FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Narver, H AF Narver, H. TI Ancillary Care Improves Outcome in a Mouse Model of Spinal Muscular Atrophy SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Narver, H.] NINDS, Anim Hlth Care Sect, NIH, Bethesda, MD 20892 USA. [Narver, H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 739 EP 740 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000094 ER PT J AU Caviness, GF Thigpen, JE Locklear, J Whiteside, T Murray, S Kissling, G Lih, F Tomer, K Grant, M Forsythe, D AF Caviness, G. F. Thigpen, J. E. Locklear, J. Whiteside, T. Murray, S. Kissling, G. Lih, F. Tomer, K. Grant, M. Forsythe, D. TI The Effects of Environmental Enrichment Devices Used in Rodent Cages on the Time of Vaginal Opening in Immature CD1 Mice SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Caviness, G. F.; Thigpen, J. E.; Locklear, J.; Whiteside, T.; Murray, S.; Grant, M.; Forsythe, D.] NIH, Res Triangle Pk, NC USA. [Kissling, G.; Lih, F.; Tomer, K.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 744 EP 744 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000114 ER PT J AU Thigpen, JE Setchell, K Locklear, J Kissling, G Caviness, GF Whiteside, T Belcher, S Brown, N Collins, B Lih, F Tomer, K Grant, M Forsythe, D AF Thigpen, J. E. Setchell, K. Locklear, J. Kissling, G. Caviness, G. F. Whiteside, T. Belcher, S. Brown, N. Collins, B. Lih, F. Tomer, K. Grant, M. Forsythe, D. TI The Effects of Bisphenol A on the Timing of Vaginal Opening in CD1 Mice Fed a High- or Low-Phytoestrogen Diet SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Thigpen, J. E.; Locklear, J.; Caviness, G. F.; Whiteside, T.; Grant, M.; Forsythe, D.] Natl Inst Environm Hlth Sci, Comparat Med Branch, Res Triangle Pk, NC USA. [Kissling, G.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. [Collins, B.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Res Triangle Pk, NC USA. [Lih, F.; Tomer, K.] Natl Inst Environm Hlth Sci, Lab Struct Biol, Res Triangle Pk, NC USA. [Setchell, K.; Brown, N.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Belcher, S.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 744 EP 744 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000115 ER PT J AU Kehler, J Baran, SW Roelke-Parker, M AF Kehler, J. Baran, S. W. Roelke-Parker, M. TI Monitoring and Supporting Respiratory Function during Laparoscopic Procedures SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Kehler, J.; Baran, S. W.] Vet Biosci Inst, Harleysville, PA USA. [Kehler, J.; Roelke-Parker, M.] NCI, Lab Genom Divers, NIH, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 745 EP 745 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000118 ER PT J AU Cronise, HE Swerczek, JM Szarowicz, MD Beauregard, MA Reeder, RJ Pao, DC Kerekes, K Morin, LC Keating, NW Oden, JA Herbert, RL AF Cronise, H. E. Swerczek, J. M. Szarowicz, M. D. Beauregard, M. A. Reeder, R. J. Pao, D. C. Kerekes, K. Morin, L. C. Keating, N. W. Oden, J. A. Herbert, R. L. TI Collaborative Effort to Promote the Physical and Social Wellbeing of an Orphaned African Green Infant through Fostering SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Cronise, H. E.; Swerczek, J. M.] NIAID LMM, Dickerson, MD USA. [Szarowicz, M. D.; Beauregard, M. A.; Reeder, R. J.; Pao, D. C.] NIAID CMB, Dickerson, MD USA. [Kerekes, K.; Morin, L. C.; Keating, N. W.; Oden, J. A.] DVR, Dickerson, MD USA. [Herbert, R. L.] NIH NIHAC, NIAID DIR CMB, Dickerson, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 749 EP 749 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000135 ER PT J AU Taylor, J Lucas, K AF Taylor, J. Lucas, K. TI A Different Approach to Hemostasis of Femoral Vessels in Swine SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Taylor, J.; Lucas, K.] NIH, LCE, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 751 EP 751 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000144 ER PT J AU Zeleski, KL Orr-Gonzalez, S Lambert, L AF Zeleski, K. L. Orr-Gonzalez, S. Lambert, L. TI Go for the Jugular! Blood Draw Refinement in Rats SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Zeleski, K. L.; Orr-Gonzalez, S.; Lambert, L.] NIH NIAID, Lab Malaria Immunol & Vaccinol, Bethesda, MD USA. [Zeleski, K. L.; Orr-Gonzalez, S.; Lambert, L.] Charles River Labs, Germantown, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 752 EP 752 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000149 ER PT J AU Myers, PH Blankenship, TL Thigpen, JE Rios, M Locklear, J Feldman, SH Grant, M Forsythe, D AF Myers, P. H. Blankenship, T. L. Thigpen, J. E. Rios, M. Locklear, J. Feldman, S. H. Grant, M. Forsythe, D. TI Septicemia Associated with the Opportunistic Bacteria Burkholderia cepacia in Cybb Mice SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Myers, P. H.; Blankenship, T. L.; Rios, M.] Natl Inst Environm Hlth Sci, Comparat Med Branch, Vet Med Sect, Res Triangle Pk, NC USA. [Thigpen, J. E.; Locklear, J.; Grant, M.; Forsythe, D.] NIH, Comparat Med Branch, Qual Assurance Lab, Res Triangle Pk, NC USA. [Feldman, S. H.] Univ Virginia, Ctr Comparat Med, Charlottesville, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 754 EP 754 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000160 ER PT J AU Petros, R Clarke, C AF Petros, R. Clarke, C. TI Clinical Symptoms and Supportive Care Provided to Rhesus Monkeys (Macaca mulatta) Infected with a Novel Simian-Human Immunodeficiency Virus SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Petros, R.; Clarke, C.] NIAID, CMB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 755 EP 756 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000166 ER PT J AU Whiteside, T Thigpen, JE Locklear, J Caviness, GF Murray, S Grant, M Forsythe, D AF Whiteside, T. Thigpen, J. E. Locklear, J. Caviness, G. F. Murray, S. Grant, M. Forsythe, D. TI Animal Care Staff Exposure to Methicillin-Resistant Staphylococcus aureus (MRSA) from Commercial Rodent Populations SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Whiteside, T.; Thigpen, J. E.; Locklear, J.; Caviness, G. F.; Murray, S.; Grant, M.; Forsythe, D.] Natl Inst Environm Hlth Sci, Qual Assurance Lab, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 757 EP 757 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000174 ER PT J AU Byzek, DM Hughes, L Davis-Ritchie, B Rosa, M AF Byzek, D. M. Hughes, L. Davis-Ritchie, B. Rosa, M. TI Communicating with the Principal Investigator: How Templates Reformed Our Work SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Byzek, D. M.; Hughes, L.; Davis-Ritchie, B.; Rosa, M.] NINDS, AHCS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 763 EP 763 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000199 ER PT J AU Hughes, L Byzek, DM AF Hughes, L. Byzek, D. M. TI Development of a Comprehensive Management System for Standard Operating Procedures SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Hughes, L.; Byzek, D. M.] NINDS, AHCS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 774 EP 775 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000252 ER PT J AU Despres, D AF Despres, D. TI In Vivo Imaging of the Mouse Eye by High Frequency Ultrasound SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Despres, D.] NINDS, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 794 EP 794 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000339 ER PT J AU Goulding, DR Harry, G Kissling, GE Blankenship, TL Forsythe, DB AF Goulding, D. R. Harry, G. Kissling, G. E. Blankenship, T. L. Forsythe, D. B. TI Differences in Activity in Male and Female B6C3F1 Mice Using the Open Field and Voluntary Running Wheel SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Goulding, D. R.; Blankenship, T. L.; Forsythe, D. B.] NIEHS, Comparat Med Branch, Vet Med Sect, Res Triangle Pk, NC 27709 USA. [Harry, G.] NIEHS, Lab Toxicol & Pharmacol, Neurotoxicol Grp, Res Triangle Pk, NC 27709 USA. [Kissling, G. E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 794 EP 794 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000341 ER PT J AU Locklear, J Thigpen, JE Caviness, GF Whiteside, T Saunders, H Grant, M Forsythe, D AF Locklear, J. Thigpen, J. E. Caviness, G. F. Whiteside, T. Saunders, H. Grant, M. Forsythe, D. TI The Incidence of Mouse Hepatitis Virus and Helicobacter Species in Wild Rodents and Wildlife Species around an Animal Research Facility SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Locklear, J.; Thigpen, J. E.; Caviness, G. F.; Whiteside, T.; Saunders, H.; Grant, M.; Forsythe, D.] Natl Inst Environm Hlth Sci, Comparat Med Branch, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 799 EP 799 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000362 ER PT J AU Thigpen, JE Whiteside, T Story, J Caviness, GF Locklear, J Murray, S Turner, W Hollister, B Grant, M Forsythe, D AF Thigpen, J. E. Whiteside, T. Story, J. Caviness, G. F. Locklear, J. Murray, S. Turner, W. Hollister, B. Grant, M. Forsythe, D. TI A Novel Method for Detecting Staphylococcus aureus in Haired Rats SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Thigpen, J. E.; Whiteside, T.; Caviness, G. F.; Locklear, J.; Murray, S.; Grant, M.; Forsythe, D.] NIH, Res Triangle Pk, NC USA. [Story, J.; Turner, W.; Hollister, B.] NIEHS, Comparat Med Branch, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 800 EP 800 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000367 ER PT J AU Idris, NM AF Idris, N. M. TI Effective Decapsulation of Artemia Cyst SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Idris, N. M.] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 10 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 808 EP 808 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000399 ER PT J AU Byrum, RA Alexander, I Rosa, B Oberlander, N Cooper, K Rojas, O AF Byrum, R. A. Alexander, I. Rosa, B. Oberlander, N. Cooper, K. Rojas, O. TI Use of Body Surface Temperature Obtained with an Infrared Thermometer as Early Endpoint Criteria in Orthopox Infection Studies SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Byrum, R. A.; Alexander, I.; Rosa, B.; Oberlander, N.; Cooper, K.; Rojas, O.] NIAID, EVPS, Integrated Res Facil, NIH, Frederick, MD USA. [Byrum, R. A.; Alexander, I.; Rosa, B.; Oberlander, N.; Cooper, K.; Rojas, O.] Charles River Labs, CSS, Germantown, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 810 EP 810 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000410 ER PT J AU Miller, FG Wertheimer, A AF Miller, Franklin G. Wertheimer, Alan TI The Fair Transaction Model of Informed Consent: An Alternative to Autonomous Authorization SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID THERAPEUTIC MISCONCEPTION; ETHICS AB The doctrine of informed consent in bioethics has relied on the view that consent is valid when it represents a patient or research subject's autonomous authorization. In this article we challenge this reigning conception of the validity of informed consent in clinical research, focusing in particular on the problem of the therapeutic misconception. We argue that the autonomous authorization model of informed consent suffers from four defects: (1) it fails to do justice to the relevance of risk-benefit considerations in shaping the criteria for the validity of consent, (2) it compromises the interests of subjects by preventing them from consenting to research participation with less than substantial understanding when doing so would likely be consistent with their preferences and beneficial to them or at least be unlikely to cause them harm, (3) it jeopardizes the interests of investigators by denying them fair notice regarding when the consent of research subjects can be considered valid and thus make it permissible for them to be enrolled in research, and (4) it threatens the reasonable limits on the responsibility of investigators to assure the adequacy of subjects' understanding of what research participation involves. In place of the autonomous authorization model, we present and defend a fair transaction model of informed consent, which better reflects the values served by consent. C1 [Miller, Franklin G.; Wertheimer, Alan] NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. [Miller, Franklin G.] NIMH, Intramural Res Program, Bethesda, MD USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. NR 14 TC 14 Z9 14 U1 0 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD SEP PY 2011 VL 21 IS 3 BP 201 EP 218 PG 18 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 833RY UT WOS:000295903800002 PM 22073815 ER PT J AU Scott, JE Blasinsky, M Dufour, M Mandal, RJ Philogene, GS AF Scott, Jack E. Blasinsky, Margaret Dufour, Mary Mandal, Rachel J. Philogene, G. Stephane TI An evaluation of the Mind Body Interactions and Health Program: assessing the impact of an NIH program using the Payback Framework SO RESEARCH EVALUATION LA English DT Article AB This paper describes the first direct application of the Payback Framework (PF) in the United States for an evaluation of the Mind Body Interactions and Health Program, a trans-National Institutes of Health program funded over a ten-year period beginning in 1999. The program funded 15 research centers and 44 investigator-initiated research projects. We present results from an initial planning study and describe how we selected the PF as a conceptual framework for an outcome evaluation of the program. We outline the overall design for the outcome evaluation study and describe how we adapted the PF with reference to the initial phase of the study focusing in the 15 research centers. C1 [Scott, Jack E.; Blasinsky, Margaret; Dufour, Mary] Madrillon Grp Inc, Vienna, VA 22182 USA. [Mandal, Rachel J.; Philogene, G. Stephane] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP Scott, JE (reprint author), Madrillon Grp Inc, 8142 Madrillon Court, Vienna, VA 22182 USA. EM jscott@madrillongroup.com NR 11 TC 6 Z9 6 U1 1 U2 7 PU BEECH TREE PUBLISHING PI GUILDFORD PA 10 WATFORD CLOSE,, GUILDFORD GU1 2EP, SURREY, ENGLAND SN 0958-2029 J9 RES EVALUAT JI Res. Evaluat. PD SEP PY 2011 VL 20 IS 3 SI SI BP 185 EP 192 DI 10.3152/095820211X12941371876661 PG 8 WC Information Science & Library Science SC Information Science & Library Science GA 837MF UT WOS:000296207200003 ER PT J AU De Smedt, H Verkhratsky, A Muallem, S AF De Smedt, H. Verkhratsky, A. Muallem, S. TI Ca2+ signaling mechanisms of cell survival and cell death: An introduction SO CELL CALCIUM LA English DT Editorial Material DE Ca2+ signaling; Cell death, apoptosis, autophagy; Mitochondria; Endoplasmic reticulum; Ca2+ influx ID INOSITOL TRISPHOSPHATE RECEPTOR; ENDOPLASMIC-RETICULUM; 1,4,5-TRISPHOSPHATE RECEPTOR; OXIDATIVE STRESS; CALCIUM SIGNALS; TRP CHANNELS; APOPTOSIS; ER; MITOCHONDRIA; RELEASE AB Ca2+ regulates many steps in cell death mechanisms, and is potentially involved in all types of cell death. Moreover, virtually all elements of the cellular Ca2+ toolbox seem to contribute to remodeling of the Ca2+ signaling machinery during cell death processes. As expected from the ubiquitous nature of Ca2+ signaling, these mechanisms are operative in all cell types, and their malfunction may lead to a wide diversity of pathological implications. The contributions in this Special Issue deal with many different aspects of the relation between Ca2+ signaling and cell death. They illustrate the complexity of this relation, and importantly they give an outlook on potential new therapeutic targets for treatment of diseases connected to defects in cell death pathways. (C) 2011 Elsevier Ltd. All rights reserved. C1 [De Smedt, H.] KULeuven, Dept Mol Cell Biol, Louvain, Belgium. [Verkhratsky, A.] Univ Manchester, Fac Life Sci, Manchester, Lancs, England. [Muallem, S.] NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP De Smedt, H (reprint author), KULeuven, Dept Mol Cell Biol, Campus Gasthuisberg O-N1,802, Louvain, Belgium. EM Humbert.Desmedt@med.kuleuven.be RI Verkhratsky, Alexei/J-4527-2013 OI Verkhratsky, Alexei/0000-0003-2592-9898 NR 64 TC 8 Z9 8 U1 0 U2 9 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD SEP PY 2011 VL 50 IS 3 SI SI BP 207 EP 210 DI 10.1016/j.ceca.2011.06.004 PG 4 WC Cell Biology SC Cell Biology GA 831PY UT WOS:000295744800001 PM 21741085 ER PT J AU Kiselyov, K Colletti, GA Terwilliger, A Ketchum, K Lyons, CWP Quinn, J Muallem, S AF Kiselyov, Kirill Colletti, Grace A. Terwilliger, Austen Ketchum, Kathleen Lyons, Christopher W. P. Quinn, James Muallem, Shmuel TI TRPML: Transporters of metals in lysosomes essential for cell survival? SO CELL CALCIUM LA English DT Review DE Calcium; Mucolipins; Two-pore-channels; Cell death; Lysosomes ID MUCOLIPIDOSIS TYPE-IV; VARITINT-WADDLER PHENOTYPE; RECEPTOR POTENTIAL CHANNEL; ARTERIAL SMOOTH-MUSCLE; MITOCHONDRIAL ABERRATIONS; MEMBRANE TRAFFICKING; ACIDIC ORGANELLES; ENDOSOMAL PATHWAY; STORAGE DISEASES; OXIDATIVE STRESS AB Key aspects of lysosomal function are affected by the ionic content of the lysosomal lumen and, therefore, by the ion permeability in the lysosomal membrane. Such functions include regulation of lysosomal acidification, a critical process in delivery and activation of the lysosomal enzymes, release of metals from lysosomes into the cytoplasm and the Ca(2+)-dependent component of membrane fusion events in the endocytic pathway. While the basic mechanisms of lysosomal acidification have been largely defined, the lysosomal metal transport system is not well understood. TRPML1 is a lysosomal ion channel whose malfunction is implicated in the lysosomal storage disease Mucolipidosis Type IV. Recent evidence suggests that TRPML1 is involved in Fe(2+), Ca(2+) and Zn(2+) transport across the lysosomal membrane, ascribing novel physiological roles to this ion channel, and perhaps to its relatives TRPML2 and TRPML3 and illuminating poorly understood aspects of lysosomal function. Further, alterations in metal transport by the TRPMLs due to mutations or environmental factors may contribute to their role in the disease phenotype and cell death. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kiselyov, Kirill; Colletti, Grace A.; Terwilliger, Austen; Ketchum, Kathleen; Lyons, Christopher W. P.; Quinn, James] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. [Muallem, Shmuel] NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Kiselyov, K (reprint author), Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. EM Kiselyov@pitt.edu RI Lyons, Christopher/B-1246-2010 OI Lyons, Christopher/0000-0001-8437-6651 FU National Institutes of Health [HD058577, ES01678]; NIH/NIDCR ZIA [DE000735-01] FX This work was supported by the National Institutes of Health grants HD058577 and ES01678 to Kirill Kiselyov by the intramural research funds of the NIH/NIDCR ZIA DE000735-01 to S.M. The authors would like to thank Drs. Rosa Puertollano, Emir Lloyd-Evans and Haoxing Xu for fruitful discussion. NR 77 TC 25 Z9 25 U1 2 U2 8 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD SEP PY 2011 VL 50 IS 3 SI SI BP 288 EP 294 DI 10.1016/j.ceca.2011.04.009 PG 7 WC Cell Biology SC Cell Biology GA 831PY UT WOS:000295744800010 PM 21621258 ER PT J AU Rosenblum, D Alving, B AF Rosenblum, Daniel Alving, Barbara TI The Role of the Clinical and Translational Science Awards Program in Improving the Quality and Efficiency of Clinical Research SO CHEST LA English DT Article AB Recognizing the need to increase the efficiency and quality of translating basic discovery into treatment and prevention strategies for patients and the public, the National Institutes of Health (NIH) announced the Clinical and Translational Science Awards (CTSAs) in 2006. Academic health centers that competed successfully for these awards agreed to work as a consortium and in cooperation with the NIH to improve the translation process by training the next generation of investigators to work in interdisciplinary teams, developing public-private partnerships in the movement of basic discovery to preclinical and clinical studies and trials, improving clinical research management, and engaging with communities to ensure their involvement in shaping research questions and in implementing research results. The CTSAs have addressed the crucial need to improve the quality and efficiency of clinical research by (1) providing training for clinical investigators and for bench researchers to facilitate their participation in the clinical and translational research environment, (2) developing more systematic approaches to clinical research management, and (3) engaging communities as active participants in the design and conduct of clinical research studies and trials and as leaders in implementing health advances that are of high importance to them. We provide an overview of the CTSA activities with attention to these three areas, which are essential to developing efficient clinical research efforts and effective implementation of research results on a national level. CHEST 2011; 140(3):764-767 C1 [Rosenblum, Daniel; Alving, Barbara] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RP Alving, B (reprint author), NIH, Natl Ctr Res Resources, 31 Ctr Dr,Bldg 31,Ste 3B11, Bethesda, MD 20892 USA. EM alvingb@mail.nih.gov NR 6 TC 12 Z9 12 U1 0 U2 6 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD SEP PY 2011 VL 140 IS 3 BP 764 EP 767 DI 10.1378/chest.11-0710 PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 830IS UT WOS:000295651300033 PM 21896519 ER PT J AU Andre, M Zhang, M Peinado, H Papaspyridonos, M Kaplan, R Bromberg, J Lyden, D AF Andre, M. Zhang, M. Peinado, H. Papaspyridonos, M. Kaplan, R. Bromberg, J. Lyden, D. TI Interleukin-6 Increases Metastasis Formation Through Mobilization of Immature Myeloid Cells to the Pre-metastatic Niche SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Andre, M.] Portuguese Inst Canc, Dept Med Oncol, Lisbon, Portugal. [Zhang, M.; Bromberg, J.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Peinado, H.; Papaspyridonos, M.; Lyden, D.] Weill Cornell Med Coll, Dept Paediat, New York, NY USA. [Kaplan, R.] NCI, Frederick Canc Res & Dev Ctr, Bethesda, MD 20892 USA. RI Peinado, Hector/A-6417-2013 NR 0 TC 0 Z9 0 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S115 EP S115 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752800403 ER PT J AU Caffo, O Ceribelli, A De Marinis, F Bulotta, A Novello, S Bearz, A Durante, E Grossi, F Pegoraro, MC Tiseo, M AF Caffo, O. Ceribelli, A. De Marinis, F. Bulotta, A. Novello, S. Bearz, A. Durante, E. Grossi, F. Pegoraro, M. C. Tiseo, M. TI Treatment and Clinical Outcomes of Young Patients (<= 40 Years) With Advanced Non-small Cell Lung (NSCLC) - Data From a Retrospective Multicentric Database SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Caffo, O.] Santa Chiara Hosp, Trento, Italy. [Ceribelli, A.] Regina Elena Inst Canc Res, Rome, Italy. [De Marinis, F.] San Camillo Hosp, Oncol Pulm Unit 1, Rome, Italy. [Bulotta, A.] Osped San Raffaele, Milan, Italy. [Novello, S.] Univ Turin, Thorac Oncol Unit, Turin, Italy. [Bearz, A.] Natl Canc Inst, Aviano, Italy. [Durante, E.] Mater Salutis Hosp, Legnago, Italy. [Grossi, F.] Natl Canc Inst, Lung Canc Unit, Genoa, Italy. [Pegoraro, M. C.] Civil Hosp, Montecchio Maggiore, Italy. [Tiseo, M.] Univ Hosp, Parma, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S637 EP S638 PG 2 WC Oncology SC Oncology GA 831TA UT WOS:000295752802254 ER PT J AU Helman, L Yeung, C Wan, X Cao, L Baker, L Pappo, A Patel, S AF Helman, L. Yeung, C. Wan, X. Cao, L. Baker, L. Pappo, A. Patel, S. TI IGF1R Inhibitors in the Treatment of Ewing Sarcomas SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Helman, L.; Yeung, C.; Wan, X.; Cao, L.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Baker, L.; Pappo, A.; Patel, S.] Sarcoma Alliance Res Collaborat, Ann Arbor, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S64 EP S64 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752800227 ER PT J AU Hodge, J AF Hodge, J. TI The Tipping Point for Combination Therapy - Cancer Vaccines With Radiation SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Hodge, J.] NCI, Lab Tumour Immunol & Biol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S17 EP S17 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752800054 ER PT J AU Kil, W Ko, C Kaushal, A Warren, K Ning, H Camphausen, K Smart, D AF Kil, W. Ko, C. Kaushal, A. Warren, K. Ning, H. Camphausen, K. Smart, D. TI Parotid Gland Irradiation During Craniospinal Plus Boost Treatment of Pediatric Brain Tumours - a Dosimetric Evaluation SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Kil, W.; Ko, C.; Kaushal, A.; Ning, H.; Camphausen, K.; Smart, D.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Warren, K.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S292 EP S292 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752801033 ER PT J AU Levanon, K Hirsch, M Miron, A Ligon, A Birrer, M Drapkin, R AF Levanon, K. Hirsch, M. Miron, A. Ligon, A. Birrer, M. Drapkin, R. TI Foxo3a Loss is a Key Event in High-grade Pelvic Serous Carcinogenesis SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Levanon, K.] Chaim Sheba Med Ctr, Ramat Gan, Israel. [Hirsch, M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ligon, A.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Birrer, M.] NCI, NIH, Bethesda, MD 20892 USA. RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S113 EP S114 PG 2 WC Oncology SC Oncology GA 831TA UT WOS:000295752800398 ER PT J AU Martin, LK Jia, G Grecula, J Harper, E Kefauver, C Wei, L Knopp, M Delgado, IJE Grever, M Bekaii-Saab, T AF Martin, L. K. Jia, G. Grecula, J. Harper, E. Kefauver, C. Wei, L. Knopp, M. Delgado, I. J. Espinoza Grever, M. Bekaii-Saab, T. TI A Phase I Study of Triapine and Radiation in Patients With Locally Advanced Pancreas Cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Harper, E.; Kefauver, C.] Ohio State Univ, Ctr Comprehens Canc, Med Ctr, Columbus, OH 43210 USA. [Wei, L.] Ohio State Univ, Med Ctr, Ctr Biostat, Columbus, OH 43210 USA. [Delgado, I. J. Espinoza] NIH, Invest Drug Branch, Rockville, MD USA. RI Jia, Guang/E-3312-2011; Bekaii-Saab, Tanios/E-2733-2011; Grecula, John/E-3149-2011; Jia, Guang/A-1275-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S449 EP S449 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752801562 ER PT J AU Peveling-Oberhag, J Zeuzem, S Yong, WP Kunz, T Paquet, T Bouillaud, E Urva, S Anak, O Sellami, D Kobalava, Z AF Peveling-Oberhag, J. Zeuzem, S. Yong, W. P. Kunz, T. Paquet, T. Bouillaud, E. Urva, S. Anak, O. Sellami, D. Kobalava, Z. TI A Phase I Safety and Pharmacokinetic Study of Everolimus, an Oral mTOR Inhibitor, in Subjects With Impaired Hepatic Function SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Peveling-Oberhag, J.; Zeuzem, S.] Klin JW Goethe Univ, Dept Med, Frankfurt 117548, Germany. [Yong, W. P.] Natl Univ Singapore, Inst Canc, Singapore, Singapore. [Kunz, T.; Urva, S.; Sellami, D.] Novartis Pharmaceut, NIA, Florham Pk, NJ USA. [Paquet, T.; Bouillaud, E.; Anak, O.] Novartis Pharma AG, NIA, Basel, Switzerland. [Kobalava, Z.] Peoples Friendship Univ Russia, Ctr Appl Clin Pharmacol, Moscow, Russia. RI Kobalava, Zhanna/S-3842-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S459 EP S459 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752801597 ER PT J AU Pingpank, J Royal, RE Kammula, US Kam, AW Wood, BJ Libutti, SK Hughes, MS Ohl, SE Alexander, HR AF Pingpank, J. Royal, R. E. Kammula, U. S. Kam, A. W. Wood, B. J. Libutti, S. K. Hughes, M. S. Ohl, S. E. Alexander, H. R. TI Percutaneous Hepatic Perfusion (PHP) With Melphalan for Patients With Unresectable Liver Metastases of Neuroendocrine Tumours (MNET)-NCT00096083 SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Pingpank, J.] UPMC, Div Surg Oncol, Pittsburgh, PA USA. [Royal, R. E.] MDACC, Houston, TX USA. [Kammula, U. S.; Wood, B. J.; Hughes, M. S.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Kam, A. W.] Johns Hopkins Bayview Med Ctr, Dept Imaging, Baltimore, MD USA. [Libutti, S. K.] Montefiore Med Ctr, New York, NY USA. [Alexander, H. R.] Univ Maryland, Baltimore, MD 21201 USA. NR 0 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S478 EP S478 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752801658 ER PT J AU Pingpank, JF Hughes, M Alexander, HR Faries, M Zager, J Siskin, G Agarwala, S Whitman, E Nutting, C Ozkan, OS AF Pingpank, J. F. Hughes, M. Alexander, H. R. Faries, M. Zager, J. Siskin, G. Agarwala, S. Whitman, E. Nutting, C. Ozkan, O. S. TI Percutaneous Hepatic Perfusion (PHP) Vs. Best Alternative Care (BAC) for Patients (pts) With Melanoma Liver Metastases - Efficacy Update of the Phase 3 Trial (NCT00324727) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Pingpank, J. F.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Hughes, M.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Alexander, H. R.] Univ Maryland, Dept Surg, Baltimore, MD 21201 USA. [Faries, M.] Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA. [Zager, J.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Cutaneous Oncol, Tampa, FL 33682 USA. [Siskin, G.] Albany Med Ctr, Dept Intervent Radiol, Albany, NY USA. [Agarwala, S.] St Lukes Hosp, Dept Med Oncol, Bethlehem, PA USA. [Whitman, E.] Atlantic Hlth Care, Morristown Mem Hosp, Dept Surg, Morristown, NJ USA. [Nutting, C.] Swedish Med Ctr, Dept Radiol, Englewood, CO 80110 USA. [Ozkan, O. S.] UTMB Galveston, Dept Radiol, Galveston, TX USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S653 EP S653 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752802308 ER PT J AU Zikos, E Coens, C Ediebah, DE Greimel, E Reeve, BB Ringash, J Schmucker-Von Koch, J Taphoorn, MJ Weis, J Bottomley, A AF Zikos, E. Coens, C. Ediebah, D. E. Greimel, E. Reeve, B. B. Ringash, J. Schmucker-Von Koch, J. Taphoorn, M. J. Weis, J. Bottomley, A. TI Is There Any Added Value in the Pooled Analysis of Over 120 Large Scale Phase III Randomized Clinical Trials in Health Related Quality of Life? SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Zikos, E.; Ediebah, D. E.; Bottomley, A.] Qual Life, EORTC, Brussels, Belgium. [Coens, C.] EORTC, Dept Stat, Brussels, Belgium. [Greimel, E.] Med Univ Graz, Graz, Austria. [Reeve, B. B.] NCI, Bethesda, MD 20892 USA. [Ringash, J.] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Schmucker-Von Koch, J.] Univ Regensburg, Regensburg, Germany. [Taphoorn, M. J.] Med Ctr Haaglanden, The Hague, Netherlands. [Weis, J.] Univ Freiburg, Freiburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S223 EP S223 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752800772 ER PT J AU Krebs, NF Mazariegos, M Tshefu, A Bose, C Sami, N Chomba, E Carlo, W Goco, N Kindem, M Wright, LL Hambidge, KM AF Krebs, Nancy F. Mazariegos, Manolo Tshefu, Antoinette Bose, Carl Sami, Neelofar Chomba, Elwyn Carlo, Waldemar Goco, Norman Kindem, Mark Wright, Linda L. Hambidge, K. Michael CA Complementary Feeding Study Grp TI Meat consumption is associated with less stunting among toddlers in four diverse low-income settings SO FOOD AND NUTRITION BULLETIN LA English DT Article DE Complementary feeding; infant growth; infant nutrition; stunting ID RANDOMIZED CONTROLLED-TRIAL; EDUCATIONAL INTERVENTION; COMPLEMENTARY FOODS; FEEDING PRACTICES; YOUNG-CHILDREN; ZINC INTAKE; GROWTH; INFANTS; NUTRITION; COUNTRIES AB Background. Early growth faltering is common but is difficult to reverse after the first 2 years of life. Objective. To describe feeding practices and growth in infants and young children in diverse low-income settings prior to undertaking a complementary feeding trial. Methods. This cross-sectional study was conducted through the Global Network for Women's and Children's Health Research in Guatemala, Democratic Republic of Congo, Zambia, and Pakistan. Feeding questionnaires were administered to convenience samples of mothers of 5- to 9-month old infants and 12- to 24-month-old toddlers. After standardized training, anthropometric measurements were obtained from the toddlers. Following the 2006 World Health Organization Growth Standards, stunting was defined as length-for-age < -2SD, and wasting as weight-for-length < -2SD. Logistic regression was applied to evaluate relationships between stunting and wasting and consumption of meat (including chicken and liver and not including fish). Results. Data were obtained from 1,500 infants with a mean (+/-SD) age of 6.9 +/- 1.4 months and 1,658 toddlers with a mean age of 17.2 +/- 3.5 months. The majority of the subjects in both age groups were breastfed. Less than 25% of the infants received meat regularly, whereas 62% of toddlers consumed these foods regularly, although the rates varied widely among sites. Stunting rate ranged from 44% to 66% among sites; wasting prevalence was less than 10% at all sites. After controlling for covariates, consumption of meat was associated with a reduced likelihood of stunting (OR = 0.64; 95% CI, 0.46 to 0.90). Conclusions. The strikingly high stunting rates in these toddlers and the protective effect of meat consumption against stunting emphasize the need for interventions to improve complementary feeding practices, beginning in infancy. C1 [Krebs, Nancy F.; Hambidge, K. Michael] Univ Colorado Denver, Aurora, CO 80045 USA. [Mazariegos, Manolo] Inst Nutr Cent Amer & Panama, Guatemala City, Guatemala. [Tshefu, Antoinette] Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Bose, Carl] Univ N Carolina, Chapel Hill, NC USA. [Sami, Neelofar] Aga Khan Univ, Karachi, Pakistan. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Carlo, Waldemar] Univ Alabama, Birmingham, AL USA. [Goco, Norman; Kindem, Mark] RTI Int, Res Triangle Pk, NC USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Krebs, NF (reprint author), Univ Colorado Denver, 12700 E 19th Ave,Box C225, Aurora, CO 80045 USA. EM Nancy.Krebs@ucdenver.edu FU Global Network for Women's and Children's Health Research [NICHD U01 HD040657] FX The Complementary Feeding Group consists of Ana Garces (Instituto Multidisciplinario para la Salud, Guatemala City, Guatemala); Jamie Westcott (University of Colorado Denver, Aurora, Colorado, USA); Adrien Lokangaka (Kinshasa School of Public Health, Kinshasa, Democratic Republic of Congo); Omrana Pasha (Aga Khan University, Karachi, Pakistan); Robert Goldenberg (Drexel University, Philadelphia, Pennsylvania, USA); Albert Manasyan, Edna Imenda and Melody Kunda (University Teaching Hospital, Lusaka, Zambia); and Elizabeth McClure, Abhik Das, and Tyler Hartwell (RTI International, Research Triangle Park, North Carolina, USA). This project was supported by the Global Network for Women's and Children's Health Research (NICHD U01 HD040657). NR 28 TC 22 Z9 23 U1 3 U2 11 PU INT NUTRITION FOUNDATION PI BOSTON PA 150 HARRISON AVE, BOSTON, MA 02111 USA SN 0379-5721 J9 FOOD NUTR BULL JI Food Nutr. Bull. PD SEP PY 2011 VL 32 IS 3 BP 185 EP 191 PG 7 WC Food Science & Technology; Nutrition & Dietetics SC Food Science & Technology; Nutrition & Dietetics GA 833DD UT WOS:000295861100001 PM 22073791 ER PT J AU Gericke, A Sniatecki, JJ Goloborodko, E Steege, A Zavaritskaya, O Vetter, JM Grus, FH Patzak, A Wess, J Pfeiffer, N AF Gericke, Adrian Sniatecki, Jan J. Goloborodko, Evgeny Steege, Andreas Zavaritskaya, Olga Vetter, Jan M. Grus, Franz H. Patzak, Andreas Wess, Juergen Pfeiffer, Norbert TI Identification of the Muscarinic Acetylcholine Receptor Subtype Mediating Cholinergic Vasodilation in Murine Retinal Arterioles SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CHOROIDAL BLOOD-FLOW; COMMERCIALLY AVAILABLE ANTISERA; KNOCKOUT MICE; NITRIC-OXIDE; ENDOTHELIAL DYSFUNCTION; ISOMETRIC-EXERCISE; INDUCED RELAXATION; VESSELS; PROPRANOLOL; ATROPINE AB PURPOSE. To identify the muscarinic acetylcholine receptor subtype that mediates cholinergic vasodilation in murine retinal arterioles. METHODS. Muscarinic receptor gene expression was determined in murine retinal arterioles using real-time PCR. To assess the functional relevance of muscarinic receptors for mediating vascular responses, retinal vascular preparations from muscarinic receptor-deficient mice were studied in vitro. Changes in luminal arteriole diameter in response to muscarinic and nonmuscarinic vasoactive substances were measured by video microscopy. RESULTS. Only mRNA for the M 3 receptor was detected in retinal arterioles. Thus, M 3 receptor-deficient mice (M3R(-/-)) and respective wild-type controls were used for functional studies. Acetylcholine concentration-dependently dilated retinal arterioles from wild-type mice. In contrast, vasodilation to acetylcholine was almost completely abolished in retinal arterioles from M3R(-/-) mice, whereas responses to the nitric oxide (NO) donor nitroprusside were retained. Carbachol, an acetylcholinesterase-resistant analog of acetylcholine, also evoked dilation in retinal arterioles from wild-type, but not from M3R(-/-), mice. Vasodilation responses from wild-type mice to acetylcholine were negligible after incubation with the non-subtype-selective muscarinic receptor blocker atropine or the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester, and were even reversed to contraction after endothelial damage with 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate. CONCLUSIONS. These findings provide evidence that endothelial M 3 receptors mediate cholinergic vasodilation in murine retinal arterioles via activation of NO synthase. (Invest Ophthalmol Vis Sci. 2011;52:7479-7484) DOI:10.1167/iovs.11-7370 C1 [Gericke, Adrian; Sniatecki, Jan J.; Goloborodko, Evgeny; Vetter, Jan M.; Grus, Franz H.; Pfeiffer, Norbert] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Ophthalmol, D-55131 Mainz, Germany. [Steege, Andreas] Univ Med Ctr Regensburg, Dept Internal Med 2, Regensburg, Germany. [Zavaritskaya, Olga] Univ Heidelberg, Med Fac Mannheim, Cardiovasc Physiol Ctr Biomed & Med Technol Mannh, D-6800 Mannheim, Germany. [Patzak, Andreas] Charite Univ Med Berlin, Inst Vegetat Physiol, Berlin, Germany. [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. RP Gericke, A (reprint author), Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Ophthalmol, Langenbeckstr 1, D-55131 Mainz, Germany. EM adrian.gericke@gmx.net RI Steege, Andreas/F-3885-2010; Sniatecki, Jan/C-4826-2017 OI Sniatecki, Jan/0000-0001-8945-2094 FU Ernst und Berta Grimmke Stiftung [5/08] FX Supported in part by Ernst und Berta Grimmke Stiftung Grant 5/08. NR 43 TC 12 Z9 12 U1 1 U2 5 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2011 VL 52 IS 10 BP 7479 EP 7484 DI 10.1167/iovs.11-7370 PG 6 WC Ophthalmology SC Ophthalmology GA 827YU UT WOS:000295467200058 PM 21873683 ER PT J AU Sobrin, L Green, T Sim, X Jensen, RA Tai, ES Tay, WT Wang, JJ Mitchell, P Sandholm, N Liu, YY Hietala, K Iyengar, SK Brooks, M Buraczynska, M Van Zuydam, N Smith, AV Gudnason, V Doney, ASF Morris, AD Leese, GP Palmer, CNA Swaroop, A Taylor, HA Wilson, JG Penman, A Chen, CJ Groop, PH Saw, SM Aung, T Klein, BE Rotter, JI Siscovick, DS Cotch, MF Klein, R Daly, MJ Wong, TY AF Sobrin, Lucia Green, Todd Sim, Xueling Jensen, Richard A. Tai, E. Shyong Tay, Wan Ting Wang, Jie Jin Mitchell, Paul Sandholm, Niina Liu, Yiyuan Hietala, Kustaa Iyengar, Sudha K. Brooks, Matthew Buraczynska, Monika Van Zuydam, Natalie Smith, Albert V. Gudnason, Vilmundur Doney, Alex S. F. Morris, Andrew D. Leese, Graham P. Palmer, Colin N. A. Swaroop, Anand Taylor, Herman A., Jr. Wilson, James G. Penman, Alan Chen, Ching J. Groop, Per-Henrik Saw, Seang-Mei Aung, Tin Klein, Barbara E. Rotter, Jerome I. Siscovick, David S. Cotch, Mary Frances Klein, Ronald Daly, Mark J. Wong, Tien Y. CA Family Invest Nephropathy Diabet-E Wellcome Trust Case Control Consor TI Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes: The Candidate Gene Association Resource (CARe) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; COMMON VARIANTS; RISK-FACTORS; ERYTHROPOIETIN GENE; LINKAGE ANALYSES; BLOOD-PRESSURE; UNITED-STATES; FTO GENE; COMPLICATIONS AB PURPOSE. To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe). METHODS. Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades >= 14 and >= 30. The chi(2) analyses for each CARe cohort were combined by Cochran-Mantel- Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods. RESULTS. Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging alpha-Liduronidase (IDUA) (P = 2.1 X 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively. CONCLUSIONS. Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts. (Invest Ophthalmol Vis Sci. 2011;52:7593-7602) DOI:10.1167/iovs.11-7510 C1 [Sobrin, Lucia] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Green, Todd; Daly, Mark J.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Green, Todd; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Sim, Xueling] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore. [Tai, E. Shyong; Saw, Seang-Mei] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117548, Singapore. [Aung, Tin; Wong, Tien Y.] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Jensen, Richard A.; Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Tai, E. Shyong] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Tay, Wan Ting; Aung, Tin] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Ctr Vis Res, Sydney, NSW 2006, Australia. [Wang, Jie Jin] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Sandholm, Niina; Groop, Per-Henrik] Univ Helsinki, Dept Med, Div Nephrol, Helsinki, Finland. [Sandholm, Niina; Hietala, Kustaa; Groop, Per-Henrik] Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland. [Liu, Yiyuan; Van Zuydam, Natalie; Palmer, Colin N. A.] Univ Dundee, Inst Biomed Res, Dundee, Scotland. [Hietala, Kustaa] Univ Helsinki, Cent Hosp, Dept Ophthalmol, Helsinki, Finland. [Iyengar, Sudha K.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Brooks, Matthew; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Buraczynska, Monika] Med Univ Lublin, Lab DNA Anal & Mol Diagnost, Dept Nephrol, Lublin, Poland. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Doney, Alex S. F.; Morris, Andrew D.; Leese, Graham P.] Univ Dundee, Ninewells Hosp & Med Sch, Dept Med & Therapeut, Populat Pharmacogenet Grp, Dundee DD1 9SY, Scotland. [Taylor, Herman A., Jr.; Penman, Alan] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Penman, Alan] Univ Mississippi, Med Ctr, Dept Biostat, Jackson, MS 39216 USA. [Chen, Ching J.] Univ Mississippi, Med Ctr, Dept Ophthalmol, Jackson, MS 39216 USA. [Klein, Barbara E.; Klein, Ronald] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. RP Sobrin, L (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM lucia_sobrin@meei.harvard.edu RI Nelson, Robert/B-1470-2012; Palmer, Colin/C-7053-2008; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Blackwell, Jenefer/H-3015-2015; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; Study, GoDARTS/K-9448-2016; OI Swaroop, Anand/0000-0002-1975-1141; Gillman, Matthew/0000-0002-2340-6930; Plomin, Robert/0000-0002-0756-3629; Klein, Ronald/0000-0002-4428-6237; Tai, E Shyong/0000-0003-2929-8966; Palmer, Colin/0000-0002-6415-6560; Wang, Jie Jin/0000-0001-9491-4898; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Sandholm, Niina/0000-0003-4322-6942; Potter, Simon/0000-0003-4208-4102; Cotch, Mary Frances/0000-0002-2046-4350 FU National Eye Institute [K12-EY16335]; Research to Prevent Blindness Career Development Award; Massachusetts Lions Eye Research Fund; Sara Elizabeth O'Brien Trust; Harvard Catalyst/The Harvard Clinical and Translational Science Center; National Institutes of Health [UL1 RR 025758]; Harvard University; affiliated academic health care centers; National Heart, Lung Blood Institute (NHLBI) [N01-HC-65226]; Atherosclerosis Risk in Communities (ARIC) Study,; Cardiovascular Health Study (CHS); Jackson Heart Study (JHS); Multi-ethnic Study of Atherosclerosis (MESA) FX Supported by National Eye Institute Grant K12-EY16335; a Research to Prevent Blindness Career Development Award; the Massachusetts Lions Eye Research Fund; the Sara Elizabeth O'Brien Trust; and Harvard Catalyst/The Harvard Clinical and Translational Science Center, National Institutes of Health Award Grant UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers. The National Heart, Lung Blood Institute (NHLBI) Grant N01-HC-65226 has supported genotyping and has created a genotype-phenotype database with data and samples from nine cohorts as part of Candidate Gene Association Resource (CARe). Please see the Supplementary Material (http://www.iovs.org/lookup/suppl/doi:10.1167/iovs.11-7510/-/DC Supplemental), as well as http://public.nhlbi.nih.gov/Genetics Genomics/home/care.aspx for detailed information about the grants supporting the four cohorts in this study: Atherosclerosis Risk in Communities (ARIC) Study, Cardiovascular Health Study (CHS), Jackson Heart Study (JHS), and Multi-ethnic Study of Atherosclerosis (MESA). Please see the Supplementary Material (http://www.iovs.org/lookup/suppl/doi: 10.1167/iovs.11-7510/-/DC Supplemental) for detailed information about the grants supporting the replication cohorts. NR 69 TC 34 Z9 34 U1 0 U2 9 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2011 VL 52 IS 10 BP 7593 EP 7602 DI 10.1167/iovs.11-7510 PG 10 WC Ophthalmology SC Ophthalmology GA 827YU UT WOS:000295467200072 PM 21873659 ER PT J AU Ying, JF Wang, JB Grishaev, A Yu, P Wang, YX Bax, A AF Ying, Jinfa Wang, Jinbu Grishaev, Alex Yu, Ping Wang, Yun-Xing Bax, Ad TI Measurement of H-1-N-15 and H-1-C-13 residual dipolar couplings in nucleic acids from TROSY intensities SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE ARTSY; BEST; A-form RNA; Quantitative J correlation; TROSY; RDC; RNA; DNA ID CHEMICAL-SHIFT ANISOTROPY; RELAXATION DISPERSION NMR; INVISIBLE PROTEIN STATES; CROSS-CORRELATED RELAXATION; MULTIPLE-QUANTUM NMR; FIELD-DEPENDENCE; BINDING-PROTEIN; PULSE SEQUENCES; SPIN RELAXATION; MAGNETIC-FIELD AB Analogous to the recently introduced ARTSY method for measurement of one-bond H-1-N-15 residual dipolar couplings (RDCs) in large perdeuterated proteins, we introduce methods for measurement of base C-13-H-1 and N-15-H-1 RDCs in protonated nucleic acids. Measurements are based on quantitative analysis of intensities in H-1-N-15 and C-13-H-1 TROSY-HSQC spectra, and are illustrated for a 71-nucleotide adenine riboswitch. Results compare favorably with those of conventional frequency-based measurements in terms of completeness and convenience of use. The ARTSY method derives the size of the coupling from the ratio of intensities observed in two TROSY-HSQC spectra recorded with different dephasing delays, thereby minimizing potential resonance overlap problems. Precision of the RDC measurements is limited by the signal-to-noise ratio, S/N, achievable in the 2D TROSY-HSQC reference spectrum, and is approximately given by 30/(S/N) Hz for N-15-H-1 and 65/(S/N) Hz for C-13-H-1. The signal-to-noise ratio of both H-1-N-15 and H-1-C-13 spectra greatly benefits when water magnetization during the experiments is not perturbed, such that rapid magnetization transfer from bulk water to the nucleic acid, mediated by rapid amino and hydroxyl hydrogen exchange coupled with H-1-H-1 NOE transfer, allows for fast repetition of the experiment. RDCs in the mutated helix 1 of the riboswitch are compatible with nucleotide-specifically modeled, idealized A-form geometry and a static orientation relative to the helix 2/3 pair, which differs by ca 6 degrees relative to the X-ray structure of the native riboswitch. C1 [Ying, Jinfa; Grishaev, Alex; Bax, Ad] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Wang, Jinbu; Yu, Ping; Wang, Yun-Xing] NCI, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 126, Bethesda, MD 20892 USA. EM bax@nih.gov FU NIDDK; NCI, NIH; Office of the Director, NIH FX This work was supported by the Intramural Research Programs of the NIDDK and NCI, NIH, and by the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. NR 59 TC 12 Z9 12 U1 0 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD SEP PY 2011 VL 51 IS 1-2 BP 89 EP 103 DI 10.1007/s10858-011-9544-y PG 15 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 834TX UT WOS:000295988100010 PM 21947918 ER PT J AU Fawzi, NL Fleissner, MR Anthis, NJ Kalai, T Hideg, K Hubbell, WL Clore, GM AF Fawzi, Nicolas L. Fleissner, Mark R. Anthis, Nicholas J. Kalai, Tamas Hideg, Kalman Hubbell, Wayne L. Clore, G. Marius TI A rigid disulfide-linked nitroxide side chain simplifies the quantitative analysis of PRE data SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Paramagnetic relaxation enhancement; Site-directed spin-labeling; Electron paramagnetic resonance ID PARAMAGNETIC RELAXATION ENHANCEMENT; SPIN-LABELED PROTEINS; MOLECULAR-STRUCTURE DETERMINATION; T4 LYSOZYME; CRYSTALLOGRAPHIC CHARACTERIZATION; STRUCTURAL DETERMINANTS; PEPTIDE COMPLEX; BINDING-PROTEIN; AMINO-ACID; XPLOR-NIH AB The measurement of (1)H transverse paramagnetic relaxation enhancement (PRE) has been used in biomolecular systems to determine long-range distance restraints and to visualize sparsely-populated transient states. The intrinsic flexibility of most nitroxide and metal-chelating paramagnetic spin-labels, however, complicates the quantitative interpretation of PREs due to delocalization of the paramagnetic center. Here, we present a novel, disulfide-linked nitroxide spin label, R1p, as an alternative to these flexible labels for PRE studies. When introduced at solvent-exposed alpha-helical positions in two model proteins, calmodulin (CaM) and T4 lysozyme (T4L), EPR measurements show that the R1p side chain exhibits dramatically reduced internal motion compared to the commonly used R1 spin label (generated by reacting cysteine with the spin labeling compound often referred to as MTSL). Further, only a single nitroxide position is necessary to account for the PREs arising from CaM S17R1p, while an ensemble comprising multiple conformations is necessary for those observed for CaM S17R1. Together, these observations suggest that the nitroxide adopts a single, fixed position when R1p is placed at solvent-exposed alpha-helical positions, greatly simplifying the interpretation of PRE data by removing the need to account for the intrinsic flexibility of the spin label. C1 [Fawzi, Nicolas L.; Anthis, Nicholas J.; Clore, G. Marius] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Fleissner, Mark R.; Hubbell, Wayne L.] Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. [Fleissner, Mark R.; Hubbell, Wayne L.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Kalai, Tamas; Hideg, Kalman] Univ Pecs, Inst Organ & Med Chem, H-7624 Pecs, Hungary. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM hubbellw@jsei.ucla.edu; mariusc@mail.nih.gov RI Fawzi, Nicolas/E-2555-2013; Clore, G. Marius/A-3511-2008 OI Fawzi, Nicolas/0000-0001-5483-0577; Clore, G. Marius/0000-0003-3809-1027 FU NIH, NIDDK; Office of the Director of the NIH; NIH [R01EY05216]; Jules Stein Professorship Endowment; Hungarian National Research Funds [OTKA K81123] FX We thank Vincenzo Venditti and Mengli Cai for helpful suggestions, Dusty Baber and Jinfa Ying for assistance with NMR spectrometers, and Evan Brooks and Maria Balog for expert technical assistance. This work was in part supported by funds from the Intramural Program of the NIH, NIDDK and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G. M. C.), NIH grants R01EY05216 (to W. L. H.), and the Jules Stein Professorship Endowment (to W. L. H.). The synthesis of new spin label reagents was supported by Hungarian National Research Funds (OTKA K81123). NR 53 TC 28 Z9 28 U1 2 U2 19 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD SEP PY 2011 VL 51 IS 1-2 BP 105 EP 114 DI 10.1007/s10858-011-9545-x PG 10 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 834TX UT WOS:000295988100011 PM 21947919 ER PT J AU White, AM Hingson, RW Pan, IJ Yi, HY AF White, Aaron M. Hingson, Ralph W. Pan, I-Jen Yi, Hsiao-Ye TI Hospitalizations for Alcohol and Drug Overdoses in Young Adults Ages 18-24 in the United States, 1999-2008: Results From the Nationwide Inpatient Sample SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID FATAL POISONINGS; PROBLEM DRINKING; OPIOID OVERDOSE; DEPENDENCE; CONSUMPTION; ABUSE; MORTALITY; DEATHS; HEALTH; ONSET AB Objective: Recent reports indicate an increase in rates of hospitalizations for drug overdoses in the United States. The role of alcohol in hospitalizations for drug overdoses remains unclear. Excessive consumption of alcohol and drugs is prevalent in young adults ages 18-24. The present study explores rates and costs of inpatient hospital stays for alcohol overdoses, drug overdoses, and their co-occurrence in young adults ages 18-24 and changes in these rates between 1999 and 2008. Method: Data from the Nationwide Inpatient Sample were used to estimate numbers, rates, and costs of inpatient hospital stays stemming from alcohol overdoses (and their subcategories, alcohol poisonings and excessive consumption of alcohol), drug overdoses (and their subcategories, drug poisonings and nondependent abuse of drugs), and their co-occurrence in 18- to 24-year-olds. Results: Hospitalization rates for alcohol overdoses alone increased 25% from 1999 to 2008, reaching 29,412 cases in 2008 at a cost of $266 million. Hospitalization rates for drug overdoses alone increased 55%, totaling 113,907 cases in 2008 at a cost of $737 million. Hospitalization rates for combined alcohol and drug overdoses increased 76%, with 29,202 cases in 2008 at a cost of $198 million. Conclusions: Rates of hospitalizations for alcohol overdoses, drug overdoses, and their combination all increased from 1999 to 2008 among 18- to 24-year-olds. The cost of such hospitalizations now exceeds $1.2 billion annually. The steepest increase occurred among cases of combined alcohol and drug overdoses. Stronger efforts are needed to educate medical practitioners and the public about the risk of overdoses, particularly when alcohol is combined with other drugs. (J. Stud. Alcohol Drugs. 