 184 EP 189 DI 10.1097/ICU.0b013e32833866ee PG 6 WC Ophthalmology SC Ophthalmology GA 591NR UT WOS:000277308300004 PM 20216418 ER PT J AU Arun, I Wulu, JA Janik, JE Jasper, GA Yuan, CM Venzon, D Stetler-Stevenson, M AF Arun, Indu Wulu, Jacqueline A. Janik, John E. Jasper, Gregory A. Yuan, Constance M. Venzon, David Stetler-Stevenson, Maryalice TI Visual Inspection Versus Quantitative Flow Cytometry to Detect Aberrant CD2 Expression in Malignant T Cells SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE CD2; quantitation; ABC; lymphoma; normal T cells ID IMMUNOPHENOTYPIC ANALYSIS; LYMPHOCYTIC-LEUKEMIA; LYMPHOMA; UTILITY; LEUKEMIA/LYMPHOMA; INTENSITY; RECEPTORS; DIAGNOSIS; ANTIGENS; BEADS AB Background: Abnormal levels of T-cell antigen expression occur in T-cell neoplasia. We examined CD2 expression in malignant and normal T cells to determine if the level of CD2 expression differed significantly and if quantitation assisted in detecting this difference. Method: Flow cytometric immunophenotypic (FCI) evaluation was performed on specimens from 36 patients with mature T-cell neoplasia. Abnormal T cells were identified based upon the abnormal FCI and morphology. Levels of CD2 expression were quantitated using 1:1 PE conjugates of anti-CD2 and Quanti-BRITE bead standards to calculate the antibodies bound per cell (ABC). The efficacy of ABC measurement versus simple examination of dots plots was compared. Results: Abnormal levels of CD2 expression were frequently observed in mature T-cell malignancies. The CD2 ABC values were highly sensitive in detecting differences between malignant and normal T cells (P = 0.0028). In most cases (24/32 specimens, 75%), CD2 ABCs differed by >20%. CD2 ABCs had high variability in normal T cells. Conclusions: CD2 expression by malignant T cells differed significantly from that of normal T-cells by CD2 ABC quantitation. The high variability in normal T-cell CD2 ABCs limited the determination of normal reference ranges and, thus, its utility in the diagnosis of T-cell neoplasia. However, examination of CD2 can help in detection of tumor cells when residual normal T cells are present for comparison. Moreover, the increased sensitivity of CD2 quantitation is valuable in confirming FCI cases where abnormalities in CD2 expression are difficult to appreciate by visual inspection alone. Published 2009 Wiley-Liss, Inc.(dagger) C1 [Arun, Indu; Wulu, Jacqueline A.; Jasper, Gregory A.; Yuan, Constance M.; Stetler-Stevenson, Maryalice] NCI, Pathol Lab, NIH, Flow Cytometry Unit,Ctr Canc Res, Bethesda, MD 20892 USA. [Janik, John E.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Pathol Lab, NIH, Flow Cytometry Unit,Ctr Canc Res, Bldg 10,Room 2A-33,Mail Stop 1500, Bethesda, MD 20892 USA. EM stetler@mail.nih.gov FU NIH; NCI FX This work was supported in part by the Intramural Research Program of the NIH, NCI. NR 33 TC 6 Z9 6 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAY PY 2010 VL 78B IS 3 BP 169 EP 175 DI 10.1002/cyto.b.20507 PG 7 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 591IO UT WOS:000277293900004 PM 20020522 ER PT J AU Barrett, J AF Barrett, John TI A profusion of progenitors SO CYTOTHERAPY LA English DT Editorial Material C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Barrett, J (reprint author), NHLBI, Hematol Branch, 10 CRC Room 3E-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM mailbarrettjj@mail.nih.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD MAY PY 2010 VL 12 IS 3 BP 273 EP 274 DI 10.3109/14653241003778947 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 579IH UT WOS:000276362100001 PM 20370346 ER PT J AU Stroncek, D Berlyne, D Fox, B Gee, A Heimfeld, S Lindblad, R Loper, K Mckenna, D Rooney, C Sabatino, M Wagner, E Whiteside, T Wood, D Heath-Mondoro, T AF Stroncek, David Berlyne, Deborah Fox, Bernard Gee, Adrian Heimfeld, Shelly Lindblad, Robert Loper, Kathy Mckenna, David, Jr. Rooney, Cliona Sabatino, Marianna Wagner, Elizabeth Whiteside, Theresa Wood, Deborah Heath-Mondoro, Traci TI Developments in clinical cell therapy SO CYTOTHERAPY LA English DT Article DE cancer; cell therapy; hematopoietic stem cell transplantation; regenerative medicine ID ANTIGEN-PRESENTING CELLS; MESENCHYMAL STEM-CELLS; T-CELLS; IMMUNOTHERAPY; ENGRAFTMENT; PHASE AB Immunotherapy has become an important part of hematopoietic stem cell (HSC) transplantation and cancer therapy. Regenerative and reparative properties of somatic cell-based therapies hold tremendous promise for repairing injured tissue, preventing and reversing damage to organs, and restoring balance to compromised immune systems. The principles and practices of the diverse aspects of immune therapy for