72. 774-786, 2011) C1 [White, Aaron M.; Hingson, Ralph W.; Pan, I-Jen; Yi, Hsiao-Ye] NIAAA, Div Epidemiol & Prevent Res, NIH, Bethesda, MD 20982 USA. RP White, AM (reprint author), NIAAA, Div Epidemiol & Prevent Res, NIH, 5635 Fishers Lane,MSC 9304,Room 2074, Bethesda, MD 20982 USA. EM whitea4@mail.nih.gov NR 49 TC 41 Z9 41 U1 0 U2 3 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD SEP PY 2011 VL 72 IS 5 BP 774 EP 786 PG 13 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 829EX UT WOS:000295562500010 PM 21906505 ER PT J AU Sanders, JL Boudreau, RM Fried, LP Walston, JD Harris, TB Newman, AB AF Sanders, Jason L. Boudreau, Robert M. Fried, Linda P. Walston, Jeremy D. Harris, Tamara B. Newman, Anne B. TI Measurement of Organ Structure and Function Enhances Understanding of the Physiological Basis of Frailty: The Cardiovascular Health Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE frailty; etiology; disease burden ID OLDER-ADULTS; ELDERLY-PEOPLE; WOMENS HEALTH; ASSOCIATION; MORTALITY; DISEASE; INDEX; ATHEROSCLEROSIS; CLASSIFICATION; ACCUMULATION AB OBJECTIVES: To determine whether disease burden is associated with frailty independent of diagnosed chronic disease and whether physiological measurements provide greater understanding of the etiology of frailty. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: Two thousand four hundred thirty-seven participants in the Cardiovascular Health Study, 1992/93 examination (mean age 74.8 +/- 4.8, 43.4% male, 95.8% white). MEASUREMENTS: Disease burden and frailty were tabulated using 10-point scales (0 = healthy, 10 = unhealthy). Disease burden was the sum of measurements characterizing the vasculature, brain, kidneys, lungs, and glucose metabolism. Frailty was assessed using the frailty index reported by Fried. Multivariate linear models were used to determine the association between disease burden (predictor) and frailty (outcome). RESULTS: Unadjusted, 1-point-higher disease burden was associated with a 0.28-point-higher frailty score (P < 001). White matter grade, forced vital capacity, and cystatin-C were particularly strongly and significantly associated with frailty. Disease burden attenuated the association between frailty and age by 29%, and disease burden and age had similar associations with frailty. Disease burden attenuated the association between frailty and fibrinogen, Factor VIII, and C-reactive protein by 32%, 56%, and 83%, respectively. Frailty was associated with diagnosed depression, stroke, cognitive impairment, arthritis, and pulmonary disease but not coronary heart disease, diabetes mellitus, or kidney disease in the presence of a summary of disease burden. In the adjusted model, disease burden remained significantly associated with frailty (beta = 0.11, P < 001). CONCLUSION: Disease burden was independently and significantly associated with frailty. These results emphasize that typically unrecognized physiological changes may contribute significantly to frailty. J Am Geriatr Soc 59: 1581-1588, 2011. C1 [Sanders, Jason L.] Univ Pittsburgh, Sch Med, Med Scientist Training Program, Pittsburgh, PA USA. [Newman, Anne B.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Sanders, Jason L.; Boudreau, Robert M.; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Walston, Jeremy D.] Johns Hopkins Univ, Johns Hopkins Med Inst, Baltimore, MD USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. RP Sanders, JL (reprint author), Bellefield Profess Bldg 4th Floor,130 N Bellefiel, Pittsburgh, PA 15213 USA. EM sanders.jason@medstudent.pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Boudreau, Robert/0000-0003-0162-5187 FU National Heart, Lung, and Blood Institute [R01-AG-023629, 5-P30-AG-024827, N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079, N01-HC-85086, N01 HC-15103, N01 HC-55222, U01 HL080295]; American Geriatrics Society (AGS) FX The research reported in this article was supported by Grants R01-AG-023629 and 5-P30-AG-024827 and by contracts N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079 through N01-HC-85086, N01 HC-15103, N01 HC-55222, and U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contributions from the National Institute of Neurological Disorders and Stroke. A full list of participating CHS investigators and institutions can be found at http://www.chs-nhlbi.org.; Jason L. Sanders was awarded the 2011 Scientist-in-Training Award from the American Geriatrics Society (AGS) for this abstract submission to the 2011 AGS Annual Meeting. NR 38 TC 24 Z9 24 U1 2 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2011 VL 59 IS 9 BP 1581 EP 1588 DI 10.1111/j.1532-5415.2011.03557.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 829WD UT WOS:000295615000002 PM 21883106 ER PT J AU Semba, RD Cappola, AR Sun, K Bandinelli, S Dalal, M Crasto, C Guralnik, JM Ferrucci, L AF Semba, Richard D. Cappola, Anne R. Sun, Kai Bandinelli, Stefania Dalal, Mansi Crasto, Candace Guralnik, Jack M. Ferrucci, Luigi TI Plasma Klotho and Cardiovascular Disease in Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; atherosclerosis; cardiovascular disease; C-reactive protein; klotho ID CORONARY-ARTERY-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; GENETIC RISK-FACTOR; ENDOTHELIAL DYSFUNCTION; FUNCTIONAL VARIANT; PROTEIN; MOUSE; ASSOCIATION; EXPRESSION; CHANNELS AB OBJECTIVES: To determine whether plasma klotho, a recently discovered hormone that has been implicated in atherosclerosis, is related to prevalent cardiovascular disease (CVD) in adults. DESIGN: Cross-sectional. SETTING: Population-based sample of adults residing in Tuscany, Italy. PARTICIPANTS: One thousand twenty-three men and women aged 24 to 102 participating in the Invecchiare in Chianti (InCHIANTI) study. MEASUREMENTS: Anthropometric measures, plasma klotho, fasting plasma total, high-density lipoprotein cholesterol (HDL-C), triglycerides, glucose, creatinine, C-reactive protein (CRP). Clinical measures: medical assessment, diabetes mellitus, hypertension, coronary heart disease, heart failure, stroke, peripheral artery disease, cancer, chronic kidney disease. Logistic regression models were used to examine the relationship between plasma klotho and prevalent CVD. RESULTS: Of 1,023 participants, 259 (25.3%) had CVD. Median (25th, 75th percentile) plasma klotho concentrations were 676 pg/mL (530, 819 pg/mL). Plasma klotho was correlated with age (correlation coefficient (r) = -0.14, P<.001), HDL-C (r = 0.11, P<.001), and CRP (r = -0.10, P<.001) but not systolic blood pressure, fasting plasma glucose, or renal function. Plasma klotho age-adjusted geometric means were 626 pg/mL (95% confidence interval (CI) = 601-658 pg/mL) in participants with CVD and 671 pg/mL (95% CI = 652-692 pg/mL) in those without CVD (P = .001). Adjusting for traditional cardiovascular risk factors (age, sex, smoking, total cholesterol, HDL-C, systolic blood pressure, and diabetes mellitus), log plasma klotho was associated with prevalent CVD (odds ratio per 1 standard deviation increase = 0.85, 95% CI = 0.72-0.99). CONCLUSION: In community-dwelling adults, higher plasma klotho concentrations are independently associated with a lower likelihood of having CVD. J Am Geriatr Soc 59: 1596-1601, 2011. C1 [Semba, Richard D.; Sun, Kai; Dalal, Mansi; Crasto, Candace] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Cappola, Anne R.] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Bandinelli, Stefania] Azienda Sanit, Florence, Italy. [Guralnik, Jack M.] NIA, Epidemiol & Demog Sect, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Bethesda, MD 20892 USA. RP Semba, RD (reprint author), Smith Bldg,M015,400 N Broadway, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu FU National Institute on Aging (NIA) [R01 HL094507, R01 AG027012, 263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]; Italian Ministry of Health [ICS110.1/RF97.71]; NIA, National Institutes of Health (NIH), Baltimore, Maryland FX This work was supported by National Institute on Aging (NIA) Grant R01 HL094507, R01 AG027012, the Italian Ministry of Health (ICS110.1/RF97.71), NIA Contracts 263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, and N01-AG-5-0002, the Intramural Research Program of NIA, National Institutes of Health (NIH), Baltimore, Maryland. NR 43 TC 56 Z9 63 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2011 VL 59 IS 9 BP 1596 EP 1601 DI 10.1111/j.1532-5415.2011.03558.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 829WD UT WOS:000295615000004 PM 21883107 ER PT J AU Gamaldo, AA Ferrucci, L Rifkind, JM Zonderman, AB AF Gamaldo, Alyssa A. Ferrucci, Luigi Rifkind, Joseph M. Zonderman, Alan B. TI AGE-RELATED CHANGES IN MEAN CORPUSCULAR VOLUME IN ADULT WHITES AND AFRICAN AMERICANS SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Letter ID MEMORY PERFORMANCE; ERYTHROCYTES; ANEMIA; YOUNG C1 [Gamaldo, Alyssa A.; Ferrucci, Luigi; Rifkind, Joseph M.; Zonderman, Alan B.] NIA, Baltimore, MD 21224 USA. RP Gamaldo, AA (reprint author), NIA, Baltimore, MD 21224 USA. OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS [ZIA AG000015-56] NR 10 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2011 VL 59 IS 9 BP 1763 EP 1764 DI 10.1111/j.1532-5415.2011.03583.x PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 829WD UT WOS:000295615000036 PM 22136544 ER PT J AU Sullivan, R Peppercorn, J Sikora, K Zalcberg, J Meropol, NJ Amir, E Khayat, D Boyle, P Autier, P Tannock, IF Fojo, T Siderov, J Williamson, S Camporesi, S McVie, JG Purushotham, AD Naredi, P Eggermont, A Brennan, MF Steinberg, ML De Ridder, M McCloskey, SA Verellen, D Roberts, T Storme, G Hicks, RJ Ell, PJ Hirsch, BR Carbone, DP Schulman, KA Catchpole, P Taylor, D Geissler, J Brinker, NG Meltzer, D Kerr, D Aapro, M AF Sullivan, Richard Peppercorn, Jeffrey Sikora, Karol Zalcberg, John Meropol, Neal J. Amir, Eitan Khayat, David Boyle, Peter Autier, Philippe Tannock, Ian F. Fojo, Tito Siderov, Jim Williamson, Steve Camporesi, Silvia McVie, J. Gordon Purushotham, Arnie D. Naredi, Peter Eggermont, Alexander Brennan, Murray F. Steinberg, Michael L. De Ridder, Mark McCloskey, Susan A. Verellen, Dirk Roberts, Terence Storme, Guy Hicks, Rodney J. Ell, Peter J. Hirsch, Bradford R. Carbone, David P. Schulman, Kevin A. Catchpole, Paul Taylor, David Geissler, Jan Brinker, Nancy G. Meltzer, David Kerr, David Aapro, Matti TI Delivering affordable cancer care in high-income countries SO LANCET ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; METASTATIC COLORECTAL-CANCER; PHASE-III TRIAL; POSITRON-EMISSION-TOMOGRAPHY; COST-EFFECTIVENESS ANALYSIS; POSITIVE BREAST-CANCER; HEALTH-TECHNOLOGY-ASSESSMENT; RANDOMIZED CONTROLLED-TRIAL; ERLOTINIB PLUS GEMCITABINE; ADVANCED PANCREATIC-CANCER AB The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and disability (not including direct medical costs) was estimated to be US$895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field-eg, the huge development costs for cancer medicines-there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies. C1 [Sullivan, Richard] Kings Coll London, Kings Hlth Partners Integrated Canc Ctr, London SE1 9RT, England. [Peppercorn, Jeffrey] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. [Sikora, Karol] CancerPartnersUK, London, England. [Zalcberg, John] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Meropol, Neal J.] Case Western Reserve Univ, Univ Hosp Seidman Canc Ctr, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Amir, Eitan; Tannock, Ian F.] Princess Margaret Hosp, Div Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. [Amir, Eitan; Tannock, Ian F.] Univ Toronto, Toronto, ON, Canada. [Khayat, David] Hop La Pitie Salpetriere, Paris, France. [Boyle, Peter; Autier, Philippe] Int Prevent Res Inst, Lyon, France. [Fojo, Tito] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Siderov, Jim] Austin Hlth, Canc Serv, Heidelberg, Vic, Australia. [Camporesi, Silvia] Kings Coll London, Ctr Humanities & Hlth, London WC2R 2LS, England. [McVie, J. Gordon] European Inst Oncol, Milan, Italy. [Purushotham, Arnie D.] Kings Hlth Partners Integrated Canc Ctr, London, England. [Naredi, Peter] Umea Univ, Dept Surg, Umea, Sweden. [Eggermont, Alexander] Inst Gustave Roussy, Paris, France. [Brennan, Murray F.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Steinberg, Michael L.; McCloskey, Susan A.; Roberts, Terence] Univ Calif Los Angeles, Dept Radiat Oncol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [De Ridder, Mark; Verellen, Dirk; Storme, Guy] Vrije Univ Brussel, Dept Radiotherapy, Brussels, Belgium. [Hicks, Rodney J.] Peter MacCallum Canc Ctr, Mol Imaging & Targeted Therapeut Lab, Melbourne, Vic, Australia. [Ell, Peter J.] Univ Coll London Hosp, Inst Nucl Med, London, England. [Hirsch, Bradford R.; Schulman, Kevin A.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Hirsch, Bradford R.; Schulman, Kevin A.] Duke Univ, Sch Med, Dept Med, Durham, NC USA. [Carbone, David P.] Vanderbilt Univ, Med Ctr, Div Hematol & Med Oncol, Nashville, TN USA. [Catchpole, Paul] Assoc British Pharmaceut Ind, London SW1A 2DY, England. [Taylor, David] Univ London, Sch Pharm, London, England. [Geissler, Jan] Int Chron Myeloid Leukemia Fdn, European Canc Patient Coalit & Chron Myeloid Leuk, Munich, Germany. [Brinker, Nancy G.] Susan G Komen Cure, Dallas, TX USA. [Meltzer, David] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Meltzer, David] Univ Chicago, Harris Sch, Chicago, IL 60637 USA. [Kerr, David] Univ Oxford, Dept Clin Pharmacol, Oxford, England. [Aapro, Matti] Clin Genolier, Genolier, Switzerland. RP Sullivan, R (reprint author), Kings Coll London, Kings Hlth Partners Integrated Canc Ctr, Guys Hosp Campus, London SE1 9RT, England. EM richard.sullivan@kcl.ac.uk RI De Ridder, Mark/F-4794-2013; Meltzer, David/C-2926-2009; Autier, Philippe/A-4402-2014; Boyle, Peter/A-4380-2014; OI De Ridder, Mark/0000-0003-4433-8807; Meltzer, David/0000-0003-2790-7393; Autier, Philippe/0000-0003-1538-5321; Boyle, Peter/0000-0001-6251-0610; Naredi, Peter/0000-0002-5652-0422; Sullivan, Richard/0000-0002-6435-1825 FU Pfizer; Novartis; Celgene; Amgen; Sandoz; Helsinn; Johnson Johnson; Roche; Merck; Pierre Fabre; Hospira; Aveo Pharmaceuticals; Bayer; Genentech; Heathwell Foundation; MerckSerono; Sanofi; AstraZeneca; Genomic Health; Saladax; Sanofi-Aventis; Veridex; Actelion Pharmaceuticals; Allergan; Alnylam Pharmaceuticals; Amylin Pharmaceuticals; Astellas Pharma; Bristol-Myers Squibb; Inspire Pharmaceuticals; Kureha Corporation; Medtronic; Merck Co; Nabi Biopharmaceuticals; NovaCardia; OSI Eyetech; Sanofi-Aventis US; Scios; Tengion; Theravance; Thomson Healthcare; Vertex Pharmaceuticals; Advanced Health Media; Certified Medical Representatives Institute; Commonwealth Fund; EnablEd; Forest Laboratories; GlaxoSmithKline; LifeMasters Supported SelfCare; McKinsey Company; Medical Decisions Network Medtronic; National Pharmaceutical Council; Novo Nordisk; Orexigen Therapeutics; Quintiles Transnational Corp; Social and Scientific Systems; Wallen and Associates; WebMD; NICE; Department of Health; Alliance Boots; Pharmaceutical Research and Manufacturers of America; Conquer Cancer Foundation; Greenwall Foundation for Bioethics; Chair's Fund; UCLA Department of Radiation Oncology; Herculesstichting and Fonds Wetenschappelijk Onderzoek-Vlaanderen; UK Department of Health NIHR Biomedical Research Centre; Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre FX RS has received research funding from Pfizer and Novartis, and has received payment for lectures by Celgene. MA has received consultancy and honoraria fees from Amgen, Sandoz, Helsinn, Johnson & Johnson, Norvartis, Roche, Merck, Pierre Fabre, Hospira and Pfizer, and honoraria from Baxter. JP has received consultancy fees from Aveo Pharmaceuticals, Bayer, Celgene, Genentech, Novartis, and Heathwell Foundation. He has received honoraria from Genentech, and Novartis and research support from Novartis. JZ has acted as a consultant for Amgen, ARIAD, Novartis, Pfizer, Roche, Sanofi-Aventis, Abraxis, Abbott, Patrys, MSD, Imclone, Bayer, and Abbott and has received research funding from Amgen, MerckSerono, Novartis, Pfizer, Roche, and Sanofi. NB is employed by Susan G Komen for the Cure. NJM has received consultancy fees from AstraZeneca, Genomic Health, Saladax, Sanofi-Aventis, Helsinn, Pfizer, Veridex, Genentech, and Amgen and honoraria from Biogen. KAS has received research support from Actelion Pharmaceuticals, Allergan, Alnylam Pharmaceuticals, Amgen, Amylin Pharmaceuticals, Astellas Pharma, Bristol-Myers Squibb, Inspire Pharmaceuticals, Johnson & Johnson, Kureha Corporation, Medtronic, Merck & Co, Nabi Biopharmaceuticals, NovaCardia, Novartis, OSI Eyetech, Sanofi-Aventis US, Scios, Tengion, Theravance, Thomson Healthcare, and Vertex Pharmaceuticals. He has received consulting fees from Advanced Health Media, the Certified Medical Representatives Institute, the Commonwealth Fund, EnablEd, Forest Laboratories, GlaxoSmithKline, Johnson & Johnson, LifeMasters Supported SelfCare, McKinsey & Company, Medical Decisions Network Medtronic, Merck & Co, National Pharmaceutical Council, Novartis, Novo Nordisk, Orexigen Therapeutics, Quintiles Transnational Corp, Social and Scientific Systems, Wallen and Associates, and WebMD. He holds equity in Alnylam Pharmaceuticals, Cancer Consultants Inc, Faculty Connection, General Electric Company, the Manufacturers Life Insurance Company, PepsiCo Inc, the Physician Education Leadership Institute, Procter & Gamble, and Tellus. PC is employed by the ABPI, which is a trade association for the UK pharmaceutical industry, and until March, 2010, was employed by Roche UK. DT has received research funding from a range of public and private bodies, including NICE, the Department of Health, Alliance Boots, Pfizer, and the Pharmaceutical Research and Manufacturers of America. JG has received consultancy fees from Bristol-Myers Squibb, Novartis and Pfizer. SW has received honoraria from Amgen, ISIS Pharma, and payment for educational presentation from Roche. DKh has received consultancy fees from Roche, AstraZeneca, and Sanofi-Aventis. All other authors declared that they have no conflicts of interest.; JP is supported by the Conquer Cancer Foundation and the Greenwall Foundation for Bioethics. Research for Part 5 was funded by the Chair's Fund, UCLA Department of Radiation Oncology and by the Herculesstichting and Fonds Wetenschappelijk Onderzoek-Vlaanderen. PJE received funding from the UK Department of Health NIHR Biomedical Research Centre's funding scheme. JG and NGB thank Diana Rowden, Matthew Moore, Chandini Portteus, and Elizabeth Thompson from Susan G Komen for the Cure for support in the preparation of Part 9. ADP is supported by Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. NR 311 TC 271 Z9 276 U1 8 U2 67 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD SEP-OCT PY 2011 VL 12 IS 10 BP 933 EP 980 PG 48 WC Oncology SC Oncology GA 832FK UT WOS:000295787900008 PM 21958503 ER PT J AU Haubenberger, D Kalowitz, D Nahab, FB Toro, C Ippolito, D Luckenbaugh, DA Wittevrongel, L Hallett, M AF Haubenberger, Dietrich Kalowitz, Daniel Nahab, Fatta B. Toro, Camilo Ippolito, Dominic Luckenbaugh, David A. Wittevrongel, Loretta Hallett, Mark TI Validation of Digital Spiral Analysis as Outcome Parameter for Clinical Trials in Essential Tremor SO MOVEMENT DISORDERS LA English DT Article DE essential tremor; spirography; spiral analysis; digitizing tablet; ethanol ID DIGITIZING TABLET; PREVALENCE; 1-OCTANOL; AMPLITUDE; DISEASE AB Essential tremor, one of the most prevalent movement disorders, is characterized by kinetic and postural tremor affecting activities of daily living. Spiral drawing is commonly used to visually rate tremor intensity, as part of the routine clinical assessment of tremor and as a tool in clinical trials. We present a strategy to quantify tremor severity from spirals drawn on a digitizing tablet. We validate our method against a well-established visual spiral rating method and compare both methods on their capacity to capture a therapeutic effect, as defined by the change in clinical essential tremor rating scale after an ethanol challenge. Fifty-four Archimedes spirals were drawn using a digitizing tablet by nine ethanol-responsive patients with essential tremor before and at five consecutive time points after the administration of ethanol in a standardized treatment intervention. Quantitative spiral tremor severity was estimated from the velocity tremor peak amplitude after numerical derivation and Fourier transformation of pen-tip positions. In randomly ordered sets, spirals were scored by seven trained raters, using Bain and Findley's 0 to 10 rating scale. Computerized scores correlated with visual ratings (P < 0.0001). The correlation was significant at each time point before and after ethanol (P < 0.005). Quantitative ratings provided better sensitivity than visual rating to capture the effects of an ethanol challenge (P < 0.05). Using a standardized treatment approach, we were able to demonstrate that spirography time-series analysis is a valid, reliable method to document tremor intensity and a more sensitive measure for small effects than currently available visual spiral rating methods. (C) 2011 Movement Disorder Society C1 [Haubenberger, Dietrich; Wittevrongel, Loretta; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Haubenberger, Dietrich] Med Univ Vienna, Dept Neurol, Vienna, Austria. [Kalowitz, Daniel] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Nahab, Fatta B.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Toro, Camilo] NHGRI, Undiagnosed Dis Program, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Ippolito, Dominic] Duke Univ, Durham, NC USA. [Luckenbaugh, David A.] NIMH, NIH, Bethesda, MD 20892 USA. RP Haubenberger, D (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, 10 Ctr Dr MSC 1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. EM haubenbergerd@ninds.nih.gov FU NINDS; Austrian Science Fund, FWF [J2783-B09]; Ariston Pharmaceuticals FX This research was conducted through funding from the NINDS Intramural Research Program, the Austrian Science Fund, FWF (Erwin Schrodinger Fellowship, project no.: J2783-B09; to D. W.), and Ariston Pharmaceuticals (to L.W.). NR 23 TC 25 Z9 25 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2011 VL 26 IS 11 BP 2073 EP 2080 DI 10.1002/mds.23808 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 827VF UT WOS:000295456300019 PM 21714004 ER PT J AU Shamim, EA Chu, J Scheider, LH Savitt, J Jinnah, HA Hallett, M AF Shamim, Ejaz A. Chu, Jason Scheider, Linda H. Savitt, Joseph Jinnah, H. A. Hallett, Mark TI Extreme Task Specificity in Writer's Cramp SO MOVEMENT DISORDERS LA English DT Article DE dystonia; movement disorders; clinical neurology ID FOCAL DYSTONIA AB Background: Focal hand dystonia may be task specific, as is the case with writer's cramp. In early stages, task specificity can be so specific that it may be mistaken for a psychogenic movement disorder. Methods: We describe 4 patients who showed extreme task specificity in writer's cramp. They initially only had problems writing either a single letter or number. Although they were largely thought to be psychogenic, they progressed to typical writer's cramp. Conclusions: Early recognition of this condition may provide an opportunity for early initiation of treatment. (C) 2011 Movement Disorder Society C1 [Shamim, Ejaz A.] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Shamim, Ejaz A.] Kaiser Permanente Mid Atlantic Permanente Med Grp, Dept Neurol, Suitland, MD USA. [Chu, Jason] Emory Univ, Sch Med, Atlanta, GA USA. [Scheider, Linda H.] Virginia Commonwealth Univ, Sch Med, Richmond, VA USA. [Savitt, Joseph] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Jinnah, H. A.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. RP Shamim, EA (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, MSC 1428,10 Ctr Dr,Room 7D37, Bethesda, MD 20892 USA. EM shamime@mail.nih.gov FU National Institutes of Health [NS067501] FX This endeavor was supported, in part, by the Intramural Program of the National Institutes of Health or NS067501. NR 16 TC 8 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2011 VL 26 IS 11 BP 2107 EP 2109 DI 10.1002/mds.23827 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 827VF UT WOS:000295456300024 PM 21714006 ER PT J AU Gwinn, K Devine, MJ Jin, LW Johnson, J Bird, T Muenter, M Waters, C Adler, CH Caselli, R Houlden, H Lopez, G Singleton, A Hardy, J Singleton, A AF Gwinn, Katrina Devine, Michael J. Jin, Lee-Way Johnson, Janel Bird, Thomas Muenter, Manfred Waters, Cheryl Adler, Charles H. Caselli, Richard Houlden, Henry Lopez, Grisel Singleton, Amanda Hardy, John Singleton, Andrew TI Clinical Features, with Video Documentation, of the Original Familial Lewy Body Parkinsonism Caused By alpha-Synuclein Triplication (Iowa Kindred) SO MOVEMENT DISORDERS LA English DT Letter ID CHROMOSOME 4P; DEMENTIA; DISEASE C1 [Devine, Michael J.; Houlden, Henry; Hardy, John] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Gwinn, Katrina; Johnson, Janel; Singleton, Amanda] NINDS, Bethesda, MD 20892 USA. [Jin, Lee-Way; Bird, Thomas] Univ Washington, Seattle, WA 98195 USA. [Muenter, Manfred; Adler, Charles H.; Caselli, Richard] Mayo Clin, Scottsdale, AZ USA. [Waters, Cheryl] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Lopez, Grisel] NHGRI, Bethesda, MD 20892 USA. [Singleton, Andrew] NIA, Bethesda, MD 20892 USA. RP Devine, MJ (reprint author), UCL Inst Neurol, Dept Mol Neurosci, London, England. EM m.devine@ion.ucl.ac.uk RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Houlden, Henry/C-1532-2008 OI Houlden, Henry/0000-0002-2866-7777 FU Intramural NIH HHS [ZIA AG000958-08]; Medical Research Council [G108/638, G0701075, G0800437, G0802760, G1001253]; Parkinson's UK [G-0907] NR 6 TC 17 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2011 VL 26 IS 11 BP 2134 EP 2136 DI 10.1002/mds.23776 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 827VF UT WOS:000295456300032 PM 21656851 ER PT J AU Hasler, W May, KP Pasricha, PJ Parkman, H Abell, T Koch, K Snape, W Mccallum, R Nguyen, L Farrugia, G Lee, L Unalp, A Tonascia, J Hamilton, F AF Hasler, W. May, K. P. Pasricha, P. J. Parkman, H. Abell, T. Koch, K. Snape, W. Mccallum, R. Nguyen, L. Farrugia, G. Lee, L. Unalp, A. Tonascia, J. Hamilton, F. TI Changes in depression and anxiety are associated with corresponding changes in patient-rated gastroparesis symptom severity and quality of life on 48 week follow-up SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [Hasler, W.; May, K. P.; Pasricha, P. J.; Parkman, H.; Abell, T.; Koch, K.; Snape, W.; Mccallum, R.; Nguyen, L.; Farrugia, G.; Lee, L.; Unalp, A.; Tonascia, J.; Hamilton, F.] NIDDK Gastroparesis Consortium, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD SEP PY 2011 VL 23 SU 1 SI SI MA 128 BP 37 EP 37 PG 1 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 822NL UT WOS:000295055100128 ER PT J AU Parkman, HP Yates, K Mccallum, RW Pasricha, PJ Abell, TL Snape, WJ Nyugen, LA Hasler, WL Koch, K Farrugia, G Lee, LA Unalp-Arida, A Tonascia, J Hamilton, FA AF Parkman, H. P. Yates, K. Mccallum, R. W. Pasricha, P. J. Abell, T. L. Snape, W. J. Nyugen, L. A. Hasler, W. L. Koch, K. Farrugia, G. Lee, L. A. Unalp-Arida, A. Tonascia, J. Hamilton, F. A. TI Influence of cholecystectomy on clinical presentations of gastroparesis SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [Parkman, H. P.; Yates, K.; Mccallum, R. W.; Pasricha, P. J.; Abell, T. L.; Snape, W. J.; Nyugen, L. A.; Hasler, W. L.; Koch, K.; Farrugia, G.; Lee, L. A.; Unalp-Arida, A.; Tonascia, J.; Hamilton, F. A.] NIDDK Gastroparesis Clin Res Consortium GpCRC, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD SEP PY 2011 VL 23 SU 1 SI SI MA 136 BP 39 EP 40 PG 2 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 822NL UT WOS:000295055100136 ER PT J AU Sun, R Notari, L Vanuytsel, T Stiltz, JA Wynn, T Urban, JF Zhao, A Shea-Donohue, T AF Sun, R. Notari, L. Vanuytsel, T. Stiltz, J. A. Wynn, T. Urban, J. F. Zhao, A. Shea-Donohue, T. TI Rethinking the role of claudin-2 in IL-13-mediated changes in intestinal permeability SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [Sun, R.; Notari, L.; Vanuytsel, T.; Stiltz, J. A.; Zhao, A.; Shea-Donohue, T.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Sun, R.; Notari, L.; Vanuytsel, T.; Stiltz, J. A.; Zhao, A.; Shea-Donohue, T.] Univ Maryland, Sch Med, MBRC, Baltimore, MD 21201 USA. [Wynn, T.] NIH, Bethesda, MD 20892 USA. [Urban, J. F.] USDA, DGIL, BHNRC, Beltsville, MD 20705 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD SEP PY 2011 VL 23 SU 1 SI SI MA 152 BP 43 EP 44 PG 2 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 822NL UT WOS:000295055100152 ER PT J AU Seo, DW Saxinger, WC Guedez, L Cantelmo, AR Albini, A Stetler-Stevenson, WG AF Seo, Dong-Wan Saxinger, W. Carl Guedez, Liliana Cantelmo, Anna Rita Albini, Adriana Stetler-Stevenson, William G. TI An integrin-binding N-terminal peptide region of TIMP-2 retains potent angio-inhibitory and anti-tumorigenic activity in vivo SO PEPTIDES LA English DT Article DE Angiogenesis; Angiogenesis inhibitors; Tissue inhibitor of metalloproteinases-2 (TIMP-2); Peptide inhibitors; Kaposi's sarcoma ID HUMAN TISSUE INHIBITOR; METALLOPROTEINASES-2 TIMP-2; GROWTH-FACTOR; ANGIOGENESIS; MECHANISM; RECEPTOR; NETRINS; PROTEIN; DOMAIN; DIFFERENTIATION AB Tissue inhibitor of metalloproteinases-2 (TIMP-2) inhibits angiogenesis by several mechanisms involving either MMP inhibition or direct endothelial cell binding. The primary aim of this study was to identify the TIMP-2 region involved in binding to the previously identified receptor integrin alpha 3 beta 1, and to determine whether synthetic peptides derived from this region retained angio-inhibitory and tumor suppressor activity. We demonstrated that the N-terminal domain of TIMP-2 (N-TIMP-2) binds to alpha 3 beta 1 and inhibits vascular endothelial growth factor-stimulated endothelial cell growth in vitro, suggesting that both the alpha 3 beta 1-binding domain and the growth suppressor activity of TIMP-2 localize to the N-terminal domain. Using a peptide array approach we identify a 24 amino acid region of TIMP-2 primary sequence, consisting of residues Ile43-Ala66, which shows alpha 3 beta 1-binding activity. Subsequently we demonstrate that synthetic peptides from this region compete for TIMP-2 binding to alpha 3 beta 1 and suppress endothelial growth in vitro. We define a minimal peptide sequence (peptide 8-9) that possesses both angio-inhibitory and, using a murine xenograft model of Kaposi's sarcoma, anti-tumorigenic activity in vivo. Thus, both the alpha 3 beta 1-binding and the angio-inhibitory activities co-localize to a solvent exposed, flexible region in the TIMP-2 primary sequence that is unique in amino acid sequence compared with other members of the TIMP family. Furthermore, comparison of the TIMP-2 and TIMP-1 protein 3-D structures in this region also identified unique structural differences. Our findings demonstrate that the integrin binding, tumor growth suppressor and in vivo angio-inhibitory activities of TIMP-2 are intimately associated within a unique sequence/structural loop (B-C loop). Published by Elsevier Inc. C1 [Seo, Dong-Wan; Guedez, Liliana; Stetler-Stevenson, William G.] NCI, Radiat Oncol Branch, Adv Technol Ctr, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Saxinger, W. Carl] Frederick Canc Res Facil, Basic Res Lab, Frederick, MD 21702 USA. [Cantelmo, Anna Rita; Albini, Adriana] IRCCS Multimedia, Resp Ric Oncol, Milan, Italy. RP Stetler-Stevenson, WG (reprint author), Kangwon Natl Univ, Dept Mol Biosci, Inst Biosci & Biotechnol, Coll Biomed Sci, Chunchon 200701, South Korea. EM sstevenw@mail.nih.gov RI Stetler-Stevenson, William/H-6956-2012; Guedez, Liliana/H-4951-2012; OI Stetler-Stevenson, William/0000-0002-5500-5808; Seo, Dong-Wan/0000-0003-4971-834X FU National Cancer Institute, Center for Cancer Research [Z01SC009179]; National Research Foundation of Korea [2009-0065896] FX This work was supported by intramural research funds from the National Cancer Institute, Center for Cancer Research Project # Z01SC009179 and by the National Research Foundation of Korea Grant # 2009-0065896. NR 36 TC 16 Z9 16 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD SEP PY 2011 VL 32 IS 9 BP 1840 EP 1848 DI 10.1016/j.peptides.2011.08.010 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 831YQ UT WOS:000295767400009 PM 21871510 ER PT J AU Butterworth, AS Braund, PS Farrall, M Hardwick, RJ Saleheen, D Peden, JF Soranzo, N Chambers, JC Sivapalaratnam, S Kleber, ME Keating, B Qasim, A Klopp, N Erdmann, J Assimes, TL Ball, SG Balmforth, AJ Barnes, TA Basart, H Baumert, J Bezzina, CR Boerwinkle, E Boehm, BO Brocheton, J Bugert, P Cambien, F Clarke, R Codd, V Collins, R Couper, D Cupples, LA de Jong, JS Diemert, P Ejebe, K Elbers, CC Elliott, P Fornage, M Franzosi, MG Frossard, P Garner, S Goel, A Goodall, AH Hengstenberg, C Hunt, SE Kastelein, JJP Klungel, OH Kluter, H Koch, K Konig, IR Kooner, AS Laaksonen, R Lathrop, M Li, MY Liu, K McPherson, R Musameh, MD Musani, S Nelson, CP O'Donnell, CJ Ongen, H Papanicolaou, G Peters, A Peters, BJM Potter, S Psaty, BM Qu, LM Rader, DJ Rasheed, A Rice, C Scott, J Seedorf, U Sehmi, JS Sotoodehnia, N Stark, K Stephens, J van der Schoot, CE van der Schouw, YT Thorsteinsdottir, U Tomaszewski, M van der Harst, P Vasan, RS Wilde, AAM Willenborg, C Winkelmann, BR Zaidi, M Zhang, WH Ziegler, A de Bakker, PIW Koenig, W Marz, W Trip, MD Reilly, MP Kathiresan, S Schunkert, H Hamsten, A Hall, AS Kooner, JS Thompson, SG Thompson, JR Deloukas, P Ouwehand, WH Watkins, H Danesh, J Samani, NJ AF Butterworth, Adam S. Braund, Peter S. Farrall, Martin Hardwick, Robert J. Saleheen, Danish Peden, John F. Soranzo, Nicole Chambers, John C. Sivapalaratnam, Suthesh Kleber, Marcus E. Keating, Brendan Qasim, Atif Klopp, Norman Erdmann, Jeanette Assimes, Themistocles L. Ball, Stephen G. Balmforth, Anthony J. Barnes, Timothy A. Basart, Hanneke Baumert, Jens Bezzina, Connie R. Boerwinkle, Eric Boehm, Bernhard O. Brocheton, Jessy Bugert, Peter Cambien, Francois Clarke, Robert Codd, Veryan Collins, Rory Couper, David Cupples, L. Adrienne de Jong, Jonas S. Diemert, Patrick Ejebe, Kenechi Elbers, Clara C. Elliott, Paul Fornage, Myriam Franzosi, Maria-Grazia Frossard, Philippe Garner, Stephen Goel, Anuj Goodall, Alison H. Hengstenberg, Christian Hunt, Sarah E. Kastelein, John J. P. Klungel, Olaf H. Klueter, Harald Koch, Kerstin Koenig, Inke R. Kooner, Angad S. Laaksonen, Reijo Lathrop, Mark Li, Mingyao Liu, Kiang McPherson, Ruth Musameh, Muntaser D. Musani, Solomon Nelson, Christopher P. O'Donnell, Christopher J. Ongen, Halit Papanicolaou, George Peters, Annette Peters, Bas J. M. Potter, Simon Psaty, Bruce M. Qu, Liming Rader, Daniel J. Rasheed, Asif Rice, Catherine Scott, James Seedorf, Udo Sehmi, Joban S. Sotoodehnia, Nona Stark, Klaus Stephens, Jonathan van der Schoot, C. Ellen van der Schouw, Yvonne T. Thorsteinsdottir, Unnur Tomaszewski, Maciej van der Harst, Pim Vasan, Ramachandran S. Wilde, Arthur A. M. Willenborg, Christina Winkelmann, Bernhard R. Zaidi, Moazzam Zhang, Weihua Ziegler, Andreas de Bakker, Paul I. W. Koenig, Wolfgang Maerz, Winfried Trip, Mieke D. Reilly, Muredach P. Kathiresan, Sekar Schunkert, Heribert Hamsten, Anders Hall, Alistair S. Kooner, Jaspal S. Thompson, Simon G. Thompson, John R. Deloukas, Panos Ouwehand, Willem H. Watkins, Hugh Danesh, John Samani, Nilesh J. CA IBC 50K CAD Consortium TI Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MYOCARDIAL-INFARCTION; SUSCEPTIBILITY LOCI; RISK; ATHEROSCLEROSIS; METAANALYSIS; LIPOPROTEIN AB Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in similar to 2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5x10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other similar to 4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes. C1 [Butterworth, Adam S.; Saleheen, Danish; Thompson, Simon G.; Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Braund, Peter S.; Hardwick, Robert J.; Barnes, Timothy A.; Codd, Veryan; Goodall, Alison H.; Musameh, Muntaser D.; Nelson, Christopher P.; Tomaszewski, Maciej; van der Harst, Pim; Samani, Nilesh J.] Univ Leicester, Dept Cardiovas Sci, Glenfield Gen Hosp, Leicester, Leics, England. [Braund, Peter S.; Hardwick, Robert J.; Barnes, Timothy A.; Codd, Veryan; Goodall, Alison H.; Musameh, Muntaser D.; Nelson, Christopher P.; Tomaszewski, Maciej; van der Harst, Pim; Samani, Nilesh J.] Glenfield Gen Hosp, Leicester Natl Inst Hlth Res Biomed Res Unit Card, Leicester LE3 9QP, Leics, England. [Farrall, Martin; Peden, John F.; Goel, Anuj; Ongen, Halit; Watkins, Hugh] Univ Oxford, Dept Cardiovasc Med, Oxford, England. [Farrall, Martin; Peden, John F.; Goel, Anuj; Ongen, Halit; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Hardwick, Robert J.] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. [Saleheen, Danish; Frossard, Philippe; Rasheed, Asif; Zaidi, Moazzam] Ctr Noncommunicable Dis, Karachi, Pakistan. [Soranzo, Nicole; Hunt, Sarah E.; Potter, Simon; Rice, Catherine; Deloukas, Panos; Ouwehand, Willem H.] Wellcome Trust Sanger Inst, Hinxton, England. [Chambers, John C.; Zhang, Weihua] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England. [Sivapalaratnam, Suthesh; Basart, Hanneke; Kastelein, John J. P.; Trip, Mieke D.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Kleber, Marcus E.] LURIC Non Profit LLC, Freiburg, Germany. [Keating, Brendan] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Qasim, Atif; Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Med Ctr, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Klopp, Norman; Baumert, Jens; Peters, Annette] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Erdmann, Jeanette; Diemert, Patrick; Willenborg, Christina; Schunkert, Heribert] Univ Lubeck, Med Klin 2, Lubeck, Germany. [Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Ball, Stephen G.] Univ Leeds, Fac Med & Hlth, LIGHT Res Inst, Leeds, W Yorkshire, England. [Balmforth, Anthony J.] Univ Leeds, Div Cardiovasc & Diabet Res, Multidisciplinary Cardiovasc Res Ctr, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England. [Bezzina, Connie R.; de Jong, Jonas S.; Wilde, Arthur A. M.; Trip, Mieke D.] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, Dept Clin & Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Boehm, Bernhard O.] Univ Ulm, Div Endocrinol & Diabet, Ctr Excellence Metab Dis, Dept Internal Med, Ulm, Germany. [Brocheton, Jessy; Cambien, Francois] Univ Paris 06, INSERM, UMRS 937, Paris, France. [Brocheton, Jessy; Cambien, Francois] Sch Med, Paris, France. [Bugert, Peter; Klueter, Harald] Univ Heidelberg, Inst Transfus Med & Immunol, Germany Red Cross Blood Serv, Baden Wurttemberg Hessen gGmbH,Med Fac Mannheim, D-6800 Mannheim, Germany. [Clarke, Robert; Collins, Rory] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Clarke, Robert; Collins, Rory] Univ Oxford, Epidemiol Studies Unit, Oxford, England. [Couper, David] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Cupples, L. Adrienne; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ejebe, Kenechi; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ejebe, Kenechi; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Ejebe, Kenechi; Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA USA. [Elbers, Clara C.; van der Schouw, Yvonne T.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Elbers, Clara C.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Div Biomed Genet, Dept Med Genet, Utrecht, Netherlands. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, London, England. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Franzosi, Maria-Grazia] Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy. [Garner, Stephen; Koch, Kerstin; Stephens, Jonathan; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Garner, Stephen; Koch, Kerstin; Stephens, Jonathan; Ouwehand, Willem H.] NHS Blood & Transplant, Cambridge, England. [Hengstenberg, Christian; Stark, Klaus] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany. [Klungel, Olaf H.; Peters, Bas J. M.] Utrecht Inst Pharmaceut Sci, Utrecht, Netherlands. [Koenig, Inke R.; Ziegler, Andreas] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany. [Kooner, Angad S.; Scott, James; Sehmi, Joban S.; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England. [Laaksonen, Reijo] Tampere Univ Hosp, Ctr Sci, Tampere, Finland. [Lathrop, Mark] CEA, Inst Genom, Ctr Natl Genotypage, F-91057 Evry, France. [Lathrop, Mark] Fdn Jean Dausset CEPH, F-75010 Paris, France. [Li, Mingyao; Qu, Liming] Univ Penn, Med Ctr, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [McPherson, Ruth] Univ Ottawa, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON, Canada. [Musani, Solomon] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. [Papanicolaou, George; Reilly, Muredach P.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Seedorf, Udo] Univ Munster, Leibniz Inst Arterioskleroseforsch, Munster, Germany. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [van der Schoot, C. Ellen] Sanquin Res, Dept Expt Immunohematol, Amsterdam, Netherlands. [Thorsteinsdottir, Unnur] deCODE Genet, IS-101 Reykjavik, Iceland. [Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Echocardiog Vasc Lab, Framingham, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Dept Med, Prevent Med & Epidemiol Sect, Framingham, MA USA. [Winkelmann, Bernhard R.] Cardiol Grp Frankfurt Sachsenhausen, Frankfurt, Germany. [Winkelmann, Bernhard R.] Clin Phen GmbH, Frankfurt, Germany. [de Bakker, Paul I. W.; Kathiresan, Sekar] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet,Dept Med, Boston, MA 02115 USA. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, Ulm, Germany. [Maerz, Winfried] Synlab Serv GmbH, Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Maerz, Winfried] Univ Heidelberg, Inst Publ Heath Social Med & Epidemiol, Med Fac Mannheim, D-6800 Mannheim, Germany. [Hamsten, Anders] Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Stockholm, Sweden. [Hall, Alistair S.] Univ Leeds, Inst Genet Hlth & Therapeut, Multidisciplinary Cardiovasc Res Ctr, Div Cardiovasc & Neuronal Remodelling, Leeds, W Yorkshire, England. [Thompson, Simon G.] Med Res Council Biostat Unit, Cambridge, England. [Thompson, Simon G.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. RP Butterworth, AS (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. EM hugh.watkins@cardiov.ox.ac.uk; jd292@medschl.cam.ac.uk; njs@leicester.ac.uk RI Stark, Klaus/D-3813-2009; Willenborg, Christina/D-2668-2012; Boehm, Bernhard/F-8750-2015; Peters, Annette/A-6117-2011; Ejebe, Kenechi/I-9238-2016; Martinelli, Nicola/J-5622-2016; Klungel, Olaf/I-9563-2016; Konig, Inke/A-4544-2009; Deloukas, Panos/B-2922-2013; Morgan, Tom/C-3478-2012; de Bakker, Paul/B-8730-2009; Laaksonen, Reijo/D-6323-2014; Strawbridge, Rona/H-5422-2012; Erdmann, Jeanette/A-4417-2009; Leander, Karin/C-7261-2017; Smith, Albert Vernon/K-5150-2015; Erdmann, Jeanette/P-7513-2014; OI Ouwehand, Willem/0000-0002-7744-1790; Kleber, Marcus/0000-0003-0663-7275; Dehghan, Abbas/0000-0001-6403-016X; Sabater Lleal, Maria/0000-0002-0128-379X; Stark, Klaus/0000-0002-7832-1942; Willenborg, Christina/0000-0001-5217-6882; Ejebe, Kenechi/0000-0002-6090-8657; Martinelli, Nicola/0000-0001-6465-5119; Deloukas, Panos/0000-0001-9251-070X; de Bakker, Paul/0000-0001-7735-7858; Strawbridge, Rona/0000-0001-8506-3585; Leander, Karin/0000-0002-1404-9222; Meisinger, Christa/0000-0002-9026-6544; ELOSUA, ROBERTO/0000-0001-8235-0095; Hunt, Sarah/0000-0002-8350-1235; Smith, Albert Vernon/0000-0003-1942-5845; Stewart, Alexandre/0000-0003-2673-9164; Seedorf, Udo/0000-0003-4652-5358; Ramachandran, Vasan/0000-0001-7357-5970; Erdmann, Jeanette/0000-0002-4486-6231; Peyvandi, Flora/0000-0001-7423-9864; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Wijmenga, Cisca/0000-0002-5635-1614; Ziegler, Andreas/0000-0002-8386-5397; Ferguson, Jane/0000-0001-6896-1025; Nothen, Markus/0000-0002-8770-2464; Watkins, Hugh/0000-0002-5287-9016; Jones, Gregory T/0000-0002-6950-4210 FU British Heart Foundation (BHF); UK Medical Research Council; Leicester NIHR Biomedical Research Unit in Cardiovascular Disease; AMC (The Netherlands); LURIC (Germany); University of Cambridge (UK); Wellcome Trust Sanger Institute (UK); Bloodomics [LSHM-CT-2004-503485]; British Heart Foundation [RG/09/12/28096]; National Institute for Health Research [RP-PG-0310-1002]; Netherlands Heart Foundation [2001D019, 2003T302, 2007B202]; Leducq Foundation [05-CVD]; Center for Translational Molecular Medicine (CTMM COHFAR); Interuniversity Cardiology Institute of The Netherlands; LURIC [LSHM-CT-2004-503485]; European Union [201668, LSHM-CT-2006-037593]; National Heart, Lung, and Blood Institute; Helmholtz Zentrum Munchen; German Research Center for Environmental Health; Neuherberg, Germany; German Federal Ministry of Education and Research (BMBF); German National Genome Research Network [01GS0834]; University of Ulm; Munich Center of Health Sciences (MC Health); Penn Cardiovascular Institute; GlaxoSmithKline; British Heart Foundation; European Community [LSHM-CT-2007-037273]; AstraZeneca; Wellcome Trust; United Kingdom Medical Research Council; Swedish Heart-Lung Foundation; Swedish Medical Research Council; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Soderberg Foundation; Karolinska Institutet and Stockholm County Council; Foundation for Strategic Research; Stockholm County Council [560283]; University of Cambridge and in Pakistan; EU Framework 6-funded Bloodomics Integrated Project [LSHM-CT-2004-503485]; Yousef Jameel Foundation; European Commission (SANCO); Dutch Ministry of Health; Dutch Cancer Society; ZonMW; Netherlands Organisation for Health Research and Development; World Cancer Research Fund (WCRF); NL Agency [IGE 05012]; Organization for Scientific Research (NWO); Netherlands Heart Foundation (NHS) [2001.064]; TI Pharma [T6-101]; Novo Nordisk; Top Institute Pharma; Dutch Medicines Evaluation Board FX BHF-FHS: Recruitment of CAD cases for the BHF-FHS study was supported by the British Heart Foundation (BHF) and the UK Medical Research Council. Controls were provided by the Wellcome Trust Case Control Consortium. Genotyping of the IBC 50K array for the BHF-FHS study was funded by the BHF. NJS and SGB hold personal chairs supported by the BHF. The work described in this paper forms part of the portfolio of translational research supported by the Leicester NIHR Biomedical Research Unit in Cardiovascular Disease. BLOODOMICS: The Bloodomics partners from AMC (The Netherlands), LURIC (Germany), the University of Cambridge (UK), and the Wellcome Trust Sanger Institute (UK) received funding through the 6th Framework funded Integrated Project Bloodomics (grant LSHM-CT-2004-503485). The University of Cambridge group in the Department of Haematology also received programme grant funding from the British Heart Foundation (RG/09/12/28096) and the National Institute for Health Research (RP-PG-0310-1002). BLOODOMICS-Dutch: This study was supported by research grants from The Netherlands Heart Foundation (grants 2001D019, 2003T302 and 2007B202), the Leducq Foundation (grant 05-CVD), the Center for Translational Molecular Medicine (CTMM COHFAR), and the Interuniversity Cardiology Institute of The Netherlands (project 27). BLOODOMICS-German: LURIC has received funding through the 6th Framework Program (integrated project Bloodomics, grant LSHM-CT-2004-503485) and 7th Framework Program (integrated project Atheroremo, Grant Agreement number 201668) of the European Union. CARe Consortium: CARe was performed with the support of the National Heart, Lung, and Blood Institute and acknowledges the contributions of the research institutions, study investigators, and field staff in creating this resource for biomedical research. Full details of the studies in the CARe Consortium can be found in Text S1. LOLIPOP: Genotyping of the IBC 50K array for the LOLIPOP Study was funded by the British Heart Foundation. Paul Elliott is a National Institute for Health Research Senior Investigator. MONICA-KORA: The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFNPlus, project number 01GS0834) and through additional funds from the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of LMU innovative. PennCATH: Muredach P Reilly and Daniel J Rader have been supported by the Penn Cardiovascular Institute and GlaxoSmithKline. PROCARDIS: The PROCARDIS study has been supported by the British Heart Foundation, the European Community Sixth Framework Program (LSHM-CT-2007-037273), AstraZeneca, the Wellcome Trust, the United Kingdom Medical Research Council, the Swedish Heart-Lung Foundation, the Swedish Medical Research Council, the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Soderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283). PROMIS: Epidemiological field work in PROMIS was supported by unrestricted grants to investigators at the University of Cambridge and in Pakistan.; Genotyping for this study was funded by the Wellcome Trust and the EU Framework 6-funded Bloodomics Integrated Project(LSHM-CT-2004-503485). The British Heart Foundation has supported some biochemical assays. The Yousef Jameel Foundation supported D Saleheen. The cardiovascular disease epidemiology group of J Danesh is underpinned by programme grants from the British Heart Foundation and the UK Medical Research Council. EPIC-NL: The EPIC-NL study was funded by "Europe against Cancer'' Programme of the European Commission (SANCO); the Dutch Ministry of Health; the Dutch Cancer Society; ZonMW the Netherlands Organisation for Health Research and Development; World Cancer Research Fund (WCRF). We thank the institute PHARMO for follow-up data on diabetes. Genotyping was funded by IOP Genomics grant IGE 05012 from NL Agency. UCP: The project was funded by Veni grant Organization for Scientific Research (NWO), Grant no. 2001.064 Netherlands Heart Foundation (NHS), and TI Pharma Grant T6-101 Mondriaan. Cardiogenics: Cardiogenics was funded through the 6th Framework Programme (integrated project Cardiogenics, grant LSHM-CT-2006-037593) of the European Union. None of the sponsors had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.; Muredach P Reilly and Daniel J Rader have a research grant from GlaxoSmithKline. The division of Pharmacoepidemiology and Clinical Pharmacology employing Bas Peters, Olaf Klungel, Anthonius de Boer, and Anke-Hilse Maitland-van der Zee has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, Novo Nordisk, the private-public funded Top Institute Pharma (www.tipharma.nl ,includes co-funding from universities, government, and industry), the Dutch Medicines Evaluation Board, and the Dutch Ministry of Health. Arthur AM Wilde is a consultant for Transgenomics (Familion test) and Sorin. No other disclosures were reported. NR 32 TC 15 Z9 15 U1 0 U2 38 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2011 VL 7 IS 9 AR e1002260 DI 10.1371/journal.pgen.1002260 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100015 ER PT J AU Hendel, A Krijger, PHL Diamant, N Goren, Z Langerak, P Kim, J Reissner, T Lee, KY Geacintov, NE Carell, T Myung, K Tateishi, S D'Andrea, A Jacobs, H Livneh, Z AF Hendel, Ayal Krijger, Peter H. L. Diamant, Noam Goren, Zohar Langerak, Petra Kim, Jungmin Reissner, Thomas Lee, Kyoo-young Geacintov, Nicholas E. Carell, Thomas Myung, Kyungjae Tateishi, Satoshi D'Andrea, Alan Jacobs, Heinz Livneh, Zvi TI PCNA Ubiquitination Is Important, But Not Essential for Translesion DNA Synthesis in Mammalian Cells SO PLOS GENETICS LA English DT Article ID POLYMERASE-ETA; 2-POLYMERASE MECHANISMS; MONOUBIQUITINATED PCNA; XERODERMA-PIGMENTOSUM; GENOMIC INSTABILITY; REPLICATION FORK; BINDING DOMAINS; NUCLEAR ANTIGEN; MUTATION LOAD; POL-ETA AB Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and it is usually associated with mutagenesis. In Saccharomyces cerevisiae a key event in TLS is the monoubiquitination of PCNA, which enables recruitment of the specialized polymerases to the damaged site through their ubiquitin-binding domain. In mammals, however, there is a debate on the requirement for ubiquitinated PCNA (PCNA-Ub) in TLS. We show that UV-induced Rpa foci, indicative of single-stranded DNA (ssDNA) regions caused by UV, accumulate faster and disappear more slowly in Pcna(K164R/K164R) cells, which are resistant to PCNA ubiquitination, compared to Pcna(+/+) cells, consistent with a TLS defect. Direct analysis of TLS in these cells, using gapped plasmids with site-specific lesions, showed that TLS is strongly reduced across UV lesions and the cisplatin-induced intrastrand GG crosslink. A similar effect was obtained in cells lacking Rad18, the E3 ubiquitin ligase which monoubiquitinates PCNA. Consistently, cells lacking Usp1, the enzyme that de-ubiquitinates PCNA exhibited increased TLS across a UV lesion and the cisplatin adduct. In contrast, cells lacking the Rad5-homologs Shprh and Hltf, which polyubiquitinate PCNA, exhibited normal TLS. Knocking down the expression of the TLS genes Rev3L, PolH, or Rev1 in Pcna(K164R/K164R) mouse embryo fibroblasts caused each an increased sensitivity to UV radiation, indicating the existence of TLS pathways that are independent of PCNA-Ub. Taken together these results indicate that PCNA-Ub is required for maximal TLS. However, TLS polymerases can be recruited to damaged DNA also in the absence of PCNA-Ub, and perform TLS, albeit at a significantly lower efficiency and altered mutagenic specificity. C1 [Hendel, Ayal; Diamant, Noam; Goren, Zohar; Livneh, Zvi] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. [Krijger, Peter H. L.; Langerak, Petra; Jacobs, Heinz] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands. [Kim, Jungmin; D'Andrea, Alan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol & Pediat Oncol, Boston, MA 02115 USA. [Reissner, Thomas; Carell, Thomas] Univ Munich, Dept Chem & Biochem, Munich, Germany. [Lee, Kyoo-young; Myung, Kyungjae] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Geacintov, Nicholas E.] NYU, Dept Chem, New York, NY 10003 USA. [Tateishi, Satoshi] Kumamoto Univ, Inst Mol Embryol & Genet, Kumamoto, Japan. RP Hendel, A (reprint author), Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. EM h.jacobs@nki.nl; zvi.livneh@weizmann.ac.il RI Carell, Thomas/G-4799-2012; OI Krijger, Peter/0000-0003-1702-348X; Jacobs, Heinz/0000-0001-6227-9850; Carell, Thomas/0000-0001-7898-2831 FU Flight Attendant Medical Research Institute; Leona M. and Harry B. Helmsley Charitable Trust; Israel Science Foundation [1136/08]; Netherlands Organization for Scientific Research; Dutch Cancer Foundation [917.56.328, 2008-4112]; NIH USA [CA099194] FX ZL is the incumbent of the Maxwell Ellis Professorial Chair in Biomedical Research. This work was supported by grants to ZL from the Flight Attendant Medical Research Institute, the Leona M. and Harry B. Helmsley Charitable Trust, and the Israel Science Foundation (no. 1136/08); to HJ from The Netherlands Organization for Scientific Research and the Dutch Cancer Foundation (VIDI program 917.56.328 and KWF 2008-4112); and to NEG from NIH USA (no. CA099194). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 49 Z9 50 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2011 VL 7 IS 9 AR e1002262 DI 10.1371/journal.pgen.1002262 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100017 PM 21931560 ER PT J AU Hertzano, R Elkon, R Kurima, K Morrisson, A Chan, SL Sallin, M Biedlingmaier, A Darling, DS Griffith, AJ Eisenman, DJ Strome, SE AF Hertzano, Ronna Elkon, Ran Kurima, Kiyoto Morrisson, Annie Chan, Siaw-Lin Sallin, Michelle Biedlingmaier, Andrew Darling, Douglas S. Griffith, Andrew J. Eisenman, David J. Strome, Scott E. TI Cell Type-Specific Transcriptome Analysis Reveals a Major Role for Zeb1 and miR-200b in Mouse Inner Ear Morphogenesis SO PLOS GENETICS LA English DT Article ID PROGRESSIVE HEARING-LOSS; EXPRESSION PATTERNS; GENE-EXPRESSION; NETWORKS; MIR-96; MICROARRAY; DROSOPHILA; MICRORNAS; BINDING; PROTEIN AB Cellular heterogeneity hinders the extraction of functionally significant results and inference of regulatory networks from wide-scale expression profiles of complex mammalian organs. The mammalian inner ear consists of the auditory and vestibular systems that are each composed of hair cells, supporting cells, neurons, mesenchymal cells, other epithelial cells, and blood vessels. We developed a novel protocol to sort auditory and vestibular tissues of newborn mouse inner ears into their major cellular components. Transcriptome profiling of the sorted cells identified cell type-specific expression clusters. Computational analysis detected transcription factors and microRNAs that play key roles in determining cell identity in the inner ear. Specifically, our analysis revealed the role of the Zeb1/miR-200b pathway in establishing epithelial and mesenchymal identity in the inner ear. Furthermore, we detected a misregulation of the ZEB1 pathway in the inner ear of Twirler mice, which manifest, among other phenotypes, malformations of the auditory and vestibular labyrinth. The association of misregulation of the ZEB1/miR-200b pathway with auditory and vestibular defects in the Twirler mutant mice uncovers a novel mechanism underlying deafness and balance disorders. Our approach can be employed to decipher additional complex regulatory networks underlying other hearing and balance mouse mutants. C1 [Hertzano, Ronna; Morrisson, Annie; Chan, Siaw-Lin; Sallin, Michelle; Biedlingmaier, Andrew; Eisenman, David J.; Strome, Scott E.] Univ Maryland, Dept Otorhinolaryngol Head & Neck Surg, Baltimore, MD 21201 USA. [Elkon, Ran] Netherlands Canc Inst, Div Gene Regulat, Amsterdam, Netherlands. [Kurima, Kiyoto; Griffith, Andrew J.] Natl Inst Deafness & Other Commun Disorders, Mol Biol & Genet Sect, Otolaryngol Branch, NIH, Rockville, MD USA. [Darling, Douglas S.] Univ Louisville, Dept Oral Hlth & Rehabil, Louisville, KY 40292 USA. [Darling, Douglas S.] Univ Louisville, Ctr Genet & Mol Med, Louisville, KY 40292 USA. RP Hertzano, R (reprint author), Univ Maryland, Dept Otorhinolaryngol Head & Neck Surg, Baltimore, MD 21201 USA. EM rhertzano@smail.umaryland.edu FU Deafness Research Foundation; NIH [Z01-DC000060-10] FX This work was funded by a Deafness Research Foundation grant (RH) and NIH intramural research fund Z01-DC000060-10 (AJG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 30 Z9 30 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2011 VL 7 IS 9 AR e1002309 DI 10.1371/journal.pgen.1002309 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100053 PM 21980309 ER PT J AU Johnson, AD Leslie, R O'Donnell, CJ AF Johnson, Andrew D. Leslie, Richard O'Donnell, Christopher J. TI Temporal Trends in Results Availability from Genome-Wide Association Studies SO PLOS GENETICS LA English DT Article C1 [Johnson, Andrew D.] NHLBI, Div Intramural Res, Framingham, MA USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Johnson, AD (reprint author), NHLBI, Div Intramural Res, Framingham, MA USA. EM johnsonad2@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013 NR 9 TC 10 Z9 10 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2011 VL 7 IS 9 AR e1002269 DI 10.1371/journal.pgen.1002269 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100022 PM 21931563 ER PT J AU Kurima, K Hertzano, R Gavrilova, O Monahan, K Shpargel, KB Nadaraja, G Kawashima, Y Lee, KY Ito, T Higashi, Y Eisenman, DJ Strome, SE Griffith, AJ AF Kurima, Kiyoto Hertzano, Ronna Gavrilova, Oksana Monahan, Kelly Shpargel, Karl B. Nadaraja, Garani Kawashima, Yoshiyuki Lee, Kyu Yup Ito, Taku Higashi, Yujiro Eisenman, David J. Strome, Scott E. Griffith, Andrew J. TI A Noncoding Point Mutation of Zeb1 Causes Multiple Developmental Malformations and Obesity in Twirler Mice SO PLOS GENETICS LA English DT Article ID HAIR CELL DEGENERATION; GENOME-WIDE SCAN; INNER-EAR; CHARGE SYNDROME; C-MYB; TRANSCRIPTION FACTOR; CORNEAL-DYSTROPHY; GENE-EXPRESSION; TRANSGENIC MICE; ZINC-FINGER AB Heterozygous Twirler (Tw) mice develop obesity and circling behavior associated with malformations of the inner ear, whereas homozygous Tw mice have cleft palate and die shortly after birth. Zeb1 is a zinc finger protein that contributes to mesenchymal cell fate by repression of genes whose expression defines epithelial cell identity. This developmental pathway is disrupted in inner ears of Tw/Tw mice. The purpose of our study was to comprehensively characterize the Twirler phenotype and to identify the causative mutation. The Tw/+ inner ear phenotype includes irregularities of the semicircular canals, abnormal utricular otoconia, a shortened cochlear duct, and hearing loss, whereas Tw/Tw ears are severely malformed with barely recognizable anatomy. Tw/+ mice have obesity associated with insulin-resistance and have lymphoid organ hypoplasia. We identified a noncoding nucleotide substitution, c.58+181G>A, in the first intron of the Tw allele of Zeb1 (Zeb1(Tw)). A knockin mouse model of c.58+181G>A recapitulated the Tw phenotype, whereas a wild-type knockin control did not, confirming the mutation as pathogenic. c.58+181G>A does not affect splicing but disrupts a predicted site for Myb protein binding, which we confirmed in vitro. In comparison, homozygosity for a targeted deletion of exon 1 of mouse Zeb1, Zeb1(Delta Ex1), is associated with a subtle abnormality of the lateral semicircular canal that is different than those in Tw mice. Expression analyses of E13.5 Twirler and Zeb1(Delta Ex1) ears confirm that Zeb1(Delta Ex1) is a null allele, whereas Zeb1(Tw) RNA is expressed at increased levels in comparison to wild-type Zeb1. We conclude that a noncoding point mutation of Zeb1 acts via a gain-of-function to disrupt regulation of Zeb1(Tw) expression, epithelial-mesenchymal cell fate or interactions, and structural development of the inner ear in Twirler mice. This is a novel mechanism underlying disorders of hearing or balance. C1 [Kurima, Kiyoto; Monahan, Kelly; Shpargel, Karl B.; Nadaraja, Garani; Kawashima, Yoshiyuki; Lee, Kyu Yup; Ito, Taku; Griffith, Andrew J.] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, Rockville, MD USA. [Hertzano, Ronna; Eisenman, David J.; Strome, Scott E.] Univ Maryland, Dept Otorhinolaryngol Head & Neck Surg, Baltimore, MD 21201 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD USA. [Higashi, Yujiro] Aichi Human Serv Ctr, Inst Dev Res, Dept Perinatol, Kasugai, Aichi, Japan. RP Kurima, K (reprint author), Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, Rockville, MD USA. EM griffita@nidcd.nih.gov FU NIDCD [Z01-DC-000060] FX This study was supported by NIDCD intramural research fund Z01-DC-000060. GN was a Howard Hughes Medical Institute/NIH Research Scholar. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 10 Z9 10 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2011 VL 7 IS 9 AR e1002307 DI 10.1371/journal.pgen.1002307 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100052 PM 21980308 ER PT J AU Le, MTN Shyh-Chang, N Khaw, SL Chin, LZ Teh, C Tay, J O'Day, E Korzh, V Yang, H Lal, A Lieberman, J Lodish, HF Lim, B AF Le, Minh T. N. Shyh-Chang, Ng Khaw, Swea Ling Chin, Lingzi Teh, Cathleen Tay, Junliang O'Day, Elizabeth Korzh, Vladimir Yang, Henry Lal, Ashish Lieberman, Judy Lodish, Harvey F. Lim, Bing TI Conserved Regulation of p53 Network Dosage by MicroRNA-125b Occurs through Evolving miRNA-Target Gene Pairs SO PLOS GENETICS LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; HEMATOPOIETIC STEM-CELLS; NEGATIVE REGULATOR; ESCHERICHIA-COLI; BAK1 EXPRESSION; CANCER CELLS; C-ELEGANS; MIR-125B; PROLIFERATION; CANALIZATION AB MicroRNAs regulate networks of genes to orchestrate cellular functions. MiR-125b, the vertebrate homologue of the Caenorhabditis elegans microRNA lin-4, has been implicated in the regulation of neural and hematopoietic stem cell homeostasis, analogous to how lin-4 regulates stem cells in C. elegans. Depending on the cell context, miR-125b has been proposed to regulate both apoptosis and proliferation. Because the p53 network is a central regulator of both apoptosis and proliferation, the dual roles of miR-125b raise the question of what genes in the p53 network might be regulated by miR-125b. By using a gain-and loss-of-function screen for miR-125b targets in humans, mice, and zebrafish and by validating these targets with the luciferase assay and a novel miRNA pull-down assay, we demonstrate that miR-125b directly represses 20 novel targets in the p53 network. These targets include both apoptosis regulators like Bak1, Igfbp3, Itch, Puma, Prkra, Tp53inp1, Tp53, Zac1, and also cell-cycle regulators like cyclin C, Cdc25c, Cdkn2c, Edn1, Ppp1ca, Sel1l, in the p53 network. We found that, although each miRNA-target pair was seldom conserved, miR-125b regulation of the p53 pathway is conserved at the network level. Our results lead us to propose that miR-125b buffers and fine-tunes p53 network activity by regulating the dose of both proliferative and apoptotic regulators, with implications for tissue stem cell homeostasis and oncogenesis. C1 [Le, Minh T. N.; Shyh-Chang, Ng; Khaw, Swea Ling; Chin, Lingzi; Tay, Junliang; Lim, Bing] Genome Inst Singapore, Singapore, Singapore. [Le, Minh T. N.; O'Day, Elizabeth; Lal, Ashish; Lieberman, Judy] Harvard Univ, Sch Med, Childrens Hosp Boston, Immune Dis Inst, Boston, MA USA. [Le, Minh T. N.; O'Day, Elizabeth; Lal, Ashish; Lieberman, Judy] Harvard Univ, Sch Med, Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Le, Minh T. N.; Lodish, Harvey F.; Lim, Bing] Singapore MIT Alliance, Computat & Syst Biol, Singapore, Singapore. [Shyh-Chang, Ng] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Khaw, Swea Ling; Korzh, Vladimir] NUS Grad Sch Integrat Sci & Engn, Singapore, Singapore. [Teh, Cathleen] Natl Univ Singapore, Inst Mol & Cell Biol, Singapore 117548, Singapore. [Yang, Henry] Singapore Immunol Network, Bioinformat Grp, Singapore, Singapore. [Lal, Ashish] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Lodish, Harvey F.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Lodish, Harvey F.] MIT, Dept Biol, Cambridge, MA USA. [Lim, Bing] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Le, MTN (reprint author), Genome Inst Singapore, Singapore, Singapore. EM lodish@wi.mit.edu; limb1@gis.a-star.edu.sg RI ASTAR, IMCB/E-2320-2012; Xie, Huangming/B-2260-2012; Le, Minh/D-7651-2013; Lieberman, Judy/A-2717-2015; Korzh, Vladimir/H-1596-2011; OI Shyh-Chang, Ng/0000-0003-3138-9525; Korzh, Vladimir/0000-0002-6580-7986; LE, Thi Nguyet Minh/0000-0002-6077-1566 FU ASTAR, Singapore; SMA [C-382-641-001-091]; NIH [R01 DK068348] FX MTNL, NS-C, SLK, LC, JT, CT, VK, and BL were supported by ASTAR, Singapore. MTNL was a L'Oreal Singapore for Women in Science National Fellow. BL and HFL were partially supported by SMA grant C-382-641-001-091. HFL was supported by NIH grant R01 DK068348. JL, EO, MTNL, and AL were supported by NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 65 Z9 71 U1 0 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2011 VL 7 IS 9 AR e1002242 DI 10.1371/journal.pgen.1002242 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100005 PM 21935352 ER PT J AU Liu, CT Garnaas, MK Tin, A Kottgen, A Franceschini, N Peralta, CA de Boer, IH Lu, XN Atkinson, E Ding, JZ Nalls, M Shriner, D Coresh, J Kutlar, A Bibbins-Domingo, K Siscovick, D Akylbekova, E Wyatt, S Astor, B Mychaleckjy, J Li, M Reilly, MP Townsend, RR Adeyemo, A Zonderman, AB de Andrade, M Turner, ST Mosley, TH Harris, TB Rotimi, CN Liu, YM Kardia, SLR Evans, MK Shlipak, MG Kramer, H Flessner, MF Dreisbach, AW Goessling, W Cupples, LA Kao, WL Fox, CS AF Liu, Ching-Ti Garnaas, Maija K. Tin, Adrienne Kottgen, Anna Franceschini, Nora Peralta, Carmen A. de Boer, Ian H. Lu, Xiaoning Atkinson, Elizabeth Ding, Jingzhong Nalls, Michael Shriner, Daniel Coresh, Josef Kutlar, Abdullah Bibbins-Domingo, Kirsten Siscovick, David Akylbekova, Ermeg Wyatt, Sharon Astor, Brad Mychaleckjy, Josef Li, Man Reilly, Muredach P. Townsend, Raymond R. Adeyemo, Adebowale Zonderman, Alan B. de Andrade, Mariza Turner, Stephen T. Mosley, Thomas H. Harris, Tamara B. Rotimi, Charles N. Liu, Yongmei Kardia, Sharon L. R. Evans, Michele K. Shlipak, Michael G. Kramer, Holly Flessner, Michael F. Dreisbach, Albert W. Goessling, Wolfram Cupples, L. Adrienne Kao, W. Linda Fox, Caroline S. CA CKDGen Consortium TI Genetic Association for Renal Traits among Participants of African Ancestry Reveals New Loci for Renal Function SO PLOS GENETICS LA English DT Article ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; DIABETIC-NEPHROPATHY; UNITED-STATES; ZEBRAFISH; POPULATIONS; PROGRESSION; SUSCEPTIBILITY; PREDICTORS; MUTATIONS AB Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR,60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR>30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3x10(-7)) and FNDC1 (p-value = 3.0x10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6x10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish. C1 [Liu, Ching-Ti; Lu, Xiaoning; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Garnaas, Maija K.; Goessling, Wolfram] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Garnaas, Maija K.; Goessling, Wolfram; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Garnaas, Maija K.; Goessling, Wolfram; Kao, W. Linda] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Tin, Adrienne; Kottgen, Anna; Li, Man] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Kottgen, Anna] Univ Hosp Freiburg, Div Renal, Freiburg, Germany. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Peralta, Carmen A.] Univ Calif San Francisco, Sch Med, Div Nephrol, San Francisco, CA USA. [Peralta, Carmen A.] San Francisco VA Med Ctr, San Francisco, CA USA. [de Boer, Ian H.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [de Boer, Ian H.] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Atkinson, Elizabeth; de Andrade, Mariza] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Ding, Jingzhong] Wake Forest Univ Hlth Sci, J Paul Sticht Ctr Aging, Winston Salem, NC USA. [Nalls, Michael] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Shriner, Daniel; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Coresh, Josef] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Kutlar, Abdullah] Med Coll Georgia, Augusta, GA 30912 USA. [Siscovick, David] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Siscovick, David] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Akylbekova, Ermeg] Jackson State Univ, Jackson, MS USA. [Wyatt, Sharon] Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA. [Astor, Brad] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Mychaleckjy, Josef] Ctr Publ Hlth Genom, Charlottesville, VA USA. [Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Townsend, Raymond R.] Univ Penn, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Zonderman, Alan B.] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. [Turner, Stephen T.] Mayo Clin, Div Nephrol & Hypertens, Dept Internal Med, Rochester, MN USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr, Jackson, MS 39216 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Evans, Michele K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Kramer, Holly] Loyola Univ, Maywood, IL 60153 USA. [Flessner, Michael F.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. [Dreisbach, Albert W.] Univ Mississippi, Div Nephrol, Jackson, MS 39216 USA. [Goessling, Wolfram] Brigham & Womens Hosp, Dept Med, Div Gastroenterol, Boston, MA 02115 USA. [Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Boston, MA USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Liu, CT (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. EM wgoessling@partners.org; wkao@jhsph.edu; foxca@nhlbi.nih.gov RI Kottgen, Anna/D-2920-2012; OI Cupples, L. Adrienne/0000-0003-0273-7965; Kramer, Holly/0000-0002-6374-837X; Adeyemo, Adebowale/0000-0002-3105-3231; Goessling, Wolfram/0000-0001-9972-1569; Zonderman, Alan B/0000-0002-6523-4778 FU NHLBI [R01-HL087660]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C, S06GM008016-320107, S06GM008016-380111, 2M01RR010284]; NIH, National Institute on Aging. Howard University Family Study; Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362]; NIH, National Institute on Aging; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; National Heart, Lung, and Blood Institute FX The following nine parent studies have contributed parent study data, ancillary study data, and DNA samples through the Massachusetts Institute of Technology - Broad Institute (N01-HC-65226) to create this genotype/phenotype data base for wide dissemination to the biomedical research community: Atherosclerotic Risk in Communities (ARIC): University of North Carolina at Chapel Hill (N01-HC-55015), Baylor Medical College (N01-HC-55016), University of Mississippi Medical Center (N01-HC-55021), University of Minnesota (N01-HC-55019), Johns Hopkins University (N01-HC-55020), University of Texas Houston (N01-HC-55022), University of North Carolina Forsyth County (N01-HC-55018); Cardiovascular Health Study (CHS): University of Washington (N01-HC-85079), Wake Forest University (N01-HC-85080), Johns Hopkins University (N01-HC-85081), University of Pittsburgh (N01-HC-85082), University of California Davis (N01-HC-85083), University of California Irvine (N01-HC-85084), New England Medical Center (N01-HC-85085), University of Vermont (N01-HC-85086), Georgetown University (N01-HC-35129), Johns Hopkins University (N01 HC-15103), University of Wisconsin (N01-HC-75150), Geisinger Clinic (N01-HC-45133), University of Washington (N01 HC-55222, U01 HL080295); Cleveland Family Study (CFS): Case Western Reserve University (NIH HL 46380, M01RR00080); Cooperative Study of Sickle Cell Disease (CSSCD): University of Illinois (N01-HB-72982, N01-HB-97062), Howard University (N01-HB-72991, N01-HB-97061), University of Miami (N01-HB-72992, N01-HB-97064), Duke University (N01-HB-72993), George Washington University (N01-HB-72994), University of Tennessee (N01-HB-72995, N01-HB-97070), Yale University (N01-HB-72996, N01-HB-97072), Children's Hospital-Philadelphia (N01-HB-72997, N01-HB-97056), University of Chicago (N01-HB-72998, N01-HB-97053), Medical College of Georgia (N01-HB-73000, N01-HB-97060), Washington University (N01-HB-73001, N01-HB-97071), Jewish Hospital and Medical Center of Brooklyn (N01-HB-73002), Trustees of Health and Hospitals of the City of Boston (N01-HB-73003), Children's Hospital-Oakland (N01-HB-73004, N01-HB-97054), University of Mississippi (N01-HB-73005), St. Luke's Hospital-New York (N01-HB-73006), Alta Bates-Herrick Hospital (N01-HB-97051), Columbia University (N01-HB97058), St.; Jude's Children's Research Hospital (N01-HB-97066), Research Foundation of the State University of New York-Albany (N01-HB-97068, N01-HB-97069), New England Research Institute (N01-HB-97073), Interfaith Medical Center-Brooklyn (N01-HB-97085); Coronary Artery Risk in Young Adults (CARDIA): University of Alabama at Birmingham (N01-HC-48047), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), University of Alabama at Birmingham (N01-HC-95095), Tufts-New England Medical Center (N01-HC-45204), Wake Forest University (N01-HC45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California Irvine (N01-HC-45134, N01-HC-95100); Framingham Heart Study (FHS): Boston University (N01-HC-25195, R01HL092577-01A1, RO1 HL076784, R01 AG028321); Jackson Heart Study (JHS): Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), Tougaloo College (N01-HC-95172); Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern Universiy (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205), University of Virginia (subcontract to R01-HL-071205); Sleep Heart Health Study (SHHS): Johns Hopkins University (U01 HL064360), Case Western University (U01 HL063463), University of California, Davis (U01 HL053916), University of Arizona (U01 HL053938), University of Minnesota (relocating in 2006 to Univ Arizona) (U01 HL053934), University of Pittsburgh (U01 HL077813), Boston University (U01 HL053941), MedStar Research Institute (U01 HL063429), Johns Hopkins University (U01 HL053937). GENOA: The GENOA Study genome-wide association study was funded by NHLBI R01-HL087660. HABC: This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Howard University Family Study: The Howard University Family Study was supported by National Institutes of Health grants S06GM008016-320107 and S06GM008016-380111. Enrollment was carried out at the Howard University General Clinical Research Center, supported by National Institutes of Health grant 2M01RR010284. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health. The Center for Research on Genomics and Global Health is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). Genotyping support was provided by the Coriell Institute for Medical Research. We thank the participants of the Howard University Family Study.; The contents of this publicationare solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. HANDLS: This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (Intramural Project # Z01-AG000513 and human subjects protocol # 2009-149). Data analyses for the HANDLS study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. (http://biowulf.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. The authors wish to thank Andrea Calhoun and Dr. Susan Hagen at the Electron Microscopy Core Facility at Beth Israel Deaconess Medical Center for expert assistance with electron microscopy and Drs. Dirk Hentschel and Helmut Rennke at Brigham and Women's Hospital for advice on electron microscopy images. We thank Dr. Iain Drummond at Massachusetts General Hospital and Dr. Rebecca Wingert at the University of Notre Dame for in situ probes. NR 42 TC 57 Z9 58 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2011 VL 7 IS 9 AR e1002264 DI 10.1371/journal.pgen.1002264 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100018 PM 21931561 ER PT J AU Mishra, PK Au, WC Choy, JS Kuich, PH Baker, RE Foltz, DR Basrai, MA AF Mishra, Prashant K. Au, Wei-Chun Choy, John S. Kuich, P. Henning Baker, Richard E. Foltz, Daniel R. Basrai, Munira A. TI Misregulation of Scm3p/HJURP Causes Chromosome Instability in Saccharomyces cerevisiae and Human Cells SO PLOS GENETICS LA English DT Article ID HISTONE H3 VARIANT; E3 UBIQUITIN LIGASE; FISSION YEAST SCM3; CENP-A; BUDDING YEAST; KINETOCHORE BIORIENTATION; CENTROMERIC CHROMATIN; TRANSMISSION FIDELITY; PROTEIN; HJURP AB The kinetochore (centromeric DNA and associated proteins) is a key determinant for high fidelity chromosome transmission. Evolutionarily conserved Scm3p is an essential component of centromeric chromatin and is required for assembly and function of kinetochores in humans, fission yeast, and budding yeast. Overexpression of HJURP, the mammalian homolog of budding yeast Scm3p, has been observed in lung and breast cancers and is associated with poor prognosis; however, the physiological relevance of these observations is not well understood. We overexpressed SCM3 and HJURP in Saccharomyces cerevisiae and HJURP in human cells and defined domains within Scm3p that mediate its chromosome loss phenotype. Our results showed that the overexpression of SCM3 (GALSCM3) or HJURP (GALHJURP) caused chromosome loss in a wild-type yeast strain, and overexpression of HJURP led to mitotic defects in human cells. GALSCM3 resulted in reduced viability in kinetochore mutants, premature separation of sister chromatids, and reduction in Cse4p and histone H4 at centromeres. Overexpression of CSE4 or histone H4 suppressed chromosome loss and restored levels of Cse4p at centromeres in GALSCM3 strains. Using mutant alleles of scm3, we identified a domain in the N-terminus of Scm3p that mediates its interaction with CEN DNA and determined that the chromosome loss phenotype of GALSCM3 is due to centromeric association of Scm3p devoid of Cse4p/H4. Furthermore, we determined that similar to other systems the centromeric association of Scm3p is cell cycle regulated. Our results show that altered stoichiometry of Scm3p/HJURP, Cse4p, and histone H4 lead to defects in chromosome segregation. We conclude that stringent regulation of HJURP and SCM3 expression are critical for genome stability. C1 [Mishra, Prashant K.; Au, Wei-Chun; Choy, John S.; Basrai, Munira A.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kuich, P. Henning; Foltz, Daniel R.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA. [Baker, Richard E.] Univ Massachusetts, Sch Med, Dept Mol Genet & Microbiol, Worcester, MA 01655 USA. RP Mishra, PK (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM basraim@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX Support for this research was provided by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 28 Z9 28 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2011 VL 7 IS 9 AR e1002303 DI 10.1371/journal.pgen.1002303 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100049 PM 21980305 ER PT J AU Rose, A Fagan, P Lawrence, D Hart, A Shavers, VL Gibson, JT AF Rose, Allison Fagan, Pebbles Lawrence, Deirdre Hart, Alton, Jr. Shavers, Vickie L. Gibson, James Todd TI The Role of Worksite and Home Smoking Bans in Smoking Cessation Among US Employed Adult Female Smokers SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Article DE Cigarette Smoking; Tobacco; Smoking Bans; Policies; Women; Female Smokers; Intention to Quit Smoking; Smoking Cessation; Prevention Research ID POTENTIAL UNINTENDED CONSEQUENCES; TOBACCO-CONTROL POLICIES; 4 COUNTRY SURVEY; UNITED-STATES; CIGARETTE CONSUMPTION; NICOTINE DEPENDENCE; FAGERSTROM TEST; FREE WORKPLACES; PUBLIC PLACES; IMPACT AB Purpose. Examine the association of work and home smoking bans with quitting behaviors among employed female smokers in the United States. Design. Secondary analyses using cross-sectional data from the 2006/2007 Tobacco Use Supplement to the Current Population Survey. Subjects. Nationally representative sample of 7610 US. employed female smokers, aged 18 to 64 years, who reported working indoors. Setting. N/A. Methods. Multivariate logistic regression analyses were conducted to examine the association of smoking ban policies (complete work and home bans, complete work ban only, complete home ban only, and no complete work or home ban) with intention to quit in the next 30 days, at least one quit attempt in the past year, and sustained abstinence of at least 3 months in the past year. Results. Twenty-nine percent of women reported complete work and home smoking bans. Smoking bans were not associated with intention to quit and were marginally associated with sustained abstinence. Regardless of intention to quit, women with complete work and home bans were significantly more likely than those without complete work and home bans to report quit attempts. Among women with no intention to quit, the odds of having a quit attempt were significantly higher among women who had a complete home ban only compared with women without complete work and home bans. Conclusions. Efforts to promote quitting behaviors among employed female smokers may be facilitated by increasing rates of complete smoking bans at both work and home settings. (Am] Health Promot 2011;26[1]:26-36.) C1 [Rose, Allison] NCI, SAIC Frederick Inc, Clin Monitoring Res Program, Frederick, MD 21701 USA. [Fagan, Pebbles; Lawrence, Deirdre; Shavers, Vickie L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Hart, Alton, Jr.] Virginia Commonwealth Univ, Div Qual Hlth Care, Dept Internal Med, Ctr Hlth Dispar, Richmond, VA USA. [Gibson, James Todd] Informat Management Syst, Silver Spring, MD USA. RP Rose, A (reprint author), NCI Frederick, SAIC Frederick Inc, 6130 Execut Blvd,EPN 4047, Bethesda, MD 20892 USA. EM rosea@mail.nih.gov FU PHS HHS [HHSN261200800001E] NR 63 TC 7 Z9 7 U1 2 U2 4 PU AMER JOURNAL HEALTH PROMOTION INC PI TROY PA PO BOX 1254, TROY, MI 48099-1254 USA SN 0890-1171 J9 AM J HEALTH PROMOT JI Am. J. Health Promot. PD SEP-OCT PY 2011 VL 26 IS 1 BP 26 EP 36 DI 10.4278/ajhp.091214-QUAN-391 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 825DC UT WOS:000295250100008 PM 21879940 ER PT J AU Munchel, AT Kasamon, YL Fuchs, EJ AF Munchel, Ashley T. Kasamon, Yvette L. Fuchs, Ephraim J. TI Treatment of hematological malignancies with nonmyeloablative, HLA-haploidentical bone marrow transplantation and high dose, post-transplantation cyclophosphamide SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE stem cell transplantation; nonmyeloablative; HLA-haploidentical; hematological malignancies; cyclophosphamide ID STEM-CELL TRANSPLANTATION; SKIN ALLOGRAFT TOLERANCE; VERSUS-HOST-DISEASE; RISK ACUTE-LEUKEMIA; INTRATHYMIC CLONAL DELETION; TOTAL-BODY IRRADIATION; IDENTICAL SIBLINGS; ALLOGENEIC MARROW; IMPROVED SURVIVAL; MULTIPLE-MYELOMA AB Hematopoietic stern cell transplantation provides the only potential curative option in many patients with hematological malignancies. Finding a suitably matched donor in a timely manner is often difficult. However, most patients have a partially HLA-mismatched (HLA-haploidentical) first-degree relative readily available. Historically, HLA-haploidentical bone marrow transplantation (BMT) has been considered extremely high risk due to high rates of life-threatening graft-versus-host disease (GVHD) and non-relapse mortality (NRM). Modifications of the stem cell graft, such as T-cell depletion, have resulted in poor rates of engraftment. We have recently completed a phase II clinical trial of nonmyeloablative HLA-haploidentical hematopoietic BMT followed by post-transplantation high-cyclophosphamide. High-dose cyclophosphamide has been shown to create immunogenic tolerance by specifically killing activated mature T-cells. As a result, alloreactive T-cells in the donor graft are selectively destroyed thereby decreasing the incidence of severe GVHD. As well, host-versus-graft reactive T-cells are also selectively eliminated thereby increasing rates of engraftment. Among 210 patients with hematological malignancies receiving nonmyeloablative, HLA-haploidentical BMT with post-transplantation cyclophosphamide, the rate of sustained donor cell engraftment has been 87%. The cumulative incidence of grade 2-4 acute GVHD is 27%, grade 3-4 acute GVHD is 5% and chronic GVHD is 15%. Interestingly, increasing HLA disparity between donor and recipient was not associated with increasing incidence of GVHD or decreased event-free survival. Nonmyeloablative haploidentical stem cell transplantation with post-transplantation cyclophosphamide seems to be a promising, potentially curative, option for patients with hematological malignancies who either lack an HLA-matched related or unrelated donor, or in whom a myeloablative preparative regimen is contraindicated due to significant co-morbidities or history of extensive pre-treatment. Published by Elsevier Ltd. C1 [Munchel, Ashley T.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Div Pediat Oncol, Baltimore, MD USA. [Munchel, Ashley T.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Kasamon, Yvette L.; Fuchs, Ephraim J.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Div Hematol Malignancies, Baltimore, MD USA. RP Fuchs, EJ (reprint author), 288 Canc Res Bldg,1650 Orleans St, Baltimore, MD 21287 USA. EM fuchsep@jhmi.edu FU National Cancer Institute [P01 CA15396] FX Supported by P01 CA15396 from the National Cancer Institute. NR 54 TC 23 Z9 24 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD SEP PY 2011 VL 24 IS 3 BP 359 EP 368 DI 10.1016/j.beha.2011.05.001 PG 10 WC Hematology SC Hematology GA 830KH UT WOS:000295655400006 PM 21925089 ER PT J AU Rane, NS Sandhu, AK Zhawar, VS Kaur, G Popescu, NC Kandpal, RP Jhanwar-Uniyal, M Athwal, RS AF Rane, Neena S. Sandhu, Arbansjit K. Zhawar, Vikramjit S. Kaur, Gurpreet Popescu, Nicholas C. Kandpal, Raj P. Jhanwar-Uniyal, Meena Athwal, Raghbir S. TI Restoration of Senescence in Breast and Ovarian Cancer Cells Following the Transfer of the YAC Carrying SEN6A Gene Located at 6q16.3 SO CANCER GENOMICS & PROTEOMICS LA English DT Article DE Cell senescence; SEN6A gene; breast cancer; ovarian cancer ID YEAST ARTIFICIAL CHROMOSOMES; IMMORTAL HUMAN FIBROBLASTS; REPLICATIVE SENESCENCE; CELLULAR SENESCENCE; PROSTATE-CANCER; TUMOR-CELLS; 6Q; TUMORIGENICITY; IDENTIFICATION; PROGRESSION AB We previously located a senescence gene locus (SEN6A), at chromosome 6q14-21 by a functional strategy using chromosome transfer into immortal ovarian tumor cells. To further elucidate the SEN6A locus, intact chromosome 6 or 6q was transferred into rat ovarian tumor cells and a panel of immortal revertant clones of senescent cells was generated. The panel of independent colonies as well as mixed populations of revertant cells was analyzed for the presence or absence of chromosome 6 specific markers. These investigations led to the identification of a fine deletion of approximately 1cM at chromosomal interval 6q16.3. A contiguous stretch containing five yeast artificial chromosome (YAC) clones was constructed across the deleted region. The non-chimeric YAC clones were retrofitted and transferred into mouse A9 cells by spheroplast fusion to generate YAC/A9 hybrids. YAC DNA present in YAC/A9 hybrids was subsequently transferred by microcell fusion into immortal tumor cells, and the hybrid cells were characterized for their senescence phenotype. Using this functional strategy, the transfer of YAC clone 966b10 was shown to restore senescence in both rat and human ovarian and breast tumor cells. Our results demonstrate that the SEN6A gene is carried on a 1 Mb YAC, 966b10, which maps at 6q16.3. C1 [Rane, Neena S.; Sandhu, Arbansjit K.; Zhawar, Vikramjit S.; Kaur, Gurpreet; Athwal, Raghbir S.] Temple Univ, Sch Med, Fels Inst Canc Res, Philadelphia, PA 19140 USA. [Popescu, Nicholas C.] NCI, NIH, Bethesda, MD 20892 USA. [Kandpal, Raj P.] Western Univ Hlth Sci, Dept Basic Med Sci, Pomona, CA 91766 USA. [Jhanwar-Uniyal, Meena] New York Med Coll, Dept Neurosurg Pathol, Valhalla, NY 10595 USA. RP Athwal, RS (reprint author), Temple Univ, Sch Med, Fels Inst Canc Res, 3307 N Broad St AHP,Room 202, Philadelphia, PA 19140 USA. EM rkandpal@westernu.edu; rathwal@temple.edu FU [NIH-CA7493]; [DAMD 17-99-1-9393]; [DAMD 17-02-1-0574]; [BCTR9830]; [BCTR1092]; [DAMD 17-99-9394] FX Work presented in this paper was supported in part by grants NIH-CA7493, DAMD 17-99-1-9393, DAMD 17-02-1-0574, BCTR9830 and BCTR1092 to RSA and DAMD 17-99-9394 to RPK. NR 35 TC 2 Z9 2 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 1109-6535 J9 CANCER GENOM PROTEOM JI Cancer Genomics Proteomics PD SEP-OCT PY 2011 VL 8 IS 5 BP 227 EP 233 PG 7 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 830PF UT WOS:000295668200002 PM 21980037 ER PT J AU Zohreh, R Reza, NR Asad, VR Mohammad-Reza, S Ziba, R Abbas, P AF Zohreh, Rahimi Reza, Nourozi-Rad Asad, Vaisi-Raygani Mohammad-Reza, Saidi Ziba, Rahimi Abbas, Parsian TI Association between cholesteryl ester transfer protein taqIB variants and risk of coronary artery disease in population of west of Iran SO CLINICAL BIOCHEMISTRY LA English DT Meeting Abstract DE CETP TaqIB; Coronary artery disease; HDL-C C1 [Zohreh, Rahimi; Reza, Nourozi-Rad; Asad, Vaisi-Raygani] Sch Med, Dept Biochem, Kermanshah, Iran. [Mohammad-Reza, Saidi] Sch Med, Dept Cardiol, Kermanshah, Iran. [Ziba, Rahimi] Med Biol Res Ctr, Kermanshah, Iran. [Abbas, Parsian] NIAAA, Div Neurosci Behav, NIH, Rockville, MD 20852 USA. EM rahimizus@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 J9 CLIN BIOCHEM JI Clin. Biochem. PD SEP PY 2011 VL 44 IS 13 SU S BP S282 EP S282 DI 10.1016/j.clinbiochem.2011.08.702 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 827OK UT WOS:000295437601315 ER PT J AU Dimitrakakis, C AF Dimitrakakis, Constantine TI Androgens and Breast Cancer in Men and Women SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Androgens; Testosterone; Breast cancer; Hormone therapy; Menopause; Male breast cancer ID HORMONE-REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; CAG REPEAT POLYMORPHISM; POSTMENOPAUSAL WOMEN; PROSTATE-CANCER; SEX-HORMONES; RISK-FACTORS; MAMMOGRAPHIC DENSITY; SERUM CONCENTRATIONS; PREMENOPAUSAL WOMEN AB Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Clinical and nonhuman primate studies support the notion that androgens inhibit mammary proliferation and, thus, may protect from breast cancer. On the other hand, administration of conventional estrogen treatment suppresses endogenous androgens and may, thus, enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk, but the impact of this combined use on mammary gland homeostasis still needs evaluation. C1 [Dimitrakakis, Constantine] NICHHD, Dev Endocrinol Branch, NIH, CRC, Bethesda, MD 20892 USA. [Dimitrakakis, Constantine] Univ Athens, Sch Med, Dept Obstet & Gynecol 1, Alexandra Hosp, Athens 11528, Greece. RP Dimitrakakis, C (reprint author), NICHHD, Dev Endocrinol Branch, NIH, CRC, Room 1-3330,10 Ctr Dr,MSC-1103, Bethesda, MD 20892 USA. EM dimitrac@mail.nih.gov NR 73 TC 11 Z9 11 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD SEP PY 2011 VL 40 IS 3 BP 533 EP + DI 10.1016/j.ecl.2011.05.007 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 829RN UT WOS:000295602100008 PM 21889719 ER PT J AU Andreani, A Granaiola, M Leoni, A Locatelli, A Morigi, R Rambaldi, M Varoli, L Lannigan, D Smith, J Scudiero, D Kondapaka, S Shoemaker, RH AF Andreani, Aldo Granaiola, Massimiliano Leoni, Alberto Locatelli, Alessandra Morigi, Rita Rambaldi, Mirella Varoli, Lucilla Lannigan, Deborah Smith, Jeff Scudiero, Dominic Kondapaka, Sudhir Shoemaker, Robert H. TI Imidazo[2,1-b]thiazole guanylhydrazones as RSK2 inhibitors [1] SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Imidazo[2,1-b]thiazole; Guanylhydrazones; Antitumor activity; RSK2 ID POTENTIAL ANTITUMOR AGENTS; TERMINAL KINASE DOMAIN; S6 KINASE; IN-VIVO; IDENTIFICATION; CELLS AB The activity of a series of imidazo[2,1-b]thiazole guanylhydrazones as inhibitors of p90 ribosomal S6 kinase 2 (RSK2) is described. It was found that a small subset of compounds show both potent inhibition of RSK2 kinase activity and tumor cell growth in vitro. Detailed study of one of the most active compounds indicates a high degree of selectivity for inhibition of RSK2 compared to a spectrum of other related kinases. Selective inhibition of the MCF-7 breast tumor cell line compared to MCF-10A non-transformed cells, as well as selective inhibition of the biomarker GSK3 provides evidence that the compounds can affect the RSK2 target in cells. (C) 2011 Elsevier Masson SAS. All rights reserved. C1 [Andreani, Aldo; Granaiola, Massimiliano; Leoni, Alberto; Locatelli, Alessandra; Morigi, Rita; Rambaldi, Mirella; Varoli, Lucilla] Univ Bologna, Dipartimento Sci Farmaceut, I-40126 Bologna, Italy. [Lannigan, Deborah] Univ Virginia, Dept Microbiol, Ctr Cell Signaling, Charlottesville, VA 22908 USA. [Smith, Jeff] Univ Virginia, Dept Pathol, Ctr Cell Signaling, Charlottesville, VA 22908 USA. [Scudiero, Dominic] NCI, SAIC Frederick, Frederick, MD 21702 USA. [Kondapaka, Sudhir; Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, 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; shoemakr@mail.nih.gov FU University of Bologna; Division of Cancer Treatment of the National Cancer Institute FX This work has been supported by a grant from the University of Bologna and by the Developmental Therapeutics Program of the Division of Cancer Treatment of the National Cancer Institute. NR 23 TC 28 Z9 29 U1 0 U2 10 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD SEP PY 2011 VL 46 IS 9 BP 4311 EP 4323 DI 10.1016/j.ejmech.2011.07.001 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 824YF UT WOS:000295237400084 PM 21794960 ER PT J AU Obasogie, OK Duster, T AF Obasogie, Osagie K. Duster, Troy TI All That Glitters Isn't Gold SO HASTINGS CENTER REPORT LA English DT Article ID DATABASES C1 [Obasogie, Osagie K.] Univ Calif San Francisco, Dept Social & Behav Sci, San Francisco, CA 94143 USA. [Obasogie, Osagie K.] Ctr Genet & Soc, Berkeley, CA USA. [Duster, Troy] NYU, New York, NY 10003 USA. [Duster, Troy] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Duster, Troy] NIH, Dept Educ Advisory Comm Eth Legal & Social Issues, Human Genome Project, Bethesda, MD USA. RP Obasogie, OK (reprint author), Univ Calif San Francisco, Dept Social & Behav Sci, San Francisco, CA 94143 USA. NR 13 TC 1 Z9 1 U1 0 U2 1 PU HASTINGS CENTER PI BRIARCLIFF MANOR PA 255 ELM ROAD, BRIARCLIFF MANOR, NY 10510 USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD SEP-OCT PY 2011 VL 41 IS 5 BP 15 EP 18 PG 4 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 825DV UT WOS:000295252000015 PM 21980894 ER PT J AU Breman, JG Bridbord, K Kupfer, LE Glass, RI AF Breman, Joel G. Bridbord, Kenneth Kupfer, Linda E. Glass, Roger I. TI Global Health: The Fogarty International Center, National Institutes of Health: Vision and Mission, Programs, and Accomplishments SO INFECTIOUS DISEASE CLINICS OF NORTH AMERICA LA English DT Article DE Fogarty International Center; NIH; Research training in poor countries; Infectious and noninfectious diseases training ID DISEASE-CONTROL PRIORITIES; INFECTIOUS-DISEASES; HIV TRANSMISSION; RISK-FACTORS; INFLUENZA; ZAMBIA; TUBERCULOSIS; MORTALITY; CHILDREN; SERVICES AB The Fogarty International Center (FIC) of the US National Institutes of Health has supported long-term training and research for more than 3600 future leaders in science and public health from low-income and middle-income countries; tens of thousands more persons have received short-term training. More than 23 extramural training and research programs plus an intramural program are now operating. Newer FIC training programs are addressing chronic, noncommunicable diseases and strengthening the quality of medical schools and health care provider training. Most FIC trainees return to their countries of origin, where they mentor and train thousands of individuals in their home countries. C1 [Breman, Joel G.; Bridbord, Kenneth; Kupfer, Linda E.; Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Breman, JG (reprint author), NIH, Fogarty Int Ctr, 16 Ctr Dr, Bethesda, MD 20892 USA. EM joel.breman@nih.gov OI Kupfer, Linda/0000-0002-6886-6818 FU Intramural NIH HHS [Z99 TW999999] NR 57 TC 6 Z9 6 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0891-5520 EI 1557-9824 J9 INFECT DIS CLIN N AM JI Infect. Dis. Clin. North Am. PD SEP PY 2011 VL 25 IS 3 BP 511 EP + DI 10.1016/j.idc.2011.06.003 PG 27 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 828HT UT WOS:000295492800004 PM 21896356 ER PT J AU Hanna, EB Chen, AY Roe, MT Wiviott, SD Fox, CS Saucedo, JF AF Hanna, Elias B. Chen, Anita Y. Roe, Matthew T. Wiviott, Stephen D. Fox, Caroline S. Saucedo, Jorge F. TI Characteristics and In-Hospital Outcomes of Patients With Non-ST-Segment Elevation Myocardial Infarction and Chronic Kidney Disease Undergoing Percutaneous Coronary Intervention SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE acute coronary syndrome; chronic kidney disease; myocardial infarction; percutaneous coronary intervention ID RENAL-INSUFFICIENCY; SUBSEQUENT MORTALITY; CREATININE CLEARANCE; CLINICAL-OUTCOMES; RANDOMIZED-TRIAL; BIVALIRUDIN; ASSOCIATION; FAILURE; IMPACT; REVASCULARIZATION AB Objectives This study sought to evaluate the characteristics, therapies, and outcomes of patients with chronic kidney disease (CKD) presenting with non-ST-segment elevation myocardial infarction (NSTEMI) and managed with percutaneous coronary intervention (PCI). This specific population has not been evaluated previously. Background Among patients with acute coronary syndrome, the presence of renal dysfunction is associated with an increased risk of death and major bleeding. Methods We examined data on 40,074 NSTEMI patients managed with PCI who were captured by the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) registry. Patients were divided according to baseline renal function in 4 groups: no CKD and CKD stages 3, 4, and 5. Results Overall, 31.1% (n = 12,045) of patients with NSTEMI undergoing PCI had CKD. Compared with patients with normal renal function, CKD patients managed with PCI had significantly more history of myocardial infarction, heart failure, and more 3-vessel coronary artery disease. They received fewer antithrombotic therapies but were treated more frequently with bivalirudin. In addition, they had significantly higher rates of in-hospital mortality and major bleeding. CKD stage 4 was associated with the highest risk of adverse events relative to no CKD. The multivariable adjusted odds ratios of in-hospital mortality for CKD stages 3, 4, and 5 relative to no CKD were 2.0, 2.8, and 2.6, respectively (global p value <0.0001), and the analogous adjusted odds ratios of major bleeding were 15, 2.8, and 1.8, respectively (global p value <0.0001). Conclusions CKD patients presenting with NSTEMI and managed with PCI have more comorbidities and receive guideline-recommended therapies less frequently than do patients without CKD. CKD is strongly associated with in-hospital mortality and bleeding in NSTEMI patients undergoing PCI. (J Am Coll Cardiol Intv 2011;4:1002-8) 2011 (C) by the American College of Cardiology Foundation C1 [Hanna, Elias B.] Louisiana State Univ, Dept Med, Cardiovasc Sect, New Orleans, LA 70112 USA. [Chen, Anita Y.; Roe, Matthew T.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Wiviott, Stephen D.] Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02115 USA. [Wiviott, Stephen D.] Brigham & Womens Hosp, Thrombolysis Myocardial Infarct Study Grp, Boston, MA 02115 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Saucedo, Jorge F.] Univ Oklahoma, Hlth Sci Ctr, Cardiovasc Div, Oklahoma City, OK USA. RP Hanna, EB (reprint author), Louisiana State Univ, Dept Med, Cardiovasc Sect, 1542 Tulane Ave,Room 323, New Orleans, LA 70112 USA. EM ehanna10@yahoo.com FU Eli Lilly; Roche; Bristol-Myers Squibb; American College of Cardiology; American Heart Association; KAI Pharmaceuticals; Sanofi Aventis; Merck; Orexigen; Holsinn Pharmaceuticals; AstraZeneca; Regeneron; Daiichi Sankyo; Schering-Plough; Pfizer Inc.; Abbott; Boston Scientific; Medtronic FX From the *Department of Medicine, Cardiovascular Section, Louisiana State University, New Orleans, Louisiana; dagger Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina; double dagger Cardiovascular Division and Thrombolysis In Myocardial Infarction Study Group, Brigham and Women's Hospital, Boston, Massachusetts; Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and the parallel to National Heart, Lung, and Blood Institutes' Framingham Heart Study, Framingham, Massachusetts; Cardiovascular Division, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Dr. Roe has received research Binding and has been a consultant and member of the Speakers' Bureaus for the companies that fund the ACTION registry via the American College of Cardiology-Bristol-Myers Squibb/sanofi aventis and Schering-Plough; has received research funding from Eli Lilly, Roche, Bristol-Myers Squibb, American College of Cardiology, and the American Heart Association; and consulting fees or honoraria from KAI Pharmaceuticals, Bristol-Myers Squibb, Sanofi Aventis, Merck, Orexigen, Holsinn Pharmaceuticals, AstraZeneca, and Regeneron. Dr. Wiviott has been a consultant to sanofi-aventis, Bristol-Myers Squibb, and AstraZeneca; has received research support and/or honoraria from Eli Lilly, Daiichi Sankyo, AstraZeneca, Schering-Plough, Merck, and Pfizer Inc.; and does CME speaking for Eli Lilly, AstraZeneca, and Daiichi Sankyo. Dr. Saucedo has been a consultant to Eli Lilly, Bristol-Myers Squibb/sanofi-aventis, and The Medicines Company; and has received research support and/or honoraria from Schering-Plough, Pfizer Inc., Merck, Eli Lilly, Abbott, Boston Scientific, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 29 TC 32 Z9 34 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD SEP PY 2011 VL 4 IS 9 BP 1002 EP 1008 DI 10.1016/j.jcin.2011.05.022 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 829RU UT WOS:000295602800008 PM 21939940 ER PT J AU de Moraes, JC Toscano, CM de Barros, ENC Kemp, B Lievano, F Jacobson, S Afonso, AMS Strebel, PM Cairns, KL AF de Moraes, Jose Cassio Toscano, Cristiana M. de Barros, Eliana N. C. Kemp, Brigina Lievano, Fabio Jacobson, Steven Afonso, Ana Maria S. Strebel, Peter M. Cairns, K. Lisa CA VigiFex Grp TI Etiologies of Rash and Fever Illnesses in Campinas, Brazil SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; RUBELLA-LIKE ILLNESSES; MONOCLONAL-ANTIBODIES; COMMERCIAL TESTS; MEASLES; DIAGNOSIS; CHILDREN; SURVEILLANCE; IGM AB Background. Few population-based studies of infectious etiologies of fever-rash illnesses have been conducted. This study reports on enhanced febrile-rash illness surveillance in Campinas, Brazil, a setting of low measles and rubella virus transmission. Methods. Cases of febrile-rash illnesses in individuals aged < 40 years that occurred during the period 1 May 2003-30 May 2004 were reported. Blood samples were collected for laboratory diagnostic confirmation, which included testing for adenovirus, dengue virus, Epstein-Barr virus (EBV), enterovirus, human herpes virus 6 (HHV6), measles virus, parvovirus-B19, Rickettsia rickettsii, rubella virus, and group A streptococci (GAS) infections. Notification rates were compared with the prestudy period. Results. A total of 1248 cases were notified, of which 519 (42%) had laboratory diagnosis. Of these, HHV-6 (312 cases), EBV (66 cases), parvovirus (30 cases), rubella virus (30 cases), and GAS (30 cases) were the most frequent causes of infection. Only 10 rubella cases met the rubella clinical case definition currently in use. Notification rates were higher during the study than in the prestudy period (181 vs 52.3 cases per 100,000 population aged < 40 years). Conclusions. Stimulating a passive surveillance system enhanced its sensitivity and resulted in additional rubella cases detected. In settings with rubella elimination goals, rubella testing may be considered for all cases of febrile-rash illness, regardless of suspected clinical diagnosis. C1 [de Moraes, Jose Cassio] Santa Casa Sao Paulo Med Sci Univ, Sao Paulo, Brazil. [Afonso, Ana Maria S.] Inst Adolfo Lutz Sao Paulo, Sao Paulo, Brazil. [Toscano, Cristiana M.] Pan Amer Hlth Org, Brasilia, DF, Brazil. [de Barros, Eliana N. C.; Kemp, Brigina] Municipal Hlth Dept, Campinas, SP, Brazil. [Toscano, Cristiana M.; Lievano, Fabio; Strebel, Peter M.; Cairns, K. Lisa] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Jacobson, Steven] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Toscano, CM (reprint author), Av T-05,715 Apto,301 Setor Bueno, Goiania, Go, Brazil. EM ctoscano@terra.com.br RI Iats, Inct/K-2300-2013 FU US Centers for Disease Control and Prevention; Pan American Health Organization FX This work was supported by the US Centers for Disease Control and Prevention and the Pan American Health Organization. Laboratory and surveillance personnel were funded by the municipal and state health department. The Campinas Medicine and Surgery Society, State University of Campinas (UNICAMP), and PUC-Campinas University provided funds for the communication strategies and the symposium. NR 36 TC 5 Z9 6 U1 0 U2 0 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 SEP 1 PY 2011 VL 204 SU 2 BP S627 EP S636 DI 10.1093/infdis/jir490 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 828OO UT WOS:000295511800012 PM 21954258 ER PT J AU Taber, DR Stevens, J Lytle, LA Foreman, RD Moody, J Parra-Medina, D Pratt, CA AF Taber, Daniel R. Stevens, June Lytle, Leslie A. Foreman, Robyn D. Moody, Jamie Parra-Medina, Deborah Pratt, Charlotte A. TI Association Between School- and Nonschool-Based Activity Programs and Physical Activity in Adolescent Girls SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE accelerometry; intervention; sports; community ID ACADEMIC-ACHIEVEMENT; UNITED-STATES; SOCIAL DESIRABILITY; FEMALE ADOLESCENTS; AFRICAN-AMERICAN; CHILDREN; HEALTH; TRIAL; EDUCATION; YOUTH AB Background: Some researchers have questioned if activity programs would be more effective if based outside school (eg, community leagues) rather than within schools. This study compared participation in activity programs based within and outside of school, and estimated the associations between participation and moderate-vigorous physical activity (MVPA) among adolescent girls. Methods: Within the Trial of Activity for Adolescent Girls, independent samples of 1559 6th-grade girls (age 11 to 12) and 3282 8th-grade girls (age 13 to 14) reported program participation using questionnaires. MVPA was measured using accelerometers. Linear mixed models accounted for school and site clustering. Results: Sixth-grade girls reported 5 times as many programs outside school as within school (4.1 vs. 0.8); daily MVPA was 0.29 minutes higher (1.2% of the mean) for each additional program outside school. Compared with 6th-grade girls, 8th-grade girls participated in 1.3 fewer programs outside school, while programs' association with MVPA was unchanged. Conversely, school programs' association with MVPA was greater in 8th grade. Daily MVPA was 1.33 minutes higher per school program, and participation declined 0.13. Conclusion: Programs within and outside schools can both increase activity among adolescent girls. Intervention research should focus on increasing participation in school programs, and increasing movement during programs outside school. C1 [Taber, Daniel R.; Stevens, June] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Lytle, Leslie A.] Univ Minnesota, Dept Epidemiol & Community Hlth, Minneapolis, MN USA. [Foreman, Robyn D.] Johns Hopkins Univ, Dept Int Hlth, Baltimore, MD USA. [Moody, Jamie] San Diego State Univ, MOVE Me Muevo, San Diego, CA USA. [Parra-Medina, Deborah] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Pratt, Charlotte A.] NHLBI, Div Prevent & Populat Sci, NIH, Bethesda, MD USA. RP Taber, DR (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. FU NHLBI NIH HHS [HL66845, HL66852, HL66853, HL66855, HL66856, HL66857, HL66858, U01 HL066845, U01 HL066852, U01 HL066853, U01 HL066853-07, U01 HL066855, U01 HL066856, U01 HL066857, U01 HL066858] NR 39 TC 2 Z9 2 U1 5 U2 14 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD SEP PY 2011 VL 8 IS 7 BP 971 EP 977 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 825HD UT WOS:000295261000011 PM 21885888 ER PT J AU Hukriede, NA Dawid, IB AF Hukriede, Neil A. Dawid, Igor B. TI Making a Tubule the Noncanonical Way SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID PLANAR CELL POLARITY; CONVERGENT EXTENSION; EPITHELIAL TRANSFORMATION; METANEPHRIC MESENCHYME; KIDNEY DEVELOPMENT; XENOPUS-LAEVIS; PROTEIN DAAM1; MORPHOGENESIS; GASTRULATION; WNT-4 C1 [Dawid, Igor B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Hukriede, Neil A.] Univ Pittsburgh, Dept Dev Biol, Pittsburgh, PA USA. RP Dawid, IB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM idawid@mail.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [R01HD053287, R01 HD053287]; NIDDK NIH HHS [R01 DK069403, P30DK079307, R01DK069403, RC4DK090770, RC4 DK090770] NR 26 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD SEP PY 2011 VL 22 IS 9 BP 1575 EP 1577 DI 10.1681/ASN.2011070710 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 831CH UT WOS:000295705800002 PM 21836144 ER PT J AU Oster-Granite, ML Parisi, MA Abbeduto, L Berlin, DS Bodine, C Bynum, D Capone, G Collier, E Hall, D Kaeser, L Kaufmann, P Krischer, J Livingston, M McCabe, LL Pace, J Pfenninger, K Rasmussen, SA Reeves, RH Rubinstein, Y Sherman, S Terry, SF Whitten, MS Williams, S McCabe, ERB Maddox, YT AF Oster-Granite, Mary Lou Parisi, Melissa A. Abbeduto, Leonard Berlin, Dorit S. Bodine, Cathy Bynum, Dana Capone, George Collier, Elaine Hall, Dan Kaeser, Lisa Kaufmann, Petra Krischer, Jeffrey Livingston, Michelle McCabe, Linda L. Pace, Jill Pfenninger, Karl Rasmussen, Sonja A. Reeves, Roger H. Rubinstein, Yaffa Sherman, Stephanie Terry, Sharon F. Whitten, Michelle Sie Williams, Stephen McCabe, Edward R. B. Maddox, Yvonne T. TI Down syndrome: National conference on patient registries, research databases, and biobanks SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Down syndrome; Registry; Database; Biobank; Trisomy 21 ID UNITED-STATES; PREVALENCE; PEOPLE AB A December 2010 meeting, "Down Syndrome: National Conference on Patient Registries, Research Databases, and Biobanks," was jointly sponsored by the Eunice Kennedy Shriven National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH) in Bethesda, MD, and the Global Down Syndrome Foundation (GDSF)/Linda Crnic Institute for Down Syndrome based in Denver, CO. Approximately 70 attendees and organizers from various advocacy groups, federal agencies (Centers for Disease Control and Prevention, and various NIH Institutes, Centers, and Offices), members of industry, clinicians, and researchers from various academic institutions were greeted by Drs. Yvonne Maddox, Deputy Director of NICHD, and Edward McCabe, Executive Director of the Linda Crnic Institute for Down Syndrome. They charged the participants to focus on the separate issues of contact registries, research databases, and biobanks through both podium presentations and breakout session discussions. Among the breakout groups for each of the major sessions, participants were asked to generate responses to questions posed by the organizers concerning these three research resources as they related to Down syndrome and then to report back to the group at large with a summary of their discussions. This report represents a synthesis of the discussions and suggested approaches formulated by the group as a whole. C1 [Oster-Granite, Mary Lou; Parisi, Melissa A.; Bynum, Dana; Kaeser, Lisa; Pace, Jill; Maddox, Yvonne T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Abbeduto, Leonard] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. [Berlin, Dorit S.] Coriell Inst Med Res, Camden, NJ USA. [McCabe, Linda L.; McCabe, Edward R. B.] Univ Colorado Denver, Linda Crnic Inst Syndrome, Aurora, CO USA. [Capone, George] Hugo W Moser Kennedy Krieger Inst, Baltimore, MD USA. [Collier, Elaine] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. [Hall, Dan] NIMH, NIH, Bethesda, MD 20892 USA. [Kaufmann, Petra] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Krischer, Jeffrey] Univ S Florida, Coll Med, Tampa, FL USA. [Livingston, Michelle; Whitten, Michelle Sie] Global Syndrome Fdn, Denver, CO USA. [Rasmussen, Sonja A.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Reeves, Roger H.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Rubinstein, Yaffa] NIH, Off Rare Dis Res, Bethesda, MD 20892 USA. [Sherman, Stephanie] Emory Univ, Atlanta, GA 30322 USA. [Terry, Sharon F.] Genet Alliance, Washington, DC USA. [Williams, Stephen] SomaLogic Inc, Boulder, CO USA. RP Parisi, MA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM parisima@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Global Down Syndrome Foundation; Waisman Intellectual and Developmental Disabilities Research Center [P30HD003552]; NIGMS Human Genetic Cell Repository [HHS-N263-2009-00026C]; Rehabilitation Engineering Research Center for Advancing Cognitive Technologies, National Institute on Disability and Rehabilitation Research, US Department of Energy [H133E090003]; Rare Diseases Clinical Research Network Data Management and Coordinating Center [U54NS064808]; Colorado Clinical and Translational Science Institute, (Aurora) [UL1RR025780]; Coleman Institute for Cognitive Disabilities (Boulder); University of Colorado School of Medicine-Dean's Academic Enrichment; Department of Pediatrics; Health Resources and Services Administration cooperative agreement [U35MC15451]; NICHD [HHS-N275-2009-00011C] FX We thank the conference attendees for active participation and contribution of ideas, Palladian Partners for administrative and logistical support, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Global Down Syndrome Foundation for their organizational and financial support of the conference.; The material presented at the conference was supported, in part, by: the Waisman Intellectual and Developmental Disabilities Research Center (P30HD003552; L Abbeduto); the NIGMS Human Genetic Cell Repository Contract (HHS-N263-2009-00026C; D. Berlin); the Rehabilitation Engineering Research Center for Advancing Cognitive Technologies, National Institute on Disability and Rehabilitation Research, US Department of Energy (H133E090003; C. Bodine); the Rare Diseases Clinical Research Network Data Management and Coordinating Center (U54NS064808; J. Krischer); the Colorado Clinical and Translational Science Institute (UL1RR025780; K. Pfenninger), the Children's Hospital Research Institute (Aurora, CO; K. Pfenninger), the Coleman Institute for Cognitive Disabilities (Boulder, CO; K. Pfenninger), the University of Colorado School of Medicine-Dean's Academic Enrichment fund, and the Department of Pediatrics (K. Pfenninger); the Health Resources and Services Administration cooperative agreement (U35MC15451; S. Terry). Funding for the NICHD Brain and Tissue Bank for Developmental Disorders as discussed by M.Parisi is provided by NICHD contract HHS-N275-2009-00011C. NR 14 TC 17 Z9 18 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2011 VL 104 IS 1-2 SI SI BP 13 EP 22 DI 10.1016/j.ymgme.2011.07.005 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 823UF UT WOS:000295151300005 PM 21835664 ER PT J AU Choi, JH Stubblefield, B Cookson, MR Goldin, E Velayati, A Tayebi, N Sidransky, E AF Choi, Jae Hyuk Stubblefield, Barbara Cookson, Mark R. Goldin, Ehud Velayati, Arash Tayebi, Nahid Sidransky, Ellen TI Aggregation of alpha-synuclein in brain samples from subjects with glucocerebrosidase mutations SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Gaudier disease; Glucocerebrosidase; alpha-synuclein; Lewy body; Synucleinopathies; Parkinson disease ID GAUCHER-DISEASE; PARKINSONS-DISEASE; GENE; SUSCEPTIBILITY; DEMENTIA; ONSET; GBA AB Recent studies show an increased frequency of mutations in the glucocerebrosidase gene (GBA1) in patients with alpha-synucleinopathies including Parkinson disease. Some patients with Gaucher disease (GD) develop parkinsonism with et-synuclein-positive inclusions post mortem. Proteins were extracted from the cerebral cortex of subjects with synucleinopathies with and without GBA1 mutations, controls and patients with GD. Patients with GBA1-associated synucleinopathies showed aggregation of oligomeric forms of alpha-synuclein in the SOS-soluble fraction, while only monomeric forms of alpha-synuclein were seen in subjects with GBA1 mutations without parkinsonism. Thus, brains from patients with GBA1-associated parkinsonism show biochemical characteristics typical of Lewy body disorders. Published by Elsevier Inc. C1 [Choi, Jae Hyuk; Stubblefield, Barbara; Goldin, Ehud; Velayati, Arash; Tayebi, Nahid; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Cookson, Mark R.] NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, 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 Institute on Aging; National Institutes of Health FX This research was supported by the Intramural Research Programs of the National Human Genome Research Institute, National Institute on Aging and the National Institutes of Health. NR 18 TC 28 Z9 28 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2011 VL 104 IS 1-2 SI SI BP 185 EP 188 DI 10.1016/j.ymgme.2011.06.008 PG 4 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 823UF UT WOS:000295151300030 PM 21742527 ER PT J AU Solomon, BD Pineda-Alvarez, DE Hadley, DW Teer, JK Cherukuri, PF Hansen, NF Cruz, P Young, AC Blakesley, RW Lanpher, B Gibson, SM Sincan, M Chandrasekharappa, SC Mullikin, JC AF Solomon, Benjamin D. Pineda-Alvarez, Daniel E. Hadley, Donald W. Teer, Jamie K. Cherukuri, Praveen F. Hansen, Nancy F. Cruz, Pedro Young, Alice C. Blakesley, Robert W. Lanpher, Brendan Gibson, Stephanie Mayfield Sincan, Murat Chandrasekharappa, Settara C. Mullikin, James C. CA NISC Comparative Sequencing TI Personalized genomic medicine: Lessons from the exome SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Whole-exome sequencing; CPSI; Pulmonary artery hypertension; VACTERL ID CONGENITAL HEART-SURGERY; ESOPHAGEAL ATRESIA; ASSOCIATION; DEFECTS; SPECTRUM AB While genomic sequencing methods are powerful tools in the discovery of the genetic underpinnings of human disease, incidentally-revealed novel genomic risk factors may be equally important, both scientifically, and as relates to direct patient care. We performed whole-exome sequencing on a child with VACTERL association who suffered severe post-surgical neonatal pulmonary hypertension, and identified a potential novel genetic risk factor for this complication: a heterozygous mutation in CPSI. Newborn screening results from this patient's monozygotic twin provided evidence that this mutation, in combination with an environmental trigger (in this case, surgery), may have resulted in pulmonary artery hypertension due to inadequate nitric oxide production. Identification of this genetic risk factor allows for targeted medical preventative measures in this patient as well as relatives with the same mutation, and illustrates the power of incidental medical information unearthed by whole-exome sequencing. Published by Elsevier Inc. C1 [Solomon, Benjamin D.; Pineda-Alvarez, Daniel E.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Hadley, Donald W.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [NISC Comparative Sequencing] NHGRI, Intramural Sequencing Ctr, NIH, Rockville, MD 20852 USA. [Teer, Jamie K.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Cherukuri, Praveen F.; Hansen, Nancy F.; Cruz, Pedro; Young, Alice C.; Blakesley, Robert W.; Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Lanpher, Brendan] Childrens Natl Med Ctr, Dept Genet & Metab, Washington, DC 20010 USA. [Gibson, Stephanie Mayfield] Kentucky Dept Publ Hlth, Frankfort, KY 40621 USA. [Sincan, Murat] NIH, Undiagnosed Dis Program, Bethesda, MD 20892 USA. [Chandrasekharappa, Settara C.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Solomon, BD (reprint author), NHGRI, Med Genet Branch, NIH, MSC 3717,Bldg 35,Room 1B-207, Bethesda, MD 20892 USA. EM solomonb@mail.nih.gov; pinedaad@mail.nih.gov; dhadley@nhgri.nih.gov; teer@mail.nih.gov; cherukur@mail.nih.gov; nhansen@mail.nih.gov; cruzp@mail.nih.gov; alicey@mail.nih.gov; rblakesl@nhgri.nih.gov; BLanpher@cnmc.org; StephanieK.Mayfield@ky.gov; murat.sincan@nih.gov; sc84g@nih.gov; mullikin@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. We would like to extend our gratitude to the family for participating in this study. Sanger sequencing support was provided by the core DNA sequencing facility, National Institute of Neurological Disorders and Stroke. We would like to thank Dr. William A. Gahl for use of data (collected through the National Institutes of Health Undiagnosed Diseases Program) as controls. We would also like to thank Dr. Maximilian Muenke for his mentoring and support. NR 18 TC 8 Z9 9 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2011 VL 104 IS 1-2 SI SI BP 189 EP 191 DI 10.1016/j.ymgme.2011.06.022 PG 3 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 823UF UT WOS:000295151300031 PM 21767969 ER PT J AU Franca, A Aggarwal, P Barsov, EV Kozlov, SV Dobrovolskaia, MA Gonzalez-Fernandez, A AF Franca, Angela Aggarwal, Parag Barsov, Eugene V. Kozlov, Serguei V. Dobrovolskaia, Marina A. Gonzalez-Fernandez, Africa TI Macrophage scavenger receptor A mediates the uptake of gold colloids by macrophages in vitro SO NANOMEDICINE LA English DT Article DE cellular uptake; gold nanoparticle; phagocytosis; pinocytosis; scavenger receptor ID NANOPARTICLES; PROTEIN; SIZE; RECOGNITION; DELIVERY; BINDING; SYSTEM; CORONA; CELLS; FATE AB Aims: While numerous studies have reported on nanoparticle uptake by phagocytic cells, the mechanisms of this uptake are poorly understood. A metastudy of research focusing on biological particulate matter has postulated that nanoparticles cannot be phagocytosed and therefore must enter cells via pinocytosis. The purpose of this study was to identify the route(s) of uptake of gold nanoparticles in vitro and to determine if these route(s) depend on particle size. Materials & Methods: The parent RAW264.7 cell line and its derivatives, transduced with a virus carrying siRNA to macrophage scavenger receptor A, were used as model phagocytes. Citrate-stabilized gold colloids were used as model nanoparticles. We used chemical inhibitors known to interfere with specific routes of particulate uptake. We developed multifocal light microscopy methods including multifocal stack ana-lysis with NIH ImageJ software to analyze cell uptake. Results: Irrespective of size, gold nanoparticles are internalized by macrophages via multiple routes, including both phagocytosis and pinocytosis. If either route was blocked, the particles entered cells via the other route. Conclusion: Gold nanoparticles with hydrodynamic sizes below 100 nm can be phagocytosed. Phagocytosis of anionic gold colloids by RAW264.7 cells is mediated by macrophage scavenger receptor A. C1 [Franca, Angela; Gonzalez-Fernandez, Africa] Univ Vigo, Biomed Res Ctr CINBIO, Vigo 36310, Pontevedra, Spain. [Aggarwal, Parag; Barsov, Eugene V.; Kozlov, Serguei V.; Dobrovolskaia, Marina A.] SAIC Frederick Inc, NCI Frederick, Frederick, MD 21702 USA. RP Gonzalez-Fernandez, A (reprint author), Univ Vigo, Biomed Res Ctr CINBIO, Campus Lagoas Marcosende, Vigo 36310, Pontevedra, Spain. EM africa@uvigo.es RI Gonzalez-Fernandez, Africa/E-2641-2012; Franca, Angela/O-5560-2015; Nanotechnology Characterization Lab, NCL/K-8454-2012 OI Gonzalez-Fernandez, Africa/0000-0002-9226-4825; Franca, Angela/0000-0001-7117-6837; FU National Cancer Institute, NIH [N01-CO-12400, HHSN261200800001E]; Leonardo da Vinci Program; Xunta de Galicia (INBIOMED) [2009/63]; Ministerio de Educacion y Ciencia (Nanobiomed); SUDOE-FEDER [IMMUNONET-SOE1/P1/E014] FX We would like to thank Xunta de Galicia (INBIOMED, 2009/63), Ministerio de Educacion y Ciencia (Nanobiomed, Consolider-Ingenio-2010) and SUDOE-FEDER (IMMUNONET-SOE1/P1/E014). We thank Jennifer Hall for help in manuscript preparation. We thank Jamie Rodriguez, Sarah Skoczen and Matthew Hansen for excellent technical assistance and Jeffrey Clogston for help with dynamic light scattering and inductively coupled plasma mass spectrometry data interpretation.; The study was supported in whole or, in part, by federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400 and 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. Angela Fran a performed her studies at NCL and University of Vigo as part of her undergraduate training sponsored by the Leonardo da Vinci Program. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 30 TC 39 Z9 40 U1 1 U2 27 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1743-5889 J9 NANOMEDICINE-UK JI Nanomedicine PD SEP PY 2011 VL 6 IS 7 BP 1175 EP 1188 DI 10.2217/NNM.11.41 PG 14 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA 831EW UT WOS:000295712500017 PM 21675859 ER PT J AU Gnanakaran, S Bhattacharya, T Daniels, M Keele, BF Hraber, PT Lapedes, AS Shen, TY Gaschen, B Krishnamoorthy, M Li, H Decker, JM Salazar-Gonzalez, JF Wang, SY Jiang, CL Gao, F Swanstrom, R Anderson, JA Ping, LH Cohen, MS Markowitz, M Goepfert, PA Saag, MS Eron, JJ Hicks, CB Blattner, WA Tomaras, GD Asmal, M Letvin, NL Gilbert, PB DeCamp, AC Magaret, CA Schief, WR Ban, YEA Zhang, M Soderberg, KA Sodroski, JG Haynes, BF Shaw, GM Hahn, BH Korber, B AF Gnanakaran, S. Bhattacharya, Tanmoy Daniels, Marcus Keele, Brandon F. Hraber, Peter T. Lapedes, Alan S. Shen, Tongye Gaschen, Brian Krishnamoorthy, Mohan Li, Hui Decker, Julie M. Salazar-Gonzalez, Jesus F. Wang, Shuyi Jiang, Chunlai Gao, Feng Swanstrom, Ronald Anderson, Jeffrey A. Ping, Li-Hua Cohen, Myron S. Markowitz, Martin Goepfert, Paul A. Saag, Michael S. Eron, Joseph J. Hicks, Charles B. Blattner, William A. Tomaras, Georgia D. Asmal, Mohammed Letvin, Norman L. Gilbert, Peter B. DeCamp, Allan C. Magaret, Craig A. Schief, William R. Ban, Yih-En Andrew Zhang, Ming Soderberg, Kelly A. Sodroski, Joseph G. Haynes, Barton F. Shaw, George M. Hahn, Beatrice H. Korber, Bette TI Recurrent Signature Patterns in HIV-1 B Clade Envelope Glycoproteins Associated with either Early or Chronic Infections SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODY-RESPONSES; N-LINKED GLYCOSYLATION; SUBTYPE-C INFECTION; CYTOPLASMIC TAIL; CROSS-VALIDATION; IMMUNE EVASION; HETEROSEXUAL TRANSMISSION; SELECTIVE TRANSMISSION; VACCINE DEVELOPMENT AB Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413-415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response. C1 [Gnanakaran, S.; Bhattacharya, Tanmoy; Daniels, Marcus; Hraber, Peter T.; Lapedes, Alan S.; Shen, Tongye; Gaschen, Brian; Krishnamoorthy, Mohan; Zhang, Ming; Korber, Bette] Los Alamos Natl Lab, Los Alamos, NM USA. [Bhattacharya, Tanmoy; Korber, Bette] Santa Fe Inst, Santa Fe, NM 87501 USA. [Keele, Brandon F.] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Keele, Brandon F.; Li, Hui; Decker, Julie M.; Salazar-Gonzalez, Jesus F.; Wang, Shuyi; Goepfert, Paul A.; Saag, Michael S.; Shaw, George M.; Hahn, Beatrice H.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Keele, Brandon F.; Li, Hui; Decker, Julie M.; Salazar-Gonzalez, Jesus F.; Wang, Shuyi; Goepfert, Paul A.; Saag, Michael S.; Shaw, George M.; Hahn, Beatrice H.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Shen, Tongye] Univ Tennessee, Ctr Biophys Mol, Knoxville, TN USA. [Shen, Tongye] Univ Tennessee, Dept Biochem Cellular & Mol Biol, Knoxville, TN USA. [Jiang, Chunlai] Jilin Univ, Sch Life Sci, Natl Engn Lab AIDS Vaccine, Changchun 130023, Peoples R China. [Jiang, Chunlai; Gao, Feng; Hicks, Charles B.; Tomaras, Georgia D.; Soderberg, Kelly A.; Haynes, Barton F.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Jiang, Chunlai; Gao, Feng; Hicks, Charles B.; Tomaras, Georgia D.; Soderberg, Kelly A.; Haynes, Barton F.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Jiang, Chunlai; Gao, Feng; Hicks, Charles B.; Tomaras, Georgia D.; Soderberg, Kelly A.; Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. [Swanstrom, Ronald; Anderson, Jeffrey A.; Ping, Li-Hua; Cohen, Myron S.; Eron, Joseph J.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC USA. [Swanstrom, Ronald; Anderson, Jeffrey A.; Ping, Li-Hua; Cohen, Myron S.; Eron, Joseph J.] Univ N Carolina, Div Infect Dis, Ctr AIDS Res, Chapel Hill, NC USA. [Markowitz, Martin] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [Blattner, William A.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Asmal, Mohammed; Letvin, Norman L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Letvin, Norman L.] Harvard Univ, Sch Med, Dept Med, Div Viral Pathogenesis, Boston, MA USA. [Gilbert, Peter B.; DeCamp, Allan C.; Magaret, Craig A.] Fred Hutchinson Canc Res Ctr, Vaccine Infect Dis Div, Seattle, WA 98104 USA. [Schief, William R.; Ban, Yih-En Andrew] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Ban, Yih-En Andrew] Arzeda Corp, Seattle, WA USA. [Zhang, Ming] Univ Georgia, Coll Publ Hlth, Dept Epidemiol & Biostat, Athens, GA 30602 USA. [Sodroski, Joseph G.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Gnanakaran, S (reprint author), Los Alamos Natl Lab, Los Alamos, NM USA. EM btk@lanl.gov RI Shen, Tongye/A-9718-2008; Bhattacharya, Tanmoy/J-8956-2013; Tomaras, Georgia/J-5041-2016; OI Shen, Tongye/0000-0003-1495-3104; Bhattacharya, Tanmoy/0000-0002-1060-652X; Gnanakaran, S/0000-0002-9368-3044; Korber, Bette/0000-0002-2026-5757; Hraber, Peter/0000-0002-2920-4897 FU Division of AIDS, NIAID, NIH for the Center for HIV/AIDS Vaccine Immunology (CHAVI) [AI06785] FX This work was funded by the a grant from the Division of AIDS, NIAID, NIH for the Center for HIV/AIDS Vaccine Immunology (CHAVI) AI06785. This study was undertaken as part of our response to the CHAVI call, however, and in this sense it was at the request of the NIH that we initiated this work, but it was implemented, details were designed, and the specific experiments and analyses undertaken by CHAVI consortium. The supercomputing facility at Los Alamos National Laboratory also contributed computational resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 122 TC 63 Z9 64 U1 3 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2011 VL 7 IS 9 AR e1002209 DI 10.1371/journal.ppat.1002209 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 827DY UT WOS:000295409000017 PM 21980282 ER PT J AU Park, SW Klotzsche, M Wilson, DJ Boshoff, HI Eoh, H Manjunatha, U Blumenthal, A Rhee, K Barry, CE Aldrich, CC Ehrt, S Schnappinger, D AF Park, Sae Woong Klotzsche, Marcus Wilson, Daniel J. Boshoff, Helena I. Eoh, Hyungjin Manjunatha, Ujjini Blumenthal, Antje Rhee, Kyu Barry, Clifton E., III Aldrich, Courtney C. Ehrt, Sabine Schnappinger, Dirk TI Evaluating the Sensitivity of Mycobacterium tuberculosis to Biotin Deprivation Using Regulated Gene Expression SO PLOS PATHOGENS LA English DT Article ID COENZYME-A CARBOXYLASE; STRUCTURAL-CHARACTERIZATION; COA CARBOXYLASE; OUTER-MEMBRANE; ACID; AMICLENOMYCIN; BIOSYNTHESIS; IDENTIFICATION; SMEGMATIS; SURVIVAL AB In the search for new drug targets, we evaluated the biotin synthetic pathway of Mycobacterium tuberculosis (Mtb) and constructed an Mtb mutant lacking the biotin biosynthetic enzyme 7,8-diaminopelargonic acid synthase, BioA. In biotin-free synthetic media, Delta bioA did not produce wild-type levels of biotinylated proteins, and therefore did not grow and lost viability. Delta bioA was also unable to establish infection in mice. Conditionally-regulated knockdown strains of Mtb similarly exhibited impaired bacterial growth and viability in vitro and in mice, irrespective of the timing of transcriptional silencing. Biochemical studies further showed that BioA activity has to be reduced by approximately 99% to prevent growth. These studies thus establish that de novo biotin synthesis is essential for Mtb to establish and maintain a chronic infection in a murine model of TB. Moreover, these studies provide an experimental strategy to systematically rank the in vivo value of potential drug targets in Mtb and other pathogens. C1 [Park, Sae Woong; Klotzsche, Marcus; Blumenthal, Antje; Ehrt, Sabine; Schnappinger, Dirk] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY USA. [Wilson, Daniel J.; Aldrich, Courtney C.] Univ Minnesota, Ctr Drug Design, Minneapolis, MN USA. [Boshoff, Helena I.; Barry, Clifton E., III] NIAID, TB Res Sect, Bethesda, MD 20892 USA. [Eoh, Hyungjin; Rhee, Kyu] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Manjunatha, Ujjini] Novartis Inst Trop Dis, Singapore, Singapore. RP Park, SW (reprint author), Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY USA. EM sae2004@med.cornell.edu; dis2003@med.cornell.edu RI Barry, III, Clifton/H-3839-2012; Blumenthal, Antje/A-3608-2011 OI Blumenthal, Antje/0000-0003-3673-7015 FU Bill and Melinda Gates Foundation [42848]; Wellcome Trust through the Grand Challenges in Global Health Initiative; National Institutes of Health [AI063446, AI09179]; NIAID, NIH; Korea Research Foundation [KRF-2008-357-C00135] FX This work was supported by grants from the Bill and Melinda Gates Foundation and the Wellcome Trust through the Grand Challenges in Global Health Initiative (to D. S., S. E., U. M., C. E. B. and C. C. A.), the Bill and Melinda Gates Foundation grant 42848 (to D. S.), the National Institutes of Health (AI063446 to S. E. and AI09179 to D. S. and C. C. A.), the Intramural Research Program of the NIAID, NIH (to C. E. B.) and the Korea Research Foundation (KRF-2008-357-C00135 to S. W. P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 36 Z9 36 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2011 VL 7 IS 9 AR e1002264 DI 10.1371/journal.ppat.1002264 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 827DY UT WOS:000295409000064 ER PT J AU Striebel, JF Race, B Meade-White, KD LaCasse, R Chesebro, B AF Striebel, James F. Race, Brent Meade-White, Kimberly D. LaCasse, Rachel Chesebro, Bruce TI Strain Specific Resistance to Murine Scrapie Associated with a Naturally Occurring Human Prion Protein Polymorphism at Residue 171 SO PLOS PATHOGENS LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; FATAL FAMILIAL INSOMNIA; TRANSGENIC MOUSE MODEL; SINGLE AMINO-ACID; INCUBATION-TIME; NEUROBLASTOMA-CELLS; PRP GENOTYPES; HAMSTER PRP; CODON 219 AB Transmissible spongiform encephalopathies (TSE) or prion diseases are neurodegenerative disorders associated with conversion of normal host prion protein (PrP) to a misfolded, protease-resistant form (PrPres). Genetic variations of prion protein in humans and animals can alter susceptibility to both familial and infectious prion diseases. The N171S PrP polymorphism is found mainly in humans of African descent, but its low incidence has precluded study of its possible influence on prion disease. Similar to previous experiments of others, for laboratory studies we created a transgenic model expressing the mouse PrP homolog, PrP-170S, of human PrP-171S. Since PrP polymorphisms can vary in their effects on different TSE diseases, we tested these mice with four different strains of mouse-adapted scrapie. Whereas 22L and ME7 scrapie strains induced typical clinical disease, neuropathology and accumulation of PrPres in all transgenic mice at 99-128 average days post-inoculation, strains RML and 79A produced clinical disease and PrPres formation in only a small subset of mice at very late times. When mice expressing both PrP-170S and PrP-170N were inoculated with RML scrapie, dominant-negative inhibition of disease did not occur, possibly because interaction of strain RML with PrP-170S was minimal. Surprisingly, in vitro PrP conversion using protein misfolding cyclic amplification (PMCA), did not reproduce the in vivo findings, suggesting that the resistance noted in live mice might be due to factors or conditions not present in vitro. These findings suggest that in vivo conversion of PrP-170S by RML and 79A scrapie strains was slow and inefficient. PrP-170S mice may be an example of the conformational selection model where the structure of some prion strains does not favor interactions with PrP molecules expressing certain polymorphisms. C1 [Striebel, James F.] NIAID, Persistent Viral Dis Lab, Hamilton, MT USA. NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Striebel, JF (reprint author), NIAID, Persistent Viral Dis Lab, Hamilton, MT USA. EM bchesebro@nih.gov FU National Institute of Allergy and Infectious Diseases, Division of Intramural Research FX This work was supported by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 82 TC 6 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 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2011 VL 7 IS 9 AR e1002275 DI 10.1371/journal.ppat.1002275 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 827DY UT WOS:000295409000071 PM 21980292 ER PT J AU Pavletic, AJ AF Pavletic, Adriana J. TI Hyperkalemia Induced by Excessive Consumption of Dried Fruits-Manifestation of an Undiagnosed Eating Disorder? SO PSYCHOSOMATICS LA English DT Letter C1 NIMH, Bethesda, MD 20892 USA. RP Pavletic, AJ (reprint author), NIMH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 MH999999] NR 5 TC 2 Z9 2 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2011 VL 52 IS 5 BP 494 EP 495 PG 2 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 825BD UT WOS:000295245000021 PM 21907077 ER PT J AU Grimes, WN Seal, RP Oesch, N Edwards, RH Diamond, JS AF Grimes, William N. Seal, Rebecca P. Oesch, Nicholas Edwards, Robert H. Diamond, Jeffrey S. TI Genetic targeting and physiological features of VGLUT3+amacrine cells SO VISUAL NEUROSCIENCE LA English DT Article DE Interneurons; Transgenic Cre mice; Synaptic physiology ID VESICULAR GLUTAMATE TRANSPORTER-3; ROD BIPOLAR CELLS; AMACRINE CELLS; GANGLION-CELLS; RAT RETINA; RABBIT RETINA; DIRECTION SELECTIVITY; SURROUND INHIBITION; ACTION-POTENTIALS; MOLECULAR-BASIS AB Amacrine cells constitute a diverse class of interneurons that contribute to visual signal processing in the inner retina, but surprisingly, little is known about the physiology of most amacrine cell subtypes. Here, we have taken advantage of the sparse expression of vesicular glutamate transporter 3 (VGLUT3) in the mammalian retina to target the expression of yellow fluorescent protein (YFP) to a unique population of amacrine cells using a new transgenic mouse line. Electrophysiological recordings made from YFP-positive (VGLUT3+) amacrine cells provide the first functional data regarding the active membrane properties and synaptic connections of this recently identified cell type. We found that VGLUT3+ amacrine cells receive direct synaptic input from bipolar cells via both N-methyl-d-aspartate receptors (NMDARs) and non-NMDARs. Voltage-gated sodium channels amplified these excitatory inputs but repetitive spiking was never observed. VGLUT3+ amacrine cells responded transiently to both light increments (ON response) and decrements (OFF response); ON responses consisted exclusively of inhibitory inputs, while OFF responses comprised both excitatory and inhibitory components, although the inhibitory conductance was larger in amplitude and longer in time course. The physiological properties and anatomical features of the VGLUT3+ amacrine cells suggest that this bistratified interneuron may play a role in disinhibitory signaling and/or crossover inhibition between parallel pathways in the retina. C1 [Grimes, William N.; Oesch, Nicholas; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. [Seal, Rebecca P.] Univ Pittsburgh, Sch Med, Dept Neurobiol, Pittsburgh, PA USA. [Edwards, Robert H.] Univ Calif San Francisco, Sch Med, Dept Physiol, San Francisco, CA 94143 USA. [Edwards, Robert H.] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA USA. RP Grimes, WN (reprint author), NINDS, Synapt Physiol Sect, NIH, 35 Convent Dr,Bldg 35,Room 3C-1000, Bethesda, MD 20892 USA. EM diamondj@ninds.nih.gov RI Diamond, Jeffrey/C-1835-2015; OI Diamond, Jeffrey/0000-0002-1770-2629; Seal, Rebecca/0000-0003-4955-703X FU National Institute of Neurological Disorders and Stroke; National Institute of Mental Health FX We thank Juliette Johnson for critically reading the manuscript and Hua Tian for breeding and genotyping the mice used in this study. W.N.G., N.O., and J.S.D. were supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. R.P.S. and R.H.E. were supported by National Institute of Mental Health. NR 41 TC 24 Z9 24 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0952-5238 J9 VISUAL NEUROSCI JI Visual Neurosci. PD SEP PY 2011 VL 28 IS 5 BP 381 EP 392 DI 10.1017/S0952523811000290 PG 12 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 830ZO UT WOS:000295698600001 PM 21864449 ER PT J AU Giallauria, F Ling, SM Schreiber, C Maggio, M Shetty, V Muller, D Vigorito, C Ferrucci, L Najjar, SS AF Giallauria, Francesco Ling, Shari M. Schreiber, Catherine Maggio, Marcello Shetty, Veena Muller, Denis Vigorito, Carlo Ferrucci, Luigi Najjar, Samer S. TI Arterial Stiffness and Bone Demineralization: The Baltimore Longitudinal Study of Aging SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE aging; arterial stiffness; Baltimore Longitudinal Study of Aging; blood pressure; bone demineralization; cortical bone area; hypertension; pulse wave velocity ID PULSE-WAVE VELOCITY; SERUM PHOSPHORUS LEVELS; POSTMENOPAUSAL WOMEN; MINERAL DENSITY; CORONARY ATHEROSCLEROSIS; OSTEOPOROTIC FRACTURES; CARDIOVASCULAR-DISEASE; PHOSPHATE LEVELS; OLDER-ADULTS; CALCIFICATION AB BACKGROUND Arterial stiffening is one of the hallmarks of vascular aging, and is an important risk factor for cardiovascular morbidity and mortality. Aging is also associated with bone demineralization. Accumulating evidence indicate that arterial stiffness and bone demineralization might share common pathways. The aims of this study were to evaluate whether the association between arterial stiffness and bone demineralization is independent of age, and to explore putative mechanisms that may mediate their relationship. METHODS A cross-sectional analysis was performed using data from 321 men (68 +/- 12 years) and 312 women (65 +/- 13 years) of the Baltimore Longitudinal Study of Aging. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) and cross-sectional cortical bone area (cCSA) was assessed at the level of the mid-tibia with computed tomography (CT) imaging. RESULTS Age was significantly correlated with PWV in men (r = 0.38, P < 0.0001) and women (r = 0.35, P < 0.0001). Age was associated with cCSA in women (r = -0.14, P = 0.0008), but not in men. Age-adjusted linear regression analysis showed a significant inverse association between PWV and cCSA, in women but not in men. The association between PWV and cCSA remained significant in women after adjusting for age, mean arterial pressure (MAP), obesity, menopause, drugs, alcohol intake, physical activity, renal function, serum calcium, and total estradiol concentration. CONCLUSIONS Independent of age and other shared risk factors, arterial stiffness is inversely related to cortical bone area in women. The sex-specific signaling and molecular pathways that putatively underlie the cross-talk between central arteries and bone are not completely understood. C1 [Najjar, Samer S.] Washington Hosp Ctr, Medstar Hlth Res Inst, Washington, DC 20010 USA. [Giallauria, Francesco; Ling, Shari M.; Schreiber, Catherine; Muller, Denis; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Giallauria, Francesco; Vigorito, Carlo] Univ Naples Federico 2, Dept Clin Med Cardiovasc & Immunol Sci, Naples, Italy. [Maggio, Marcello] Univ Parma, Dept Internal Med & Biomed Sci, Sect Geriatr, I-43100 Parma, Italy. [Shetty, Veena] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Najjar, SS (reprint author), Washington Hosp Ctr, Medstar Hlth Res Inst, Washington, DC 20010 USA. EM Samer.S.Najjar@Medstar.net RI Giallauria, Francesco/B-5681-2013 OI Giallauria, Francesco/0000-0003-4119-9397 FU National Institutes of Health, National Institute on Aging; "Programma di Scambi Internazionali con Universita ed Istituti di Ricerca Stranieri per la Mobilta di Breve Durata di Docenti,Ricercatori e Studiosi" of the University of Naples Federico "II" FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging; and in part by the "Programma di Scambi Internazionali con Universita ed Istituti di Ricerca Stranieri per la Mobilta di Breve Durata di Docenti,Ricercatori e Studiosi" of the University of Naples Federico "II". NR 36 TC 8 Z9 8 U1 0 U2 5 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 SEP PY 2011 VL 24 IS 9 BP 970 EP 975 DI 10.1038/ajh.2011.80 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 809GS UT WOS:000294040400005 PM 21544148 ER PT J AU Montasser, ME Gu, DF Chen, J Shimmin, LC Gu, C Kelly, TN Jaquish, CE Rice, T Rao, DC Cao, J Chen, JC Liu, DP Whelton, PK He, J Hixson, JE AF Montasser, May E. Gu, Donfeng Chen, Jing Shimmin, Lawrence C. Gu, Charles Kelly, Tanika N. Jaquish, Cashell E. Rice, Treva Rao, Dabeeru C. Cao, Jie Chen, Jichun Liu, De-Pei Whelton, Paul K. He, Jiang Hixson, James E. TI Interactions of Genetic Variants With Physical Activity Are Associated With Blood Pressure in Chinese: The GenSalt Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; epidemiology; gene by environment interaction; genetics; hypertension; physical activity ID ESSENTIAL-HYPERTENSION; APELIN; POLYMORPHISM; POPULATION; EXERCISE; SUBUNIT; OBESITY AB BACKGROUND Blood pressure (BP) homeostasis involves complex interactions among genetic and nongenetic factors, providing major challenges to dissection of the genetic components that influence BP and hypertension. In this study, we examine the effects of interaction of genetic variants with physical activity on BP in a relatively genetically homogenous cohort of rural Chinese villagers. METHODS Generalized estimating equations analysis was used to test for associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with variants in 24 genes in BP pathways (196 single-nucleotide polymorphisms (SNPs)) among 3,142 Chinese participants divided according to physical activity (active vs. inactive groups). RESULTS In the physically active group, two SNPs in NR3C2 were significantly associated with lower SBP, and a SNP in SCNN1B was significantly associated with lower SBP and DBP. In the physically inactive group, a SNP in APLNR was associated with lower SBP, a SNP in GNB3 (guanine nucleotide binding protein, beta polypeptide 3) was associated with higher SBP and DBP, and a SNP in BDKRB2 (bradykinin receptor B2) was associated with lower DBP. Cumulative effects in carriers of minor alleles of these SNPs showed reductions of SBP and DBP as large as 8 and 5 mm Hg, respectively, in the active individuals compared to inactive individuals carrying the same number of minor alleles. CONCLUSIONS We found that physical activity modifies the effects of genetic variants on BP. However, our results also show that active individuals with specific genotypes always have lower BP than inactive individuals with the same genotypes, demonstrating the overall beneficial effects of physical activity on BP. C1 [Montasser, May E.; Shimmin, Lawrence C.; Hixson, James E.