cancer, HSC transplantation and regenerative medicine have many commonalities. This meeting report summarizes a workshop sponsored by the National Heart, Lung and Blood Institute (NHLBI) and Production Assistance for Cellular Therapies (PACT), held on 23-24 April 2009 at the National Institutes of Health (NIH, USA). A series of scientific sessions and speakers highlighted key aspects of the latest scientific, clinical and technologic developments in cell therapy, involving a unique set of cell products with a special emphasis on converging concepts in these fields. C1 [Stroncek, David; Sabatino, Marianna] NIH, Bethesda, MD 20892 USA. [Berlyne, Deborah; Lindblad, Robert; Wood, Deborah] EMMES Corp, Rockville, MD USA. [Fox, Bernard] Earle A Chiles Res Inst, Portland, OR USA. [Gee, Adrian; Rooney, Cliona] Baylor Coll Med, Houston, TX 77030 USA. [Heimfeld, Shelly] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Loper, Kathy] AABB, Bethesda, MD USA. [Mckenna, David, Jr.] Univ Minnesota, St Paul, MN 55108 USA. [Wagner, Elizabeth; Heath-Mondoro, Traci] NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. [Whiteside, Theresa] Univ Pittsburgh, Pittsburgh, PA USA. RP Stroncek, D (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM DStroncek@cc.nih.gov FU National Heart, Lung, and Blood Institute; National Institutes of Health, Department of Health and Human Services [N01-HB-37163, N01-HB-37164, N01-HB-37165, N01-HB-37166] FX The workshop planning committee wishes to thank the speakers and moderators for their participation in the workshop and their contributions to this article. This project was supported with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services under contract numbers N01-HB-37163, N01-HB-37164, N01-HB-37165 and N01-HB-37166. NR 16 TC 20 Z9 23 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD MAY PY 2010 VL 12 IS 3 BP 425 EP 428 DI 10.3109/14653240903511952 PG 4 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 579IH UT WOS:000276362100017 PM 20078383 ER PT J AU Miura, S Singh, AP Mishina, Y AF Miura, Shigeto Singh, Ajeet Pratap Mishina, Yuji TI Bmpr1a is required for proper migration of the AVE through regulation of Dkk1 expression in the pre-streak mouse embryo SO DEVELOPMENTAL BIOLOGY LA English DT Article DE BMP signaling; AVE; Dkk1; Wnt3; Wnt3a ID ANTERIOR-POSTERIOR AXIS; VISCERAL ENDODERM; PARAXIAL MESODERM; PRIMITIVE STREAK; CELL-MIGRATION; HEAD INDUCTION; GASTRULATION; GENE; MORPHOGENESIS; ASYMMETRY AB Here, we report a novel mechanism regulating migration of the anterior visceral endoderm (AVE) by BMP signaling through BMPR1A. In Bmpr1a-deficient (Bmpr-null) embryos, the AVE does not migrate at all. In embryos with an epiblast-specific deletion of Bmpr1a (Bmpr1a(null/flox); Sox2Cre embryos), the AVE cells migrate randomly from the distal end of embryos, resulting in an expansion of the AVE. Dkk1, which is normally expressed in the anterior proximal visceral endoderm (PxVE), is downregulated in Bmpr-null embryos, whereas it is circumferentially expressed in Bmpr1a(null/flox): Sox2Cre embryos at E5.75-6.5. These results demonstrate an association of the position of Dkk1 expressing cells with direction of the migration of AVE. In Bmpr1a(null/flox); Sox2Cre embryos, a drastic decrease of WNT signaling is observed at E6.0. Addition of WNT3A to the culture of Bmpr1a(null/flox); Sox2Cre embryos at E5.5 restores expression patterns of Dkk1 and Cer1. These data indicate that BMP signaling in the epiblast induces Wnt3 and Wnt3a expression to maintain WNT signaling in the VE, resulting in downregulation of Dkk1 to establish the anterior expression domain. Thus, our results suggest that BMP signaling regulates the expression patterns of Dkk1 for anterior migration of the AVE. Published by Elsevier Inc. C1 [Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Miura, Shigeto; Singh, Ajeet Pratap; Mishina, Yuji] NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Mishina, Y (reprint author), Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. EM mishina@umich.edu RI Singh, Ajeet/G-3935-2013 FU National Institute of Environmental Health Sciences [ES071003-11]; RIKEN Brain Science Institute FX We thank Drs. T. A. Rodriguez for Hex-GFP mice; A. McMahon for Sox2-Cre mice, B.G. Herrmann, B. Shaw lot, M. Shen, J. Klingensmith, H. Sasaki, Y. Saga and M. Kuehn for in situ probes. We also thank Drs. M. Yamamoto, H. Hamada, and T. A. Rodriguez for exchanging unpublished results, Ucchii Uchimura, Tanya Simmons, and the Knock Out Core at NIEHS for mouse activity, L E. Davis and I. Nwosu for technical assistance, Y. P. Young, A. Shimono, C. Kimura-Yoshida, T. A. Rodriguez, K. McCann, M. K. Ray and