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 78229 USA. [Gu, Donfeng; Cao, Jie; Chen, Jichun] Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100730, Peoples R China. [Gu, Donfeng; Cao, Jie; Chen, Jichun] Chinese Acad Med Sci, Fuwai Hosp, Beijing 100730, Peoples R China. [Gu, Donfeng; Cao, Jie; Chen, Jichun; Liu, De-Pei] Peking Union Med Coll, Beijing 100021, Peoples R China. [Gu, Donfeng; Cao, Jie; Chen, Jichun] Natl Ctr Cardiovasc Dis, Beijing, Peoples R China. [Chen, Jing] Tulane Univ, Sch Med, New Orleans, LA 70112 USA. [Gu, Charles; Rice, Treva; Rao, Dabeeru C.] Washington Univ, Sch Med, St Louis, MO USA. [Kelly, Tanika N.; He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Jaquish, Cashell E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Liu, De-Pei] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100730, Peoples R China. [Whelton, Paul K.] Loyola Univ Hlth Syst & Med Ctr, Chicago, IL USA. RP Hixson, JE (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 78229 USA. EM James.E.Hixson@uth.tmc.edu RI Gu, Charles/A-7934-2010 OI Gu, Charles/0000-0002-8527-8145 FU National Heart, Lung, and Blood Institute of the National Institutes of Health [U01HL072507]; National Institutes of Health [U01HL072507] FX This report is from the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study that is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (U01HL072507). Upsher-Smith Laboratories, has provided Klor-Con M20 potassium tablets for the GenSalt study. GenSalt Study Steering Committee: D.G., J.H. (Chair), J.E.H., C.E.J., D.L., D.C.R., P.K.W., and Zhijian Yao. GenSalt Collaborative Research Group: Tulane University Health Sciences Center, New Orleans, USA-J.H. (PI), Lydia A Bazzano, Chung-Shivan Chen, J.C., Mei Hao, Lee Hamm, T.N.K., Paul Muntner, Kristi Reynolds, P.K.W.,Wenjie Yang, and Qi Zhao. Washington University School of Medicine, St Louis, USA-D.C.R. (PI), Matthew Brown, C.G., Hongyan Huang, T.R., Karen Schwander, and Shiping Wang. University of Texas Health Sciences Center at Houston-J.E.H. (PI) and L.C.S. National Heart, Lung, and Blood Institute-C.E.J. Chinese Academy of Medical Sciences, Beijing, China-D.G. (PI), J.C., J.C.,Jingping Chen, Zhenhan Du, Jianfeng Huang, Hongwen Jiang, Jianxin Li, Xiaohua Liang, D.L., Xiangfeng Lu, Donghua Liu, Qunxia Mao, Dongling Sun, Hongwei Wang, Qianqian Wang, Xigui Wu, Ying Yang, and Dahai Yu. Shandong Academy of Medical Sciences, Shandong, China-Fanghong Lu (PI), Zhendong Liu, Shikuan Jin, Yingxin Zhao, Shangwen Sun, Shujian Wang, Qengjie Meng, Baojin Liu, Zhaodong Yang, and Chuanrui Wei. Shandong Center for Diseases Control and Prevention, Shandong, China-Jixiang Ma (PI), Jiyu Zhang, and Junli Tang. Zhengzhou University-Dongsheng Hu, Hongwei Wen, Chongjian Wang, Minghui Shen, Jingjing Pan, and Liming Yang. Xinle Traditional Chinese Medicine Hospital, Hebei, China-Xu Ji (PI), Rongyan Li, Haijun Zu, and Junwei Song. Ganyu Center for Disease Control and Prevention-Delin Wu (PI), Xushan Wang, and Xiaofeng Zhang. Xi'an Jiaotong University, Shanxi, China-Jianjun Mu (PI), Enrang Chen, Fuqiang Liu, and Guanji Wu. Chinese National Human Genome Center at Beijing-Zhi-Jian Yao (PI), Shufeng Chen, D.G., Hongfan Li, Laiyuan Wang, and Penghua Zhang. Support-National Institutes of Health grant U01HL072507 NR 39 TC 10 Z9 10 U1 0 U2 4 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 SEP PY 2011 VL 24 IS 9 BP 1035 EP 1040 DI 10.1038/ajh.2011.97 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 809GS UT WOS:000294040400014 PM 21654856 ER PT J AU Milner, GR Ferrell, RJ AF Milner, George R. Ferrell, Rebecca J. TI Conflict and death in a late prehistoric community in the American Midwest SO ANTHROPOLOGISCHER ANZEIGER LA English DT Article DE Prehistoric warfare; skeletal trauma; age estimation ID WEST-CENTRAL ILLINOIS; TRIBAL POPULATION; ONEOTA POPULATION; WARFARE; WAR; AGE; DISTRIBUTIONS; ARCHAEOLOGY; MORTALITY; LEWIS AB Over the past two decades, it has been recognized that the effects of intergroup conflict in prehistoric small-scale societies were greater than previously thought. Osteological evidence provides otherwise unobtainable information on the number of people who were killed, and who was most likely to become a casualty. One such site is Norris Farms #36 in the American Midwest, dating to ca. AD 1300. Skeletal evidence of injuries (blunt force trauma and arrow wounds), body mutilation (scalping, decapitation, and dismemberment), and scavenger damage indicate that one-third of the adults died in a series of ambushes, although children were mostly spared. Both young and old adults were killed, and the age distributions of the male and female victims were similar. Individuals with disabilities that interfered with mobility were more likely to be killed than their healthier counterparts. This level of conflict-related mortality almost certainly had an effect on the community's ability to conduct its affairs and, indeed, to survive as a viable economic and social group. C1 [Milner, George R.] Penn State Univ, Dept Anthropol, University Pk, PA 16802 USA. [Ferrell, Rebecca J.] NIA, Sci Review Branch, NIH, Bethesda, MD 20892 USA. RP Milner, GR (reprint author), Penn State Univ, Dept Anthropol, 409 Carpenter Bldg, University Pk, PA 16802 USA. EM ost@psu.edu; rebecca.ferrell@nih.gov NR 74 TC 5 Z9 5 U1 2 U2 18 PU E SCHWEIZERBARTSCHE VERLAGS PI STUTTGART PA NAEGELE U OBERMILLER, SCIENCE PUBLISHERS, JOHANNESSTRASSE 3A, D 70176 STUTTGART, GERMANY SN 0003-5548 J9 ANTHROPOL ANZ JI Anthropol. Anz. PD SEP PY 2011 VL 68 IS 4 BP 415 EP 436 DI 10.1127/0003-5548/2011/0152 PG 22 WC Anthropology SC Anthropology GA 824XB UT WOS:000295234400006 PM 21957646 ER PT J AU Sharma, M Joshi, MC Kumar, V Malhotra, SV Rawat, DS AF Sharma, Mukul Joshi, Mukesh C. Kumar, Vineet Malhotra, Sanjay V. Rawat, Diwan S. TI Synthesis and Anticancer Activity of 13-Membered Cyclic Enediynes SO ARCHIV DER PHARMAZIE LA English DT Article DE Anticancer; Cell lines; Enediyne ID BERGMAN CYCLIZATION; ANTITUMOR AGENTS; ATOM ABSTRACTION; CELL-CYCLE; ANTIBIOTICS; DESIGN; DNA; LIDAMYCIN; CHEMISTRY; DYNEMICIN AB We herein describe the synthesis of 15 novel 13-membered cyclic enediyne derivatives using simple and straightforward approach. Representative examples were screened for their anticancer activities on 60 different human tumor cell lines representing various histologies viz. leukemia, melanoma, and cancers of lung, colon, kidney, ovary, breast, prostate, and central nervous system. The enediyne derivatives with halogen substitutions, especially fluorides were found to be active against most of the cell lines. The initial results indicates marginal to good inhibition for the growth of tumor cells for several cell lines, which shows the potential of these class of compound towards anticancer application. C1 [Sharma, Mukul; Joshi, Mukesh C.; Rawat, Diwan S.] Univ Delhi, Dept Chem, Delhi 110007, India. [Kumar, Vineet; Malhotra, Sanjay V.] NCI, Lab Synthet Chem, SAIC, Frederick Inc, Frederick, MD 21701 USA. RP Rawat, DS (reprint author), Univ Delhi, Dept Chem, Delhi 110007, India. EM dsrawat@chemistry.du.ac.in OI Joshi, Mukesh Chandra/0000-0002-4926-8871; Rawat, Diwan/0000-0002-5473-7476 FU Department of Science and Technology, New Delhi, India [SR/FTP/CSA-18/2003, SR/S1/OC-08/2008]; CSIR FX DSR thanks Department of Science and Technology (DO No: SR/FTP/CSA-18/2003; and SR/S1/OC-08/2008), New Delhi, India for financial support. MS is thankful to CSIR for the award of senior research fellowship. Thanks to USIC-CIF, University of Delhi, Delhi, India for NMR data. The authors would like to thank the NCI Developmental Therapeutics Program for 60 cell line screen. NR 30 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0365-6233 J9 ARCH PHARM JI Arch. Pharm. PD SEP PY 2011 VL 344 IS 9 BP 564 EP 571 DI 10.1002/ardp.201000309 PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 825PT UT WOS:000295293800002 PM 21887797 ER PT J AU Tektonidou, MG Dasgupta, A Ward, MM AF Tektonidou, Maria G. Dasgupta, Abhijit Ward, Michael M. TI Suicidal Ideation Among Adults With Arthritis: Prevalence and Subgroups at Highest Risk. Data From the 2007-2008 National Health and Nutrition Examination Survey SO ARTHRITIS CARE & RESEARCH LA English DT Article ID GENERAL-POPULATION; RHEUMATOID-ARTHRITIS; CHRONIC PAIN; PSYCHOLOGICAL AUTOPSY; PSYCHIATRIC-PATIENTS; DEPRESSION; BEHAVIOR; COHORT; THOUGHTS; ASSOCIATION AB Objective. To evaluate the prevalence, correlates, and subgroups at highest risk for suicidal ideation among adults with arthritis. Methods. We used data on US adults with arthritis, ages >= 40 years, participating in the 2007-2008 National Health and Nutrition Examination Survey. Suicidal ideation was assessed by item 9 of the Patient Health Questionnaire 9 (PHQ-9). Sociodemographic factors, health behaviors, and comorbid conditions were examined as potential correlates. Depression was measured by the PHQ-8 score (range 1-24). We used random forests to identify subgroups at highest risk for suicidal ideation. To determine if any correlates were unique to arthritis, we compared results to those for persons with diabetes mellitus and cancer. Results. The prevalence +/- SEM of suicidal ideation was 5.6% +/- 0.8% among persons with arthritis and 2.4% +/- 0.4% among those without. The most important correlates for suicidal ideation in adults with arthritis were depression, anxiety, duration of arthritis, age, income: poverty ratio, number of close friends, pain, alcohol, excessive daytime sleepiness, and comorbidities. Eleven of the 16 most important contributors for suicidal ideation among adults with arthritis were also important for people with diabetes mellitus and cancer. Among persons with arthritis, subgroups at highest risk for suicidal ideation were those with a PHQ-8 score between 18 and 24 and less than 4.5 years of arthritis (96.5%), and those with a PHQ-8 score between 7 and 17, >= 1.24 days of binges/month, and either an income of >=$45,000/year (85.4%) or an income of <$45,000/year and >3 comorbidities (70.8%). Conclusion. Depression, short duration of arthritis, binge drinking, income, and >3 comorbidities identified subgroups of adults with arthritis at greatest risk for suicidal ideation. C1 [Tektonidou, Maria G.] Natl Univ Athens, Dept Internal Med 1, Sch Med, Athens 11527, Greece. [Dasgupta, Abhijit; Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Tektonidou, MG (reprint author), Natl Univ Athens, Dept Internal Med 1, Sch Med, 75 M Asias Str, Athens 11527, Greece. EM mtektonidou@gmail.com FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH FX Supported in part by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. NR 49 TC 13 Z9 13 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD SEP PY 2011 VL 63 IS 9 BP 1322 EP 1333 DI 10.1002/acr.20516 PG 12 WC Rheumatology SC Rheumatology GA 825EX UT WOS:000295254900014 PM 21671421 ER PT J AU Jin, DJ Zhou, YN Shaw, G Ji, XH AF Jin, Ding Jun Zhou, Yan Ning Shaw, Gary Ji, Xinhua TI Structure and function of RapA: A bacterial Swi2/Snf2 protein required for RNA polymerase recycling in transcription SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE RapA; Bacterial Swi2/Snf2; RNA polymerase recycling; Structure of Swi2/Snf2; Transcription complex remodeling ID ESCHERICHIA-COLI; THERMODYNAMIC ANALYSIS; SNF2 FAMILY; COMPLEXES; HELICASES; HOMOLOG; DNA; SUBFAMILIES; RESOLUTION; PROMOTERS AB One of the hallmarks of the Swi2/Snf2 family members is their ability to modify the interaction between DNA-binding protein and DNA in controlling gene expression. The studies of Swi2/Snf2 have been mostly focused on their roles in chromatin and/or nucleosome remodeling in eukaryotes. A bacterial Swi2/Snf2 protein named RapA from Escherichia coli is a unique addition to these studies. RapA is an RNA polymerase (RNAP)associated protein and an ATPase. It binds nucleic acids including RNA and DNA. The ATPase activity of RapA is stimulated by its interaction with RNAP, but not with nucleic acids. RapA and the major sigma factor sigma 70 compete for binding to core RNAP. After one transcription cycle in vitro. RNAP is immobilized in an undefined posttranscription/posttermination complex (PTC), thus becoming unavailable for reuse. RapA stimulates RNAP recycling by ATPase-dependent remodeling of PTC, leading to the release of sequestered RNAP, which then becomes available for reuse in another cycle of transcription. Recently, the crystal structure of RapA that is also the first full-length structure for the entire Swi2/Snf2 family was determined. The structure provides a framework for future studies of the mechanism of RNAP recycling in transcription. This article is part of a Special Issue entitled: Snf2/Swi2 ATPase structure and function. Published by Elsevier B.V. C1 [Jin, Ding Jun] NCI, Transcript Control Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Jin, DJ (reprint author), NCI, Transcript Control Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res,NIH, 1050 Boyles St, Frederick, MD 21702 USA. EM djjin@helix.nih.gov RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank our colleagues, both former and current members of our laboratories, for their contributions in the RapA research and Dr. Mikhail Kashlev for comments on the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 31 TC 4 Z9 4 U1 1 U2 8 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 SEP PY 2011 VL 1809 IS 9 SI SI BP 470 EP 475 DI 10.1016/j.bbagrm.2011.03.003 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 829FR UT WOS:000295564500002 PM 21419241 ER PT J AU Solomon, BD Pineda-Alvarez, DE Hadley, DW Keaton, AA Agochukwu, NB Raam, MS Carlson-Donohoe, HE Kamat, A Chandrasekharappa, SC AF Solomon, Benjamin D. Pineda-Alvarez, Daniel E. Hadley, Donald W. Keaton, Amelia A. Agochukwu, Nneamaka B. Raam, Manu S. Carlson-Donohoe, Hannah E. Kamat, Aparna Chandrasekharappa, Settara C. TI De Novo Deletion of Chromosome 20q13.33 in a Patient with Tracheo-esophageal Fistula, Cardiac Defects and Genitourinary Anomalies Implicates GTPBP5 as a Candidate Gene SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE tracheo-esophageal fistula; TE fistula; VACTERL association; 20q13.33 deletion; GTPBP5 ID RESPIRATORY-CHAIN DEFICIENCY; COPY-NUMBER VARIATION; VACTERL ASSOCIATION; ESOPHAGEAL ATRESIA; LAMININ ALPHA-5; GENOME AB BACKGROUND: Tracheo-esophageal fistula (TEF) with/or without esophageal atresia (EA) is a common congenital malformation that is often accompanied by other anomalies. The causes of this condition are thought to be heterogeneous but are overall not well understood. CASE REPORT: We identified a patient with a TEF/EA, as well as cardiac and genitourinary anomalies, who was found to have a 0.7 Mb de novo deletion of chromosome 20q13.33. One gene within the deleted interval, GTPBP5, is of particular interest as a candidate gene. CONCLUSIONS: GTPBP5 bears further study as a cause of TEF/EA accompanied by other malformations. Birth Defects Research (Part A) 91:862-865, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Solomon, Benjamin D.; Pineda-Alvarez, Daniel E.; Keaton, Amelia A.; Agochukwu, Nneamaka B.; Raam, Manu S.; Carlson-Donohoe, Hannah E.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Hadley, Donald W.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Keaton, Amelia A.; Raam, Manu S.] Howard Hughes Med Inst, HHMI NIH Res Scholars Program, Chevy Chase, MD USA. [Kamat, Aparna; Chandrasekharappa, Settara C.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Solomon, BD (reprint author), NHGRI, Med Genet Branch, NIH, MSC 3717,Bldg 35,Room 1B-207, Bethesda, MD 20892 USA. EM solomonb@mail.nih.gov FU Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health and Human Services, United States of America FX Grant information: This research was supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health and Human Services, United States of America. NR 20 TC 12 Z9 12 U1 0 U2 3 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 SEP PY 2011 VL 91 IS 9 BP 862 EP 865 DI 10.1002/bdra.20821 PG 4 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 827BP UT WOS:000295400900009 PM 21608104 ER PT J AU Ramsden, CE Hibbeln, JR Majchrzak-Hong, SF Davis, JM AF Ramsden, Christopher E. Hibbeln, Joseph R. Majchrzak-Hong, Sharon F. Davis, John M. TI Don't disregard the essential distinction between PUFA species SO BRITISH JOURNAL OF NUTRITION LA English DT Letter ID CORONARY-HEART-DISEASE; DIETARY FATTY-ACIDS; CONTROLLED-TRIALS; ARTERY DISEASE; RISK; METAANALYSIS; PROGRESSION; WOMEN C1 [Ramsden, Christopher E.; Hibbeln, Joseph R.; Majchrzak-Hong, Sharon F.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Davis, John M.] Univ Illinois, Dept Psychiat, Sch Med, Chicago, IL 60612 USA. RP Ramsden, CE (reprint author), NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. EM chris.ramsden@nih.gov NR 30 TC 1 Z9 1 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD SEP PY 2011 VL 106 IS 6 BP 953 EP 957 DI 10.1017/S0007114511001061 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 827CF UT WOS:000295403000022 PM 21679480 ER PT J AU Ramsden, CE Hibbeln, JR Majchrzak-Hong, SF Davis, JM AF Ramsden, Christopher E. Hibbeln, Joseph R. Majchrzak-Hong, Sharon F. Davis, John M. TI Don't disregard the essential distinction between PUFA species Comment on Ramsden et al Response SO BRITISH JOURNAL OF NUTRITION LA English DT Letter ID ALPHA-LINOLENIC ACID; DIET; RISK; FAT C1 [Ramsden, Christopher E.; Hibbeln, Joseph R.; Majchrzak-Hong, Sharon F.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Davis, John M.] Univ Illinois, Dept Psychiat, Sch Med, Chicago, IL 60612 USA. RP Ramsden, CE (reprint author), NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. EM chris.ramsden@nih.gov NR 13 TC 0 Z9 0 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD SEP PY 2011 VL 106 IS 6 BP 959 EP 960 DI 10.1017/S0007114511001668 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 827CF UT WOS:000295403000024 ER PT J AU Yang, JC AF Yang, James C. TI Melanoma Vaccines SO CANCER JOURNAL LA English DT Review DE Vaccines; metastatic melanoma; whole-cell vaccines; tumor response rates ID COLONY-STIMULATING FACTOR; TUMOR-INFILTRATING LYMPHOCYTES; INCOMPLETE FREUNDS-ADJUVANT; RESISTANT PROSTATE-CANCER; HUMORAL IMMUNE-RESPONSE; METASTATIC MELANOMA; T-CELLS; COMPLETE RESECTION; PEPTIDE VACCINE; DISEASE-FREE AB There is much renewed activity in the testing of vaccines that target metastatic melanoma, driven by successes in other areas, most notably prostate cancer. Yet, sound evidence that any stand-alone vaccination approach has clinical benefit against melanoma remains lacking. With phase III studies showing no efficacy of promising whole-cell vaccines and heat shock proteins, peptide and dendritic cell vaccines remain the most common approaches. A major obstacle to progress is the lack of any surrogate measures in phase II studies that associate meaningfully with clinical benefit, and this is further complicated by phase III evidence in prostate cancer that immunologic monitoring, tumor response rates, or even times to tumor progression may not accurately predict survival benefit. The area with the most progress has been in combining vaccines with other systemic immunostimulatory agents. Although no vaccine has been found which fulfills the prediction from murine models that they can enhance the efficacy of ipilimumab, combining a peptide vaccination with high-dose interleukin 2 was shown to enhance complete and overall response rates compared with interleukin 2 alone. These promising combinations continue to struggle with the same unresolved issues that have plagued melanoma vaccines from the beginning-what are the best antigens to target, what are the best methods of vaccination, and what constitutes a sufficient immune response to be of value? Virtually no progress has been made toward answering these questions. C1 NCI, Surg Branch, Tumor Immunol Sect, NIH,Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NCI, Surg Branch, Tumor Immunol Sect, NIH,Hatfield Clin Res Ctr, Bldg 10-CRC,Room 3-5952,10 Ctr Dr, Bethesda, MD 20892 USA. EM JamesYang@mail.nih.gov NR 46 TC 5 Z9 5 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD SEP-OCT PY 2011 VL 17 IS 5 BP 277 EP 282 DI 10.1097/PPO.0b013e3182325f72 PG 6 WC Oncology SC Oncology GA 825YU UT WOS:000295319100003 PM 21952276 ER PT J AU Kelly, RJ Giaccone, G AF Kelly, Ronan J. Giaccone, Giuseppe TI Lung Cancer Vaccines SO CANCER JOURNAL LA English DT Review DE Lung cancer; vaccines ID GROWTH-FACTOR-BETA; ACTIVE SPECIFIC IMMUNOTHERAPY; DENDRITIC CELL VACCINES; BLP25 LIPOSOME VACCINE; CARCINOEMBRYONIC ANTIGEN; HUMAN MUC1; TGF-BETA; T-CELLS; PHASE-I; IMMUNE-RESPONSES AB To date, in lung cancer, early attempts to modulate the immune system via vaccine-based therapeutics have been unsuccessful. An improved understanding of tumor immunology has facilitated the production of more sophisticated lung cancer vaccines. It is anticipated that it will likely require multiple epitopes of a diverse set of genes restricted to multiple haplotypes to generate a truly effective vaccine that is able to overcome the various immunologic escape mechanisms that tumors employ. Other issues to overcome include optimal patient selection, which adjuvant agent to use, and how to adequately monitor for an immunologic response. This review discusses the most promising vaccination strategies for non-small cell lung cancer including the allogeneic tumor cell vaccine belagenpumatucel-L, which is a mixture of 4 allogeneic non-small cell lung cancer cell lines genetically modified to secrete an antisense oligonucleotide to transforming growth factor beta(2) and 3 other target protein-specific vaccines designed to induce responses against melanoma-associated antigen A3, mucin 1, and epidermal growth factor. C1 [Kelly, Ronan J.; Giaccone, Giuseppe] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Room 12N226, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU Intramural NIH HHS [Z01 BC010854-02] NR 74 TC 18 Z9 18 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1528-9117 EI 1540-336X J9 CANCER J JI Cancer J. PD SEP-OCT PY 2011 VL 17 IS 5 BP 302 EP 308 DI 10.1097/PPO.0b013e318233e6b4 PG 7 WC Oncology SC Oncology GA 825YU UT WOS:000295319100007 PM 21952280 ER PT J AU Larocca, C Schlom, J AF Larocca, Cecilia Schlom, Jeffrey TI Viral Vector-Based Therapeutic Cancer Vaccines SO CANCER JOURNAL LA English DT Review DE Cancer vaccines; viral vaccines; immunotherapy; MVA vaccines; TRICOM vaccines; prime-boost vaccination; adenovirus; poxvirus vaccines ID ANTIGEN 5T4 TROVAX; METASTATIC COLORECTAL-CANCER; RESISTANT PROSTATE-CANCER; COLONY-STIMULATING FACTOR; POTENT IMMUNE-RESPONSES; RANDOMIZED PHASE-II; LONG-TERM SURVIVAL; CELL LUNG-CANCER; COMBINATION THERAPY; COSTIMULATORY MOLECULES AB Most viruses are naturally immunogenic and can be engineered to express tumor antigen transgenes. Moreover, many types of recombinant viruses have been shown to infect professional antigen-presenting cells, specifically dendritic cells, and express their transgenes. This enhanced presentation of tumor antigens to the immune system has led to an increase in the frequency and avidity of cytotoxic T lymphocytes that target tumor cells expressing the tumor antigen(s) encoded in the vaccine vector. Logistically, recombinant viruses can be produced, administered, and quality controlled more easily compared with other immunotherapy strategies. The intrinsic properties of each virus have distinct advantages and disadvantages, which can determine their applicability in a particular therapeutic setting. The disadvantage of some vectors is the development of host-induced neutralizing antibodies to the vector itself, thus limiting its continued use. The "off-the-shelf" nature of viral vaccine platforms renders them exceptionally suitable for multicenter randomized trials. This review described and discussed the strategies used and results using viral-based vaccines, with emphasis on phases II and III clinical trials. Future directions will involve the evaluation of viral-based vaccines in the adjuvant and neoadjuvant settings, in patients with low burden metastatic disease, and in combination with other forms of therapy including immunotherapy. C1 [Larocca, Cecilia; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [Larocca, Cecilia] NCI, Howard Hughes Med Inst, Res Scholars Program, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov FU Center for Cancer Research, National Cancer Institute, NIH; Howard Hughes Medical Institute FX Conflicts of Interest and Sources of Funding: Funding was received from the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH; Howard Hughes Medical Institute. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 103 TC 39 Z9 42 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD SEP-OCT PY 2011 VL 17 IS 5 BP 359 EP 371 DI 10.1097/PPO.0b013e3182325e63 PG 13 WC Oncology SC Oncology GA 825YU UT WOS:000295319100014 PM 21952287 ER PT J AU Lathia, JD Hitomi, M Gallagher, J Gadani, SP Adkins, J Vasanji, A Liu, L Eyler, CE Heddleston, JM Wu, Q Minhas, S Soeda, A Hoeppner, DJ Ravin, R McKay, RDG McLendon, RE Corbeil, D Chenn, A Hjelmeland, AB Park, D Rich, J AF Lathia, J. D. Hitomi, M. Gallagher, J. Gadani, S. P. Adkins, J. Vasanji, A. Liu, L. Eyler, C. E. Heddleston, J. M. Wu, Q. Minhas, S. Soeda, A. Hoeppner, D. J. Ravin, R. McKay, R. D. G. McLendon, R. E. Corbeil, D. Chenn, A. Hjelmeland, A. B. Park, D. M. Rich, J. N. TI Distribution of CD133 reveals glioma stem cells self-renew through symmetric and asymmetric cell divisions SO CELL DEATH & DISEASE LA English DT Article DE cancer stem cell; glioma; asymmetric cell division ID APICAL PLASMA-MEMBRANE; TUMOR-INITIATING CELLS; SIGNALING PATHWAYS; HUMAN GLIOBLASTOMA; PROMININ-1 CD133; IN-VITRO; CANCER; DIFFERENTIATION; IDENTIFICATION; PROTRUSIONS AB Malignant gliomas contain a population of self-renewing tumorigenic stem-like cells; however, it remains unclear how these glioma stem cells (GSCs) self-renew or generate cellular diversity at the single-cell level. Asymmetric cell division is a proposed mechanism to maintain cancer stem cells, yet the modes of cell division that GSCs utilize remain undetermined. Here, we used single-cell analyses to evaluate the cell division behavior of GSCs. Lineage-tracing analysis revealed that the majority of GSCs were generated through expansive symmetric cell division and not through asymmetric cell division. The majority of differentiated progeny was generated through symmetric pro-commitment divisions under expansion conditions and in the absence of growth factors, occurred mainly through asymmetric cell divisions. Mitotic pair analysis detected asymmetric CD133 segregation and not any other GSC marker in a fraction of mitoses, some of which were associated with Numb asymmetry. Under growth factor withdrawal conditions, the proportion of asymmetric CD133 divisions increased, congruent with the increase in asymmetric cell divisions observed in the lineage-tracing studies. Using single-cell-based observation, we provide definitive evidence that GSCs are capable of different modes of cell division and that the generation of cellular diversity occurs mainly through symmetric cell division, not through asymmetric cell division. Cell Death and Disease (2011) 2, e200; doi:10.1038/cddis.2011.80; published online 1 September 2011 C1 [Lathia, J. D.; Hitomi, M.; Gallagher, J.; Gadani, S. P.; Liu, L.; Heddleston, J. M.; Wu, Q.; Minhas, S.; Hjelmeland, A. B.; Rich, J. N.] Cleveland Clin, Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44118 USA. [Adkins, J.; Chenn, A.] Northwestern Univ, Dept Pathol, Sch Med, Chicago, IL 60611 USA. [Eyler, C. E.] Duke Univ, Dept Pharmacol & Canc Biol, Med Ctr, Durham, NC 27705 USA. [Soeda, A.; Park, D. M.] Univ Pittsburgh, Inst Canc, Dept Neurol Surg, Pittsburgh, PA 15232 USA. [Hoeppner, D. J.; Ravin, R.; McKay, R. D. G.] NINDS, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. [McLendon, R. E.] Duke Univ, Dept Pathol, Ctr Med, Durham, NC 27705 USA. [Corbeil, D.] Tech Univ Dresden, BIOTEC, Tissue Engn Labs, Dresden, Germany. [Park, D. M.] Univ Virginia, Dept Neurol Surg, Charlottesville, VA 22908 USA. RP Lathia, JD (reprint author), Cleveland Clin, Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, 9500 Euclid Ave,NE 30, Cleveland, OH 44118 USA. EM lathiaj@ccf.org; richj@ccf.org RI Corbeil, Denis/A-6519-2010; Rich, Jeremy/A-9501-2012; Park, Deric/C-5675-2013 FU McDonnell Foundation; NIH [NS054276, CA154130, CA129958, CA116659, CA151522]; National Brain Tumor Society; American Cancer Society; National Institutes of Neurological Disorders and Stroke (NINDS) [F30 NS063496, R21 NS063057]; American Brain Tumor Association; National Cancer Institute (NCI) [F32 CA142159]; Deutsche Forschungsgemeinschaft [SFB 655] FX We thank Dr. Mike Cook, Dr. Beth Harvat, Cathy Shemo, Sage O'Bryant, and Moneen Morgan for assistance with flow cytometry, and the members of the Rich laboratory for critical review of the manuscript. We also thank Dr. Judy Drazba and Eric Diskin from LRI Imaging Core and Kevin Ryan from W. Nuhsbaum Inc. for critical assistance with time-lapse microscopy, and Linda Vargo for assistance with histology. We thank Xiaobo Liu from the Quantitative Health Sciences Department for statistical analysis assistance. We are also grateful to Drs. Nicholas Gaiano, Shideng Bao, Monica Venere, Mahendra S. Rao, Richard Ransohoff, Thomas Egelhoff, and Yogen Saunthararajah for valuable insight and comments on the manuscript. The Rich laboratory is supported by the McDonnell Foundation and NIH Grants NS054276, CA154130, CA129958, and CA116659. ABH was supported by grants from the National Brain Tumor Society and the NIH (CA151522). SPG was supported by an American Cancer Society Silber Summer Research Fellowship. CEE is supported by a National Research Service Award from the National Institutes of Neurological Disorders and Stroke (NINDS F30 NS063496). JDL is supported by an American Brain Tumor Association Basic Research Fellowship (sponsored by the Joelle Syverson Fund) and a National Research Service Award from the National Cancer Institute (NCI F32 CA142159). MH is supported by a grant from the National Institutes of Neurological Disorders and Stroke (NINDS R21 NS063057). DC is supported by the Deutsche Forschungsgemeinschaft (SFB 655). NR 31 TC 76 Z9 78 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD SEP PY 2011 VL 2 AR e200 DI 10.1038/cddis.2011.80 PG 11 WC Cell Biology SC Cell Biology GA 827CS UT WOS:000295404600004 PM 21881602 ER PT J AU Boja, ES Rodriguez, H AF Boja, Emily S. Rodriguez, Henry TI Regulatory Considerations for Clinical Mass Spectrometry: Multiple Reaction Monitoring SO CLINICS IN LABORATORY MEDICINE LA English DT Article DE Clinical proteomics; Multiplex; Multiple reaction monitoring mass spectrometry; In vitro diagnostics; Regulatory science ID CONTROL MAQC PROJECT; VALIDATION; ASSAYS; REPRODUCIBILITY; QUANTIFICATION; ENRICHMENT; PLATFORMS; PROTEINS; PLASMA AB Clinical proteomics provides valuable information to the study of diseases at the molecular level, with the potential to discover biomarkers for disease states. The discovery of protein/peptide signatures "leaked" by cancerous tumors into clinically accessible fluids could possibly lead to developing quantitative assays for diagnosing cancer early. Despite having over 1,200 cancer-related protein biomarker candidates published in the scientific literature,(1) the rate of introduction of new protein biomarkers to market as approved by FDA has averaged 1.5 new proteins per year for 15 years. This discrepancy points to an ineffective translation of proteomics from the bench to the bedside. C1 [Boja, Emily S.; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, NIH, Bethesda, MD 20892 USA. RP Rodriguez, H (reprint author), NCI, Off Canc Clin Prote Res, NIH, 31 Ctr Dr,MS 2590, Bethesda, MD 20892 USA. EM rodriguezh@mail.nih.gov NR 25 TC 2 Z9 2 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-2712 J9 CLIN LAB MED JI Clin. Lab. Med. PD SEP PY 2011 VL 31 IS 3 BP 443 EP + DI 10.1016/j.cll.2011.07.001 PG 12 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 828HS UT WOS:000295492700007 PM 21907108 ER PT J AU Cookson, MR AF Cookson, Mark R. TI Drugs Targets in Parkinson's Disease: Where Are We and Where should We Go? SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Editorial Material C1 NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD SEP PY 2011 VL 10 IS 6 BP 650 EP 650 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 827CO UT WOS:000295404000002 PM 21838673 ER PT J AU Rudrabhatla, P Pant, HC AF Rudrabhatla, P. Pant, H. C. TI Role of Protein Phosphatase 2A in Alzheimer's Disease SO CURRENT ALZHEIMER RESEARCH LA English DT Article DE Alzheimer's disease; tau; Neurofilaments; protein dephosphorylation; protein kinases and phosphatases; protein phosphatase 2A; Pin1 ID MICROTUBULE-ASSOCIATED PROTEINS; SERINE THREONINE PHOSPHATASES; XENOPUS-LAEVIS OOCYTES; RABBIT SKELETAL-MUSCLE; TAU-PROTEIN; NEUROFILAMENT PHOSPHORYLATION; CATALYTIC SUBUNIT; TRANSGENIC MICE; NEUROFIBRILLARY DEGENERATION; PHOSPHOTYROSYL PHOSPHATASE AB Alzheimer disease (AD) is the most common cause of dementia in adults. Aberrant hyperphosphorylation of microtubule associated protein Tau and neurofilament-M/H is one of the pathological hallmarks of AD. Most of the therapeutic strategies for treating AD are based on the inhibition of protein kinases such as glycogen synthase kinase-3 beta, cyclin-dependent kinase 5, and other Tau kinases. Here, we focus on protein phosphatase 2A (PP2A) as a key player in AD. PP2A expression and activity are downregulated in AD brain, contributing to the aberrant phosphorylation of Tau and NF proteins in AD. Recent data published from our lab as well as others on PP2A deregulation in AD is reviewed. The role of peptidyl prolyl isomerase Pin1 in regulation of PP2A mediated neurodegeneration is further analyzed. Development of drugs for AD could be based on restoration of PP2A activity or targeting Pin1. C1 [Pant, H. C.] NINDS, Cytoskeletal Regulatory Prot Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINDS, Cytoskeletal Regulatory Prot Sect, Neurochem Lab, NIH, Bldg 49,Room 2A28, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov FU NINDS, NIH FX We thank intramural NINDS, NIH grants for funding our research. NR 115 TC 17 Z9 18 U1 0 U2 6 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD SEP PY 2011 VL 8 IS 6 BP 623 EP 632 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 827DA UT WOS:000295406000004 PM 21605044 ER PT J AU Barron, L Wynn, TA AF Barron, Luke Wynn, Thomas A. TI Macrophage activation governs schistosomiasis-induced inflammation and fibrosis SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Host/pathogen interactions; Immune regulation; Immunopathology; Infectious disease; Macrophages ID L-ARGININE METABOLISM; REGULATORY T-CELLS; GRANULOMATOUS PATHOLOGY; MURINE SCHISTOSOMIASIS; EXPRESSION; INFECTION; RESPONSES; RECEPTOR; IL-4; TH2 AB Macrophages regulate the initiation, maintenance, and resolution of chronic inflammatory responses and their function depends on their activation status. Studies in mice infected with the helminth parasite Schistosoma mansoni have been particularly helpful in defining the in vivo function of classically and alternatively activated macrophages (AAM phi s). These studies have shown that AAM phi s protect mice from acute and chronic S. mansoni infection through distinct mechanisms, which are discussed in this Viewpoint. C1 [Barron, Luke; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wynn, TA (reprint author), 50 South Dr,Rm 6154,MSC 8003, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU NIAID/NIH FX The authors thank Margaret Mentink-Kane, Thirumalai Ramalingam, Robert Thompson, Kevin Vannella, Lee Borthwick, and Allen Cheever for helpful discussions, and Ethan Tyler for transforming scratch paper sketches into appealing graphics. This work was supported by the intramural research program of the NIAID/NIH. NR 50 TC 52 Z9 56 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD SEP PY 2011 VL 41 IS 9 BP 2509 EP 2514 DI 10.1002/eji.201141869 PG 6 WC Immunology SC Immunology GA 825HC UT WOS:000295260800012 PM 21952807 ER PT J AU Blystone, CR Elmore, SA Witt, KL Malarkey, DE Foster, PMD AF Blystone, Chad R. Elmore, Susan A. Witt, Kristine L. Malarkey, David E. Foster, Paul M. D. TI Toxicity and carcinogenicity of androstenedione in F344/N rats and B6C3F1 mice SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Androstenedione; Rat; Mice; Cancer; Two-year bioassay; Toxicity ID ANABOLIC-ANDROGENIC STEROIDS; ZERO DOSE CONTROL; SERUM TESTOSTERONE; ORAL ANDROSTENEDIONE; HEPATIC-TUMORS; FISCHER-344 RATS; SEX STEROIDS; CELL TUMORS; YOUNG MEN; X-ZONE AB Androstenedione was marketed as a dietary supplement to increase muscle mass during training. Due to concern over long-term use, the NTP evaluated the subchronic and chronic toxicity and carcinogenicity of androstenedione in male and female F344/N rats and B6C3F1 mice. In subchronic studies, dose limiting effects were not observed. A chronic (2-year) exposure by gavage at 10, 20, or 50 mg/kg in rats and male mice, and 2, 10, or 50 mg/kg in female mice (50 mg/kg, maximum feasible dose) was conducted. Increased incidences of lung alveolar/bronchiolar adenoma and carcinoma occurred in the 20 mg/kg male rats and increases in mononuclear cell leukemia occurred in the 20 and 50 mg/kg female rats, which may have been related to androstenedione administration. In male and female mice, androstenedione was carcinogenic based upon a significant increase in hepatocellular tumors. A marginal increase in pancreatic islet cell adenomas in male (50 mg/kg) and female (2, 10, 50 mg/kg) mice was considered to be related to androstenedione administration. Interestingly, incidences of male rat Leydig cell adenomas and female rat mammary gland fibroadenomas decreased. In conclusion, androstenedione was determined to be carcinogenic in male and female mice, and may have been carcinogenic in rats. Published by Elsevier Ltd. C1 [Blystone, Chad R.; Elmore, Susan A.; Witt, Kristine L.; Malarkey, David E.; Foster, Paul M. D.] NIEHS, Natl Toxicol Program, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Blystone, CR (reprint author), NIEHS, Natl Toxicol Program, NIH, Dept Hlth & Human Serv, POB 12233,MD K2-13, Res Triangle Pk, NC 27709 USA. EM blystonecr@niehs.nih.gov FU NIH, NIEHS [1 Z01 ES045004-11 BB, N01-ES-35514] FX This research was supported in part by the Intramural Research Program of the NIH, NIEHS under Research Project Number 1 Z01 ES045004-11 BB and contract number N01-ES-35514. NR 61 TC 1 Z9 1 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD SEP PY 2011 VL 49 IS 9 BP 2116 EP 2124 DI 10.1016/j.fct.2011.05.026 PG 9 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 824FU UT WOS:000295188600030 PM 21651954 ER PT J AU Ell, K Katon, W Xie, B Lee, PJ Kapetanovic, S Guterman, J Chou, CP AF Ell, Kathleen Katon, Wayne Xie, Bin Lee, Pey-Jiuan Kapetanovic, Suad Guterman, Jeffrey Chou, Chih-Ping TI One-year postcollaborative depression care trial outcomes among predominantly Hispanic diabetes safety net patients SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Depression; Diabetes; Collaborative care; Safety net; Hispanic ID RANDOMIZED CONTROLLED-TRIAL; COLLABORATIVE CARE; LOW-INCOME; REGRESSION-MODELS; MAJOR DEPRESSION; CANCER; PREFERENCES; MANAGEMENT; RISK AB Objective: The aim of this study was to determine sustained effectiveness in reducing depression symptoms and improving depression care I year following intervention completion. Method: Of 387 low-income, predominantly Hispanic diabetes patients with major depression symptoms randomized to 12-month socioculturally adapted collaborative care (psychotherapy and/or antidepressants, telephone symptom monitoring/relapse prevention) or enhanced usual care, 264 patients completed 2-year follow-up. Depression symptoms (Symptom Checklist-20 [SCL-20], Patient Health Questionnaire-9 [PHQ-9]), treatment receipt, diabetes symptoms and quality of life were assessed 24 months postenrollment using intent-to-treat analyses. Results: At 24 months, more intervention patients received ongoing antidepressant treatment (38% vs. 25%, chi(2)=5.11, df=1, P=.02); sustained depression symptom improvement [SCL-20 <0.5 (adjusted odds ratio=2.06, 95% confidence interval=1.09-3.90, P=.03), SCL-20 score (adjusted mean difference -0.22, P=.001) and PHQ-9 >= 50% reduction (adjusted odds ratio=1.87, 95% confidence interval=1.05-3.32, P=.03)]. Over 2 years, improved effects were found in significant study group by time interaction for Short Form-12 mental health, Sheehan Disability Scale (SDS) functional impairment, diabetes symptoms, anxiety and socioeconomic stressors (P=.02 for SDS; P<.0001 for all others); however, group differences narrowed over time and were no longer significant at 24 months. Conclusions: Socioculturally tailored collaborative care that included maintenance antidepressant medication, ongoing symptom monitoring and behavioral activation relapse prevention was associated with depression improvement over 24 months for predominantly Hispanic patients in primary safety net care. (C) 2011 Elsevier Inc. All rights reserved. C1 [Ell, Kathleen; Lee, Pey-Jiuan] Univ So Calif, Sch Social Work, Los Angeles, CA 90089 USA. [Katon, Wayne] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Xie, Bin] Claremont Grad Univ, Sch Community & Global Hlth, San Dimas, CA 91773 USA. [Kapetanovic, Suad] NIMH, NIH, Bethesda, MD 20892 USA. [Guterman, Jeffrey] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Guterman, Jeffrey] Los Angeles Cty Dept Hlth Serv, Sylmar, CA 91342 USA. [Chou, Chih-Ping] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. RP Ell, K (reprint author), Univ So Calif, Sch Social Work, MRF 102R,MC 0411, Los Angeles, CA 90089 USA. EM ell@usc.edu; wkaton@u.washington.edu; bin.xie@cgu.edu; peylee@usc.edu; kapetanovics@mail.nih.gov; jguterman@ladhs.org; cchou@usc.edu FU National Institute of Mental Health [R01 MH068468] FX The study is supported by R01 MH068468 from the National Institute of Mental Health (Principal Investigator, Dr. Ell). NR 33 TC 14 Z9 14 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD SEP-OCT PY 2011 VL 33 IS 5 BP 436 EP 442 DI 10.1016/j.genhosppsych.2011.05.018 PG 7 WC Psychiatry SC Psychiatry GA 824MP UT WOS:000295206300006 PM 21774987 ER PT J AU Wang, YJ Shen, DF Wang, VM Sen, HN Chan, CC AF Wang, Yujuan Shen, Defen Wang, Vinson M. Sen, H. Nida Chan, Chi-Chao TI Molecular Biomarkers for the Diagnosis of Primary Vitreoretinal Lymphoma SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Article DE primary vireoretinal lymphoma; biomarker; immunoglobulin heavy chain; T-cell receptor; gene arrangement; microdissection; polymerase chain reaction ID PRIMARY INTRAOCULAR LYMPHOMA; CENTRAL-NERVOUS-SYSTEM; POLYMERASE-CHAIN-REACTION; AQUEOUS-HUMOR; VITRECTOMY SPECIMENS; GENE REARRANGEMENT; ANTIBODY DIVERSITY; CLINICAL-FEATURES; OCULAR LYMPHOMA; T-CELLS AB Primary vitreoretinal lymphoma (PVRL) or primary intraocular lymphoma, a subtype of primary central nervous system lymphoma, often masquerades as uveitis. The diagnosis of PVRL requires identification of lymphoma cells inside the eye, which is often challenging due to the frequent necrosis and admixing of PVRL cells with reactive lymphocytes. Therefore, detection of immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) gene rearrangements provide molecular diagnosis of B-and T-cell lymphoma, respectively. We retrospectively evaluated 208 cases with a clinical diagnosis of masquerade syndrome from 1998 to 2010. In 200 cases with molecular analyses using microdissection and polymerase chain reaction, we found that 110 cases had IgH gene rearrangement, 5 cases had TCR gene rearrangement, and 85 cases were negative for these two gene arrangements. The molecular data corroborated the cytopathological diagnoses of PVRL and uveitis in the majority of cases. Cytokine above the detected levels in the specimens were also measured in 80 of the 208 cases. A ratio of vitreous IL-10 to IL-6 greater than 1, suggesting PVRL, was found in 56/80 cases; 53/56 had the correct diagnosis. A ratio less than 1, suggesting uveitis, was found in 24/80 cases; 17/24 correctly confirmed the diagnosis. Moreover, the molecular data corresponded well with the clinical course of the diseases. The sensitivity and specificity of these molecular biomarkers for the diagnosis of PVRL are higher than 95%. C1 [Wang, Yujuan; Shen, Defen; Wang, Vinson M.; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Yujuan] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China. [Sen, H. Nida] NEI, Clin Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM yujuan.wang@nih.gov; shend@nei.nih.gov; vinson.wang@nih.gov; senh@nei.nih.gov; chanc@nei.nih.gov RI wang, yujuan/C-8428-2016 FU National Eye Institute FX The National Eye Institute Intramural Research Program supported the study. NR 47 TC 21 Z9 27 U1 0 U2 7 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD SEP PY 2011 VL 12 IS 9 BP 5684 EP 5697 DI 10.3390/ijms12095684 PG 14 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA 824PE UT WOS:000295213600018 PM 22016619 ER PT J AU Hanania, NA King, MJ Braman, SS Saltoun, C Wise, RA Enright, P Falsey, AR Mathur, SK Ramsdell, JW Rogers, L Stempel, DA Lima, JJ Fish, JE Wilson, SR Boyd, C Patel, KV Irvin, CG Yawn, BP Halm, EA Wasserman, SI Sands, MF Ershler, WB Ledford, DK AF Hanania, Nicola A. King, Monroe J. Braman, Sidney S. Saltoun, Carol Wise, Robert A. Enright, Paul Falsey, Ann R. Mathur, Sameer K. Ramsdell, Joe W. Rogers, Linda Stempel, David A. Lima, John J. Fish, James E. Wilson, Sandra R. Boyd, Cynthia Patel, Kushang V. Irvin, Charles G. Yawn, Barbara P. Halm, Ethan A. Wasserman, Stephen I. Sands, Mark F. Ershler, William B. Ledford, Dennis K. CA Asthma Elderly Workshop Participan TI Asthma in the elderly: Current understanding and future research needs-a report of a National Institute on Aging (NIA) workshop SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Aging; airway; allergy; asthma; elderly; immune mechanisms; immunosenescence ID OBSTRUCTIVE PULMONARY-DISEASE; QUALITY-OF-LIFE; EXHALED NITRIC-OXIDE; GEORGES RESPIRATORY QUESTIONNAIRE; LONGITUDINAL GOMPERTZIAN ANALYSIS; 10-WEEK REHABILITATION PROGRAM; GENERAL-POPULATION SAMPLE; SYNCYTIAL VIRUS-INFECTION; LOWER-EXTREMITY FUNCTION; HEALTH-CARE UTILIZATION AB Asthma in the elderly is underdiagnosed and undertreated, and there is a paucity of knowledge on the subject. The National Institute on Aging convened this workshop to identify what is known and what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of asthma in the elderly. Asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger patients, but comorbid illnesses and the psychosocial effects of aging might affect the diagnosis, clinical presentation, and care of asthma in this population. At least 2 phenotypes exist among elderly patients with asthma; those with longstanding asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. Many challenges exist in the recognition and treatment of asthma in the elderly. Furthermore, the pathophysiologic mechanisms of asthma in the elderly are likely to be different from those seen in young asthmatic patients, and these differences might influence the clinical course and outcomes of asthma in this population. (J Allergy Clin Immunol 2011;128:S4-24.) C1 [Hanania, Nicola A.] Baylor Coll Med, Sect Pulm & Crit Care Med, Asthma Clin Res Ctr, Houston, TX 77030 USA. [King, Monroe J.; Ledford, Dennis K.] Univ S Florida, Div Allergy & Immunol, Dept Med, Tampa, FL USA. [Braman, Sidney S.] Brown Univ, Providence, RI 02912 USA. [Saltoun, Carol] Northwestern Univ, Chicago, IL 60611 USA. [Wise, Robert A.; Boyd, Cynthia] Johns Hopkins Univ, Baltimore, MD USA. [Enright, Paul] Univ Arizona, Tucson, AZ USA. [Falsey, Ann R.] Univ Rochester, Rochester, NY 14627 USA. [Mathur, Sameer K.] Univ Wisconsin, Dept Med, Sect Allergy Pulm & Crit Care, Madison, WI 53706 USA. [Ramsdell, Joe W.; Wasserman, Stephen I.] Univ Calif San Diego, San Diego, CA 92103 USA. [Rogers, Linda] NYU, Sch Med, New York, NY USA. [Stempel, David A.] GlaxoSmithKline, Bellevue, WA USA. [Lima, John J.] Nemours Children Clin, Jacksonville, FL USA. [Fish, James E.] Genentech Inc, Gladwyne, England. [Wilson, Sandra R.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Patel, Kushang V.] NIA, Bethesda, MD 20892 USA. [Yawn, Barbara P.] Univ Minnesota, Dept Family & Community Hlth, Rochester, MN USA. [Irvin, Charles G.] Univ Vermont, Burlington, VT 05405 USA. [Halm, Ethan A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Sands, Mark F.] SUNY Buffalo, Dept Veteran Affairs, Med Ctr, Buffalo, NY 14260 USA. [Ershler, William B.] Inst Adv Studies Aging, Gaithersburg, MD USA. RP King, MJ (reprint author), Univ S Florida, Div Allergy & Immunol, Dept Med, 7674 Cumberland Ct, Largo, FL 33777 USA. EM m.james.king@me.com OI Wise, Robert/0000-0002-8353-2349 FU National Institute on Aging; GlaxoSmithKline; Genentech; Novartis; Pfizer; Boehringer Ingelheim; Forest; Merck; Sanofi Pasteur; NIH; American Lung Association; National Heart, Lung, and Blood Institute/NIH; Agency for Healthcare Research and Quality FX Publication of this article was supported by the National Institute on Aging.; N. A. Hanania is on the speakers' bureau for GlaxoSmithKline, AstraZeneca, and Genentech; is on advisory boards for GlaxoSmithKline, Genentech, Novartis, and Pfizer; and receives research support from GlaxoSmithKline, Genentech, Novartis, and Pfizer. M. J. King has consultant arrangements with the National Institutes of Health (NIH). R. A. Wise has consultant arrangements with AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sunovion, and Merck and receives research support from GlaxoSmithKline, Boehringer Ingelheim, Forest, and Merck. A. R. Falsey has consultant arrangements with MedImmune and Sanofi Pasteur and receives research support from Sanofi Pasteur and GlaxoSmithKline. S. K. Mathur receives research support from the NIH and is vice-chair of the American Academy of Allergy, Asthma & Immunology (AAAAI)'s Asthma and Allergic Diseases in the Elderly committee. D. A. Stempel is employed by GlaxoSmithKline. J. J. Lima receives research support from the NIH and the American Lung Association. J. E. Fish is employed by Merck & Co, Inc. S. R. Wilson receives research support from the National Heart, Lung, and Blood Institute/NIH. C. G. Irvin is on the speakers' bureau for Merck and the advisory board for MethaPharm, receives research support from the NIH and the American Lung Association, and is on the advisory board for the Vermont Department of Health. B. P. Yawn has consulted for the American Thoracic Society, receives research support from the Agency for Healthcare Research and Quality, and is the chair of the state coalition for asthma for the American Lung Association. S. I. Wasserman receives research support from the American Lung Association, has provided legal consultation or expert witness testimony in cases related to mold injury and medical malpractice, and is president of the American Board of Allergy and Immunology. The rest of the authors have declared that they have no conflict of interest. NR 241 TC 83 Z9 84 U1 4 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD SEP PY 2011 VL 128 IS 3 SU S BP S4 EP S24 DI 10.1016/j.jaci.2011.06.048 PG 21 WC Allergy; Immunology SC Allergy; Immunology GA 828XB UT WOS:000295536500002 PM 21872730 ER PT J AU Cheng, TJ Li, QL Wang, YL Bryant, SH AF Cheng, Tiejun Li, Qingliang Wang, Yanli Bryant, Stephen H. TI Identifying Compound-Target Associations by Combining Bioactivity Profile Similarity Search and Public Databases Mining SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID DIHYDROFOLATE-REDUCTASE; BIOLOGICAL-ACTIVITY; SMALL MOLECULES; DRUG DISCOVERY; GROWTH-INHIBITION; SCORING FUNCTIONS; STRUCTURAL BASIS; BETA-TUBULIN; IDENTIFICATION; DOCKING AB Molecular target identification is of central importance to drug discovery. Here, we developed a computational approach, named bioactivity profile similarity search (BASS), for associating targets to small molecules by using the known target annotations of related compounds from public databases. To evaluate BASS, a bioactivity profile database was constructed using 4296 compounds that were commonly tested in the US National Cancer Institute 60 human tumor cell line anticancer drug screen (NCI-60). Each compound was used as a query to search against the entire bioactivity profile database, and reference compounds with similar bioactivity profiles above a threshold of 0.75 were considered as neighbor compounds of the query. Potential targets were subsequently linked to the identified neighbor compounds by using the known targets of the query compound. About 45% of the predicted compound-target associations were successfully verified retrospectively, suggesting the possible application of BASS in identifying the targets of uncharacterized compounds and thus providing insight into the study of promiscuity and polypharmacology. Furthermore, BASS identified a significant fraction of structurally diverse compounds with similar bioactivities, indicating its feasibility of "scaffold hopping in searching novel molecules against the target of interest. C1 [Cheng, Tiejun; Li, Qingliang; Wang, Yanli; Bryant, Stephen H.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov RI Cheng, Tiejun/A-5344-2010 OI Cheng, Tiejun/0000-0002-4486-3356 FU National Institutes of Health (NIH), National Library of Medicine (NLM) FX We thank the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM) for funding support. We also thank the NIH Fellows Editorial Board (FEB) for manuscript revision. NR 65 TC 34 Z9 34 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD SEP PY 2011 VL 51 IS 9 BP 2440 EP 2448 DI 10.1021/ci200192v PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA 823IC UT WOS:000295114700039 PM 21834535 ER PT J AU Aligianis, I Handley, M Carpanini, S Bern, D Yoshimura, S Nunes-Bastos, R Bond, F Kurian, M Rahman, F Hadzhiev, Y Pasha, S Kirby, G Straatman-Iwanowska, A Cullinane, A McNeill, A Gissen, P Muller, F Maher, E Barr, F AF Aligianis, Irene Handley, M. Carpanini, S. Bern, D. Yoshimura, S. Nunes-Bastos, R. Bond, F. Kurian, M. Rahman, F. Hadzhiev, Y. Pasha, S. Kirby, G. Straatman-Iwanowska, A. Cullinane, A. McNeill, A. Gissen, P. Mueller, F. Maher, E. Barr, F. TI Micro and Martsolf Syndromes SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract CT British Human Genetics Conference CY SEP 05-07, 2011 CL Univ Warwick, Coventry, ENGLAND HO Univ Warwick C1 [Aligianis, Irene; Handley, M.; Carpanini, S.] MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Bern, D.; Rahman, F.; Hadzhiev, Y.; Pasha, S.; Kirby, G.; Mueller, F.; Maher, E.] Univ Birmingham, Sch Clin & Expt Med, Birmingham B15 2TT, W Midlands, England. [Bern, D.; Rahman, F.; Hadzhiev, Y.; Pasha, S.; Kirby, G.; Mueller, F.; Maher, E.] Univ Birmingham, Ctr Rare Dis & Personalised Med, Birmingham B15 2TT, W Midlands, England. [Yoshimura, S.] Osaka Univ, Grad Sch Med, Dept Cell Biol, Osaka 565087, Japan. [Nunes-Bastos, R.; Barr, F.] Univ Liverpool, Canc Res Ctr, Liverpool L69 3BX, Merseyside, England. [Bond, F.] Birmingham Womens Hosp, W Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Kurian, M.; Straatman-Iwanowska, A.; Gissen, P.] Inst Child Hlth, London, England. [Cullinane, A.] NHGRI, NIH, Bethesda, MD 20892 USA. [McNeill, A.] UCL, Inst Neurol, London WC1E 6BT, England. RI Gissen, Paul/A-4352-2010; mcneill, alisdair/B-1267-2012 OI Gissen, Paul/0000-0002-9712-6122; NR 0 TC 0 Z9 0 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2011 VL 48 SU 1 BP S36 EP S36 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 823DY UT WOS:000295103800062 ER PT J AU Urquhart, J Hanson, D Murray, PG O'Sullivan, J Daly, S Bhaskar, SS Biesecker, LG Skae, M Smith, C Cole, T Kirk, J Chandler, K Kingston, H Donnai, D Clayton, PE Black, GCM AF Urquhart, Jill Hanson, D. Murray, P. G. O'Sullivan, J. Daly, S. Bhaskar, S. S. Biesecker, L. G. Skae, M. Smith, C. Cole, T. Kirk, J. Chandler, K. Kingston, H. Donnai, D. Clayton, P. E. Black, G. C. M. TI Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract CT British Human Genetics Conference CY SEP 05-07, 2011 CL Univ Warwick, Coventry, ENGLAND HO Univ Warwick C1 [Urquhart, Jill; Hanson, D.; Murray, P. G.; O'Sullivan, J.; Daly, S.; Bhaskar, S. S.; Chandler, K.; Kingston, H.; Donnai, D.; Clayton, P. E.; Black, G. C. M.] Univ Manchester, Sch Biomed, Manchester Acad Hlth Sci Ctr MAHSC, Manchester M13 9PL, Lancs, England. [Biesecker, L. G.] Intramural Sequencing Ctr NISC, NIH, Bethesda, MD USA. [Skae, M.] Cent Manchester Univ Hosp Fdn Trust, Manchester, Lancs, England. [Smith, C.] E Lancashire Hosp NHS Trust, Manchester, Lancs, England. [Cole, T.] Birmingham Womens Hosp, W Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Kirk, J.] Birmingham Childrens Hosp, Dept Paediat Endocrinol, Birmingham, W Midlands, England. EM jill.urquhart@cmft.nhs.uk NR 0 TC 0 Z9 0 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2011 VL 48 SU 1 BP S16 EP S16 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 823DY UT WOS:000295103800007 ER PT J AU Yang, IV Jiang, WW Rutledge, HR Lackford, B Warg, LA De Arras, L Alper, S Schwartz, DA Pisetsky, DS AF Yang, Ivana V. Jiang, Weiwen Rutledge, Holly R. Lackford, Brad Warg, Laura A. De Arras, Lesly Alper, Scott Schwartz, David A. Pisetsky, David S. TI Identification of novel innate immune genes by transcriptional profiling of macrophages stimulated with TLR ligands SO MOLECULAR IMMUNOLOGY LA English DT Article DE Innate immunity; Gene expression; RNA interference; Lipopolysaccharide; Poly (I:C); CpG DNA; PLEC1; TPST1 ID POLYINOSINIC-POLYCYTIDYLIC ACID; TOLL-LIKE RECEPTORS; CPG DNA; EXPRESSION; RELEASE; LIPOPOLYSACCHARIDE; APOPTOSIS; SULFATION; PATTERN; HMGB1 AB Toll-like receptors (TLRs) are key receptors in innate immunity and trigger responses following interaction with pathogen-associated molecular patterns (PAMPs). TLR3, TLR4 and TLR9 recognize double stranded RNA, lipopolysaccharide (LPS) and CpG DNA, respectively. These receptors differ importantly in downstream adaptor molecules. TLR4 signals through MyD88 and TRIF; in contrast, the TLR3 pathway involves only TRIF while TLR9 signals solely through MyD88. To determine how differences in downstream signaling could influence gene expression in innate immunity, gene expression patterns were determined for the RAW264.7 macrophage cell line stimulated with LPS, poly (I:C), or CpG DNA. Gene expression profiles 6 and 24h post-stimulation were analyzed to determine genes, pathways and transcriptional networks induced. As these experiments showed, the number and extent of genes expressed varied with stimulus. LPS and poly (I:C) induced an abundant array of genes in RAW264.7 cells at 6h and 24 h following treatment while CpG DNA induced many fewer. By analyzing data for networks and pathways, we prioritized differentially expressed genes with respect to those common to the three TLR ligands as well as those shared by LPS and poly (I:C) but not CpG DNA. The importance of changes in gene expression was demonstrated by experiments indicating that RNA interference-mediated inhibition of two genes identified in this analysis, PLEC1 and TPST1, reduced IL-6 production by J774A.1 and RAW264.7 macrophages stimulated with LPS. Together, these findings delineate macrophage gene response patterns induced by different PAMPs and identify new genes that have not previously been implicated in innate immunity. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Yang, Ivana V.; Warg, Laura A.; De Arras, Lesly; Alper, Scott; Schwartz, David A.] Natl Jewish Hlth, Ctr Genes Environm & Hlth, Denver, CO 80206 USA. [Yang, Ivana V.; Schwartz, David A.] Univ Colorado Denver, Dept Med, Aurora, CO 80010 USA. [Jiang, Weiwen; Pisetsky, David S.