W. Shawlot for comments on the manuscript. This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences (ES071003-11) and a conditional gift from RIKEN Brain Science Institute to Y.M. NR 40 TC 17 Z9 17 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAY 1 PY 2010 VL 341 IS 1 BP 246 EP 254 DI 10.1016/j.ydbio.2010.02.038 PG 9 WC Developmental Biology SC Developmental Biology GA 586VT UT WOS:000276943100021 PM 20211162 ER PT J AU Martin, B Shin, YK White, CM Ji, S Kim, W Carlson, OD Napora, JK Chadwick, W Chapter, M Waschek, JA Mattson, MP Maudsley, S Egan, JM AF Martin, Bronwen Shin, Yu-Kyong White, Caitlin M. Ji, Sunggoan Kim, Wook Carlson, Olga D. Napora, Joshua K. Chadwick, Wayne Chapter, Megan Waschek, James A. Mattson, Mark P. Maudsley, Stuart Egan, Josephine M. TI Vasoactive Intestinal Peptide-Null Mice Demonstrate Enhanced Sweet Taste Preference, Dysglycemia, and Reduced Taste Bud Leptin Receptor Expression SO DIABETES LA English DT Article ID COEXPRESSION PATTERNS; MAMMALIAN TASTE; BITTER TASTE; CELLS; RAT; MOUSE; IMMUNOREACTIVITY; SEROTONIN; NEUROPEPTIDES; SENSITIVITIES AB OBJECTIVE It is becoming apparent that there is a strong link between taste perception and energy homeostasis. Recent evidence implicates gut-related hormones in taste perception, including glucagon-like peptide 1 and vasoactive intestinal peptide (VIP). We used VIP knockout mice to investigate VIP's specific role in taste perception and connection to energy regulation. RESEARCH DESIGN AND METHODS Body weight, food intake, and plasma levels of multiple energy-regulating hormones were measured and pancreatic morphology was determined. In addition, the immunocytochemical profile of taste cells and gustatory behavior were examined in wild-type and VIP knockout mice. RESULTS VIP knockout mice demonstrate elevated plasma glucose, insulin, and leptin levels, with no islet beta-cell number/topography alteration. VIP and its receptors (VPAC1, VPAC2) were identified in type II taste cells of the taste bud, and VIP knockout mice exhibit enhanced taste preference to sweet tastants. VIP knockout mouse taste cells show a significant decrease in leptin receptor expression and elevated expression of glucagon-like peptide 1, which may explain sweet taste preference of VIP knockout mice. CONCLUSIONS This study suggests that the tongue can play a direct role in modulating energy intake to correct peripheral glycemic imbalances. In this way, we could view the tongue as a sensory mechanism that is bidirectionally regulated and thus forms a bridge between available foodstuffs and the intricate hormonal balance in the animal itself. Diabetes 59:1143-1152, 2010 C1 [Martin, Bronwen; Shin, Yu-Kyong; White, Caitlin M.; Ji, Sunggoan; Kim, Wook; Carlson, Olga D.; Napora, Joshua K.; Chadwick, Wayne; Chapter, Megan; Mattson, Mark P.; Maudsley, Stuart; Egan, Josephine M.] NIA, NIH, Baltimore, MD 21224 USA. [Waschek, James A.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Mental Retardat Res Ctr, Dept Psychiat & Behav Sci, Los Angeles, CA USA. RP Egan, JM (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM eganj@mail.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institutes of Health, National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 46 TC 46 Z9 49 U1 0 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2010 VL 59 IS 5 BP 1143 EP 1152 DI 10.2337/db09-0807 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 594RI UT WOS:000277554700005 PM 20150284 ER PT J AU Ingelsson, E Langenberg, C Hivert, MF Prokopenko, I Lyssenko, V Dupuis, J Magi, R Sharp, S Jackson, AU Assimes, TL Shrader, P Knowles, JW Zethelius, B Abbasi, FA Bergman, RN Bergmann, A Berne, C Boehnke, M Bonnycastle, LL Bornstein, SR Buchanan, TA Bumpstead, SJ Bottcher, Y Chines, P Collins, FS Cooper, CC Dennison, EM Erdos, MR Ferrannini, E Fox, CS Graessler, J Hao, K Isomaa, B Jameson, KA Kovacs, P Kuusisto, J Laakso, M Ladenval, C Mohlke, KL Morken, MA Narisu, N Nathan, DM Pascoe, L Payne, F Petrie, JR Sayer, AA Schwarz, PEH Scott, LJ Stringham, HM Stumvoll, M Swift, AJ Syvanen, AC Tuomi, T Tuomilehto, J Tonjes, A Valle, TT Williams, GH Lind, L Barroso, I Quertermous, T Walker, M Wareham, NJ Meigs, JB McCarthy, MI Groop, L Watanabe, RM Florez, JC AF Ingelsson, Erik Langenberg, Claudia Hivert, Marie-France Prokopenko, Inga Lyssenko, Valeriya Dupuis, Josee Maegi, Reedik Sharp, Stephen Jackson, Anne U. Assimes, Themistocles L. Shrader, Peter Knowles, Joshua W. Zethelius, Bjorn Abbasi, Fahim A. Bergman, Richard N. Bergmann, Antje Berne, Christian Boehnke, Michael Bonnycastle, Lori L. Bornstein, Stefan R. Buchanan, Thomas A. Bumpstead, Suzannah J. Boettcher, Yvonne Chines, Peter Collins, Francis