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Jiang, Weiwen; Pisetsky, David S.] Durham VA Med Ctr, Durham, NC 27710 USA. [Rutledge, Holly R.; Lackford, Brad] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Alper, Scott; Schwartz, David A.] Univ Colorado, Sch Med, Denver, CO 80206 USA. [Alper, Scott; Schwartz, David A.] Natl Jewish Hlth, Integrated Dept Immunol, Denver, CO 80206 USA. RP Yang, IV (reprint author), Natl Jewish Hlth, Ctr Genes Environm & Hlth, 1400 Jackson St, Denver, CO 80206 USA. EM yangi@njhealth.org FU NIH; National Institute of the Environmental Health Sciences; National Heart Lung and Blood Institute; VA Merit Review grant; American Lung Association [RG-169529-N] FX This study was funded by the Intramural Research Program of the NIH, National Institute of the Environmental Health Sciences and National Heart Lung and Blood Institute, a VA Merit Review grant, and American Lung Association grant RG-169529-N. NR 31 TC 10 Z9 10 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2011 VL 48 IS 15-16 BP 1886 EP 1895 DI 10.1016/j.molimm.2011.05.015 PG 10 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 826ZY UT WOS:000295395300019 PM 21665277 ER PT J AU Wurster, AL Precht, P Pazin, MJ AF Wurster, Andrea L. Precht, Patricia Pazin, Michael J. TI NF-kappa B and BRG1 bind a distal regulatory element in the IL-3/GM-CSF locus SO MOLECULAR IMMUNOLOGY LA English DT Article DE Gene regulation; T cell regulation; Chromatin remodeling; BRG1; SWI/SNF; Cytokine transcription; Distal regulatory elements ID CHROMATIN-REMODELING COMPLEX; COLONY-STIMULATING FACTOR; CYTOKINE GENE-EXPRESSION; GM-CSF PROMOTER; T-CELL DEVELOPMENT; TRANSCRIPTIONAL REGULATION; BAF COMPLEX; COLORECTAL-CANCER; SWI/SNF COMPLEX; CONTROL REGION AB We investigated gene regulation at the IL-3/GM-CSF gene cluster. We found BRG1, a SWI/SNF remodeling ATPase, bound a distal element, CNSa. BRG1 binding was strongest in differentiated, stimulated T helper cells, paralleling IL-3 and GM-CSF expression. Depletion of BRG1 reduced IL-3 and GM-CSF transcription. BAF-specific SWI/SNF subunits bound to this locus and regulated IL-3 expression. CNSa was in closed chromatin in fibroblasts, open chromatin in differentiated T helper cells, and moderately open chromatin in naive (undifferentiated) T helper cells; BRG1 was required for the most open state. CNSa increased transcription of a reporter in an episomal expression system, in a BRG1-dependent manner. The NF-kappa B subunit RelA/p65 bound CNSa in activated T helper cells. Inhibition of NF-kappa B blocked BRG1 binding to CNSa, chromatin opening at CNSa, and activation of IL-3 and GM-CSF. Together, these findings suggest CNSa is a distal enhancer that binds BRG1 and NF-kappa B. Published by Elsevier Ltd. C1 [Wurster, Andrea L.; Precht, Patricia; Pazin, Michael J.] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Pazin, MJ (reprint author), NHGRI, NIH, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM pazinm@mail.nih.gov FU NIH, National Institute on Aging [1 Z01 AG000524] FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging, 1 Z01 AG000524. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 9 Z9 9 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2011 VL 48 IS 15-16 BP 2178 EP 2188 DI 10.1016/j.molimm.2011.07.016 PG 11 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 826ZY UT WOS:000295395300052 PM 21831442 ER PT J AU Uppalapati, D Ohta, N Zhang, YQ Kawabata, A Pyle, MM Becker, KG Troyer, D Tamura, M AF Uppalapati, Deepthi Ohta, Naomi Zhang, Yongqing Kawabata, Atsushi Pyle, Marla M. Becker, Kevin G. Troyer, Deryl Tamura, Masaaki TI Identification and Characterization of Unique Tumoricidal Genes in Rat Umbilical Cord Matrix Stem Cells SO MOLECULAR PHARMACEUTICS LA English DT Article DE rat umbilical cord matrix stem cells; rat mammary tumor cells; Mat B III; microarray; real-time PCR; thymidine uptake; tumor suppressor genes; ADRP; GPI; SULF-1 ID DIFFERENTIATION-RELATED PROTEIN; BREAST-CANCER; LUNG ADENOCARCINOMA; DELIVERY VEHICLES; RENAL-CARCINOMA; IN-VIVO; GROWTH; EXPRESSION; THERAPY; FIBROBLASTS AB Rat umbilical cord matrix stem cells (UCMSC) have been shown to exhibit a remarkable ability to control nit mammary adenocarcinoma (Mat B III) cell proliferation both in vivo and in vitro. To study the underlying mechanisms and genes involved in Mat B III growth attenuation, total RNA was extracted from the naive rat UCMSC alone and those cocultured with Mat B III in Transwell culture dishes. Gene expression profiles of naive rat UCMSC alone and those cocultured with Mat B III cells were investigated by microarray analysis using an Illumina RatRef-12 Expression BeadChip. The comparison of gene expression profiles between untreated and cocultured rat UCMSC identified five upregulated candidate genes (follistatin (FST), sulfatasel (SULF-1), glucose phosphate isomerase (GPI), HtrA serine peptidase (HTRA1), and adipocyte differentiation-related protein (ADRP)) and two downregulated candidate genes (transforming growth factor, beta-induced, 68 kDa (TGF beta I) and podoplanin (PDPN)) based upon the following screening criteria: (1) expression of the candidate genes should show at least a 1.5-fold change in rat UCMSC cocultured with Mat B III cells; (2) candidate genes encode secretory proteins; and (3) they encode cell growth-related proteins. Following confirmation of gene expression by real-time PCR, ADRP, SULF-1 and GPI were selected for further analysis. Addition of specific neutralizing antibodies against these three gene products or addition of gene-specific siRNA's individually in cocultures of 1:20 rat UCMSC:Mat B III cells significantly increased cell proliferation, implying that these gene products are produced under the cocultured condition and functionally attenuate cell growth. Immunoprecipitation followed by Western blot analysis demonstrated that these proteins are indeed secreted into the culture medium. Individual overexpression of these three genes in rat UCMSC significantly enhanced UCMSC-dependent inhibition of cell proliferation in coculture. These results suggest that ADRP, SULF-1 and GPI act as tumor suppressor genes, and these genes might be involved in rat UCMSC-dependent growth attenuation of rat mammary tumors. C1 [Uppalapati, Deepthi; Ohta, Naomi; Kawabata, Atsushi; Pyle, Marla M.; Troyer, Deryl; Tamura, Masaaki] Kansas State Univ, Coll Vet Med, Dept Anat & Physiol, Manhattan, KS 66506 USA. [Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Res Resources Branch, NIH, Baltimore, MD 21224 USA. RP Tamura, M (reprint author), Kansas State Univ, Coll Vet Med, Dept Anat & Physiol, Manhattan, KS 66506 USA. EM mtamura@vet.ksu.edu OI Becker, Kevin/0000-0002-6794-6656; Ohta, Naomi/0000-0001-5790-3137 FU Kansas State University (KSU) Terry C. Johnson Center for Basic Cancer Research; Kansas Bioscience Authority Collaborative Cancer Research Initiative; Kansas State Legislative Appropriation; KSU College of Veterinary Medicine; NIH [P20 RR017686, P20 RR016475, P20 RR01556, R21 CA135599]; NIH, National Institute on Aging FX We are grateful to Mr. William H. Wood III (National Institute on Aging, NIH) for his excellent technical assistance in microarray analysis. This work was supported by Kansas State University (KSU) Terry C. Johnson Center for Basic Cancer Research, Kansas Bioscience Authority Collaborative Cancer Research Initiative grant, Kansas State Legislative Appropriation, KSU College of Veterinary Medicine Dean's fund, NIH Grants P20 RR017686, P20 RR016475, P20 RR01556 and R21 CA135599 and the Intramural Research Program of the NIH, National Institute on Aging. NR 36 TC 7 Z9 7 U1 0 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD SEP-OCT PY 2011 VL 8 IS 5 BP 1549 EP 1558 DI 10.1021/mp2001582 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 826IJ UT WOS:000295347500012 PM 21851062 ER PT J AU Quan, QM Xie, J Gao, HK Yang, M Zhang, F Liu, G Lin, X Wang, A Eden, HS Lee, S Zhang, GX Chen, XY AF Quan, Qimeng Xie, Jin Gao, Haokao Yang, Min Zhang, Fan Liu, Gang Lin, Xin Wang, Andrew Eden, Henry S. Lee, Seulki Zhang, Guixiang Chen, Xiaoyuan TI HSA Coated Iron Oxide Nanoparticles as Drug Delivery Vehicles for Cancer Therapy SO MOLECULAR PHARMACEUTICS LA English DT Article DE iron oxide nanoparticle; theranostic nanomedicine; magnetic resonance imaging; doxorubicin; drug delivery; breast cancer ID HUMAN SERUM-ALBUMIN; PHOTODYNAMIC THERAPY; BOUND PACLITAXEL; BREAST-CANCER; EFFICACY; TUMORS AB An ongoing effort in the field of nanomedicine is to develop nanoplatforms with both imaging and therapeutic functions, the "nanotheranostics". We have previously developed a human serum albumin (HSA) coated iron oxide nanoparticle (HINP) formula and used multiple imaging modalities to validate its tumor targeting attributes. In the current study, we sought to impart doxorubicin (Dox) onto the HINPs and to assess the potential of the conjugates as theranostic agents. In a typical preparation, we found that about 0.5 mg of Dox and 1 mg of iron oxide nanoparticles (IONPs, Fe content) could be loaded into 10 mg of HSA matrices. The resulting D-HINPs (Dox loaded HINPs) have a hydrodynamic size of 50 nm and are able to release Dox in a sustained fashion. More impressively, the HINPs can assist the translocation of Dox across the cell membrane and even its accumulation in the nucleus. In vivo, D-HINPs retained a tumor targeting capability of HINPs, as manifested by both in vivo MRI and ex vivo immunostaining results. In a follow-up therapeutic study on a 4T1 murine breast cancer xenograft model, D-HINPs showed a striking tumor suppression effect that was comparable to that of Doxil and greatly outperformed free Dox. Such a strategy can be readily extended to load other types of small molecules, making HINP a promising theranostic nanoplatform. C1 [Quan, Qimeng; Xie, Jin; Gao, Haokao; Yang, Min; Zhang, Fan; Liu, Gang; Lin, Xin; Lee, Seulki; Zhang, Guixiang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Quan, Qimeng; Zhang, Guixiang] Shanghai Jiao Tong Univ, Dept Radiol, Shanghai Peoples Hosp 1, Shanghai 200080, Peoples R China. [Wang, Andrew] Ocean NanoTech, Springdale, AR 72764 USA. [Eden, Henry S.] NIBIB, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Zhang, GX (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, 31 Ctr Dr,Bldg 31,1C22, Bethesda, MD 20892 USA. EM guixiangzhang@sina.com; shawn.chen@nih.gov RI Xie, Jin/E-8193-2010 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH; National Science Foundation of China (NSFC) [81028009]; China Scholarship Council (CSC); NIH [K99/R00]; National Institute of Standards and Technology (NIST) FX This work was supported by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH and the International Cooperative Program of National Science Foundation of China (NSFC) (81028009). Q.Q. is enrolled in the NIH Graduate Partnerships Program (GPP) and partially supported by the China Scholarship Council (CSC). J.X. is partially supported by an NIH Pathway to Independence Grant (K99/R00). S.L. acknowledges a National Research Council Research Associateship Award funded by the National Institute of Standards and Technology (NIST) and the IRP of NIBIB, NIH. NR 28 TC 80 Z9 86 U1 5 U2 49 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD SEP-OCT PY 2011 VL 8 IS 5 BP 1669 EP 1676 DI 10.1021/mp200006f PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 826IJ UT WOS:000295347500024 PM 21838321 ER PT J AU Gao, HK Niu, G Yang, M Quan, QM Ma, Y Murage, EN Ahn, JM Kiesewetter, DO Chen, XY AF Gao, Haokao Niu, Gang Yang, Min Quan, Qimeng Ma, Ying Murage, Eunice N. Ahn, Jung-Mo Kiesewetter, Dale O. Chen, Xiaoyuan TI PET of Insulinoma Using F-18-FBEM-EM3106B, a New GLP-1 Analogue SO MOLECULAR PHARMACEUTICS LA English DT Article DE insulinoma; glucagon-like peptide-1 receptor; bicyclic GLP-1 analogue; F-18-FBEM; PET ID NEUROENDOCRINE TUMORS; PEPTIDE-1 GLP-1; LOCALIZATION; STIMULATION; EXPRESSION; RECEPTORS AB Derived from endocrine pancreatic beta cells, insulinomas express glucagon-like peptide-1 (GLP-1) receptor with high density and incidence. In this study, we labeled a novel GLP-1 analogue, EM3106B, with F-18 and performed PET imaging to visualize insulinoma tumors in an animal model. A GLP-1 analogue that contains multiple lactam bridges, EM3106B, was labeled with F-18 through a maleimide-based prosthetic group, N-2-(4-F-18-fluorobenzamido)ethylmaleimide (F-18-FBEM). The newly developed radiotracer was characterized by cell based receptor-binding assay, cell uptake and efflux assay. The stability in serum was evaluated by radio-HPLC analysis. In vivo PET imaging was performed in nude mice bearing subcutaneous INS-1 insulinoma tumors and MDA-MB-435 tumors of melanoma origin. Ex vivo biodistribution study was performed to confirm the PET imaging data. EM3106B showed high binding affinity (IC50 = 1.38 nM) and high cell uptake (5.25 +/- 0.61% after 120 mm incubation). F-18-FBEM conjugation of EM3106B resulted in high labeling yield (24.9 +/- 2.4%) and high specific activity (>75 GBq/mu mol at the end of bombardment). EM3106B specifically bound and was internalized by GLP-1Rpositive INS-1 cells. After intravenous injection of 3.7 MBq (100 mu Ci) of F-18-FBEM-EM3106B, the INS-1 tumors were clearly visible with high contrast in relation to the contralateral background on PET images, and tumor uptake of F-18-FBEM-EM3106B was determined to be 28.5 +/- 4.7 and 25.4 +/- 4.1% ID/g at 60 and 120 min, respectively. F-18-FBEM-EM3106B showed low uptake in MB-MDA-435 tumors with low level of GLP-1R expression. Direct tissue sampling biodistribution experiment confirmed high tracer uptake in INS-1 tumors and receptor specificity in both INS-1 tumor and pancreas. In conclusion, F-18-FBEM-EM3106B exhibited GLP-1 R-receptor-specific targeting properties in insulinomas. The favorable characteristics of F-18-FBEM-EM3106B, such as high specific activity and high tumor uptake, and high tumor to nontarget uptake, demonstrate that it is a promising tracer for clinical insulinoma imaging. C1 [Gao, Haokao; Niu, Gang; Yang, Min; Quan, Qimeng; Ma, Ying; Kiesewetter, Dale O.; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Gao, Haokao] Fourth Mil Med Univ, Xijing Hosp, Dept Cardiol, Xian 710032, Peoples R China. [Murage, Eunice N.; Ahn, Jung-Mo] Univ Texas Dallas, Dept Chem, Richardson, TX 75080 USA. RP Kiesewetter, DO (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, 31 Ctr Dr,Suite 1C14, Bethesda, MD 20892 USA. EM dk7k@nih.gov; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); Juvenile Diabetes Research Foundation [37-2011-20]; National Science Foundation of China (NSFC) [81028009]; Radiology and Imaging Sciences Department, NIH Clinical Center FX This work was supported by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Juvenile Diabetes Research Foundation (37-2011-20, Jungmo Ahn), and the International Cooperative Program of the National Science Foundation of China (NSFC) (81028009). G.N. holds an Imaging Sciences Training Fellowship, which is jointly supported by the Radiology and Imaging Sciences Department, NIH Clinical Center and the Intramural Research Program, NIBIB, NIH. We acknowledge the NIH/CC cyclotron facility for isotope production. NR 22 TC 38 Z9 40 U1 0 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD SEP-OCT PY 2011 VL 8 IS 5 BP 1775 EP 1782 DI 10.1021/mp200141x PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 826IJ UT WOS:000295347500035 PM 21800885 ER PT J AU Yellayi, S Hilliard, B Ghazanfar, M Tsingalia, A Nantz, MH Bollinger, L de Kok-Mercado, F Hecker, JG AF Yellayi, Srikanth Hilliard, Brendan Ghazanfar, Mustafa Tsingalia, Akivaga Nantz, Michael H. Bollinger, Laura de Kok-Mercado, Fabian Hecker, James G. TI A Single Intrathecal Injection of DNA and an Asymmetric Cationic Lipid as Lipoplexes Ameliorates Experimental Autoimmune Encephalomyelitis SO MOLECULAR PHARMACEUTICS LA English DT Article DE CNS gene delivery; asymmetric lipids; animal model; experimental autoimmune encephalomyelitis ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; NONVIRAL GENE DELIVERY; REGULATORY T-CELLS; MULTIPLE-SCLEROSIS; OX40 LIGAND; THERAPY; RAT; EXPRESSION; DISEASE AB Intrathecal delivery of gene therapeutics is a route of administration that overcomes several of the limitations that plague current immunosuppressive treatments for autoimmune diseases of the central nervous system (CNS). Here we report intrathecal delivery of small amounts (3 mu g) of plasmid DNA that codes for an immunomodulatory fusion protein, OX40-TRAIL, composed of OX40, a tumor necrosis factor receptor, and tumor necrosis factor related apoptosis inducing ligand (TRAIL). This DNA was delivered in a formulated nucleic acid lipid complex (lipoplexes) with an asymmetric two-chain cationic lipid myristoyl (14:0) and lauroyl (12:1) rosenthal inhibitor-substituted compound (MLRI) formed from the tetraalkylammonium glycerol-based compound N-(1-(2,3-dioleoyloxy)-propyl-N-1-(2-hydroxy)ethyl)-N,N-dimethyl ammonium iodide. Delivery and expression in the CNS of OX40-TRAIL in the mouse prior to onset of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, decreased the severity of clinical disease. We believe this preclinical demonstration of rapid, widespread, and biologically therapeutic nonviral gene delivery to the CNS is important in further development of clinical lipid-based therapeutics for CNS disorders. C1 [Yellayi, Srikanth; Hilliard, Brendan; Ghazanfar, Mustafa; Tsingalia, Akivaga] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Yellayi, Srikanth; Bollinger, Laura; de Kok-Mercado, Fabian] NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. [Nantz, Michael H.] Univ Louisville, Dept Chem, Louisville, KY 40292 USA. [Hecker, James G.] Univ Penn, Dept Anesthesia & Crit Care, Philadelphia, PA 19104 USA. RP Hecker, JG (reprint author), Univ Washington, Dept Anesthesiol & Pain Med, Box 359724,329 9th Ave, Seattle, WA 98104 USA. EM heckerj@uw.edu OI Hilliard, Brendan /0000-0002-4689-6821 FU NIH NINDS [R01 NS046591] FX We thank Dr. Mark Tykocinski for providing the fusion protein (OX40-TRAIL) plasmid. We also thank Shaomin Zou and Yvette Liu for their technical assistance. This study was supported by NIH NINDS R01 NS046591 (J.H.). NR 27 TC 5 Z9 5 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD SEP-OCT PY 2011 VL 8 IS 5 BP 1980 EP 1984 DI 10.1021/mp2002413 PG 5 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 826IJ UT WOS:000295347500056 PM 21732666 ER PT J AU Tuncbag, N Gursoy, A Nussinov, R Keskin, O AF Tuncbag, Nurcan Gursoy, Attila Nussinov, Ruth Keskin, Ozlem TI Predicting protein-protein interactions on a proteome scale by matching evolutionary and structural similarities at interfaces using PRISM SO NATURE PROTOCOLS LA English DT Article ID HOT-SPOTS; FUNCTIONAL COVERAGE; DRUG DISCOVERY; BINDING-SITES; DOCKING; SEQUENCE; DATABASE; COMPLEXES; ALGORITHM; ARCHITECTURES AB Prediction of protein-protein interactions at the structural level on the proteome scale is important because it allows prediction of protein function, helps drug discovery and takes steps toward genome-wide structural systems biology. We provide a protocol (termed PRISM, protein interactions by structural matching) for large-scale prediction of protein-protein interactions and assembly of protein complex structures. The method consists of two components: rigid-body structural comparisons of target proteins to known template protein-protein interfaces and flexible refinement using a docking energy function. The PRISM rationale follows our observation that globally different protein structures can interact via similar architectural motifs. PRISM predicts binding residues by using structural similarity and evolutionary conservation of putative binding residue 'hot spots'. Ultimately, PRISM could help to construct cellular pathways and functional, proteome-scale annotation. PRISM is implemented in Python and runs in a UNIX environment. The program accepts Protein Data Bank-formatted protein structures and is available at http://prism.ccbb.ku.edu.tr/prism_protocol/. C1 [Tuncbag, Nurcan; Gursoy, Attila; Keskin, Ozlem] Koc Univ, Coll Engn, Ctr Computat Biol & Bioinformat, Istanbul, Turkey. [Nussinov, Ruth] NCI Frederick, Ctr Canc Res Nanobiol Program, SAIC Frederick Inc, Basic Sci Program, Frederick, MD USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Gursoy, A (reprint author), Koc Univ, Coll Engn, Ctr Computat Biol & Bioinformat, Istanbul, Turkey. EM agursoy@ku.edu.tr; okeskin@ku.edu.tr RI Tuncbag, Nurcan/D-3383-2011; Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU TUBITAK [109T343, 109E207]; National Cancer Institute, US National Institutes of Health [HHSN261200800001E]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Turkish Academy of Sciences (TUBA) FX We thank all members of the Koc University Computational Systems Biology group, especially C. Ulubas, A. Selim Aytuna and U. Ogmen (former PRISM development team). We thank former and current members of the Tel Aviv University Structural Bioinformatics group, particularly M. Shatsky (MultiProt) and E. Mashiach (FiberDock). This work has been supported by TUBITAK (Research Grant numbers: 109T343 and 109E207). This project has been funded in whole or in part with federal funds from the National Cancer Institute, US National Institutes of Health (contract number HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. O.K. acknowledges support from the Turkish Academy of Sciences (TUBA). NR 52 TC 106 Z9 107 U1 3 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 J9 NAT PROTOC JI Nat. Protoc. PD SEP PY 2011 VL 6 IS 9 BP 1341 EP 1354 DI 10.1038/nprot.2011.367 PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 826OG UT WOS:000295362900006 PM 21886100 ER PT J AU Sakairi, T Abe, Y Kopp, JB AF Sakairi, Toru Abe, Yoshifusa Kopp, Jeffrey B. TI TGF-beta1 reduces Wilms' tumor suppressor gene expression in podocytes SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE FSGS; podocytes; TGF-beta1; Wilms' tumor suppressor gene ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; TGF-BETA; WT1 GENE; TRANSGENIC MICE; BREAST-CANCER; PATHWAY; GROWTH; TRANSCRIPTION; PATHOGENESIS; PROGRESSION AB Background. Wilms' tumor suppressor gene (WT1) is essential for normal podocyte function, and transforming growth factor (TGF)-beta contributes to focal segmental glomerulosclerosis (FSGS). We aimed to address whether TGF-beta affects WT1 expression in podocytes. Methods. A human podocyte cell line treated with TGF-beta1 and kidneys in Alb/TGF-beta1-transgenic mice were analyzed for WT1 expression. Results. In cultured podocytes, TGF-beta1 reduced WT1 protein expression determined by western blotting beginning at 8 h and decreased WT1 messenger RNA (mRNA) expression measured by quantitative reverse transcription-polymerase chain reaction beginning at 3 h. Knockdown of Smad4 by small hairpin (sh) RNA partially rescued the TGF-beta1-induced reduction of both WT1 protein and mRNA expressions in the cultured podocytes. TGF-beta1 did not alter luciferase activity of the reporter construct for a human WT1 promoter but reduced that for a human WT1 5' enhancer construct, suggesting that TGF-beta1 may regulate WT1 expression by altering the 5' enhancer activity. In the transgenic mice, WT1 protein expression in podocytes was decreased at 1 and 3 weeks of age, while glomeruloclerosis developed after 3 weeks. Conclusion. TGF-beta1 reduces WT1 expression in cultured human podocytes and podocytes in mice before overt glomerulosclerosis begins. The effects are at least partially Smad4 dependent. Our findings identify a novel pathway linking TGF-beta1 to podocyte injury and FSGS. The WT1 reduction may be a useful marker for early podocyte injury. C1 [Sakairi, Toru; Abe, Yoshifusa; Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. [Sakairi, Toru] Gunma Univ, Grad Sch Med, Dept Med & Clin Sci, Maebashi, Gumma 371, Japan. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU NIDDK, NIH FX This study was supported by Intramural Research Program, NIDDK, NIH. NR 36 TC 12 Z9 12 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD SEP PY 2011 VL 26 IS 9 BP 2746 EP U1501 DI 10.1093/ndt/gfr061 PG 7 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 824VZ UT WOS:000295231600007 PM 21378152 ER PT J AU Landau, M Kurella-Tamura, M Shlipak, MG Kanaya, A Strotmeyer, E Koster, A Satterfield, S Simsonick, EM Goodpaster, B Newman, AB Fried, LF AF Landau, Michael Kurella-Tamura, Manjula Shlipak, Michael G. Kanaya, Alka Strotmeyer, Elsa Koster, Annemarie Satterfield, Suzanne Simsonick, Eleanor M. Goodpaster, Bret Newman, Anne B. Fried, Linda F. CA Hlth Aging Body Composition Study TI Correlates of insulin resistance in older individuals with and without kidney disease SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE chronic kidney disease; cystatin C; insulin resistance; subcutaneous fat ID CHRONIC-RENAL-FAILURE; GLOMERULAR-FILTRATION-RATE; METABOLIC SYNDROME; ADIPOSE-TISSUE; PLASMA ADIPONECTIN; MUSCLE COMPOSITION; ABDOMINAL OBESITY; BODY-COMPOSITION; VISCERAL FAT; SENSITIVITY AB Background. Chronic kidney disease (CKD) is associated with insulin resistance (IR). Prior studies have found that in individuals with CKD, leptin is associated with fat mass but resistin is not and the associations with adiponectin are conflicting. This suggests that the mechanism and factors associated with IR in CKD may differ. Methods. Of the 2418 individuals without reported diabetes at baseline, participating in the Health, Aging and Body Composition study, a study in older individuals aged 70-79 years, 15.6% had CKD defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m(2) based on cystatin C. IR was defined as the upper quartile of the homeostasis model assessment. The association of visceral and subcutaneous abdominal fat, percent body fat, muscle fat, lipids, inflammatory markers and adiponectin were tested with logistic regression. Interactions were checked to assess whether the factors associated with IR were different in those with and without CKD. Results. Individuals with IR had a lower eGFR (80.7 +/- 20.9 versus 75.6 +/- 19.6, P < 0.001). After multivariable adjustment, eGFR (odds ratio per 10 mL/min/1.73m(2) 0.92, 95% confidence interval 0.87-0.98) and CKD (1.41, 1.04-1.92) remained independently associated with IR. In individuals with and without CKD, the significant predictors of IR were male sex, black race, higher visceral fat, abdominal subcutaneous fat and triglycerides. In individuals without CKD, IR was associated with lower high-density lipoprotein and current nonsmoking status in multivariate analysis. In contrast, among individuals with CKD, interleukin-6 (IL-6) was independently associated with IR. There was a significant interaction of eGFR with race and IL-6 with a trend for adionectin but no significant interactions with CKD (P > 0.1). In the fully adjusted model, there was a trend for an interaction with adiponectin for eGFR (P = 0.08) and significant for CKD (P = 0.04), where adiponectin was associated with IR in those without CKD but not in those with CKD. Conclusions. In mainly Stage 3 CKD, kidney function is associated with IR; except for adiponectin, the correlates of IR are similar in those with and without CKD. C1 [Strotmeyer, Elsa; Newman, Anne B.; Fried, Linda F.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Landau, Michael] Cleveland Clin, Dept Pathol, Cleveland, OH 44106 USA. [Kurella-Tamura, Manjula] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Shlipak, Michael G.] San Francisco VA, Gen Internal Med Sect, San Francisco, CA USA. [Shlipak, Michael G.; Kanaya, Alka] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Shlipak, Michael G.; Kanaya, Alka] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA USA. [Shlipak, Michael G.; Kanaya, Alka] Univ Calif San Francisco, Dept Biostat, San Francisco, CA USA. [Koster, Annemarie] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Koster, Annemarie] Sch Publ Hlth & Primary Care CAPHRI, Maastricht, Netherlands. [Koster, Annemarie] Maastricht Univ, Dept Internal Med, Maastricht, Netherlands. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Simsonick, Eleanor M.] NIA, NIH, Baltimore, MD 21224 USA. [Goodpaster, Bret; Newman, Anne B.; Fried, Linda F.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Fried, Linda F.] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. RP Fried, LF (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. EM linda.fried@va.gov RI Koster, Annemarie/E-7438-2010; Newman, Anne/C-6408-2013; Strotmeyer, Elsa/F-3015-2014; Kurella Tamura, Manjula/C-8284-2014; OI Newman, Anne/0000-0002-0106-1150; Kurella Tamura, Manjula/0000-0001-5227-2479; Strotmeyer, Elsa/0000-0002-4093-6036 FU NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIH, National Institute on Aging FX The Health, Aging and Body Composition Study is supported by NIA contract numbers of all participating centers (N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106). This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. The results presented in this paper have not been published previously in whole or part. NR 45 TC 19 Z9 19 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD SEP PY 2011 VL 26 IS 9 BP 2814 EP 2819 DI 10.1093/ndt/gfq817 PG 6 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 824VZ UT WOS:000295231600016 PM 21248294 ER PT J AU O'Seaghdha, CM Hwang, SJ Muntner, P Melamed, ML Fox, CS AF O'Seaghdha, Conall M. Hwang, Shih-Jen Muntner, Paul Melamed, Michal L. Fox, Caroline S. TI Serum phosphorus predicts incident chronic kidney disease and end-stage renal disease SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE CKD; ESRD; phosphorus ID GLOMERULAR-FILTRATION-RATE; DIETARY-PROTEIN; CARDIOVASCULAR-DISEASE; RISK-FACTOR; PHOSPHATE; INSUFFICIENCY; PROGRESSION; MORTALITY; INJURY; HYPERTENSION AB Background. Elevations in serum phosphorus are associated with renal decline in animal models and progression of established chronic kidney disease (CKD) in human observational studies. We examined whether serum phosphorus levels increase the risk of incident CKD or end-stage renal disease (ESRD) in two population-based prospective cohort studies. Methods. Overall, 2269 participants free of CKD [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73(2)] from the Framingham Heart Study (FHS; mean age 42 years; 53% women) and 13 372 participants from the Third National Health and Nutrition Examination Survey (NHANES III; mean age 44.3 years, 52% women) contributed to the present study. In the FHS, we evaluated the relationship between baseline phosphorus category (< 2.5 mg/dL, 2.5-3.49 mg/dL, 3.5-3.99 mg/dL and >= 4 mg/dL) and incident CKD (n 267). In NHANES, we examined the relationship between phosphorus below and above 4 mg/dL in relation to incident ESRD (n 65). Results. FHS participants in the highest phosphorus category had an increased risk of CKD [odds ratio 2.14; 95% confidence interval (CI), 1.07-4.28; P = 0.03] in multivariable-adjusted models when compared to the referent group (2.5-3.49 mg/dL). Similarly, NHANES III participants with phosphorus levels >= 4 mg/dL demonstrated an increased risk of incident ESRD compared to those < 4 mg/dL (relative risk 1.90; 95% CI 1.03-3.53; P = 0.04). Conclusions. In prospective studies of the general population, serum phosphorus levels in the upper-normal range were associated with a doubling in the risk of developing incident CKD and ESRD. C1 [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Brigham & Womens Hosp, Div Renal, Boston, MA 02114 USA. [O'Seaghdha, Conall M.] Harvard Univ, Sch Med, Boston, MA USA. [Muntner, Paul] Univ Alabama Birmingham, Dept Med, Div Nephrol, Birmingham, AL 35294 USA. [Muntner, Paul] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Melamed, Michal L.] Albert Einstein Coll Med, Dept Med, Div Nephrol, Bronx, NY 10467 USA. [Melamed, Michal L.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Fox, CS (reprint author), Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. EM foxca@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute [N01-HC-25195]; [K23- DK 078774] FX The Framingham Offspring Study is supported by the National Heart, Lung, and Blood Institute (N01-HC-25195). M.L.M. is supported by grant K23- DK 078774. NR 47 TC 30 Z9 31 U1 0 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD SEP PY 2011 VL 26 IS 9 BP 2885 EP 2890 DI 10.1093/ndt/gfq808 PG 6 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 824VZ UT WOS:000295231600025 PM 21292817 ER PT J AU Kolmakova, EV Haller, ST Kennedy, DJ Isachkina, AN Budny, GV Frolova, EV Piecha, G Nikitina, ER Malhotra, D Fedorova, OV Shapiro, JI Bagrov, AY AF Kolmakova, Elena V. Haller, Steven T. Kennedy, David J. Isachkina, Alina N. Budny, George V. Frolova, Elena V. Piecha, Grzegorz Nikitina, Elena R. Malhotra, Deepak Fedorova, Olga V. Shapiro, Joseph I. Bagrov, Alexei Y. TI Endogenous cardiotonic steroids in chronic renal failure SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE chronic renal failure; marinobufagenin; monoclonal antibody; Na/K-ATPase; ouabain ID EXPERIMENTAL UREMIC CARDIOMYOPATHY; SODIUM-PUMP INHIBITOR; CARDIOVASCULAR-DISEASE; ATPASE INHIBITION; NA/K-ATPASE; MARINOBUFAGENIN; OUABAIN; HYPERTENSION; DIGOXIN; PREECLAMPSIA AB Background. Previous reports demonstrated that digitalis-like cardiotonic steroids (CTS) contribute to the pathogenesis of end-stage renal disease. The goal of the present study was to define the nature of CTS in patients with chronic kidney disease (CKD) and in partially nephrectomized (PNx) rats. Methods. In patients with CKD and in healthy controls, we determined plasma levels of marinobufagenin (MBG) and endogenous ouabain (EO) and erythrocyte Na/K-ATPase activity in the absence and in the presence of 3E9 anti-MBG monoclonal antibody (mAb) and Digibind. Levels of MBG and EO were also determined in sham-operated Sprague-Dawley rats and in rats following 4 weeks of PNx. Results. In 25 patients with CKD plasma, MBG but not EO was increased (0.86 +/- 0.07 versus 0.28 +/- 0.02 nmol/L, P < 0.01) and erythrocyte Na/K-ATPase was inhibited (1.24 +/- 0.10 versus 2.80 +/- 0.09 mu mol Pi/mL/h, P < 0.01) as compared to that in 19 healthy subjects. Ex vivo, 3E9 mAb restored Na/K-ATPase in erythrocytes from patients with CKD but did not affect Na/K-ATPase from control subjects. Following chromatographic fractionation of uremic versus normal plasma, a competitive immunoassay based on anti-MBG mAb detected a 3-fold increase in the level of endogenous material having retention time similar to that seen with MBG. A similar pattern of CTS changes was observed in uremic rats. As compared to sham-operated animals, PNx rats exhibited 3-fold elevated levels of MBG but not that of EO. Conclusions. In chronic renal failure, elevated levels of a bufadienolide CTS, MBG, contribute to Na/K-ATPase inhibition and may represent a potential target for therapy. C1 [Piecha, Grzegorz; Fedorova, Olga V.; Bagrov, Alexei Y.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Kolmakova, Elena V.; Isachkina, Alina N.] Mechnikov Med Acad, Chron Dialysis Div, St Petersburg, Russia. [Haller, Steven T.; Kennedy, David J.; Budny, George V.; Malhotra, Deepak; Shapiro, Joseph I.] Univ Toledo, Coll Med, Toledo, OH 43606 USA. [Frolova, Elena V.; Nikitina, Elena R.] IM Sechenov Evolutionary Physiol & Biochem Inst, St Petersburg 194223, Russia. [Piecha, Grzegorz] Univ Heidelberg, Dept Internal Med, Div Nephrol, D-6900 Heidelberg, Germany. [Piecha, Grzegorz] Med Univ Silesia, Dept Nephrol Endocrinol & Metab Dis, Katowice, Poland. RP Bagrov, AY (reprint author), NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. EM bagrova@mail.nih.gov FU National Institute on Aging, National Institutes of Health (NIH); NIH [HL071556] FX These studies were supported by Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH) (O.V.F., G.P. and A.Y.B.) and by NIH grant HL071556 (J.I.S.). The authors are grateful to Anton Bzhelyansky, MA (MedStar Research Institute, Hyattsville, MD), for advice and HPLC analyses. NR 33 TC 23 Z9 24 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD SEP PY 2011 VL 26 IS 9 BP 2912 EP U1511 DI 10.1093/ndt/gfq772 PG 8 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 824VZ UT WOS:000295231600029 PM 21292813 ER PT J AU Wise, HM Barbezange, C Jagger, BW Dalton, RM Gog, JR Curran, MD Taubenberger, JK Anderson, EC Digard, P AF Wise, Helen M. Barbezange, Cyril Jagger, Brett W. Dalton, Rosa M. Gog, Julia R. Curran, Martin D. Taubenberger, Jeffery K. Anderson, Emma C. Digard, Paul TI Overlapping signals for translational regulation and packaging of influenza A virus segment 2 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GENOMIC RNA SEGMENTS; EUKARYOTIC RIBOSOMES; POLYMERASE-ACTIVITY; COMPLEX-FORMATION; MESSENGER-RNA; PB1 PROTEIN; PA-BINDING; REPLICATION; IDENTIFICATION; INITIATION AB Influenza A virus segment 2 mRNA expresses three polypeptides: PB1, PB1-F2 and PB1-N40, from AUGs 1, 4 and 5 respectively. Two short open reading frames (sORFs) initiated by AUGs 2 and 3 are also present. To understand translational regulation in this system, we systematically mutated AUGs 1-4 and monitored polypeptide synthesis from plasmids and recombinant viruses. This identified sORF2 as a key regulatory element with opposing effects on PB1-F2 and PB1-N40 expression. We propose a model in which AUGs 1-4 are accessed by leaky ribosomal scanning, with sORF2 repressing synthesis of downstream PB1-F2. However, sORF2 also up-regulates PB1-N40 expression, most likely by a reinitiation mechanism that permits skipping of AUG4. Surprisingly, we also found that in contrast to plasmid-driven expression, viruses with improved AUG1 initiation contexts produced less PB1 in infected cells and replicated poorly, producing virions with elevated particle:PFU ratios. Analysis of the genome content of virus particles showed reduced packaging of the mutant segment 2 vRNAs. Overall, we conclude that segment 2 mRNA translation is regulated by a combination of leaky ribosomal scanning and reinitiation, and that the sequences surrounding the PB1 AUG codon are multifunctional, containing overlapping signals for translation initiation and for segment-specific packaging. C1 [Wise, Helen M.; Jagger, Brett W.; Dalton, Rosa M.; Digard, Paul] Univ Cambridge, Dept Pathol, Div Virol, Cambridge CB2 1QP, England. [Barbezange, Cyril; Anderson, Emma C.] Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. [Jagger, Brett W.; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Gog, Julia R.] Univ Cambridge, Dept Appl Math & Theoret Phys, Cambridge CB3 0WA, England. [Curran, Martin D.] Addenbrookes Hosp, Hlth Protect Agcy, Clin Microbiol & Publ Hlth Lab, Cambridge CB2 2QW, England. RP Digard, P (reprint author), Univ Cambridge, Dept Pathol, Div Virol, Cambridge CB2 1QP, England. EM pd1@mole.bio.cam.ac.uk RI Digard, Paul/B-7717-2008; OI Digard, Paul/0000-0002-0872-9440; Barbezange, Cyril/0000-0001-9606-2983 FU Medical Research Council [G0700815, G0701220]; National Institutes of Health-Oxford/Cambridge; Lab funds FX Medical Research Council (grant numbers G0700815 to P. D. and G0701220 to E. C. A.); National Institutes of Health-Oxford/Cambridge Research Scholars Program (to B.W.J., P. D., and J.K.T.); and Intramural program of the NIH and the NIAID. Funding for open access charge: Lab funds. NR 57 TC 36 Z9 37 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2011 VL 39 IS 17 BP 7775 EP 7790 DI 10.1093/nar/gkr487 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 824EI UT WOS:000295184800042 PM 21693560 ER PT J AU Stagno, JR Altieri, AS Bubunenko, M Tarasov, SG Li, J Court, DL Byrd, RA Ji, XH AF Stagno, Jason R. Altieri, Amanda S. Bubunenko, Mikhail Tarasov, Sergey G. Li, Jess Court, Donald L. Byrd, R. Andrew Ji, Xinhua TI Structural basis for RNA recognition by NusB and NusE in the initiation of transcription antitermination SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RIBOSOMAL-PROTEIN S10; ESCHERICHIA-COLI NUSA; HK022 NUN PROTEIN; LAMBDA N PROTEIN; PHAGE-LAMBDA; BACTERIOPHAGE-LAMBDA; PROCESSIVE ANTITERMINATION; NUCLEOTIDE-SEQUENCE; GENE-EXPRESSION; BOXA RNA AB Processive transcription antitermination requires the assembly of the complete antitermination complex, which is initiated by the formation of the ternary NusB-NusE-BoxA RNA complex. We have elucidated the crystal structure of this complex, demonstrating that the BoxA RNA is composed of 8 nt that are recognized by the NusB-NusE heterodimer. Functional biologic and biophysical data support the structural observations and establish the relative significance of key protein-protein and protein-RNA interactions. Further crystallographic investigation of a NusB-NusE-dsRNA complex reveals a heretofore unobserved dsRNA binding site contiguous with the BoxA binding site. We propose that the observed dsRNA represents BoxB RNA, as both single-stranded BoxA and double-stranded BoxB components are present in the classical lambda antitermination site. Combining these data with known interactions amongst antitermination factors suggests a specific model for the assembly of the complete antitermination complex. C1 [Stagno, Jason R.; Ji, Xinhua] SAIC Frederick Inc, Lab Macromol Crystallog, Frederick, MD 21702 USA. [Altieri, Amanda S.; Tarasov, Sergey G.; Li, Jess; Byrd, R. Andrew] SAIC Frederick Inc, Struct Biophys Lab, Frederick, MD 21702 USA. [Bubunenko, Mikhail; Court, Donald L.] SAIC Frederick Inc, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. [Bubunenko, Mikhail] SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. NCI, Frederick, MD 21702 USA. RP Ji, XH (reprint author), SAIC Frederick Inc, Lab Macromol Crystallog, Frederick, MD 21702 USA. EM jix@mail.nih.gov RI Ji, Xinhua/C-9664-2012; Byrd, R. Andrew/F-8042-2015 OI Ji, Xinhua/0000-0001-6942-1514; Byrd, R. Andrew/0000-0003-3625-4232 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health [N01-CO-12400]; National Institutes of Health Intramural Research FX We thank Jennifer Briggs and Aaren King for EcNusB mutant protein preparation; Mikhail Kashlev, Yun-Xing Wang and Alexander Wlodawer for discussion and Paul Wingfield for analytical ultracentrifugation data. X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) 22-BM beamline at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at 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. 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.; The Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; a Trans NIH/FDA Intramural Biodefense Program Grant from National Institute of Allergy and Infectious Diseases (to D. L. C.) and federal funds from the National Cancer Institute, National Institutes of Health (N01-CO-12400). Funding for open access charge: The National Institutes of Health Intramural Research Program. NR 53 TC 15 Z9 15 U1 2 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2011 VL 39 IS 17 BP 7803 EP 7815 DI 10.1093/nar/gkr418 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 824EI UT WOS:000295184800044 PM 21652641 ER PT J AU Cuneo, MJ Gabel, SA Krahn, JM Ricker, MA London, RE AF Cuneo, Matthew J. Gabel, Scott A. Krahn, Joseph M. Ricker, Melissa A. London, Robert E. TI The structural basis for partitioning of the XRCC1/DNA ligase III-alpha BRCT-mediated dimer complexes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-REPAIR PROTEIN; STRAND BREAK REPAIR; DIFFRACTION DATA; TERMINAL DOMAIN; INTERACTS; POLYMERASE; SCATTERING; STABILITY; REGION; XRCC4 AB The ultimate step common to almost all DNA repair pathways is the ligation of the nicked intermediate to form contiguous double-stranded DNA. In the mammalian nucleotide and base excision repair pathways, the ligation step is carried out by ligase III-alpha. For efficient ligation, ligase III-alpha is constitutively bound to the scaffolding protein XRCC1 through interactions between the C-terminal BRCT domains of each protein. Although structural data for the individual domains has been available, no structure of the complex has been determined and several alternative proposals for this interaction have been advanced. Interpretation of the models is complicated by the formation of homodimers that, depending on the model, may either contribute to, or compete with heterodimer formation. We report here the structures of both homodimer complexes as well as the heterodimer complex. Structural characterization of the heterodimer formed from a longer XRCC1 BRCT domain construct, including residues comprising the interdomain linker region, revealed an expanded heterodimer interface with the ligase III-alpha BRCT domain. This enhanced linker-mediated binding interface plays a significant role in the determination of heterodimer/homodimer selectivity. These data provide fundamental insights into the structural basis of BRCT-mediated dimerization, and resolve questions related to the organization of this important repair complex. C1 [Cuneo, Matthew J.; Gabel, Scott A.; Krahn, Joseph M.; Ricker, Melissa A.; London, Robert E.] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-98CH10886, W-31-109-Eng-38]; National Institute of Environmental Health Sciences, National Institutes of Health; [Z01-ES050111] FX Use of the X9 beamline is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886. Data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID (or 22-BM) beamline at the Advanced Photon Source, Argonne National Laboratory. 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. Funding for open access charge: The Research Project (Number Z01-ES050111 to R.E.L.); Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 35 TC 21 Z9 23 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2011 VL 39 IS 17 BP 7816 EP 7827 DI 10.1093/nar/gkr419 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 824EI UT WOS:000295184800045 PM 21652643 ER PT J AU Csuros, M Rogozin, IB Koonin, EV AF Csuros, Miklos Rogozin, Igor B. Koonin, Eugene V. TI A Detailed History of Intron-rich Eukaryotic Ancestors Inferred from a Global Survey of 100 Complete Genomes SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID MESSENGER-RNA DECAY; MAXIMUM-LIKELIHOOD; SPLICEOSOMAL INTRONS; GENE-EXPRESSION; EVOLUTION; GAIN; CONSERVATION; PHYLOGENIES; POSITIONS; PATTERNS AB Protein-coding genes in eukaryotes are interrupted by introns, but intron densities widely differ between eukaryotic lineages. Vertebrates, some invertebrates and green plants have intron-rich genes, with 6-7 introns per kilobase of coding sequence, whereas most of the other eukaryotes have intron-poor genes. We reconstructed the history of intron gain and loss using a probabilistic Markov model (Markov Chain Monte Carlo, MCMC) on 245 orthologous genes from 99 genomes representing the three of the five supergroups of eukaryotes for which multiple genome sequences are available. Intron-rich ancestors are confidently reconstructed for each major group, with 53 to 74% of the human intron density inferred with 95% confidence for the Last Eukaryotic Common Ancestor (LECA). The results of the MCMC reconstruction are compared with the reconstructions obtained using Maximum Likelihood (ML) and Dollo parsimony methods. An excellent agreement between the MCMC and ML inferences is demonstrated whereas Dollo parsimony introduces a noticeable bias in the estimations, typically yielding lower ancestral intron densities than MCMC and ML. Evolution of eukaryotic genes was dominated by intron loss, with substantial gain only at the bases of several major branches including plants and animals. The highest intron density, 120 to 130% of the human value, is inferred for the last common ancestor of animals. The reconstruction shows that the entire line of descent from LECA to mammals was intron-rich, a state conducive to the evolution of alternative splicing. C1 [Csuros, Miklos] Univ Montreal, Dept Comp Sci & Operat Res, Montreal, PQ, Canada. [Rogozin, Igor B.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. RP Csuros, M (reprint author), Univ Montreal, Dept Comp Sci & Operat Res, Montreal, PQ, Canada. EM csuros@iro.umontreal.ca; koonin@ncbi.nlm.nih.gov FU Natural Sciences and Engineering Research Council of Canada; US Department of Health and Human Services (National Library of Medicine, NIH) FX The research of MC is supported by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada. The research of IBR and EVK is supported by intramural funds of the US Department of Health and Human Services (National Library of Medicine, NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 51 Z9 53 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD SEP PY 2011 VL 7 IS 9 AR e1002150 DI 10.1371/journal.pcbi.1002150 PG 9 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 827CU UT WOS:000295404900010 PM 21935348 ER PT J AU Elemans, M al Basatena, NKS Klatt, NR Gkekas, C Silvestri, G Asquith, B AF Elemans, Marjet al Basatena, Nafisa-Katrin Seich Klatt, Nichole R. Gkekas, Christos Silvestri, Guido Asquith, Becca TI Why Don't CD8+T Cells Reduce the Lifespan of SIV-Infected Cells In Vivo? SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID IMMUNODEFICIENCY VIRUS-INFECTION; CYTOTOXIC T-LYMPHOCYTES; TYPE-1 INFECTION; REPLICATION; DYNAMICS; INDIVIDUALS; INHIBITOR; TURNOVER; MACAQUES; VIREMIA AB In January 2010 two groups independently published the observation that the depletion of CD8+ cells in SIV-infected macaques had no detectable impact on the lifespan of productively infected cells. This unexpected observation led the authors to suggest that CD8+ T cells control SIV viraemia via non-lytic mechanisms. However, a number of alternative plausible explanations, compatible with a lytic model of CD8+ T cell control, were proposed. This left the field with no consensus on how to interpret these experiments and no clear indication whether CD8+ T cells operated primarily via a lytic or a non-lytic mechanism. The aim of this work was to investigate why CD8+ T cells do not appear to reduce the lifespan of SIV-infected cells in vivo. C1 [Elemans, Marjet; al Basatena, Nafisa-Katrin Seich; Gkekas, Christos; Asquith, Becca] Univ London Imperial Coll Sci Technol & Med, Dept Immunol, London, England. [Klatt, Nichole R.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Silvestri, Guido] Emory Univ, Sch Med, Atlanta, GA USA. RP Elemans, M (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Immunol, London, England. EM m.elemans@imperial.ac.uk OI Asquith, Becca/0000-0002-5911-3160 FU Medical Research Council [G0601072-79700]; Wellcome Trust FX This study was supported by the Medical Research Council (http://www.mrc.ac.uk, G0601072-79700) and the Wellcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 17 Z9 17 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD SEP PY 2011 VL 7 IS 9 AR e1002200 DI 10.1371/journal.pcbi.1002200 PG 8 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 827CU UT WOS:000295404900030 PM 21990968 ER PT J AU Spencer, BR Simone, G Kleinman, S Murphy, E Busch, MP Wright, DJ Kiss, JE Mast, AE Benjamin, RJ Cable, RG AF Spencer, B. R. Simone, G. Kleinman, S. Murphy, E. Busch, M. P. Wright, D. J. Kiss, J. E. Mast, A. E. Benjamin, R. J. Cable, R. G. TI Potential Impact on Blood Availability of Changes to Male Donor Hemoglobin Cutoff and to Minimum Donation Intervals in US Donors SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Spencer, B. R.; Cable, R. G.] Amer Red Cross, Biomed Serv, Dedham, MA USA. [Simone, G.] NHLBI, Transfus Med & Cellular Therapeut Branch, Bethesda, MD 20892 USA. [Kleinman, S.] AABB, Bethesda, MD USA. [Murphy, E.; Busch, M. P.] Blood Syst Res Inst, San Francisco, CA USA. [Benjamin, R. J.] Amer Red Cross, Holland Labs, Rockville, MD USA. [Wright, D. J.] Westat Corp, Rockville, MD USA. [Kiss, J. E.] Inst Transfus Med, Pittsburgh, PA USA. [Mast, A. E.] BloodCtr Wisconsin, Milwaukee, WI USA. EM spencerb@usa.redcross.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 2A EP 2A PG 1 WC Hematology SC Hematology GA 822YC UT WOS:000295085500004 ER PT J AU O'Donghaile, D Kelley, WE Diggs, K Vasu, S Childs, R Barrett, AJ Leitman, SF AF O'Donghaile, D. Kelley, W. E. Diggs, K. Vasu, S. Childs, R. Barrett, A. J. Leitman, S. F. TI Tandem Granulocyte and Peripheral Blood Stem Cell (PBSC) Collection SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [O'Donghaile, D.; Kelley, W. E.; Diggs, K.; Leitman, S. F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Vasu, S.; Childs, R.; Barrett, A. J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM diarmaid.odonghaile@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 11A EP 11A PG 1 WC Hematology SC Hematology GA 822YC UT WOS:000295085500027 ER PT J AU Spencer, BR Simone, G Kleinman, S Murphy, E Benjamin, RJ Busch, MP Wright, DJ Kiss, JE Mast, AE Cable, RG AF Spencer, B. R. Simone, G. Kleinman, S. Murphy, E. Benjamin, R. J. Busch, M. P. Wright, D. J. Kiss, J. E. Mast, A. E. Cable, R. G. TI Prevalence of Restless Legs Syndrome and Pica, and Association with Iron Status in REDS-II RISE Donors SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Spencer, B. R.; Cable, R. G.] Amer Red Cross Biomed Serv, Dedham, MA USA. [Simone, G.] NHLBI, Transfus Med & Cellular Therapeut Branch, Bethesda, MD 20892 USA. [Kleinman, S.] AABB, Bethesda, MD USA. [Murphy, E.; Busch, M. P.] Blood Syst Res Inst, San Francisco, CA USA. [Benjamin, R. J.] Amer Red Cross Holland Labs, Rockville, MD USA. [Wright, D. J.] Westat Corp, Rockville, MD USA. [Kiss, J. E.] Inst Transfus Med, Pittsburgh, PA USA. [Mast, A. E.] BloodCtr Wisconsin, Milwaukee, WI USA. EM spencerb@usa.redcross.org NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 34A EP 34A PG 1 WC Hematology SC Hematology GA 822YC UT WOS:000295085500080 ER PT J AU Wagner, SJ Park, J Piknova, B Seetharaman, S Kurtz, J Moroff, G Schechter, AN AF Wagner, S. J. Park, J. Piknova, B. Seetharaman, S. Kurtz, J. Moroff, G. Schechter, A. N. TI Measurement of Nitric Oxide Metabolites in Apheresis Platelet Aliquots During Storage SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Wagner, S. J.; Seetharaman, S.; Kurtz, J.; Moroff, G.] Amer Red Cross, Blood Components Dept, Rockville, MD USA. [Park, J.; Piknova, B.; Schechter, A. N.] NIDDK, NIH, Bethesda, MD USA. EM WagnerS@usa.redcross.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 37A EP 37A PG 1 WC Hematology SC Hematology GA 822YC UT WOS:000295085500088 ER PT J AU Wagner, SJ Park, J Piknova, B Seetharaman, S Kurtz, J Moroff, G Schechter, AN AF Wagner, S. J. Park, J. Piknova, B. Seetharaman, S. Kurtz, J. Moroff, G. Schechter, A. N. TI Nitrite Accumulation in Platelet Storage Containers During Storage SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Wagner, S. J.; Seetharaman, S.; Kurtz, J.; Moroff, G.] Amer Red Cross, Blood Components Dept, Rockville, MD USA. [Park, J.; Piknova, B.; Schechter, A. N.] NIDDK, NIH, Bethesda, MD USA. EM WagnerS@usa.redcross.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 54A EP 55A PG 2 WC Hematology SC Hematology GA 822YC UT WOS:000295085500132 ER PT J AU Jackson, B Wood, K Case, R Motevalli, M Lockwood, K Bolton, S Lihvarchik, S Rehman, T Beigel, J King, KE AF Jackson, B. Wood, K. Case, R. Motevalli, M. Lockwood, K. Bolton, S. Lihvarchik, S. Rehman, T. Beigel, J. King, K. E. TI H1N1 Antibody Titers in Screening Healthy Individuals as Donors for Plasma Collection SO TRANSFUSION LA English DT Meeting Abstract CT 64th Annual Meeting of American-Association-of-Blood-Banks / Cellular Therapy and Transfusion Medicine Expo (AABB/CTTXPO) CY OCT 22-25, 2011 CL San Diego, CA SP Amer Assoc Blood Banks (AABB) C1 [Jackson, B.; Case, R.; Motevalli, M.; Lockwood, K.; Bolton, S.; Lihvarchik, S.; King, K. E.] Johns Hopkins Univ, Baltimore, MD 20892 USA. [Wood, K.] Frontier Sci, Buffalo, NY USA. [Rehman, T.; Beigel, J.] SAIC Frederick Inc, Div Intramural Res, NIH, Frederick, MD USA. [Beigel, J.] NIAID, Bethesda, MD USA. EM bjackso@jhmi.edu 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 81A EP 81A PG 1 WC Hematology SC Hematology GA 822YC UT WOS:000295085500196 ER PT J AU Kelley, WE O'Donghaile, D Salit, RB Fowler, DH Lozier, JN Leitman, SF AF Kelley, W. E. O'Donghaile, D. Salit, R. B. Fowler, D. H. Lozier, J. N. Leitman, S. F. TI Heparin Induced Thrombocytopenia and Thrombosis (HITT) in a Peripheral Blood Stem Cell (PBSC) Donor - A Rare, Potentially Fatal Complication SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Kelley, W. E.; O'Donghaile, D.; Leitman, S. F.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. [Salit, R. B.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Fowler, D. H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Lozier, J. N.] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. EM walterkelleydo@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 82A EP 82A PG 1 WC Hematology SC Hematology GA 822YC UT WOS:000295085500198 ER PT J AU Pope, ML Sigmon, JM Trenbeath, JL Yau, YY Byrne, KM Leitman, SF AF Pope, M. L. Sigmon, J. M. Trenbeath, J. L. Yau, Y. Y. Byrne, K. M. Leitman, S. F. TI Experience with Donor Reentry Testing for Hepatitis B Core Antibody SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Pope, M. L.; Sigmon, J. M.; Trenbeath, J. L.; Yau, Y. Y.; Byrne, K. M.; Leitman, S. F.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. EM poped123@aol.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 91A EP 91A PG 1 WC Hematology SC Hematology GA 822YC UT WOS:000295085500222 ER PT J AU Huvard, MJ Schmid, P Flegel, WA AF Huvard, M. J. Schmid, P. Flegel, W. A. TI Human Neutrophil Antigen-3 (HNA-3): Allele Frequencies in the African American Population SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Huvard, M. J.; Schmid, P.; Flegel, W. A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM mjhuvard@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 118A EP 119A PG 2 WC Hematology SC Hematology GA 822YC UT WOS:000295085500294 ER PT J AU O'Donghaile, D Lee-Stroka, A Childs, R Flegel, WA AF O'Donghaile, D. Lee-Stroka, A. Childs, R. Flegel, W. A. TI Donor Derived Anti-D Antibody Causing Clinically Significant Hemolysis After Allogeneic Stem Cell Transplantation SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [O'Donghaile, D.; Lee-Stroka, A.; Flegel, W. A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Childs, R.] NHLBI, Hematol Branch, Ctr Clin, NIH, Bethesda, MD 20892 USA. EM diarmaid.odonghaile@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 157A EP 157A PG 1 WC Hematology SC Hematology GA 822YC UT WOS:000295085500399 ER PT J AU Nieves, S Brunker, PA Flegel, WA AF Nieves, S. Brunker, P. A. Flegel, W. A. TI A Novel Approach to Multiplex Genotyping for the Scianna, Colton, and Dombrock Blood Groups Using Ligation Detection Reaction (LDR) SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Nieves, S.; Brunker, P. A.; Flegel, W. A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM jasnieves@aol.com NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 165A EP 166A PG 2 WC Hematology SC Hematology GA 822YC UT WOS:000295085500421 ER PT J AU Schmid, P Huvard, MJ Lee-Stroka, A Lee, JY Byrne, KM Sheldon, SL Flegel, WA AF Schmid, P. Huvard, M. J. Lee-Stroka, A. Lee, J. Y. Byrne, K. M. Sheldon, S. L. Flegel, W. A. TI A Comparison of Small Volume Red Blood Cell Preservation Methods SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Schmid, P.; Huvard, M. J.; Lee-Stroka, A.; Lee, J. Y.; Byrne, K. M.; Sheldon, S. L.; Flegel, W. A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM pirmin.schmid@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 170A EP 171A PG 2 WC Hematology SC Hematology GA 822YC UT WOS:000295085500435 ER PT J AU Zeng, P Wang, J Guo, X Li, J Wen, G Tonghan, Y Yun, Z Schulman, J Simone, G Shan, H AF Zeng, P. Wang, J. Guo, X. Li, J. Wen, G. Tonghan, Y. Yun, Z. Schulman, J. Simone, G. Shan, H. TI The Human Immunodeficiency Virus-1 Genotype Diversity and Drug Resistance Mutations Profile of Blood Donors from Five Chinese Blood Centers SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Zeng, P.; Wang, J.] CAMS, Inst Blood Transfus, Chengdu, Peoples R China. [Li, J.] Guangxi Blood Ctr, Liuzhou, Peoples R China. [Guo, X.] Mianyang Blood Ctr, Mianyang, Peoples R China. [Wen, G.] Urumqi City Blood Ctr, Urumqi, Peoples R China. [Tonghan, Y.] Yunnan Kunming Blood Ctr, Kunming, Peoples R China. [Yun, Z.] Luoyang Blood Ctr, Luoyang, Peoples R China. [Schulman, J.] WESTAT Corp, Rockville, MD 20850 USA. [Simone, G.] NHLBI, Bethesda, MD 20892 USA. [Shan, H.] Johns Hopkins Univ, Baltimore, MD USA. EM zengpeibin@live.cn NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 211A EP 211A PG 1 WC Hematology SC Hematology GA 822YC UT WOS:000295085500541 ER PT J AU Khuu, H Fowler, DH Stroncek, D AF Khuu, H. Fowler, D. H. Stroncek, D. TI CD4 Immunomagnetic Cell Selection Effectively Isolates T-CD4+Cells from CD8+and CD19+Cells but Is Limited by Monocyte Contamination and Occasionally Cell Aggregates SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Khuu, H.; Stroncek, D.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Fowler, D. H.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. EM hkhuu@mail.cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 221A EP 222A PG 2 WC Hematology SC Hematology GA 822YC UT WOS:000295085500569 ER PT J AU Bakker, GR Uribe, MR Adams, SD Flegel, WA AF Bakker, G. R. Uribe, M. R. Adams, S. D. Flegel, W. A. TI Distribution of Minor Histocompatibility Antigens (mHags) in African Americans SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Bakker, G. R.; Uribe, M. R.; Adams, S. D.; Flegel, W. A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM gina.bakker@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 227A EP 227A PG 1 WC Hematology SC Hematology GA 822YC UT WOS:000295085500584 ER PT J AU Lesho, E Forestiero, FJ Hirata, MH Hirata, RD Cecon, L Melo, FF Paik, SH Murata, Y Ferguson, EW Wang, ZN Ooi, GT AF Lesho, Emil Forestiero, Francisco J. Hirata, Mario H. Hirata, Rosario D. Cecon, Leticia Melo, Fernando F. Paik, Sun H. Murata, Yoko Ferguson, Earl W. Wang, Zhining Ooi, Guck T. TI Transcriptional responses of host peripheral blood cells to tuberculosis infection SO TUBERCULOSIS LA English DT Article DE Tuberculosis; Microarray analysis; Genes; Peripheral blood cells; Insulin signaling ID GENE-EXPRESSION PROFILES; ANGELMAN SYNDROME; E6 ONCOPROTEIN; PROTEIN; MYCOBACTERIA; IMMUNITY; CYTOKINE; SUSCEPTIBILITY; MACROPHAGES; VACCINATION AB Host responses following exposure to Mycobacterium tuberculosis (TB) are complex and can significantly affect clinical outcome. These responses, which are largely mediated by complex immune mechanisms involving peripheral blood cells (PBCs) such as T-lymphocytes, NK cells and monocyte-derived macrophages, have not been fully characterized. We hypothesize that different clinical outcome following TB exposure will be uniquely reflected in host gene expression profiles, and expression profiling of PBCs can be used to discriminate between different TB infectious outcomes. In this study, microarray analysis was performed on PBCs from three TB groups (BCG-vaccinated, latent TB infection, and active TB infection) and a control healthy group. Supervised learning algorithms were used to identify signature genomic responses that differentiate among group samples. Gene Set Enrichment Analysis was used to determine sets of genes that were co-regulated. Multivariate permutation analysis (p < 0.01) gave 645 genes differentially expressed among the four groups, with both distinct and common patterns of gene expression observed for each group. A 127-probeset, representing 77 known genes, capable of accurately classifying samples into their respective groups was identified. In addition, 13 insulin-sensitive genes were found to be differentially regulated in all three TB infected groups, underscoring the functional association between insulin signaling pathway and TB infection. Published by Elsevier Ltd. C1 [Lesho, Emil] Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. [Forestiero, Francisco J.; Hirata, Mario H.; Hirata, Rosario D.; Cecon, Leticia] Univ Sao Paulo, Sch Pharmaceut Sci, Sao Paulo, Brazil. [Melo, Fernando F.] Clemente Ferreira Inst, Sao Paulo, Brazil. [Paik, Sun H.; Murata, Yoko; Ferguson, Earl W.; Ooi, Guck T.] Sun BioMed Technol Inc, Ridgecrest, CA 93555 USA. [Wang, Zhining] NCI, SRA Int Inc, NIH, Bethesda, MD 20892 USA. RP Lesho, E (reprint author), Walter Reed Army Inst Res, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM Emil.Lesho@us.army.mil RI Hirata, Mario/D-3593-2012; Hirata, Rosario/A-7284-2011; Hirata, Mario/C-9718-2013 FU Center for Disease Control and Prevention (CDC) Small Business Innovative Research (SBIR) [200-2006-M-19004, 200-2008-27867] FX This study was funded through the Center for Disease Control and Prevention (CDC) Small Business Innovative Research (SBIR) grant awards (Award Number 200-2006-M-19004 & 200-2008-27867) to Sun BioMedical Technologies, Inc. (SHP, YM, EWF, GTO). Besides funding, CDC does not participate in the study design, data collection, data analysis and interpretation, preparation of the manuscript and decision to publish the work described in this study. NR 56 TC 36 Z9 36 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PD SEP PY 2011 VL 91 IS 5 SI SI BP 390 EP 399 DI 10.1016/j.tube.2011.07.002 PG 10 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA 827XE UT WOS:000295462300007 PM 21835698 ER PT J AU Raman, B Stopfer, M Semancik, S AF Raman, Baranidharan Stopfer, Mark Semancik, Steve TI Mimicking Biological Design and Computing Principles in Artificial Olfaction SO ACS CHEMICAL NEUROSCIENCE LA English DT Review DE odor; chemical sensing; sensory system; pattern recognition and classification; electronic nose; neuromorphic engineering ID CHEMICAL SENSOR ARRAYS; ODORANT RECEPTOR; ELECTRONIC-NOSE; ANTENNAL LOBE; DIMENSIONALITY-REDUCTION; COMPUTATIONAL PARALLELS; CONTRAST ENHANCEMENT; NEURONAL NETWORK; BULB; PATTERNS AB Biology has inspired solutions to many engineering problems, including those encountered in chemical sensing. Modern approaches to chemical sensing have been based on the biological principle of combining cross-selective chemical sensors with a pattern recognition engine to identify odors. Here, we review some recent advances made in mimicking biological design and computing principles to develop an electronic nose. The resulting technology will have important applications in fundamental biological research, as well as in industrial, security, and medical domains. C1 [Raman, Baranidharan] Washington Univ, Dept Biomed Engn, St Louis, MO 63130 USA. [Stopfer, Mark] Natl Inst Child Hlth & Dev, NIH, Bethesda, MD 20892 USA. [Semancik, Steve] Natl Inst Stand & Technol, Div Biochem Sci, Gaithersburg, MD 20899 USA. RP Raman, B (reprint author), Washington Univ, Dept Biomed Engn, St Louis, MO 63130 USA. EM barani@wustl.edu RI Sanders, Susan/G-1957-2011 FU Department of Biomedical Engineering in Washington University; McDonnell Center for Systems Neuroscience; NIH/NICHD; Department of Homeland Security FX The authors would like to thank the following for funding this work: generous start-up funds from the Department of Biomedical Engineering in Washington University and a McDonnell Center for Systems Neuroscience grant to B.R.; an intramural grant from NIH/NICHD to M.S. and partial support from Department of Homeland Security to S.S. NR 101 TC 10 Z9 10 U1 4 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD SEP PY 2011 VL 2 IS 9 BP 487 EP 499 DI 10.1021/cn200027r PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA 824FF UT WOS:000295187100002 PM 22081790 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Obituary: Walter Fitch and the orthology paradigm SO BRIEFINGS IN BIOINFORMATICS LA English DT Biographical-Item C1 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. FU Intramural NIH HHS NR 1 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1467-5463 J9 BRIEF BIOINFORM JI Brief. Bioinform. PD SEP PY 2011 VL 12 IS 5 SI SI BP 377 EP 378 DI 10.1093/bib/bbr058 PG 2 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 824AS UT WOS:000295171700002 PM 21949265 ER PT J AU Kristensen, DM Wolf, YI Mushegian, AR Koonin, EV AF Kristensen, David M. Wolf, Yuri I. Mushegian, Arcady R. Koonin, Eugene V. TI Computational methods for Gene Orthology inference SO BRIEFINGS IN BIOINFORMATICS LA English DT Article DE homolog; ortholog; paralog; xenolog; orthologous groups; tree reconciliation; comparative genomics ID WHOLE-GENOME DUPLICATION; PHYLOGENETIC TREES; PROKARYOTIC EVOLUTION; FUNCTIONAL GENOMICS; MAXIMUM-LIKELIHOOD; EUKARYOTIC GENOMES; MULTIPLE GENOMES; ENZYME EVOLUTION; ARCHAEAL GENOMES; COG DATABASE AB Accurate inference of orthologous genes is a pre-requisite for most comparative genomics studies, and is also important for functional annotation of new genomes. Identification of orthologous gene sets typically involves phylogenetic tree analysis, heuristic algorithms based on sequence conservation, synteny analysis, or some combination of these approaches. The most direct tree-based methods typically rely on the comparison of an individual gene tree with a species tree. Once the two trees are accurately constructed, orthologs are straightforwardly identified by the definition of orthology as those homologs that are related by speciation, rather than gene duplication, at their most recent point of origin. Although ideal for the purpose of orthology identification in principle, phylogenetic trees are computationally expensive to construct for large numbers of genes and genomes, and they often contain errors, especially at large evolutionary distances. Moreover, in many organisms, in particular prokaryotes and viruses, evolution does not appear to have followed a simple 'tree-like' mode, which makes conventional tree reconciliation inapplicable. Other, heuristic methods identify probable orthologs as the closest homologous pairs or groups of genes in a set of organisms. These approaches are faster and easier to automate than tree-based methods, with efficient implementations provided by graph-theoretical algorithms enabling comparisons of thousands of genomes. Comparisons of these two approaches show that, despite conceptual differences, they produce similar sets of orthologs, especially at short evolutionary distances. Synteny also can aid in identification of orthologs. Often, tree-based, sequence similarity- and synteny-based approaches can be combined into flexible hybrid methods. C1 [Kristensen, David M.; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Mushegian, Arcady R.] Stowers Inst Med Res, Kansas City, MO USA. [Mushegian, Arcady R.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. RP Koonin, EV (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov OI Mushegian, Arcady/0000-0002-6809-9225 FU National Library of Medicine at the US National Institutes of Health; Stowers Institute for Medical Research FX Intramural Research Program of the National Library of Medicine at the US National Institutes of Health; Stowers Institute for Medical Research. NR 134 TC 76 Z9 82 U1 2 U2 38 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1467-5463 J9 BRIEF BIOINFORM JI Brief. Bioinform. PD SEP PY 2011 VL 12 IS 5 SI SI BP 379 EP 391 DI 10.1093/bib/bbr030 PG 13 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 824AS UT WOS:000295171700003 PM 21690100 ER PT J AU Braunlin, E Tolar, J Mackey-Bojack, S Masinde, T Krivit, W Schoen, FJ AF Braunlin, Elizabeth Tolar, Jakub Mackey-Bojack, Shannon Masinde, Tiwanda Krivit, William Schoen, Frederick J. TI Clear cells in the atrioventricular valves of infants with severe human mucopolysaccharidosis (Hurler syndrome) are activated valvular interstitial cells SO CARDIOVASCULAR PATHOLOGY LA English DT Article DE Mucopolysaccharide; Valve; Fibroblast ID MITRAL-VALVES; HEART-VALVES; PROTEOGLYCANS; PATHOBIOLOGY AB Background: Severe mucopolysaccharidosis type I (Hurler syndrome) is an autosomal recessive lysosomal storage disease of childhood that results in accumulation of glycosaminoglycans within cardiac valves and consequent valve dysfunction. Valve thickening in mucopolysaccharidosis type 1 (Hurler syndrome) is due, in part, to the presence of glycosaminoglycan-laden cells (the so-called "clear" or "Hurler" cells) within the valve that remain largely unstudied with respect to identity, origin, and function. We hypothesized that the "clear" or "Hurler" cells within the atrioventricular valves from individuals with untreated mucopolysaccharidosis type I are activated valvular interstitial cells. Methods: We performed routine and immunohistochemical staining on atrioventricular valves from two infants with untreated severe mucopolysaccharidosis type I (Hurler syndrome) and compared them to atrioventricular valve tissue from two age-matched and gender-matched normal infants. Results: Despite the marked differences in their histological appearances, mucopolysaccharidosis type I valve cells have an immunohistochemical fingerprint identical to that of normal infant valvular interstitial cells. Both mucopolysaccharidosis type I valvular interstitial cells and normal infant valvular interstitial cells have the phenotype of activated myofibroblasts, as evidenced by positive staining for vimentin, smooth muscle actin, and metalloproteinase-9. However, the number of mucopolysaccharidosis type I valvular interstitial cells is significantly increased when compared to that of normal cells (P <.0031). Both mucopolysaccharidosis type I (Hurler syndrome) cells and normal valvular interstitial cells express CD34(+), a hematopoietic and capillary endothelial progenitor cell marker, suggesting a common response to activation. Conclusions: We conclude that "clear" or "Hurler" cells are valvular interstitial cells with the immunohistochemical phenotype of activated myofibroblasts and may be engaged, albeit ineffectively, in valve repair. (C) 2011 Elsevier Inc. All rights reserved. C1 [Braunlin, Elizabeth; Tolar, Jakub; Krivit, William] Univ Minnesota Hosp Fairview, Dept Pediat, Minneapolis, MN 55455 USA. [Mackey-Bojack, Shannon] Jesse E Edwards Registry Cardiovasc Dis, St Paul, MN USA. [Masinde, Tiwanda] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Schoen, Frederick J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Schoen, Frederick J.] Harvard Univ, Sch Med, Boston, MA USA. RP Braunlin, E (reprint author), Univ Minnesota Hosp Fairview, Dept Pediat, MMC 94, Minneapolis, MN 55455 USA. EM braun002@umn.edu OI Tolar, Jakub/0000-0002-0957-4380 FU University of Minnesota Medical Foundation FX This work was supported by a grant from the Vikings Fund at the University of Minnesota Medical Foundation. NR 19 TC 5 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-8807 J9 CARDIOVASC PATHOL JI Cardiovasc. Pathol. PD SEP-OCT PY 2011 VL 20 IS 5 BP 315 EP 321 DI 10.1016/j.carpath.2010.06.004 PG 7 WC Cardiac & Cardiovascular Systems; Pathology SC Cardiovascular System & Cardiology; Pathology GA 822TT UT WOS:000295073200009 PM 20619689 ER PT J AU Gorodeski, EZ Ishwaran, H Kogalur, UB Blackstone, EH Hsich, E Zhang, ZM Vitolins, MZ Manson, JE Curb, JD Martin, LW Prineas, RJ Lauer, MS AF Gorodeski, Eiran Z. Ishwaran, Hemant Kogalur, Udaya B. Blackstone, Eugene H. Hsich, Eileen Zhang, Zhu-ming Vitolins, Mara Z. Manson, JoAnn E. Curb, J. David Martin, Lisa W. Prineas, Ronald J. Lauer, Michael S. TI Use of Hundreds of Electrocardiographic Biomarkers for Prediction of Mortality in Postmenopausal Women The Women's Health Initiative SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE electrocardiography; epidemiology; women; prognosis ID CONGESTIVE-HEART-FAILURE; RANDOM FORESTS; ECG ABNORMALITIES; CLASSIFICATION; SELECTION; REGRESSION; EVENTS; RISK AB Background-Simultaneous contribution of hundreds of electrocardiographic (ECG) biomarkers to prediction of long-term mortality in postmenopausal women with clinically normal resting ECGs is unknown. Methods and Results-We analyzed ECGs and all-cause mortality in 33 144 women enrolled in the Women's Health Initiative trials who were without baseline cardiovascular disease or cancer and had normal ECGs by Minnesota and Novacode criteria. Four hundred and seventy-seven ECG biomarkers, encompassing global and individual ECG findings, were measured with computer algorithms. During a median follow-up of 8.1 years (range for survivors, 0.5 to 11.2 years), 1229 women died. For analyses, the cohort was randomly split into derivation (n = 22 096; deaths, 819) and validation (n = 11 048; deaths, 410) subsets. ECG biomarkers and demographic and clinical characteristics were simultaneously analyzed using both traditional Cox regression and random survival forest, a novel algorithmic machine-learning approach. Regression modeling failed to converge. Random survival forest variable selection yielded 20 variables that were independently predictive of long-term mortality, 14 of which were ECG biomarkers related to autonomic tone, atrial conduction, and ventricular depolarization and repolarization. Conclusions-We identified 14 ECG biomarkers from among hundreds that were associated with long-term prognosis using a novel random forest variable selection methodology. These biomarkers were related to autonomic tone, atrial conduction, ventricular depolarization, and ventricular repolarization. Quantitative ECG biomarkers have prognostic importance and may be markers of subclinical disease in apparently healthy postmenopausal women. (Circ Cardiovasc Qual Outcomes. 2011;4:521-532.) C1 [Lauer, Michael S.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Gorodeski, Eiran Z.; Blackstone, Eugene H.; Hsich, Eileen] Cleveland Clin, Inst Heart & Vasc, Cleveland, OH 44106 USA. [Ishwaran, Hemant; Kogalur, Udaya B.] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Zhang, Zhu-ming; Vitolins, Mara Z.; Prineas, Ronald J.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol, Winston Salem, NC USA. [Manson, JoAnn E.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Curb, J. David] Univ Hawaii Manoa, John A Burns Sch Med, Div Cardiovasc Med, Honolulu, HI 96822 USA. [Martin, Lisa W.] George Washington Univ, Div Cardiol, Washington, DC USA. RP Lauer, MS (reprint author), NHLBI, Div Cardiovasc Sci, NIH, Rockledge Ctr 2,Rm 10122,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013; OI Lauer, Michael/0000-0002-9217-8177; Gorodeski, Eiran/0000-0003-3756-8831; Martin, Lisa Warsinger/0000-0003-4352-0914 FU National Heart, Lung, and Blood Institute [8324207] FX Supported by National Heart, Lung, and Blood Institute CAN # 8324207 (to Drs Gorodeski and Lauer). NR 31 TC 14 Z9 15 U1 0 U2 3 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 SEP PY 2011 VL 4 IS 5 BP 521 EP U80 DI 10.1161/CIRCOUTCOMES.110.959023 PG 24 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 822FH UT WOS:000295028800009 PM 21862719 ER PT J AU Zhu, BP Guo, WK Shen, GZ Zhou, QF Shung, KK AF Zhu, Ben Peng Guo, Wan Ke Shen, Guo Zhen Zhou, Qifa Shung, K. Kirk TI Structure and Electrical Properties of (111)-Oriented Pb(Mg1/3Nb2/3)O-3-PbZrO3-PbTiO3 Thin Film for Ultra-High-Frequency Transducer Applications SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article; Proceedings Paper CT Joint Meeting of the 19th IEEE International Symposium on the Applications of Ferroelectrics/10th European Conference on the Applications of Polar Dielectrics CY AUG 09-12, 2010 CL Edinburgh, SCOTLAND SP IEEE ID DEPOSITION; ACTUATORS AB Ternary lead magnesium niobate-lead zirconate titanate system 0.4Pb(Mg1/3Nb2/3)O-3-0.25PbZrO(3)-0.35PbTiO(3) (40PMN-25PZ-35PT) thin film with a thickness of 1.5 mu m was grown on Pt(111)/Ti/SiO2/Si substrate via chemical solution deposition. X-ray diffraction and transmission electron microscopy results suggested the film obtained was highly (111)-oriented. The remanent polarization and coercive electric field of the film were found to be 25.5 mu C/cm(2) and 51 kV/cm, respectively. In addition, at 1 kHz, the dielectric constant was measured to be 1960 and the dielectric loss 0.036. The film was observed to undergo a diffuse ferroelectric-to-paraelectric phase transition at around 209 degrees C. The leakage current appeared to depend on the voltage polarity. If the Au electrode was biased positively, the leakage current was dominated by the Schottky emission mechanism. When the Pt electrode was biased positively, the conduction current curve showed an ohmic behavior at a low electric field and space-charge-limited current characteristics at a high electric field. C1 [Zhu, Ben Peng; Guo, Wan Ke] Huazhong Univ Sci & Technol, Dept Elect Sci & Technol, Wuhan 430074, Peoples R China. [Zhu, Ben Peng; Zhou, Qifa; Shung, K. Kirk] NIH Transducer Resource Ctr, Los Angeles, CA USA. [Zhu, Ben Peng; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Zhu, Ben Peng] Wuhan Univ, Minist Educ, Sch Phys & Technol, Wuhan 430072, Peoples R China. [Shen, Guo Zhen] Wuhan Natl Lab Optoelect, Wuhan 430074, Peoples R China. [Shen, Guo Zhen] Huazhong Univ Sci & Technol, Coll Optoelect Sci & Engn, Wuhan 430074, Peoples R China. RP Zhu, BP (reprint author), Huazhong Univ Sci & Technol, Dept Elect Sci & Technol, Wuhan 430074, Peoples R China. EM gzshen@mail.hust.edu.cn; qifazhou@usc.edu OI Shen, Guozhen/0000-0002-9755-1647 FU NIBIB NIH HHS [P41-EB2182, P41 EB002182, P41 EB002182-14] NR 23 TC 0 Z9 0 U1 0 U2 13 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0885-3010 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD SEP PY 2011 VL 58 IS 9 BP 1962 EP 1967 DI 10.1109/TUFFC.2011.2038 PG 6 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA 823DE UT WOS:000295101600032 PM 21937332 ER PT J AU Chen, HC Schiffman, M Lin, CY Pan, MH You, SL Chuang, LC Hsieh, CY Liaw, KL Hsing, AW Chen, CJ AF Chen, Hui-Chi Schiffman, Mark Lin, Ching-Yu Pan, Mei-Hung You, San-Lin Chuang, Li-Chung Hsieh, Chang-Yao Liaw, Kai-Li Hsing, Ann W. Chen, Chien-Jen CA CBCSP-HPV Study Grp TI Persistence of Type-Specific Human Papillomavirus Infection and Increased Long-term Risk of Cervical Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID INTRAEPITHELIAL NEOPLASIA; YOUNG-WOMEN; ABSOLUTE RISK; FOLLOW-UP; HPV; WORLDWIDE; LESIONS; TESTS; DNA; COHORT AB Background Human papillomavirus (HPV) persistence is the pivotal event in cervical carcinogenesis. We followed a large-scale community-based cohort for 16 years to investigate the role of genotype-specific HPV persistence in predicting cervical cancer including invasive and in situ carcinoma. Methods At the baseline examination in 1991-1992, 11 923 participants (aged 30-65 years) consented to HPV testing and cytology; 6923 participants were reexamined in 1993-1995. For HPV testing, we used a polymerase chain reaction-based assay that detected 39 HPV types. Women who developed cervical cancer were identified from cancer and death registries. Cumulative risks for developing cervical cancer among infected and persistently infected women were calculated by the Kaplan-Meier method. Results Of 10 123 women who were initially cytologically normal, 68 developed cervical cancer. The 16-year cumulative risks of subsequent cervical cancer for women with HPV16, HPV58 (without HPV16), or other carcinogenic HPV types (without HPV16 or HPV58) were 13.5%, 10.3%, and 4.0%, respectively, compared with 0.26% for HPV-negative women. Women with type-specific persistence of any carcinogenic HPV had greatly increased risk compared with women who were HPV-negative at both visits (hazard ratio = 75.4, 95% confidence interval = 31.8 to 178.9). The cumulative cervical cancer risks following persistent carcinogenic HPV infections increased with age: The risks were 5.5%, 14.4%, and 18.1% for women aged 30-44 years, 45-54 years, and 55 years and older, respectively. However, newly acquired infections were associated with a low risk of cervical cancer regardless of age. Conclusions HPV negativity was associated with a very low long-term risk of cervical cancer. Persistent detection of HPV among cytologically normal women greatly increased risk. Thus, it is useful to perform repeated HPV testing following an initial positive test. C1 [Chen, Hui-Chi; Pan, Mei-Hung; You, San-Lin; Chuang, Li-Chung; Chen, Chien-Jen] Acad Sinica, Genom Res Ctr, Taipei 11529, Taiwan. [Chen, Hui-Chi; Chen, Chien-Jen] Natl Taiwan Univ, Grad Inst Epidemiol, Taipei 10764, Taiwan. [Schiffman, Mark; Hsing, Ann W.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lin, Ching-Yu] Taipei Med Univ, Sch Med Lab Sci & Biotechnol, Taipei, Taiwan. [You, San-Lin; Chuang, Li-Chung] Natl Def Med Ctr, Sch Publ Hlth, Taipei, Taiwan. [Hsieh, Chang-Yao] Natl Taiwan Univ Hosp, Dept Obstet & Gynecol, Taipei, Taiwan. [Liaw, Kai-Li] Merck & Co Inc, Dept Epidemiol, N Wales, PA USA. RP Chen, CJ (reprint author), Acad Sinica, Genom Res Ctr, 128 Acad Rd,Sect 2, Taipei 11529, Taiwan. EM cjchen@ntu.edu.tw RI Chen, Chien-Jen/C-6976-2008; OI Lin, Ching-Yu/0000-0001-8269-797X FU Bureau of Health Promotion, Department of Health [93-028]; National Science Council (NSC) in Taiwan [94-2314-B-001-011, 95-2314-B-001-007, 96-2314-B-001-004, 97-2314-B-001-001-MY3]; National Institutes of Health, USA; Department of Health (Taiwan) FX This work was supported by the Bureau of Health Promotion, Department of Health (93-028) and the National Science Council (NSC 94-2314-B-001-011 and 95-2314-B-001-007; 96-2314-B-001-004 and 97-2314-B-001-001-MY3) in Taiwan. There were no financial contributions from any other organization or industry, such as Merck and Company or King-Car Company. Dr Schiffman and Dr Hsing were supported by the Intramural Research Program of the National Institutes of Health, USA.; The authors are grateful to research assistants in the genomics research center of Academia Sinica and to colleagues at the Yuan-Shan Institute of King-Car Co. We appreciate the help of Mr. Ruey-Wen Lin and Ms. Chiou-Mein You for setting up the standard operation protocols of HPV genotyping, and Dr Mahboobeh Safaeian (NCI and NIH) for sharing important comments. The enrollment of participants and collection of specimens were co-funded by the Department of Health (Taiwan) and the National Institutes of Health (USA). NR 30 TC 75 Z9 83 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD SEP PY 2011 VL 103 IS 18 BP 1387 EP 1396 DI 10.1093/jnci/djr283 PG 10 WC Oncology SC Oncology GA 824DH UT WOS:000295181700010 PM 21900119 ER PT J AU Zhao, LX Huang, SX Tang, SK Jiang, CL Duan, YW Beutler, JA Henrich, CJ McMahon, JB Schmid, T Blees, JS Colburn, NH Rajski, SR Shen, B AF Zhao, Li-Xing Huang, Sheng-Xiong Tang, Shu-Kun Jiang, Chen-Lin Duan, Yanwen Beutler, John A. Henrich, Curtis J. McMahon, James B. Schmid, Tobias Blees, Johanna S. Colburn, Nancy H. Rajski, Scott R. Shen, Ben TI Actinopolysporins A-C and Tubercidin as a Pdcd4 Stabilizer from the Halophilic Actinomycete Actinopolyspora erythraea YIM 90600 SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID TUMOR-SUPPRESSOR PDCD4; TRANSLATION; EXPRESSION; TUMORIGENESIS; DEGRADATION AB Our current natural product program utilizes new actinomycetes originating from unexplored and underexplored ecological niches, employing cytotoxicity against a selected panel of cancer cell lines as the preliminary screen to identify hit strains for natural product dereplication, followed by mechanism-based assays of the purified natural products to discover potential anticancer drug leads. Three new linear polyketides, actinopolysporins A (1), B (2), and C (3), along with the known antineoplastic antibiotic tubercidin (4), were isolated from the halophilic actinomycete Actinopolyspora erythraea YIM 90600, and the structures of the new compounds were elucidated on the basis of spectroscopic data interpretation. All four compounds were assayed for their ability to stabilize the tumor suppressor programmed cell death protein 4 (Pdcd4), which is known to antagonize critical events in oncogenic pathways. Only 4 significantly inhibited proteasomal degradation of a model Pdcd4 luciferase fusion protein, with an IC(50) of 0.88 +/- 0.09 mu M, unveiling a novel biological activity for this well-studied natural product. C1 [Zhao, Li-Xing; Rajski, Scott R.; Shen, Ben] Univ Wisconsin, Div Pharmaceut Sci, Madison, WI 53705 USA. [Zhao, Li-Xing; Tang, Shu-Kun; Jiang, Chen-Lin] Yunnan Univ, Yunnan Inst Microbiol, Yunnan 650091, Peoples R China. [Huang, Sheng-Xiong; Shen, Ben] Scripps Florida, Dept Chem, Jupiter, FL 33458 USA. [Shen, Ben] Scripps Florida, Dept Mol Therapeut, Jupiter, FL 33458 USA. [Shen, Ben] Scripps Florida, Nat Prod Lib Initiat TSRL, Jupiter, FL 33458 USA. [Huang, Sheng-Xiong; Duan, Yanwen] Hunan Engn Res Ctr Combinatorial Biosynth & Nat P, Changsha 410329, Hunan, Peoples R China. [Beutler, John A.; Henrich, Curtis J.; McMahon, James B.] Mol Targets Lab, Frederick, MD 21702 USA. [Henrich, Curtis J.] SAIC Frederick Inc, Frederick, MD 21702 USA. [Colburn, Nancy H.] NCI, Lab Canc Prevent, Frederick, MD 21702 USA. [Schmid, Tobias; Blees, Johanna S.] Goethe Univ Frankfurt, Inst Biochem I ZAFES, Fac Med, D-60590 Frankfurt, Germany. RP Shen, B (reprint author), Univ Wisconsin, Div Pharmaceut Sci, Madison, WI 53705 USA. EM shenb@scripps.edu RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU NIH, NCI, Center for Cancer Research; NCI [HHSN261200800001E]; NSF of China [2162028, U0932601]; SRF for ROCS, Chinese Ministry of Education; Chinese Ministry of Education [B08034]; NIH [CA113297, GM086184] FX We thank the Analytical Instrumentation Center of the School of Pharmacy, UW-Madison, for support in obtaining the MS and NMR data. This project was supported in part by the Intramural Research Program of NIH, NCI, Center for Cancer Research and federal funds from NCI under contract HHSN261200800001E and by NSF of China grants 2162028 and U0932601, and a grant from SRF for ROCS, Chinese Ministry of Education (all to L.X.Z.), the Chinese Ministry of Education 111 Project B08034 (to Y.D.), and NIH grants CA113297 and GM086184 (to B.S.). 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 24 TC 23 Z9 24 U1 0 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD SEP PY 2011 VL 74 IS 9 BP 1990 EP 1995 DI 10.1021/np200603g PG 6 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 823CS UT WOS:000295100400023 PM 21870828 ER PT J AU Riscuta, G AF Riscuta, G. TI NUTRITION FUNDING OPPORTUNITIES AND CHALLENGES SO JOURNAL OF PHYCOLOGY LA English DT Meeting Abstract C1 [Riscuta, G.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. EM gabriela.riscuta@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3646 J9 J PHYCOL JI J. Phycol. PD SEP PY 2011 VL 47 SU 2 SI SI BP S5 EP S5 PG 1 WC Plant Sciences; Marine & Freshwater Biology SC Plant Sciences; Marine & Freshwater Biology GA 822ZO UT WOS:000295090200017 ER PT J AU Anderson, WF Katki, HA Rosenberg, PS AF Anderson, William F. Katki, Hormuzd A. Rosenberg, Philip S. TI Incidence of Breast Cancer in the United States: Current and Future Trends SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID INCIDENCE RATES; TEMPORAL VARIATION; RECEPTOR STATUS; COHORT MODELS; AGE PERIOD; ESTROGEN; WOMEN; TRIAL AB Background The incidence of breast cancer increased in the United States until circa 2000 then decreased, mostly among women with estrogen receptor (ER)-positive cancers. Time trends provide important clues for cancer etiology and prevention; however, the observed trends of ER-positive and ER-negative breast cancers can be biased by missing ER data. Methods We developed a simple imputation method to correct invasive female breast cancer incidence for missing or unknown ER expression, using nationally representative data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program during 1980-2008, including 588 720 invasive female breast cancer patients with 471 336 233 woman-years of follow-up. Corrected rates of ER-positive and ER-negative breast cancers were used to calculate age-standardized incidence rates, estimated annual percentage changes, and projections derived from age-period-cohort models. Results The recent decrease in the incidence of breast cancer overall stabilized near 200 per 100 000 woman-years by 2007-2008, reflecting a transient decrease in ER-positive cancers and a steady decrease in ER-negative cancers. The projected incidence rate for breast cancer overall through the year 2016 was similar to the incidence rate during 2007-2008. In contrast, rates of ER-positive breast cancers were projected to increase 5.3% (95% confidence interval = 5.2% to 5.4%), whereas rates of ER-negative breast cancers were projected to decrease 11.4% (95% confidence interval = 11.3% to 11.6%) during 2009-2016. Conclusion Recent changes in breast cancer incidence overall reflect the superimposition of divergent trends in ER-positive and ER-negative cancers. If current trends continue, the incidence of ER-positive breast cancers will increase, the incidence of ER-negative breast cancers will continue to decrease, and the incidence of breast cancer overall will remain similar to its current level. C1 [Anderson, William F.; Katki, Hormuzd A.; Rosenberg, Philip S.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Anderson, WF (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, Dept Hlth & Human Serv,NIH, Execut Plaza S,Rm 8036,6120 Execut Blvd, Bethesda, MD 20892 USA. EM wanderso@mail.nih.gov RI Katki, Hormuzd/B-4003-2015 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This research was supported entirely by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 26 TC 86 Z9 87 U1 1 U2 15 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 SEP PY 2011 VL 103 IS 18 BP 1397 EP 1402 DI 10.1093/jnci/djr257 PG 6 WC Oncology SC Oncology GA 824DH UT WOS:000295181700011 PM 21753181 ER PT J AU Prust, M Wang, J Morizono, H Messing, A Brenner, M Gordon, E Hartka, T Sokohl, A Schiffmann, R Gordish-Dressman, H Albin, R Amartino, H Brockman, K Dinopoulos, A Dotti, MT Fain, D Fernandez, R Ferreira, J Fleming, J Gill, D Griebel, M Heilstedt, H Kaplan, P Lewis, D Nakagawa, M Pedersen, R Reddy, A Sawaishi, Y Schneider, M Sherr, E Takiyama, Y Wakabayashi, K Gorospe, JR Vanderver, A AF Prust, M. Wang, J. Morizono, H. Messing, A. Brenner, M. Gordon, E. Hartka, T. Sokohl, A. Schiffmann, R. Gordish-Dressman, H. Albin, R. Amartino, H. Brockman, K. Dinopoulos, A. Dotti, M. T. Fain, D. Fernandez, R. Ferreira, J. Fleming, J. Gill, D. Griebel, M. Heilstedt, H. Kaplan, P. Lewis, D. Nakagawa, M. Pedersen, R. Reddy, A. Sawaishi, Y. Schneider, M. Sherr, E. Takiyama, Y. Wakabayashi, K. Gorospe, J. R. Vanderver, A. TI GFAP mutations, age at onset, and clinical subtypes in Alexander disease SO NEUROLOGY LA English DT Article ID FIBRILLARY ACIDIC PROTEIN; JUVENILE FORM; GENE; PATIENT; SPECTROSCOPY; DIAGNOSIS; ATAXIA AB Objective: To characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein (GFAP) mutations. Methods: We present 30 new cases of AxD and reviewed 185 previously reported cases. We conducted Wilcoxon rank sum tests to identify variables scaling with AAO, survival analysis to identify predictors of mortality, and chi(2) tests to assess the effects of common GFAP mutations. Finally, we performed latent class analysis (LCA) to statistically define AxD subtypes. Results: LCA identified 2 classes of AxD. Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features. Survival analysis predicted a nearly 2-fold increase in mortality among patients with type I AxD relative to those with type II. R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course. Conclusions: AAO and the GFAP mutation site are important clinical predictors in AxD, with clear correlations to defined patterns of phenotypic expression. We propose revised AxD subtypes, type I and type II, based on analysis of statistically defined patient groups. Neurology (R) 2011; 77: 1287-1294 C1 [Prust, M.; Wang, J.; Hartka, T.; Sokohl, A.; Gordish-Dressman, H.; Vanderver, A.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Messing, A.] Univ Wisconsin, Madison, WI 53706 USA. [Brenner, M.] Univ Alabama, Birmingham, AL USA. [Gordon, E.] Coriell Inst Med Res, Camden, NJ USA. [Schiffmann, R.; Heilstedt, H.] Baylor Res Inst, Waco, TX USA. [Albin, R.] Univ Michigan, Vet Affairs Ann Arbor Hlth Syst Geriatr Res Educ, Ann Arbor, MI 48109 USA. [Amartino, H.] Hosp Univ Austral, Pilar, Argentina. [Brockman, K.] Univ Gottingen, Gottingen, Germany. [Dinopoulos, A.] Univ Athens, Athens, Greece. [Dotti, M. T.] Univ Siena, I-53100 Siena, Italy. [Fain, D.] Bronson Hosp, Kalamazoo, MI USA. [Fernandez, R.] Univ S Florida, Sch Med, Tampa, FL 33620 USA. Tauranga Hosp, Tauranga, New Zealand. [Gill, D.] Childrens Hosp Westmead, Dept Neurol, Sydney, NSW, Australia. [Griebel, M.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Kaplan, P.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Lewis, D.] Univ Med Ctr, Durham, NC USA. [Nakagawa, M.] Kyoto Prefectural Univ Med, Kyoto, Japan. [Pedersen, R.] Tripler Army Med Ctr, Honolulu, HI 96859 USA. [Reddy, A.] Childrens Hosp Alabama, Birmingham, AL USA. [Sawaishi, Y.] Akita Prefectural Ctr Dev & Disabil, Akita, Japan. [Schneider, M.] So Illinois Univ, Sch Med, Springfield, IL USA. [Sherr, E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Takiyama, Y.] Univ Yamanashi, Interdisciplinary Grad Sch Med & Engn, Yamanashi, Japan. [Wakabayashi, K.] Showa Univ, Fujigaoka Hosp, Yokohama, Kanagawa 227, Japan. [Gorospe, J. R.] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RP Vanderver, A (reprint author), Childrens Natl Med Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. EM avanderv@cnmc.org OI Morizono, Hiroki/0000-0002-9678-5564 FU NIH IDDRC [P30HD4067]; NIH NCMRR/NINDS [5R24 HD050846]; Delman Fund; Children's National Medical Center Neurology Department; NIH; Children's National Medical Center; Kettering Family Foundation; NIH (NINDS, NICHD); NIH (NIDDK, NHGRI); Shire plc; Amicus Therapeutics, Inc.; Baylor Research Foundation; Michael J. Fox Foundation; VA Merit Review program; Genzyme Corporation; Amicus Therapeutics, Inc; Bundesministerium fur Bildung und Forschung (BMBF) through the German Leukodystrophy Network; UCB; Pfizer; King Pharmaceuticals; Sunovion Pharmaceuticals Inc. (Dainippon Sumitomo Pharma); Lundbeck Inc.; Supernus Pharmaceuticals, Inc.; Eisai Inc.; NIH/NINDS; Appalachian State University; Ministry of Health, Labour, and Welfare of the Government of Japan; March of Dimes; Aicardi Syndrome Foundation; Weston Havens Foundation; Simons Foundation; American Academy of Neurology Foundation; Dana Foundation FX Supported in part by NIH IDDRC P30HD4067 (Intellectual and Developmental Disabilities Core) and NIH NCMRR/NINDS 5R24 HD050846 (Integrated Molecular Core for Rehabilitation Medicine). M. P. was supported by the Delman Fund and the Children's National Medical Center Neurology Department.; M. Prust and Dr. Wang report no disclosures. Dr. Morizono receives research support from the NIH, the Children's National Medical Center, and the Kettering Family Foundation. Dr. Messing receives research support from the NIH. Dr. Brenner receives research support from the NIH (NINDS, NICHD). E. Gordon serves on scientific advisory boards for Acceleron Pharma and Chesapeake Research Review Inc.; has received funding for travel and speaker honoraria from Affymetrix, Inc.; serves as a consultant for MedIQ; receives research support from the NIH (NIDDK, NHGRI); and holds stock options in Illumina, Inc.; and her spouse is employed by Illumina, Inc. Dr. Hartka and A. Sokhol report no disclosures. Dr. Schiffmann has served on scientific advisory boards for and received funding for travel and speaker honoraria from Shire plc and Amicus Therapeutics, Inc.; has a patent pending re: Tetrahydrobiopterin in Fabry disease; has served as a consultant for Zacharon Pharmaceuticals; and has received research support from Shire plc, Amicus Therapeutics, Inc., and the Baylor Research Foundation. H. Gordish-Dressman receives research support from the NIH (NINDS, NICHD). Dr. Albin serves on data safety monitoring boards for Medivation, Inc. and the NIH/NINDS; serves on the editorial boards of Neurology (R), Experimental Neurology, and Neurobiology of Disease; serves as a consultant for Best Doctors; receives research support from the NIH and the Michael J. Fox Foundation; is a staff physician at the Veteran's Affairs Ann Arbor Health System and receives grant support from the VA Merit Review program; and has served as an expert witness in medico-legal cases. Dr. Amartino serves on scientific advisory boards for Genzyme Corporation and Shire plc and has received funding for travel or speaker honoraria from Genzyme Corporation, Shire plc, and Amicus Therapeutics, Inc. Dr. Brockman serves as Co-Editor-in-Chief of Kinderarztliche Praxis, Kirchheim Verlag, Mainz, Germany (a German educational journal for pediatricians) and has received research support from the Bundesministerium fur Bildung und Forschung (BMBF) through the German Leukodystrophy Network. Dr. Dinopoulos and Dr. Dotti report no disclosures. Dr. Fain is on the speakers' bureau for and has received speaker honoraria from UCB. Dr. Fernandez reports no disclosures. Dr. Ferreira has received research support from Pfizer, King Pharmaceuticals, UCB, Sunovion Pharmaceuticals Inc. (Dainippon Sumitomo Pharma), Lundbeck Inc., Supernus Pharmaceuticals, Inc., and Eisai Inc. Dr. Fleming, Dr. Gill, Dr. Griebel, and Dr. Heilstedt report no disclosures. Dr. Kaplan has served on scientific advisory boards, as a consultant, and on the speakers' bureau for and received speaker honoraria and research support from Genzyme Corporation and serves as an Associate Editor for the European Journal of Pediatrics. Dr. Lewis receives research support from the NIH/NINDS and Appalachian State University. Dr. Nakagawa receives research support from the Ministry of Health, Labour, and Welfare of the Government of Japan. Dr. Pederson, Dr. Reddy, Dr. Sawaishi, and Dr. Schneider report no disclosures. Dr. Sherr receives support for his laboratory from Pfizer Inc; and receives research support from the NIH/NINDS, the March of Dimes, the Aicardi Syndrome Foundation, the Weston Havens Foundation, and the Simons Foundation; holds stock/stock options in Sensorin, Inc., Plexxicon, Ingenuity Systems, Inc. (spouse is employee), and ChemoCentryx; and has provided expert counsel in medico- legal cases. Dr. Takiyama, Dr. Wakabayashi, and Dr.; Grospe report no disclosures. Dr. Vanderver has a patent pending re: The use of cerebrospinal fluid asialotransferrin in the diagnosis of vanishing white matter disease and receives/has received research support from the NIH/NINDS, the American Academy of Neurology Foundation, and the Dana Foundation. NR 40 TC 59 Z9 62 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP PY 2011 VL 77 IS 13 BP 1287 EP 1294 DI 10.1212/WNL.0b013e3182309f72 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 825EM UT WOS:000295253800018 PM 21917775 ER PT J AU Nelson, KB Blair, E AF Nelson, K. B. Blair, E. TI The placenta and neurologic and psychiatric outcomes in the child: Study design matters SO PLACENTA LA English DT Article DE Clinical research; Neonatal encephalopathy; Cerebral palsy ID NEWBORN ENCEPHALOPATHY; CEREBRAL-PALSY; CLINICAL-SIGNIFICANCE; RISK-FACTORS; ASSOCIATION; EXPRESSION; HISTOLOGY; BRAIN AB Much information exists about functions of the human placenta and about potential mechanisms by which the placenta may influence human health or disease, including developmental disorders of brain. Recent studies indicate a high frequency of placental pathology in infants with developmental brain disorders, or with risk factors for such disorders. However, most clinical studies of the association of placental features with adverse neurologic or psychiatric outcome have substantial methodologic limitations. We discuss issues of study design as they relate to studies of the placenta and human brain disorders. In addition to the need for further consensus on procedures and terminology for placental evaluation, there are a number of special features that make clinical studies of the association of placental features with neurologic and psychiatric disorders especially difficult: most such disorders are not diagnosed until months or years after the majority of placentas have been discarded; these disorders are individually uncommon, so that prospective studies - needed to provide denominator data to enable estimation of risks - will require very large sample sizes; the administrative structures required to relate features of the placenta with clinical outcome will be complicated and costly. We offer some suggestions concerning study design in the face of these practical difficulties. Systematic and methodologically rigorous exploration of the role of the placenta in human developmental brain disorders has scarcely begun. A new generation of studies, difficult but potentially enormously rewarding, will be needed for clinical investigations of the placenta and fetal brain development. Published by Elsevier Ltd. C1 [Nelson, K. B.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Nelson, K. B.