S. Cooper, Cyrus C. Dennison, Elaine M. Erdos, Michael R. Ferrannini, Ele Fox, Caroline S. Graessler, Juergen Hao, Ke Isomaa, Bo Jameson, Karen A. Kovacs, Peter Kuusisto, Johanna Laakso, Markku Ladenval, Claes Mohlke, Karen L. Morken, Mario A. Narisu, Narisu Nathan, David M. Pascoe, Laura Payne, Felicity Petrie, John R. Sayer, Avan A. Schwarz, Peter E. H. Scott, Laura J. Stringham, Heather M. Stumvoll, Michael Swift, Amy J. Syvanen, Ann-Christine Tuomi, Tiinamaija Tuomilehto, Jaakko Tonjes, Anke Valle, Timo T. Williams, Gordon H. Lind, Lars Barroso, Ines Quertermous, Thomas Walker, Mark Wareham, Nicholas J. Meigs, James B. McCarthy, Mark I. Groop, Leif Watanabe, Richard M. Florez, Jose C. CA MAGIC Investigators TI Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans SO DIABETES LA English DT Article; Proceedings Paper CT 59th Annual Meeting of the American-Society-of-Human-Genetics CY OCT 20-24, 2009 CL Honolulu, HI SP Amer Soc Human Genet ID BETA-CELL FUNCTION; FASTING PLASMA-GLUCOSE; ZINC TRANSPORTER ZNT8; TYPE-2 DIABETES RISK; FATTY-ACIDS; RELATIVE CONTRIBUTIONS; 1ST-DEGREE RELATIVES; NONDIABETIC HUMANS; SENSITIVITY INDEX; GLUCOKINASE GENE AB OBJECTIVE-Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS-We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS-The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS-Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. Diabetes 59:1266-1275, 2010 C1 [Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Ingelsson, Erik; Zethelius, Bjorn] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden. [Langenberg, Claudia; Sharp, Stephen; Wareham, Nicholas J.] Addenbrookes Hosp, Inst Metab Sci, Med Res Council Epidemiol Unit, Cambridge, England. [Hivert, Marie-France] Univ Sherbrooke, Ctr Rech Med, Sherbrooke, PQ J1K 2R1, Canada. [Prokopenko, Inga; Maegi, Reedik; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Prokopenko, Inga; Maegi, Reedik; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Lyssenko, Valeriya; Ladenval, Claes; Groop, Leif] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Jackson, Anne U.; Boehnke, Michael; Scott, Laura J.; Stringham, Heather M.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Assimes, Themistocles L.; Knowles, Joshua W.; Abbasi, Fahim A.; Quertermous, Thomas] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Shrader, Peter; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Bergman, Richard N.; Buchanan, Thomas A.; Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. [Bergmann, Antje] Tech Univ Dresden, Med Fac Carl Gustav Carus, Hlth Care Ctr, Dresden, Germany. [Berne, Christian; Syvanen, Ann-Christine; Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Bonnycastle, Lori L.; Chines, Peter; Collins, Francis S.; Erdos, Michael R.; Morken, Mario A.; Narisu, Narisu; Swift, Amy J.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Bornstein, Stefan R.; Graessler, Juergen; Schwarz, Peter E. H.] Univ Dresden, Dept Med 3, Prevent & Care Diabet Div, Dresden, Germany. [Buchanan, Thomas A.] Univ So Calif, Keck Sch Med, Dept Med, Div Endocrinol & Diabet, Los Angeles, CA 90033 USA. [Bumpstead, Suzannah J.] Wellcome Trust Sanger Inst, Cambridge, England. [Boettcher, Yvonne; Stumvoll, Michael; Tonjes, Anke] Univ Leipzig, Dept Med, Leipzig, Germany. [Cooper, Cyrus C.; Dennison, Elaine M.; Jameson, Karen A.; Sayer, Avan A.] Univ Southampton, Southampton Gen Hosp, MRC, Epidemiol Resource Ctr, Southampton, Hants, England. [Ferrannini, Ele] Univ Pisa, Dept Internal Med, Pisa, Italy. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.; Williams, Gordon H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Hao, Ke] Rosetta Inpharmat LLC, Seattle, WA USA. [Isomaa, Bo; Tuomi, Tiinamaija] Folkhalsan Res Ctr, Helsinki, Finland. [Isomaa, Bo] Malmska Municipal Hlth Care Ctr & Hosp, Pietarsaari, Finland. [Kovacs, Peter] Univ Leipzig, Interdisciplinary Ctr Clin Res, Leipzig, Germany. [Kuusisto, Johanna; Laakso, Markku] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Nathan, David M.; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Nathan, David M.; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Pascoe, Laura; Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Payne, Felicity; Barroso, Ines] Wellcome Trust Sanger Inst, Metab Dis Grp, Cambridge, England. [Petrie, John R.] Univ Glasgow, British Heart Fdn Cardiovasc Res Ctr, Glasgow G12 8QQ, Lanark, Scotland. [Tuomi, Tiinamaija] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland. [Tuomi, Tiinamaija] Univ Helsinki, Res Program Mol Med, Helsinki, Finland. [Tuomilehto, Jaakko; Valle, Timo T.] Univ Helsinki, Hjelt Inst, Dept Publ Hlth, FIN-00014 Helsinki, Finland. [Tuomilehto, Jaakko; Valle, Timo T.] Natl Inst Hlth & Welf Helsinki, Unit Diabet Prevent, Helsinki, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Tonjes, Anke] Univ Leipzig, Coordinat Ctr Clin Trials, Leipzig, Germany. [Meigs, James B.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP Ingelsson, E (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. EM erik.ingelsson@ki.se; Leif.Groop@med.lu.se; rwatanab@usc.edu; jcflorez@partners.org RI Aihie Sayer, Avan/A-4359-2012; Prokopenko, Inga/H-3241-2014; Schwarz, Peter/B-5127-2013; OI Prokopenko, Inga/0000-0003-1624-7457; Schwarz, Peter/0000-0001-6317-7880; Magi, Reedik/0000-0002-2964-6011; Aihie Sayer, Avan/0000-0003-1283-6457; Tuomi, Tiinamaija/0000-0002-8306-6202; Payne, Felicity/0000-0003-4228-581X; Dupuis, Josee/0000-0003-2871-3603 FU Medical Research Council [G0701863, MC_U106179471, MC_U147574213, MC_U147574239, MC_UP_A620_1014, MC_UP_A620_1015]; NHLBI NIH HHS [R01 HL087647]; NIDDK NIH HHS [R01 DK072193, R01 DK029867] NR 55 TC 134 Z9 139 U1 2 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2010 VL 59 IS 5 BP 1266 EP 1275 DI 10.2337/DB09-1568 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 594RI UT WOS:000277554700019 PM 20185807 ER PT J AU Bian, L Hanson, RL Ossowski, V Wiedrich, K Mason, CC Traurig, M Muller, YL Kobes, S Knowler, WC Baier, LJ Bogardus, C AF Bian, Li Hanson, Robert L. Ossowski, Victoria Wiedrich, Kim Mason, Clinton C. Traurig, Michael Muller, Yunhua L. Kobes, Sayuko Knowler, William C. Baier, Leslie J. Bogardus, Clifton TI Variants in ASK1 Are Associated With Skeletal Muscle ASK1 Expression, In Vivo Insulin Resistance, and Type 2 Diabetes in Pima Indians SO DIABETES LA English DT Article ID ACTIVATED PROTEIN-KINASE; GLUCOSE-TRANSPORT; GLUT4 TRANSLOCATION; GENETIC ASSOCIATION; 3T3-L1 ADIPOCYTES; P38 MAPK; MELLITUS; DISEASE; LOCI; DYSFUNCTION AB OBJECTIVE Prior genome-wide association and exon array expression studies both provided suggestive evidence that apoptosis signal regulating kinase 1 (ASK1) may influence in vivo insulin action in Pima Indians. Genetic variants in or near ASK1 were analyzed to assess the role of this gene in insulin action and type 2 diabetes. RESEARCH DESIGN AND METHODS Genotypic data from 31 variants were used to determine the linkage disequilibrium pattern across ASK1 in Pima Indians. Eight tag SNPs were initially genotyped in 3,501 full-heritage Pima Indians. Replication for association with diabetes was assessed in a second population-based sample of 3,723 Native Americans and the published DIAGRAM study. Quantitative traits were analyzed in 536 nondiabetic Native Americans, and ASK1 expression was examined in skeletal muscle of 153 nondiabetic Native Americans. RESULTS Three tag SNPs were associated with type 2 diabetes (rs35898099, P = 0.003, odds ratio [95% Cl] 1.27 [1.08-1.47]; rs1570056, P = 0.007, 1.19 [1.05-1.36]; rs7775356, P = 0.04, 1.14 [1.01-1.28]) in the full-heritage Pima Indians. The association with rs35898099 was replicated in a second sample of Native Americans (P = 0.04, 1.22 [1.01-1.47]), while that for rs1570056 was replicated in the DIAGRAM study of Caucasians (Z statistic based P = 0.026; fixed-effect model, 1.06 [1.00-1.12]). The diabetes risk allele for rs1570056 was associated with reduced insulin action as assessed by either HOMA-IR in 2,549 nondiabetic full-heritage Pima Indians (P = 0.027) or a hyperinsulinemic-euglycemic clamp among 536 nondiabetic Native Americans (P = 0.02). Real-time PCR identified a positive correlation between ASK1 expression in skeletal muscle biopsies and in vivo insulin action (P = 0.02, r = 0.23), and the risk allele for rs1570056 was associated with lower ASK1 expression (P = 0.003, r = -0.22). CONCLUSIONS ASK1 variants may increase susceptibility to type 2 diabetes by decreasing insulin sensitivity via reduced ASK1 expression. Diabetes 59:1276-1282, 2010 C1 [Bian, Li; Hanson, Robert L.; Ossowski, Victoria; Wiedrich, Kim; Mason, Clinton C.; Traurig, Michael; Muller, Yunhua L.; Kobes, Sayuko; Knowler, William C.; Baier, Leslie J.; Bogardus, Clifton] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Dept Hlth & Human Serv, Phoenix, AZ USA. RP Bogardus, C (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Dept Hlth & Human Serv, Phoenix, AZ USA. EM cbogardus@phx.niddk.nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; American Diabetes Association FX This study was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. L.B. was supported by a grant from the American Diabetes Association. NR 33 TC 8 Z9 9 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2010 VL 59 IS 5 BP 1276 EP 1282 DI 10.2337/db09-1700 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 594RI UT WOS:000277554700020 PM 20185809 ER PT J AU Riddle, MC Ambrosius, WT Brillon, DJ Buse, JB Byington, RP Cohen, RM Goff, DC Malozowski, S Margolis, KL Probstfield, JL Schnall, A Seaquist, ER AF Riddle, Matthew C. Ambrosius, Walter T. Brillon, David J. Buse, John B. Byington, Robert P. Cohen, Robert M. Goff, David C., Jr. Malozowski, Saul Margolis, Karen L. Probstfield, Jeffrey L. Schnall, Adrian Seaquist, Elizabeth R. CA Action Control Cardiovasc Risk Dia TI Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial SO DIABETES CARE LA English DT Article ID CARDIOVASCULAR MORTALITY; DISEASE; ASSOCIATION; GLUCOSE; ADVANCE; EVENTS; RISK AB OBJECTIVE - Randomized treatment comparing an intensive glycemic treatment strategy with a standard strategy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was ended early because of an unexpected excess of mortality in the intensive arm. As part of ongoing post hoc analyses of potential mechanisms for this finding, we explored whether on-treatment A1C itself had an independent relationship with mortality. RESEARCH DESIGN AND METHODS - Participants with type 2 diabetes (n = 10,251 with mean age 62 years, median duration of diabetes 10 years, and median MC 8.1%) were randomly assigned to treatment strategies targeting either A1C <6.0% (intensive) or A1C 7.0-7.9% (standard). Data obtained during 3.4 (median) years of follow-up before cessation of intensive treatment were analyzed using several multivariable models. RESULTS Various characteristics of the participants and the study sites at baseline had significant associations with the risk of mortality. Before and after adjustment for these covariates, a higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year. Higher average A1C was associated with greater risk of death. The risk of death with the intensive strategy increased approximately linearly from 6-9% A1C and appeared to be greater with the intensive than with the standard strategy only when average A1C was >7%. CONCLUSIONS - These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD. C1 [Riddle, Matthew C.] Oregon Hlth & Sci Univ, Div Endocrinol Diabet & Clin Nutr, Portland, OR 97201 USA. [Ambrosius, Walter T.; Byington, Robert P.; Goff, David C., Jr.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Brillon, David J.] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA. [Buse, John B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Cohen, Robert M.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Malozowski, Saul] NIDDKD, Bethesda, MD 20892 USA. [Margolis, Karen L.] Hlth Partners Res Fdn, Minneapolis, MN USA. [Probstfield, Jeffrey L.] Univ Washington, Sch Med, Seattle, WA USA. [Schnall, Adrian] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Seaquist, Elizabeth R.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. RP Riddle, MC (reprint author), Oregon Hlth & Sci Univ, Div Endocrinol Diabet & Clin Nutr, Portland, OR 97201 USA. EM riddlem@ohsu.edu FU National Heart, Lung, and Blood Institute [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010]; National Institute of Diabetes and Digestive and Kidney Diseases (NIH); National Institute on Aging (NIH); National Eye Institute (NIH); Centers for Disease Control and Prevention; General Clinical Research Centers FX This work was supported by contracts (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by other components of the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; and by General Clinical Research Centers. The following companies provided study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough. NR 19 TC 205 Z9 211 U1 1 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2010 VL 33 IS 5 BP 983 EP 990 DI 10.2337/dc09-1278 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 595RV UT WOS:000277631200006 PM 20427682 ER PT J AU Feigenbaum, K Longstaff, L AF Feigenbaum, Kathryn Longstaff, Laura TI Management of the Metabolic Syndrome in Patients With Human Immunodeficiency Virus SO DIABETES EDUCATOR LA English DT Article ID HIV-INFECTED PATIENTS; ANTIRETROVIRAL THERAPY; CARDIOVASCULAR-DISEASE; LIPODYSTROPHY; ADULTS; RISK; POPULATION; DISORDERS; EDUCATION; PROGRAM AB Patients with human immunodeficiency virus (HIV) are an increasing subpopulation of patients seen in endocrine/diabetes clinics. This article explores evidence-based treatment recommendations for patients with metabolic syndrome who are also positive for HIV. Patients infected with HIV may manifest metabolic abnormalities. They often present with low high-density lipoprotein (HDL-C), hypertension, visceral adiposity, and insulin resistance, among other symptoms consistent with features of the metabolic syndrome. The etiologies of the metabolic abnormalities are not completely understood. The role of highly active antiretroviral therapy (HAART) and the separate effect of HIV on patients who are surviving longer may contribute to the increased incidence of the development of the metabolic syndrome. The role of the health care team is to provide patient education to patients with HIV concerning lifestyle modification in order to prevent complications related to the metabolic syndrome. C1 [Feigenbaum, Kathryn] NIH, Ctr Clin, Nursing & Patient Care Serv, Bethesda, MD 20892 USA. [Longstaff, Laura] US PHS, Off Gener Drugs, Ctr Drug Evaluat & Res, Food & Drug Adm, Rockville, MD USA. RP Feigenbaum, K (reprint author), NIH, Ctr Clin, Nursing & Patient Care Serv, 10 Ctr Dr,MSC 1530, Bethesda, MD 20892 USA. EM kfeigenbaum@nih.gov NR 44 TC 5 Z9 5 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-7217 J9 DIABETES EDUCATOR JI Diabetes Educ. PD MAY-JUN PY 2010 VL 36 IS 3 BP 457 EP 464 DI 10.1177/0145721710363619 PG 8 WC Endocrinology & Metabolism; Public, Environmental & Occupational Health SC Endocrinology & Metabolism; Public, Environmental & Occupational Health GA 601ME UT WOS:000278062900005 PM 20348287 ER PT J AU Vinciguerra, M Fulco, M Ladurner, A Sartorelli, V Rosenthal, N AF Vinciguerra, Manlio Fulco, Marcella Ladurner, Andreas Sartorelli, Vittorio Rosenthal, Nadia TI SirT1 in muscle physiology and disease: lessons from mouse models SO DISEASE MODELS & MECHANISMS LA English DT Review ID III HISTONE DEACETYLASE; SKELETAL-MUSCLE; CIRCADIAN CLOCK; CALORIE RESTRICTION; CARDIAC MYOCYTES; CELL-SURVIVAL; MITOCHONDRIAL-FUNCTION; ENERGY-METABOLISM; ACTIVATING SIRT1; MAMMALIAN CLOCK AB Sirtuin 1 (SirT1) is the largest of the seven members of the sirtuin family of class III nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylases, whose activation is beneficial for metabolic, neurodegenerative, inflammatory and neoplastic diseases, and augments life span in model organisms (Finkel et al., 2009; Lavu et al., 2008). In vitro studies show that SirT1 protects genome integrity and is involved in circadian physiological rhythms (Asher et al., 2008; Nakahata et al., 2008; Oberdoerffer et al., 2008). In the last few years, a fundamental role for SirT1 in the metabolism and differentiation of skeletal muscle cells has been uncovered (Fulco et al., 2003), and the use of specific transgenic or knockout SirT1 mouse models implicates it in the protection of heart muscle from oxidative and hypertrophic stresses (Alcendor et al., 2007). In this Perspective, we review the recent exciting findings that have established a key role for the 'longevity' protein SirT1 in skeletal and heart muscle physiology and disease. Furthermore, given the multiple biological functions of SirT1, we discuss the unique opportunities that SirT1 mouse models can offer to improve our integrated understanding of the metabolism, as well as the regeneration and aging-associated changes in the circadian function, of skeletal and heart muscle. C1 [Vinciguerra, Manlio; Rosenthal, Nadia] European Mol Biol Lab, Mouse Biol Unit, I-00016 Monterotondo, Italy. [Vinciguerra, Manlio; Ladurner, Andreas] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany. [Fulco, Marcella; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Vinciguerra, M (reprint author), European Mol Biol Lab, Mouse Biol Unit, Campus A Buzzati Traverso, I-00016 Monterotondo, Italy. EM manlio.vinciguerra@embl.it OI Vinciguerra, Manlio/0000-0002-1768-3894; Rosenthal, Nadia/0000-0002-7599-7365 FU European Union [LSHM-CT-2005-018630, LSHG-CT-2006-037188]; National Institute of Arthritis, Musculoskeletal, and Skin Diseases (NIH-NIAMS); EMBL FX We would like to thank members of the Rosenthal lab for helpful discussions. N.R. acknowledges support by the European Union grants 'Heart Repair' (LSHM-CT-2005-018630) and EUMODIC (LSHG-CT-2006-037188), and V. S. acknowledges support from the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases (NIH-NIAMS). M. V. is the recipient of an EIPOD fellowship from the EMBL. We apologize to colleagues whose research work we could not cite for length limits. Deposited in PMC for release after 12 months. NR 77 TC 35 Z9 37 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 J9 DIS MODEL MECH JI Dis. Model. Mech. PD MAY-JUN PY 2010 VL 3 IS 5-6 BP 298 EP 303 DI 10.1242/dmm.004655 PG 6 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 622YA UT WOS:000279701700014 PM 20354108 ER PT J AU Sharma, S Ellis, ECS Dorko, K Zhang, SM Mattison, DR Caritis, SN Venkataramanan, R Strom, SC AF Sharma, Shringi Ellis, Ewa C. S. Dorko, Kenneth Zhang, Shimin Mattison, Donald R. Caritis, Steve N. Venkataramanan, Raman Strom, Stephen C. TI Metabolism of 17 alpha-Hydroxyprogesterone Caproate, an Agent for Preventing Preterm Birth, by Fetal Hepatocytes SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID CYTOCHROME-P450 3A EXPRESSION; ADULT LIVER-MICROSOMES; DRUG-METABOLISM AB Preterm delivery (i.e., delivery before 37 completed weeks of gestation) is a major determinant of neonatal morbidity and mortality. Until recently, no effective therapies for prevention of preterm birth existed. In a recent multicentered trial, 17 alpha-hydroxyprogesterone caproate (17-OHPC) was shown to reduce the rate of preterm birth by 33% in a group of high-risk women. Limited pharmacologic data exist for this drug. Previous studies have shown that CYP3A is involved in the metabolism of 17-OHPC. In this study, we evaluated the metabolism of 17-OHPC in adult and fetal human hepatocytes and in expressed cytochrome P450 enzymes. 17-OHPC was metabolized by expressed CYP3A7 and by fetal hepatocytes. The metabolite profile was qualitatively different between expressed CYP3A4 and CYP3A7. Expressed CYP3A4 demonstrated a significantly higher (>10 times) capacity to metabolize 17-OHPC than CYP3A7. Based on retention times, two unique metabolites were observed in the fetal and adult hepatocyte systems along with one common metabolite. The intrinsic clearance of 17-OHPC by fetal hepatocytes was observed to be one-half of that in adults. In summary, this study demonstrates that fetal hepatocytes and, in particular, the fetal form of CYP3A (i.e., CYP3A7) can metabolize 17-OHPC. C1 [Ellis, Ewa C. S.; Dorko, Kenneth; Venkataramanan, Raman; Strom, Stephen C.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15260 USA. [Mattison, Donald R.] NICHHD, Ctr Res Mothers & Children, Obstetr Fetal Pharmacol Res Units Network, Bethesda, MD 20892 USA. [Caritis, Steve N.] Magee Womens Hosp, Dept Obstet & Gynecol & Reprod Sci, Pittsburgh, PA USA. [Sharma, Shringi; Zhang, Shimin; Venkataramanan, Raman] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. RP Strom, SC (reprint author), Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15260 USA. EM strom@pitt.edu RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013; Ellis, Ewa/D-5370-2014; OI Mattison, Donald/0000-0001-5623-0874; Ellis, Ewa/0000-0002-3057-5337; Strom, Stephen/0000-0002-2889-3387; caritis, steve/0000-0002-2169-0712 FU National Institutes of Health National Institute of Child Health and Human Development [HD-047905-2]; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [N01-DK-7-0004/HHSN26700700004C] FX This work was supported in part by the National Institutes of Health National Institute of Child Health and Human Development [Grant HD-047905-2]; and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Contract Number N01-DK-7-0004/HHSN26700700004C] (Liver Tissue and Cell Distribution System). NR 17 TC 13 Z9 14 U1 1 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD MAY PY 2010 VL 38 IS 5 BP 723 EP 727 DI 10.1124/dmd.109.029918 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 583QT UT WOS:000276694400001 PM 20097724 ER PT J AU Beigel, JH AF Beigel, J. H. TI ANTIVIRAL COMPOUNDS IN THE PIPELINE TO TACKLE H1N1 INFLUENZA INFECTION SO DRUGS OF THE FUTURE LA English DT Review ID SIALIDASE FUSION PROTEIN; CYCLOPENTANE NEURAMINIDASE INHIBITORS; RANDOMIZED CONTROLLED-TRIAL; IN-VIVO ACTIVITIES; A VIRUS-INFECTION; H5N1 VIRUS; CELL-CULTURE; MOUSE MODEL; OSELTAMIVIR; MICE AB The recent pandemic of H1N1 has demonstrated the potential vulnerability of the human population to novel influenza viruses. While there is recent increased interest and effort in developing effective anti-influenza agents, few new products have entered clinical studies. This review will highlight the limited armamentarium of licensed influenza agents, and discuss novel compounds and strategies that have entered clinical studies and may therefore be imminently available to the treating clinician. C1 NCI, Immunoregulat Lab, Div Intramural Res, NIAID,SAIC Frederick Inc,NIH, Frederick, MD 21702 USA. RP Beigel, JH (reprint author), NCI, Immunoregulat Lab, Div Intramural Res, NIAID,SAIC Frederick Inc,NIH, Frederick, MD 21702 USA. EM jbeigel@niaid.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this pubtication 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 National Institute of Allergy and Infectious Diseases. NR 76 TC 4 Z9 4 U1 0 U2 3 PU PROUS SCIENCE, SA-THOMSON REUTERS PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0377-8282 J9 DRUG FUTURE JI Drug Future PD MAY PY 2010 VL 35 IS 5 BP 385 EP 392 DI 10.1358/dof.2010.35.5.1487081 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 627DB UT WOS:000280018100004 PM 21738286 ER EF