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Blair, E.] Univ Western Australia, Telethon Inst Child Hlth Res, Ctr Child Hlth Res, Perth, WA 6009, Australia. [Blair, E.] Univ Western Australia, Sch Paediat & Child Hlth, Perth, WA 6009, Australia. RP Nelson, KB (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Bldg 10,Room 5C438, Bethesda, MD 20892 USA. EM nelsonk@ninds.nih.gov NR 25 TC 8 Z9 8 U1 0 U2 4 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP PY 2011 VL 32 IS 9 BP 623 EP 625 DI 10.1016/j.placenta.2011.06.021 PG 3 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 822TJ UT WOS:000295072200001 PM 21762984 ER PT J AU Kvehaugen, AS Dechend, R Ramstad, H Troisi, R Fugelseth, D Staff, AC AF Kvehaugen, Anne Stine Dechend, Ralf Ramstad, Heidi Troisi, Rebecca Fugelseth, Drude Staff, Anne Cathrine TI DOES CIRCULATING BIOMARKERS ASSOCIATED WITH PLACENTAL DYSFUNCTION OR ENDOTHELIAL FUNCTION DIFFER IN MOTHER-CHILD PAIRS SEVERAL YEARS AFTER PREECLAMPTIC PREGNANCIES COMPARED TO CONTROLS? SO PLACENTA LA English DT Meeting Abstract CT Meeting of the International-Federation-of-Placenta-Associations (IFPA) CY SEP 14-17, 2011 CL Geilo, NORWAY SP Int Federat Placenta Assoc C1 [Kvehaugen, Anne Stine; Staff, Anne Cathrine] Oslo Univ Hosp, Dept Obstet, Oslo, Norway. [Kvehaugen, Anne Stine; Staff, Anne Cathrine] Oslo Univ Hosp, Dept Gynecol, Oslo, Norway. [Dechend, Ralf] Max Delbruck Ctr, Expt & Clin Res Ctr, Berlin, Germany. [Dechend, Ralf] Fac Med Charite, Berlin, Germany. [Ramstad, Heidi] Oslo Univ Hosp, Dept Pediat, Oslo, Norway. [Troisi, Rebecca] NCI, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Fugelseth, Drude] Oslo Univ Hosp, Dept Neonatal Intens Care, Oslo, Norway. [Kvehaugen, Anne Stine; Fugelseth, Drude; Staff, Anne Cathrine] Univ Oslo, Fac Med, Oslo, Norway. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP PY 2011 VL 32 IS 9 BP A9 EP A9 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 822TJ UT WOS:000295072200036 ER PT J AU Zhang, JH Fritz, J Rochman, Y Leonard, W Gommerman, J Chen, ZL Plumb, A Abraham, N Croy, BA AF Zhang, Jianhong Fritz, Jorg Rochman, Yrina Leonard, Warren Gommerman, Jennifer Chen, Zhilin Plumb, Adam Abraham, Ninan Croy, B. Anne TI FULLY DIFFERENTIATED UTERINE NATURAL KILLER CELLS BECOME CD127+IN A DECIDUAL MICROENVIRONMENT ENRICHED FOR THYMIC STROMAL CYTOKINES SO PLACENTA LA English DT Meeting Abstract CT Meeting of the International-Federation-of-Placenta-Associations (IFPA) CY SEP 14-17, 2011 CL Geilo, NORWAY SP Int Federat Placenta Assoc C1 [Zhang, Jianhong; Chen, Zhilin; Croy, B. Anne] Queens Univ, Kingston, ON, Canada. [Fritz, Jorg; Gommerman, Jennifer] Univ Toronto, Toronto, ON, Canada. [Rochman, Yrina; Leonard, Warren] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Plumb, Adam; Abraham, Ninan] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP PY 2011 VL 32 IS 9 BP A118 EP A118 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 822TJ UT WOS:000295072200261 ER PT J AU Pitisuttithum, P Rerks-Ngarm, S Chiu, J Kim, J Benenson, M Kent, SJ Tamashiro, H Manrique, A Bernstein, A Goyal, R Ditangco, RA Cooper, DA Osmanov, S Mathieson, B Sandstrom, E Esparza, J Hoff, R Shao, YM AF Pitisuttithum, Punnee Rerks-Ngarm, Supachai Chiu, Joseph Kim, Jerome Benenson, Michael Kent, Stephen J. Tamashiro, Hiko Manrique, Amapola Bernstein, Alan Goyal, Rajat Ditangco, Rossana A. Cooper, David A. Osmanov, Saladin Mathieson, Bonnie Sandstrom, Eric Esparza, Jose Hoff, Rodney Shao, Yiming CA AIDS Vaccine Asia Network TI ACCELERATING THE DEVELOPMENT OF AN AIDS VACCINE: THE AIDS VACCINE FOR ASIA NETWORK (AVAN) SO SOUTHEAST ASIAN JOURNAL OF TROPICAL MEDICINE AND PUBLIC HEALTH LA English DT Article DE AIDS; accelerating; vaccine; AIDS Vaccine for Asia Network (AVAN) ID RESEARCH-AND-DEVELOPMENT; PHASE-I TRIAL; VIRUS-VACCINE; HIV-1 VACCINE; DOUBLE-BLIND; THAILAND; EVALUATE; IMMUNOGENICITY; VOLUNTEERS; ENTERPRISE AB HIV/AIDS is a major public health problem worldwide, especially in developing countries. The development of a safe and effective HIV vaccine is central to stopping the epidemic and would be a great public health tool. The AIDS Vaccine for Asia Network (AVAN) is a group of concerned investigators committed to assisting regional and global HIV vaccine efforts. AVAN's focus on improving the coordination and harmonization of research, ethical reviews, clinical trial capacity regulatory frameworks, vaccine manufacturing, community participation, and government advocacy could help accelerate HIV vaccine efforts in the region. At a meeting in November 2010, researchers from various countries in Asia presented their progress in HIV vaccine research and development. Six working groups discussed the current status, gaps and methods to strengthen capacity and infrastructure in various areas related to AIDS vaccine research and development. These discussions led to the development of prioritized action plans for the next 5 years. This report describes the gaps and challenges HIV vaccine research faces in the region and recommends improvement and standardization of facilities, and coordination and harmonization of all activities related to AIDS vaccine research and development, including possible technology transfer when a vaccine becomes available. C1 [Pitisuttithum, Punnee] Mahidol Univ, Fac Trop Med, Bangkok 10400, Thailand. [Rerks-Ngarm, Supachai] Minist Publ Hlth, Dept Dis Control, Nonthaburi, Thailand. [Chiu, Joseph; Benenson, Michael] Armed Forces Res Inst Med Sci, US Mil HIV Res Program, Bangkok 10400, Thailand. [Kent, Stephen J.] Univ Melbourne, Melbourne, Vic 3010, Australia. [Tamashiro, Hiko] Hokkaido Univ, Sapporo, Hokkaido, Japan. [Manrique, Amapola; Bernstein, Alan] Global HIV Vaccine Enterprise, New York, NY USA. [Ditangco, Rossana A.] Res Inst Trop Med, Manila, Philippines. [Cooper, David A.] Univ NSW, Sydney, NSW, Australia. [Osmanov, Saladin] World Hlth Org Joint United Nations Programme HIV, Geneva, Switzerland. [Mathieson, Bonnie] NIH, Off AIDS Res, Washington, DC USA. [Sandstrom, Eric] Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden. [Esparza, Jose] Bill & Melinda Gates Fdn, Seattle, WA USA. [Hoff, Rodney] Reg Emerging Dis Intervent Ctr, Singapore, Singapore. [Shao, Yiming] Natl Ctr AIDS STD Control & Prevent, Beijing, Peoples R China. RP Pitisuttithum, P (reprint author), Mahidol Univ, Fac Trop Med, 420-6 Ratchawithi Rd, Bangkok 10400, Thailand. EM tmppt@mahidol.ac.th RI Tamashiro, Hidehiko/B-2403-2013; OI Kent, Stephen/0000-0002-8539-4891 FU World Health Organization; WHO-UNAIDS; Global HIV Vaccine Enterprise; International AIDS Vaccine Initiative (IAVI); US National Institutes of Health (NIH); US Military HIV Research Program (MHRP); Department of Disease Control, Ministry of Public Health, Thailand FX The annual meeting was sponsored by the World Health Organization and the joint United Nations Programme on HIV/AIDS (WHO-UNAIDS), the Global HIV Vaccine Enterprise, the International AIDS Vaccine Initiative (IAVI), the US National Institutes of Health (NIH), the US Military HIV Research Program (MHRP), and the Department of Disease Control, Ministry of Public Health, Thailand. The organizers are extremely grateful to all the participants and appreciate their presence and contributions which were critical to the success of the meeting. The organizers are also thankful to Michael Benenson, Deena Kanagaraj, Sabine Majer, Wai Lin Htun, Kaoru Takahashi, Ahmed Abdi Dahir, Yoshi Inakuma for their support as rapporteurs and Daoumpai Suwattanasilp, Sawanya Lekhachinnabut, Bussabong Nillawat, and Patcharanant Thanarojpongsatorn for their assistance in organizing the meeting. NR 23 TC 3 Z9 3 U1 0 U2 4 PU SOUTHEAST ASIAN MINISTERS EDUC ORGANIZATION PI BANGKOK PA SEAMEO-TROPMED, 420-6 RAJVITHI RD,, BANGKOK 10400, THAILAND SN 0125-1562 J9 SE ASIAN J TROP MED JI Southeast Asian J. Trop. Med. Public Health PD SEP PY 2011 VL 42 IS 5 BP 1130 EP 1146 PG 17 WC Public, Environmental & Occupational Health; Infectious Diseases; Tropical Medicine SC Public, Environmental & Occupational Health; Infectious Diseases; Tropical Medicine GA 824FC UT WOS:000295186800012 PM 22299439 ER PT J AU Narfstrom, K Raymond, MM Seeliger, M AF Narfstroem, Kristina Raymond, Marilyn Menotti Seeliger, Mathias TI Characterization of feline hereditary retinal dystrophies using clinical, functional, structural and molecular genetic studies SO VETERINARY OPHTHALMOLOGY LA English DT Review DE animal model; degeneration; dystrophy; feline; hereditary; retina ID LEBERS CONGENITAL AMAUROSIS; ROD-CONE DEGENERATION; PARTIAL DAY BLINDNESS; ABYSSINIAN CATS; EARLY-ONSET; CENTROSOMAL PROTEIN; JOUBERT-SYNDROME; NIGHT BLINDNESS; BRIARD DOGS; RDY CAT AB Only in recent years have specific mutations been elucidated for feline hereditary retinal dystrophies. Molecular genetic characterization of feline diseases has so far been a slow process but with a full genome sequence for the cat recently completed and the development of a feline single nucleotide polymorphism chip, the characterization of feline monogenic disorders will be significantly simplified. This review summarizes current knowledge with regard to specific hereditary retinal dystrophies in cats and gives an overview of how cats can be used as models in translational research. C1 [Narfstroem, Kristina] Univ Missouri, Dept Vet Med & Surg, Columbia, MO 65211 USA. [Raymond, Marilyn Menotti] NCI, NIH, Frederick, MD 21701 USA. [Seeliger, Mathias] Univ Tubingen, Inst Ophthalm Res, Div Ocular Neurodegenerat, Tubingen, Germany. RP Narfstrom, K (reprint author), Univ Missouri, Dept Vet Med & Surg, Columbia, MO 65211 USA. EM Narfstromk@missouri.edu NR 47 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1463-5216 J9 VET OPHTHALMOL JI Vet. Ophthalmol. PD SEP PY 2011 VL 14 SU 1 BP 30 EP 36 DI 10.1111/j.1463-5224.2011.00915.x PG 7 WC Veterinary Sciences SC Veterinary Sciences GA 822XY UT WOS:000295085100006 PM 21923821 ER PT J AU Araya, N Sato, T Yagishita, N Ando, H Utsunomiya, A Jacobson, S Yamano, Y AF Araya, Natsumi Sato, Tomoo Yagishita, Naoko Ando, Hitoshi Utsunomiya, Atae Jacobson, Steven Yamano, Yoshihisa TI Human T-Lymphotropic Virus Type 1 (HTLV-1) and Regulatory T Cells in HTLV-1-Associated Neuroinflammatory Disease SO VIRUSES-BASEL LA English DT Review DE HTLV-1; HAM/TSP; ATL; CD4(+)CD25(+)CCR4(+) T cell; regulatory T cell; exFoxp3(+) cell; inflammation; immune-dysfunction ID MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; I-ASSOCIATED MYELOPATHY; TRANSCRIPTION FACTOR FOXP3; KAPPA-B SITE; LEUKEMIA-VIRUS; PROVIRAL LOAD; LEUKEMIA/LYMPHOMA CELLS; NEUROLOGIC DISEASE; PERIPHERAL-BLOOD; INTERFERON-GAMMA AB Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATL) and associated with multiorgan inflammatory disorders, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. HTLV-1-infected T cells have been hypothesized to contribute to the development of these disorders, although the precise mechanisms are not well understood. HTLV-1 primarily infects CD4(+) T helper (Th) cells that play a central role in adaptive immune responses. Based on their functions, patterns of cytokine secretion, and expression of specific transcription factors and chemokine receptors, Th cells that are differentiated from naive CD4(+) T cells are classified into four major lineages: Th1, Th2, Th17, and T regulatory (Treg) cells. The CD4(+)CD25(+)CCR4(+) T cell population, which consists primarily of suppressive T cell subsets, such as the Treg and Th2 subsets in healthy individuals, is the predominant viral reservoir of HTLV-1 in both ATL and HAM/TSP patients. Interestingly, CD4(+)CD25(+)CCR4(+) T cells become Th1-like cells in HAM/TSP patients, as evidenced by their overproduction of IFN-gamma, suggesting that HTLV-1 may intracellularly induce T cell plasticity from Treg to IFN-gamma(+) T cells. This review examines the recent research into the association between HTLV-1 and Treg cells that has greatly enhanced understanding of the pathogenic mechanisms underlying immune dysregulation in HTLV-1-associated neuroinflammatory disease. C1 [Araya, Natsumi; Sato, Tomoo; Yagishita, Naoko; Ando, Hitoshi; Yamano, Yoshihisa] St Marianna Univ, Dept Rare Dis Res, Inst Med Sci, Sch Med, Kawasaki, Kanagawa 2168511, Japan. [Utsunomiya, Atae] Imamura Bun In Hosp, Dept Hematol, Kagoshima 8900064, Japan. [Jacobson, Steven] NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Yamano, Y (reprint author), St Marianna Univ, Dept Rare Dis Res, Inst Med Sci, Sch Med, Kawasaki, Kanagawa 2168511, Japan. EM araya@marianna-u.ac.jp; tomoo@marianna-u.ac.jp; yagi@marianna-u.ac.jp; hando@marianna-u.ac.jp; autsunomiya@jiaikai.jp; jacobsons@ninds.nih.gov; yyamano@marianna-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology; Japanese Ministry of Health, Labor, and Welfare; Uehara Memorial Foundation; Nagao Takeshi Nanbyo Foundation; Kanagawa Nanbyo Foundation; Mishima Kaiun Memorial Foundation; Takeda Science Foundation; ITSUU Laboratory Research Foundation; Foundation for Total Health Promotion; Sankyo Foundation of Life Science FX This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology; the Japanese Ministry of Health, Labor, and Welfare; the Uehara Memorial Foundation; the Nagao Takeshi Nanbyo Foundation; the Kanagawa Nanbyo Foundation; the Mishima Kaiun Memorial Foundation; the Takeda Science Foundation; the ITSUU Laboratory Research Foundation; the Foundation for Total Health Promotion; and the Sankyo Foundation of Life Science. NR 68 TC 20 Z9 20 U1 0 U2 1 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD SEP PY 2011 VL 3 IS 9 BP 1532 EP 1548 DI 10.3390/v3091532 PG 17 WC Virology SC Virology GA 824OK UT WOS:000295211400001 PM 21994794 ER PT J AU Delviks-Frankenberry, K Galli, A Nikolaitchik, O Mens, H Pathak, VK Hu, WS AF Delviks-Frankenberry, Krista Galli, Andrea Nikolaitchik, Olga Mens, Helene Pathak, Vinay K. Hu, Wei-Shau TI Mechanisms and Factors that Influence High Frequency Retroviral Recombination SO VIRUSES-BASEL LA English DT Review DE recombination; retrovirus; HIV-1 ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; HIV-1 REVERSE-TRANSCRIPTASE; RNASE-H ACTIVITY; DIMERIZATION INITIATION SIGNAL; HIGH NEGATIVE INTERFERENCE; DRUG-RESISTANCE MUTATIONS; SINGLE REPLICATION CYCLE; WEST-CENTRAL-AFRICA; STRAND TRANSFER AB With constantly changing environmental selection pressures, retroviruses rely upon recombination to reassort polymorphisms in their genomes and increase genetic diversity, which improves the chances for the survival of their population. Recombination occurs during DNA synthesis, whereby reverse transcriptase undergoes template switching events between the two copackaged RNAs, resulting in a viral recombinant with portions of the genetic information from each parental RNA. This review summarizes our current understanding of the factors and mechanisms influencing retroviral recombination, fidelity of the recombination process, and evaluates the subsequent viral diversity and fitness of the progeny recombinant. Specifically, the high mutation rates and high recombination frequencies of HIV-1 will be analyzed for their roles in influencing HIV-1 global diversity, as well as HIV-1 diagnosis, drug treatment, and vaccine development. C1 [Galli, Andrea; Nikolaitchik, Olga; Hu, Wei-Shau] NCI, Viral Recombinat Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Delviks-Frankenberry, Krista; Pathak, Vinay K.] NCI, Viral Mutat Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Galli, Andrea] Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen Hepatitis Program C, DK-2650 Hvidovre, Denmark. [Mens, Helene] Rigshosp, Dept Epidem Dis, DK-2100 Copenhagen, Denmark. RP Hu, WS (reprint author), NCI, Viral Recombinat Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM frankenk@mail.nih.gov; andrea.galli@hvh.regionh.dk; nikolaio@mail.nih.gov; helene.mens@gmail.com; vinay.pathak@nih.gov; wei-shau.hu@nih.gov RI Delviks-Frankenberry, Krista/M-4822-2013; OI Galli, Andrea/0000-0002-4404-430X FU NIH, National Cancer Institute, Center for Cancer Research FX This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 162 TC 25 Z9 27 U1 0 U2 15 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD SEP PY 2011 VL 3 IS 9 BP 1650 EP 1680 DI 10.3390/v3091650 PG 31 WC Virology SC Virology GA 824OK UT WOS:000295211400008 PM 21994801 ER PT J AU Park, YN Masison, D Eisenberg, E Greene, LE AF Park, Yang-Nim Masison, Daniel Eisenberg, Evan Greene, Lois E. TI Application of the FLP/FRT system for conditional gene deletion in yeast Saccharomyces cerevisiae SO YEAST LA English DT Article DE Flp recombinase; FRT; conditional gene deletion; yeast ID SITE-SPECIFIC RECOMBINATION; FLP RECOMBINASE; BUDDING YEAST; FUNCTIONAL EXPRESSION; MAMMALIAN-CELLS; PROTEIN; PROMOTER; HSP104; PRION; PROPAGATION AB The yeast Saccharomyces cerevisiae has proved to be an excellent model organism to study the function of proteins. One of the many advantages of yeast is the many genetic tools available to manipulate gene expression, but there are still limitations. To complement the many methods used to control gene expression in yeast, we have established a conditional gene deletion system by using the FLP/FRT system on yeast vectors to conditionally delete specific yeast genes. Expression of Flp recombinase, which is under the control of the GAL1 promoter, was induced by galactose, which in turn excised FRT sites flanked genes. The efficacy of this system was examined using the FRT site-flanked genes HSP104, URA3 and GFP. The pre-excision frequency of this system, which might be caused by the basal activity of the GAL1 promoter or by spontaneous recombination between FRT sites, was detected ca. 2% under the non-selecting condition. After inducing expression of Flp recombinase, the deletion efficiency achieved ca. 96% of cells in a population within 9 h. After conditional deletion of the specific gene, protein degradation and cell division then diluted out protein that was expressed from this gene prior to its excision. Most importantly, the specific protein to be deleted could be expressed under its own promoter, so that endogenous levels of protein expression were maintained prior to excision by the Flp recombinase. Therefore, this system provides a useful tool for the conditional deletion of genes in yeast. Published in 2011 by John Wiley & Sons, Ltd. C1 [Park, Yang-Nim; Eisenberg, Evan; Greene, Lois E.] NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. [Masison, Daniel] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Park, YN (reprint author), NHLBI, Cell Biol Lab, 50 South Dr,Room 2535, Bethesda, MD 20892 USA. EM parky3@mail.nih.gov NR 34 TC 10 Z9 12 U1 1 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0749-503X J9 YEAST JI Yeast PD SEP PY 2011 VL 28 IS 9 BP 673 EP 681 DI 10.1002/yea.1895 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 823SO UT WOS:000295146300004 PM 21823166 ER PT J AU Guindo, A Traore, K Diakite, S Wellems, TE Doumbo, OK Diallo, DA AF Guindo, Aldiouma Traore, Karim Diakite, Seidina Wellems, Thomas E. Doumbo, Ogobara K. Diallo, Dapa Aly TI An evaluation of concurrent G6PD (A-) deficiency and sickle cell trait in Malian populations of children with severe or uncomplicated P. falciparum malaria SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID PLASMODIUM-FALCIPARUM; HEMOGLOBIN-S; RESISTANCE; AFRICA AB Sickle cell trait (SCT) and glucose-6-phosphate dehydrogenase (G6PD (A-)) deficiency are two common genetic conditions in sub-Saharan Africa. In Mali, SCT and G6PD (A-) deficiency are found at overall frequencies of 12% and 14%, respectively. While SCT and G6PD (A-) deficiency were associated with protection against severe malaria, we have examined the occurrence of the G6PD (A-) polymorphism and SCT together in Malian populations of children with severe or uncomplicated P. falciparum malaria. No evidence for increased protection was detected in children who carried both SCT and the G6PD (A-) polymorphism. A suggestion of greater susceptibility was instead observed for the heterozygous G6PD (A-) versus G6PD normal condition in SCT females (OR 15, P = 0.003). While in addition, larger studies will be needed to further evaluate the possibility of interference between the protective effects of the SCT and G6PD (A-) conditions, we note that these results are reminiscent of the negative epistasis reported for the malaria-protective effects of alpha+-thalassemia and SCT. Better understanding of the conflicts among malaria-protective polymorphisms may shed light on their observed epidemiological distributions and improve our knowledge of the mechanisms by which they operate. C1 [Guindo, Aldiouma; Traore, Karim; Diakite, Seidina; Doumbo, Ogobara K.; Diallo, Dapa Aly] Univ Bamako, Malaria Res & Training Ctr, Dept Hematol, Fac Med Pharm & Dent, Bamako, Mali. [Guindo, Aldiouma; Traore, Karim; Diakite, Seidina; Doumbo, Ogobara K.; Diallo, Dapa Aly] Univ Bamako, Malaria Res & Training Ctr, Dept Parasitol, Fac Med Pharm & Dent, Bamako, Mali. [Wellems, Thomas E.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Diallo, DA (reprint author), Univ Bamako, Malaria Res & Training Ctr, Dept Hematol, Fac Med Pharm & Dent, Bamako, Mali. EM dadiallo@mrtcbko.org FU Intramural NIH HHS [Z01 AI001000-01] NR 17 TC 3 Z9 3 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD SEP PY 2011 VL 86 IS 9 BP 795 EP 796 DI 10.1002/ajh.22093 PG 2 WC Hematology SC Hematology GA 821VZ UT WOS:000295003800017 PM 21786288 ER PT J AU Martires, KJ Baird, K Citrin, DE Hakim, FT Pavletic, SZ Cowen, EW AF Martires, Kathryn J. Baird, Kristin Citrin, Deborah E. Hakim, Fran T. Pavletic, Steven Z. Cowen, Edward W. TI Localization of Sclerotic-type Chronic Graft-vs-Host Disease to Sites of Skin Injury Potential Insight Into the Mechanism of Isomorphic and Isotopic Responses SO ARCHIVES OF DERMATOLOGY LA English DT Article ID HERPES-ZOSTER; LICHEN-PLANUS; I INTERFERON; PEMPHIGUS-VULGARIS; IRRADIATED SKIN; DERMATITIS; LESIONS; AREA; MANIFESTATIONS; INFLAMMATION AB Background: The mechanisms responsible for the variable manifestations of chronic cutaneous graft-vs-host disease (cGVHD) are poorly understood. Localization of sclerotic-type chronic graft-vs-host disease to sites of skin injury (isomorphic and isotopic responses), a recognized phenomenon in morphea, suggests a potential common pathway between cGVHD and other sclerotic skin conditions. Observations: Four cases of sclerotic-type cGVHD developed at the site of disparate skin injuries (ionizing radiotherapy, repeated needle sticks, central catheter site, and varicella-zoster virus infection). We review the spectrum of previously reported cases of sclerotic and non-sclerotic cGVHD relating to external forces on the skin. Conclusions: Localization of sclerotic-type cGVHD may occur after many types of skin injury, including UV and ionizing radiotherapy, needle sticks, viral infection, and pressure or friction. Recognition of this phenomenon may be helpful for the early diagnosis of sclerotic disease. Recent insights into the immunological consequences of minor skin injury may provide important clues to the underlying pathogenesis of cGVHD-mediated skin disease. C1 [Martires, Kathryn J.; Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Baird, Kristin] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Citrin, Deborah E.] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hakim, Fran T.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU National Institutes of Health (NIH), Center for Cancer Research, National Cancer Institute; Clinical Research Training Program; NIH; Pfizer Inc FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), Center for Cancer Research, National Cancer Institute, and by the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc (via a grant to the Foundation for the NIH from Pfizer Inc) (Ms Martires). NR 49 TC 11 Z9 12 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD SEP PY 2011 VL 147 IS 9 BP 1081 EP 1086 PG 6 WC Dermatology SC Dermatology GA 821WD UT WOS:000295004200013 PM 21931046 ER PT J AU Birkeland, AC Auerbach, AD Sanborn, E Parashar, B Kuhel, WI Chandrasekharappa, SC Smogorzewska, A Kutler, DI AF Birkeland, Andrew C. Auerbach, Arleen D. Sanborn, Erica Parashar, Bhupesh Kuhel, William I. Chandrasekharappa, Settara C. Smogorzewska, Agata Kutler, David I. TI Postoperative Clinical Radiosensitivity in Patients With Fanconi Anemia and Head and Neck Squamous Cell Carcinoma SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID RADIATION-THERAPY; CANCER; RADIOTHERAPY; REGISTRY; PATHWAY; RISK AB Objective: To describe the complications and adverse effects of postoperative radiotherapy in patients with Fanconi anemia (FA). Design: Cohort study. Setting: Patients with FA treated at community and tertiary care hospitals throughout the United States. Patients: The study included patients with FA who were enrolled in the International FA Registry (IFAR) and who developed head and neck squamous cell carcinoma and received postoperative radiotherapy. Main Outcome Measures: Demographics of patients with FA and adverse effects and dosages of radiotherapy. Results: Twelve patients with FA (7 men and 5 women) were identified. They developed cancers at a mean age of 35.5 years (age range, 20-48 years). The sites of primary cancer were the oral cavity (n = 8), larynx (n = 2), pharynx (n = 1), and unknown (n = 1). The median radiation dose was 5590 cGy (range, 2500-7020 cGy). The most common adverse effects were mucositis (n = 9), dysphagia (n = 8), and pancytopenia (n = 6). Other complications included esophageal stenosis, laryngeal edema, and wound breakdown. Radiotherapy could not be completed in 5 cases. Overall, 8 patients died, 4 during the course of radiotherapy. The postoperative disease-free survival time ranged from 0 to 55 months. Conclusions: Patients with FA have a high rate of complications from radiotherapy. Common adverse effects, particularly mucositis, are especially prevalent and difficult to manage in this population. Pancytopenia is common and may lead to further complications, particularly bleeding and infection. Overall survival is poor. Further study of the response to radiotherapy in patients with FA should be attempted to establish appropriate dosages to balance treating disease while limiting adverse effects. C1 [Birkeland, Andrew C.; Kuhel, William I.; Kutler, David I.] New York Presbyterian Hosp, Dept Otolaryngol Head & Neck Surg, Weill Cornell Med Ctr, New York, NY 10021 USA. [Parashar, Bhupesh] New York Presbyterian Hosp, Dept Radiat Oncol, Weill Cornell Med Ctr, New York, NY 10021 USA. [Auerbach, Arleen D.; Sanborn, Erica; Smogorzewska, Agata] Rockefeller Univ, Lab Genome Maintenance, New York, NY 10021 USA. [Sanborn, Erica; Chandrasekharappa, Settara C.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Kutler, DI (reprint author), New York Presbyterian Hosp, Dept Otolaryngol Head & Neck Surg, Weill Cornell Med Ctr, 1305 York Ave,5th Floor, New York, NY 10021 USA. EM dik2002@med.cornell.edu OI Auerbach, Arleen/0000-0002-6911-8379 FU National Center for Research Resources [UL1RR024143]; National Institutes of Health (NIH); Burroughs Wellcome Fund Career Award for Medical Scientists FX This project was supported by grant award UL1RR024143 from the National Center for Research Resources, a component of the National Institutes of Health (NIH) and the NIH Roadmap for Medical Research. Dr Smogorzewska is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists and is a Rita Allen Foundation and Irma T. Hirschl scholar. NR 22 TC 18 Z9 18 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0886-4470 J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD SEP PY 2011 VL 137 IS 9 BP 930 EP 934 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 821VI UT WOS:000295002100009 PM 21930984 ER PT J AU Iwata, NK Kwan, JY Danielian, LE Butman, JA Tovar-Moll, F Bayat, E Floeter, MK AF Iwata, Nobue K. Kwan, Justin Y. Danielian, Laura E. Butman, John A. Tovar-Moll, Fernanda Bayat, Elham Floeter, Mary Kay TI White matter alterations differ in primary lateral sclerosis and amyotrophic lateral sclerosis SO BRAIN LA English DT Article DE diffusion tensor imaging; diffusion tensor tractography; motor neuron disorders; primary lateral sclerosis; corpus callosum ID MILD COGNITIVE IMPAIRMENT; DIFFUSION TENSOR MRI; CORTICOSPINAL TRACT; MOTOR CORTEX; TRANSCALLOSAL INHIBITION; SPATIAL STATISTICS; AXONAL PROJECTIONS; CLINICAL-FEATURES; ALS; BRAIN AB Primary lateral sclerosis is a sporadic disorder characterized by slowly progressive corticospinal dysfunction. Primary lateral sclerosis differs from amyotrophic lateral sclerosis by its lack of lower motor neuron signs and long survival. Few pathological studies have been carried out on patients with primary lateral sclerosis, and the relationship between primary lateral sclerosis and amyotrophic lateral sclerosis remains uncertain. To detect in vivo structural differences between the two disorders, diffusion tensor imaging of white matter tracts was carried out in 19 patients with primary lateral sclerosis, 18 patients with amyotrophic lateral sclerosis and 19 age-matched controls. Fibre tracking was used to reconstruct the intracranial portion of the corticospinal tract and three regions of the corpus callosum: the genu, splenium and callosal fibres connecting the motor cortices. Both patient groups had reduced fractional anisotropy, a measure associated with axonal organization, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibres compared with controls, without changes in the genu or splenium. Voxelwise comparison of the whole brain white matter using tract-based spatial statistics confirmed the differences between patients and controls in the diffusion properties of the corticospinal tracts and motor fibres of the callosum. This analysis further revealed differences in the regional distribution of white matter alterations between the patient groups. In patients with amyotrophic lateral sclerosis, the greatest reduction in fractional anisotropy occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In patients with primary lateral sclerosis, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in fractional anisotropy in the corticospinal tract in patients with amyotrophic lateral sclerosis and increased mean diffusivity and volume loss of the corticospinal tract in patients with primary lateral sclerosis. Changes in the diffusion properties of the motor fibres of the corpus callosum were strongly correlated with changes in corticospinal fibres in patients, but not in controls. These findings indicate that degeneration is not selective for corticospinal neurons, but affects callosal neurons within the motor cortex in motor neuron disorders. C1 [Iwata, Nobue K.; Kwan, Justin Y.; Danielian, Laura E.; Floeter, Mary Kay] NINDS, EMG Sect, NIH, Bethesda, MD 20892 USA. [Iwata, Nobue K.] Int Univ Hlth & Welf, Mita Hosp, Dept Neurol, Tokyo, Japan. [Butman, John A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Tovar-Moll, Fernanda] DOr Inst Res & Educ IDOR, Rio De Janeiro, Brazil. [Tovar-Moll, Fernanda] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil. [Bayat, Elham] George Washington Univ, Dept Neurol, ALS Clin, Washington, DC 20037 USA. RP Floeter, MK (reprint author), NINDS, EMG Sect, NIH, 10 Ctr Dr,Bldg 10,Room 7-5680, Bethesda, MD 20892 USA. EM floeterm@ninds.nih.gov RI Neurociencia, Inct/I-1011-2013; Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU National Institute of Neurological Disorders and Stroke [NS 002976]; National Institutes of Health [ZO1 NS002976] FX Intramural Research Program of the National Institute of Neurological Disorders and Stroke (#NS 002976), National Institutes of Health (ZO1 NS002976). NR 61 TC 46 Z9 47 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD SEP PY 2011 VL 134 BP 2642 EP 2655 DI 10.1093/brain/awr178 PN 9 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 821FH UT WOS:000294959800020 PM 21798965 ER PT J AU Ong, HL Ambudkar, IS AF Ong, Hwei Ling Ambudkar, Indu S. TI The dynamic complexity of the TRPC1 channelosome SO CHANNELS LA English DT Review DE TRPC1; Orai1; STIM1; SOCE; lipid rafts; microdomains ID OPERATED CA2+ ENTRY; RECEPTOR POTENTIAL CHANNEL-1; PLASMA-MEMBRANE LOCALIZATION; LIPID RAFTS; CALCIUM INFLUX; ENDOPLASMIC-RETICULUM; CRAC CHANNELS; ENDOTHELIAL PERMEABILITY; SIGNALING COMPLEXES; SECRETORY-CELLS AB A rise in cytoplasmic [Ca(2+)] due to store-operated Ca(2+) entry (SOCE) triggers a plethora of responses, both acute and long term. This leads to the important question of how this initial signal is decoded to regulate specific cellular functions. It is now clearly established that local [Ca(2+)] at the site of SOCE can vary significantly from the global [Ca(2+)] in the cytosol. The assembly of key Ca(2+) signaling proteins within the domains generates such Ca(2+) microdomains. For example, GPCR, IP(3) receptors, TRPC3 channels, the plasma membrane Ca(2+) pump and the endoplasmic reticulum (ER) Ca(2+) pump have all been found to be assembled in a complex and all of them contribute to the Ca(2+) signal. Recent studies have revealed that two other critical components of SOCE, STIM1 and Orai1, are also recruited to these regions. Thus, the entire machinery for activation and regulation of SOCE is compartmentalized in specific cellular domains, which facilitates the specificity and rate of protein-protein interactions that are required for activation of the channels. In the case of TRPC1-SOC channels, it appears that specific lipid domains, lipid raft domains (LRDs), in the plasma membrane, as well as cholesterol-binding scaffolding proteins such as caveolin-1 (Cav-1), are involved in assembly of the TRPC channel complexes. Thus, plasma membrane proteins and lipid domains as well as ER proteins contribute to the SOCE-Ca(2+) signaling microdomain and modulation of the Ca(2+) signals per se. Of further interest is that modulation of Ca(2+) signals, i.e., amplitude and/or frequency, can result in regulation of specific cellular functions. The emerging data reveal a dynamic Ca(2+) signaling complex composed of TRPC1/Orai1/STIM1 that is physiologically consistent with the dynamic nature of the Ca(2+) signal that is generated. This review will focus on the recent studies, which demonstrate critical aspects of the TRPC1 channelosome that are involved in the regulation of TRPC1 function and TRPC1-SOC-generated Ca(2+) signals. C1 [Ong, Hwei Ling; Ambudkar, Indu S.] Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Ambudkar, IS (reprint author), Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. EM indu.ambudkar@nih.gov NR 100 TC 34 Z9 36 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6950 J9 CHANNELS JI Channels PD SEP-OCT PY 2011 VL 5 IS 5 BP 422 EP 429 DI 10.4161/chan.5.5.16471 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 822XI UT WOS:000295083500006 PM 21747233 ER PT J AU Malhotra, SV AF Malhotra, Sanjay V. TI Hot Topic: Small Molecule Drug Agents SO CURRENT MEDICINAL CHEMISTRY LA English DT Editorial Material C1 NCI, Lab Synthet Chem, SAIC Inc, Frederick, MD 21702 USA. RP Malhotra, SV (reprint author), NCI, Lab Synthet Chem, SAIC Inc, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD SEP PY 2011 VL 18 IS 25 BP 3757 EP 3757 PG 1 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 820KB UT WOS:000294903300001 PM 21824103 ER PT J AU Kumar, A Kumar, V Alegria, AE Malhotra, SV AF Kumar, A. Kumar, V. Alegria, A. E. Malhotra, S. V. TI Synthetic and Application Perspectives of Azapodophyllotoxins: Alternative Scaffolds of Podophyllotoxin SO CURRENT MEDICINAL CHEMISTRY LA English DT Review DE Antineoplastic; azapodophyllotoxin; podophyllotoxin ID ASSISTED MULTICOMPONENT REACTIONS; ONE-POT SYNTHESIS; VASCULAR-DISRUPTING AGENTS; ANTITUMOR-ACTIVITY; 4-AZA-PODOPHYLLOTOXIN DERIVATIVES; MICROWAVE IRRADIATION; EFFICIENT SYNTHESIS; NATURAL-PRODUCTS; ANALOGS; DRUGS AB Podophyllotoxin (1) has been known to possess anti-tumor activity and is still considered an important lead for research and development of antineoplastic agents. Derivatives of podophyllotoxin, namely etoposide (2), etopophos (3) and teniposide (4) have been developed and are currently used in clinic for the treatment of a variety of malignancies. These agents are also used in combination therapies with other drugs. Due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in clinic, the search for new effective anticancer analogues of podophyllotoxin remains an intense area of research. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. These issues provide strong impetus to a search for analogues of 1 with simplified structures, which can be accessible via short synthetic sequences from simple starting materials. Even if such initial compounds might have diminished cytotoxic potencies compared with the parent cyclolignan, the ease of preparation of carefully designed libraries of analogues would lead to more informative SAR studies and expeditious structure optimization. In this regard, during the last two decades considerable efforts have been made to synthesize aza-analogs of podophyllotoxin, i.e. aza-podophyllotoxins, with hetero atoms at different positions of the podophyllotoxin skeleton, while keeping the basic podophyllotoxin structure. Recently, there have been significant efforts towards the convenient synthesis of aza-analogs of 1. The use of multicomponent reactions (MCRs) and the synergies of ultrasound and microwave irradiations have increased the synthetic speed and variety of azapodophyllotoxins which are and will be available to be tested against a diverse population of carcinomas and other diseases. It has been reported that several aza-podophyllotoxins retain a great fraction of the cytotoxicity associated with the parent lignan. This review focuses on the strategies towards synthesis of various aza-podophyllotoxin analogues and their biological activities. C1 [Kumar, V.; Malhotra, S. V.] NCI, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21719 USA. [Kumar, A.; Alegria, A. E.] Univ Puerto Rico, Dept Chem, Humacao, PR 00791 USA. RP Malhotra, SV (reprint author), NCI, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21719 USA. EM antonio.alegria1@upr.edu; malhotrasa@mail.nih.gov FU National Cancer Institute [HSN261200800001E]; National Institute of General Medical Sciences [S06-GM008216]; National Center for Research Resources (National Institutes of Health) [P20 RR016470] FX The authors are grateful to the NCI Developmental Therapeutics Program for the 60-cell line screening of the azapodophyllotoxin derivatives described in this paper, and for the support of this research from the National Cancer Institute, under contract number HSN261200800001E; the National Institute of General Medical Sciences, under grant number S06-GM008216; and the National Center for Research Resources, under grant number P20 RR016470 (from the National Institutes of Health). 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 42 TC 15 Z9 15 U1 1 U2 33 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD SEP PY 2011 VL 18 IS 25 BP 3853 EP 3870 PG 18 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 820KB UT WOS:000294903300004 PM 21824101 ER PT J AU Thurman, DJ Beghi, E Begley, CE Berg, AT Buchhalter, JR Ding, D Hesdorffer, DC Hauser, WA Kazis, L Kobau, R Kroner, B Labiner, D Liow, K Logroscino, G Medina, MT Newton, CR Parko, K Paschal, A Preux, PM Sander, JW Selassie, A Theodore, W Tomson, T Wiebe, S AF Thurman, David J. Beghi, Ettore Begley, Charles E. Berg, Anne T. Buchhalter, Jeffrey R. Ding, Ding Hesdorffer, Dale C. Hauser, W. Allen Kazis, Lewis Kobau, Rosemarie Kroner, Barbara Labiner, David Liow, Kore Logroscino, Giancarlo Medina, Marco T. Newton, Charles R. Parko, Karen Paschal, Angelia Preux, Pierre-Marie Sander, Josemir W. Selassie, Anbesaw Theodore, William Tomson, Torbjorn Wiebe, Samuel CA ILAE Commission Epidemiology TI Standards for epidemiologic studies and surveillance of epilepsy SO EPILEPSIA LA English DT Article DE Epidemiology; Surveillance; Epilepsy ID QUALITY-OF-LIFE; SEIZURE SEVERITY SCALE; INCIDENT UNPROVOKED SEIZURES; ACTIVE CONVULSIVE EPILEPSY; ACUTE SYMPTOMATIC SEIZURE; SUDDEN UNEXPECTED DEATH; POPULATION-BASED COHORT; HEALTH INTERVIEW SURVEY; ILLNESS RATING-SCALE; WELL-BEING MEASURES AB Worldwide, about 65 million people are estimated to have epilepsy. Epidemiologic studies are necessary to define the full public health burden of epilepsy; to set public health and health care priorities; to provide information needed for prevention, early detection, and treatment; to identify education and service needs; and to promote effective health care and support programs for people with epilepsy. However, different definitions and epidemiologic methods complicate the tasks of these studies and their interpretations and comparisons. The purpose of this document is to promote consistency in definitions and methods in an effort to enhance future population-based epidemiologic studies, facilitate comparison between populations, and encourage the collection of data useful for the promotion of public health. We discuss: (1) conceptual and operational definitions of epilepsy, (2) data resources and recommended data elements, and (3) methods and analyses appropriate for epidemiologic studies or the surveillance of epilepsy. Variations in these are considered, taking into account differing resource availability and needs among countries and differing purposes among studies. C1 [Thurman, David J.] CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Beghi, Ettore] Mario Negri Inst Pharmacol Res, Lab Neurol Disorders, Milan, Italy. [Begley, Charles E.] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Dept Management & Policy Sci, Houston, TX USA. [Begley, Charles E.] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Hlth Serv Res, Houston, TX USA. [Berg, Anne T.] No Illinois Univ, Dept Biol, De Kalb, IL 60115 USA. [Berg, Anne T.] Chicago NW Childrens Mem Hosp, Epilepsy Ctr, Chicago, IL USA. [Buchhalter, Jeffrey R.] Mayo Clin, Dept Child & Adolescent Neurol, Scottsdale, AZ USA. [Ding, Ding] Fudan Univ, Inst Neurol, Dept Biostat & Epidemiol, Shanghai 200433, Peoples R China. [Hesdorffer, Dale C.; Hauser, W. Allen] Columbia Univ, Dept Epidemiol, New York, NY USA. [Hesdorffer, Dale C.; Hauser, W. Allen] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA. [Hauser, W. Allen] Columbia Univ, Dept Neurol, New York, NY USA. [Kazis, Lewis] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Kroner, Barbara] RTI Int, Rockville, MD USA. [Labiner, David] Univ Arizona, Dept Neurol, Tucson, AZ USA. [Liow, Kore] Univ Hawaii, John A Burns Sch Med, Dept Internal Med Neurol, Honolulu, HI 96822 USA. [Logroscino, Giancarlo] Univ Bari, Dept Neurol, Bari, Italy. [Medina, Marco T.] Natl Autonomous Univ Honduras, Fac Med Sci, Tegucigalpa, Honduras. [Newton, Charles R.] Kenya Govt Med Res Ctr, Wellcome Trust Collaborat Programme, Kilifi, Kenya. [Newton, Charles R.] UCL, Inst Child Hlth, London, England. [Parko, Karen] UCSF Sch Med, Dept Neurol, San Francisco, CA USA. [Paschal, Angelia] Mississippi Univ Women, Dept Hlth & Kinesiol, Columbus, MS USA. [Preux, Pierre-Marie] Univ Limoges, Inst Neuroepidemiol & Trop Neurol & Trop & Compar, Limoges, France. [Sander, Josemir W.] UCL Inst Neurol, London WC1N 3BG, England. [Sander, Josemir W.] Netherlands Fdn, SEIN Epilepsy Inst, Heemstede, Netherlands. [Selassie, Anbesaw] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Theodore, William] NIH, Clin Epilepsy Sect, Bethesda, MD 20892 USA. [Tomson, Torbjorn] Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden. [Wiebe, Samuel] Univ Calgary, Dept Clin Neurol Sci, Calgary, AB, Canada. [Wiebe, Samuel] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada. RP Thurman, DJ (reprint author), CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Highway NE,Mailstop K51, Atlanta, GA 30333 USA. EM dxt9@cdc.gov RI Sander, Josemir/C-1576-2008; PREUX, Pierre-Marie/B-8393-2014; LOGROSCINO, GIANCARLO/K-5148-2016; OI Sander, Josemir/0000-0001-6041-9661; PREUX, Pierre-Marie/0000-0002-2171-2977; LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Kazis, Lewis/0000-0003-1800-5849; Newton, Charles/0000-0002-6999-5507 FU Kedrion Pharma Company; Eisai; Sanofi-Aventis; UCB Pharma; GlaxoSmithKline; UCB; Dow Agro Science; Ovation Pharmaceuticals; Pfizer; General Electric; Amgen Inc.; Genzyme; Eli Lilly and Company; Bristol Meyers Squibb; Boerhringer-Ingelheim; Astra Zeneca; Cyberonics; Esai; Ortho McNeil; Janssen-Gilag; Novartis FX The authors declare the following associations as potential conflicts of interest: David J. Thurman - None; Ettore Beghi - Honoraria/research grants from Kedrion Pharma Company, Eisai, Sanofi-Aventis, UCB Pharma, GlaxoSmithKline; Charles E. Begley - None; Anne T. Berg - Travel funding/honoraria/consulting fees from Eisai, UCB, Dow Agro Science; Jeffrey R. Buchhalter - Research grants from Ovation Pharmaceuticals, Pfizer; Ding Ding - None; Dale C. Hesdorffer - Honoraria/travel funds/stock Pfizer, GlaxoSmithKline, General Electric; W. Allen Hauser - Consultant Neuropace; Lewis Kazis - Research grants Amgen Inc., Genzyme, Eli Lilly and Company, Bristol Meyers Squibb, Sanofi-Aventis, Boerhringer-Ingelheim, and Astra Zeneca; Rosemarie Kobau - None; Barbara Kroner - None; David Labiner - Consultant/Speaker/Research grants from Cyberonics, Esai and Ortho McNeil; Kore Liow - Honoraria from UCB Pharma; Giancarlo Logroscino - None; Marco T. Medina - None; Charles R. Newton - None; Karen Parko - None; Angelia Paschal - None; Pierre-Marie Preux - None; Josemir W. Sander - Honoraria/grants/travel grants from UCB, Janssen-Gilag, Eisai, and GlaxoSmithKline; Anbesaw Selassie - None; William Theodore - Honoraria/stock Elseveir, General Electric; Torbjorn Tomson - Research grants/honoraria from Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB Pharma; Samuel Wiebe None. NR 195 TC 215 Z9 220 U1 9 U2 47 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD SEP PY 2011 VL 52 SU 7 SI SI BP 2 EP 26 DI 10.1111/j.1528-1167.2011.03121.x PG 25 WC Clinical Neurology SC Neurosciences & Neurology GA 821JO UT WOS:000294971500002 PM 21899536 ER PT J AU Gaillard, WD Cross, JH Duncan, JS Stefan, H Theodore, WH AF Gaillard, William D. Cross, J. Helen Duncan, John S. Stefan, Hermann Theodore, William H. CA Commission Diagnostics TI Epilepsy imaging study guideline criteria: Commentary on diagnostic testing study guidelines and practice parameters SO EPILEPSIA LA English DT Article DE Epilepsy; Imaging; Guidelines ID TEMPORAL-LOBE EPILEPSY; POSITRON EMISSION TOMOGRAPHY; REFRACTORY FOCAL EPILEPSY; HIPPOCAMPAL SCLEROSIS; CORTICAL DYSPLASIAS; SEIZURES; CLASSIFICATION; CHILDREN; TERMINOLOGY; COMMISSION AB Recognition of limited economic resources, as well as potential adverse effects of "over testing," has increased interest in "evidence-based" assessment of new medical technology. This creates a particular problem for evaluation and treatment of epilepsy, which are increasingly dependent on advanced imaging and electrophysiology, since there is a marked paucity of epilepsy diagnostic and prognostic studies that meet rigorous standards for evidence classification. The lack of high quality data reflects fundamental weaknesses in many imaging studies but also limitations in the assumptions underlying evidence classification schemes as they relate to epilepsy, and to the practicalities of conducting adequately powered studies of rapidly evolving technologies. We review the limitations of current guidelines and propose elements for imaging studies that can contribute meaningfully to the epilepsy literature. C1 [Gaillard, William D.] George Washington Univ, Childrens Natl Med Ctr, Dept Neurosci, Ctr Neurosci, Washington, DC 20010 USA. [Gaillard, William D.; Theodore, William H.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Cross, J. Helen] UCL, Inst Child Hlth, Neurosci Unit, London, England. [Cross, J. Helen] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Duncan, John S.] UCL, Inst Neurol, Dept Clin & Expt Epilepsy, London, England. [Stefan, Hermann] Univ Hosp Erlangen, Epilepsy Ctr, Neurol Clin, Erlangen, Germany. RP Gaillard, WD (reprint author), George Washington Univ, Childrens Natl Med Ctr, Dept Neurosci, Ctr Neurosci, 111 Michigan Ave NW, Washington, DC 20010 USA. EM wgaillar@cnmc.org FU Lundbeck Inc.; King Pharmaceuticals; PRA International, Eisai Inc.; Marinus Pharmaceuticals, Inc.; NIH [NINDS] [1R01NS44280-01]; NIH NICHD [1P30HD40677-01]; NCRR [1K12RR17613-01]; NIMH [1 R01 MH065395-01A2]; CDC-APTR [R-03] FX William D Gaillard has served on an educational course supported by Lundbeck Inc. His department derives clinical income from the evaluation and management of children with epilepsy, and receives research support from Lundbeck Inc., King Pharmaceuticals, PRA International, Eisai Inc., and Marinus Pharmaceuticals, Inc. He is supported by federal funding from the NIH [NINDS 1R01NS44280-01 (PI) and NICHD 1P30HD40677-01 (IDDRC, core director), NCRR 1K12RR17613-01 (mentor), NIMH 1 R01 MH065395-01A2 (Co-I), and CDC-APTR R-03 (Paid consultant)]. NR 31 TC 23 Z9 24 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD SEP PY 2011 VL 52 IS 9 BP 1750 EP 1756 DI 10.1111/j.1528-1167.2011.03155.x PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 821KK UT WOS:000294973700030 PM 21740417 ER PT J AU Joo, J Yu, C Yan, M Chen, F Chen, W Yang, A Coleman, WG AF Joo, J. Yu, C. Yan, M. Chen, F. Chen, W. Yang, A. Coleman, W. G., Jr. TI H. PYLORI INFECTION INDUCES A VITAMIN D IMMUNE RESPONSE SO HELICOBACTER LA English DT Meeting Abstract CT 24th International Workshop on Helicobacter and Related Bacteria in Chronic Digestive Inflammation and Gastric Cancer CY SEP 11-13, 2011 CL Dublin, IRELAND C1 [Joo, J.; Yu, C.; Yan, M.; Chen, F.; Chen, W.; Yang, A.; Coleman, W. G., Jr.] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1083-4389 J9 HELICOBACTER JI Helicobacter PD SEP PY 2011 VL 16 SU 1 SI SI BP 81 EP 81 PG 1 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA 820ZF UT WOS:000294943900020 ER PT J AU Skupin, H Natanson, C Sun, J Reinhart, K Hartog, CS AF Skupin, H. Natanson, C. Sun, J. Reinhart, K. Hartog, C. S. TI Systematic analysis of hydroxyethyl starch (HES) reviews: proliferation of low quality reviews overwhelms the results of well-performed meta-analyses SO INFECTION LA English DT Meeting Abstract C1 [Skupin, H.; Reinhart, K.; Hartog, C. S.] Univ Hosp Jena, Dept Anesthesiol & Intens Care Med, Jena, Germany. [Natanson, C.; Sun, J.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0300-8126 J9 INFECTION JI Infection PD SEP PY 2011 VL 39 SU 2 BP S128 EP S129 PG 2 WC Infectious Diseases SC Infectious Diseases GA 820EQ UT WOS:000294888800083 ER PT J AU Ianuzzi, A Pickar, JG Khalsa, PS AF Ianuzzi, Allyson Pickar, Joel G. Khalsa, Partap S. TI RELATIONSHIPS BETWEEN JOINT MOTION AND FACET JOINT CAPSULE STRAIN DURING CAT AND HUMAN LUMBAR SPINAL MOTIONS SO JOURNAL OF MANIPULATIVE AND PHYSIOLOGICAL THERAPEUTICS LA English DT Article DE Feline; Biomechanics; Low Back Pain; Mechanical; Range of Motion; Zygapophyseal Joint; Facet Joint ID IN-VIVO; MANIPULATION; RESPONSES; BIOMECHANICS AB Objective: The lumbar facet joint capsule (FJC) is innervated with mechanically sensitive neurons and is thought to contribute to proprioception and pain. Biomechanical investigations of the FJC have commonly used human cadaveric spines, whereas combined biomechanical and neurophysiological studies have typically used nonhuman animal models. The purpose of this study was to develop mathematical relationships describing vertebral kinematics and FJC strain in cat and human lumbar spine specimens during physiological spinal motions to facilitate future efforts at understanding the mechanosensory role of the FJC. Methods: Cat lumbar spine specimens were tested during extension, flexion, and lateral bending. Joint kinematics and FJC principal strain were measured optically. Facet joint capsule strain-intervertebral angle (IVA) regression relationships were established for the 3 most caudal lumbar joints using cat (current study) and human (prior study) data. The FJC strain-IVA relationships were used to estimate cat and human spine kinematics that corresponded to published sensory neuron response thresholds (5% and 10% strain) for low-threshold mechanoreceptors. Results: Significant linear relationships between IVA and strain were observed for both human and cat during motions that produced tension in the FJCs (P < .01). During motions that produced tension in the FJCs, the models predicted that FJC strain magnitudes corresponding to published sensory neuron response thresholds would be produced by IVA magnitudes within the physiological range of lumbar motion. Conclusions: Data from the current study support the proprioceptive role of lumbar spine FJC and low-threshold mechanoreceptive afferents and can be used in interpreting combined neurophysiological and biomechanical studies of cat lumbar spines. (J Manipulative Physiol Ther 2011;34:420-431) C1 [Ianuzzi, Allyson; Khalsa, Partap S.] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Pickar, Joel G.] Palmer Coll Chiropract Res, Palmer Ctr Chiropract Res, Davenport, IA USA. [Khalsa, Partap S.] NIH, Div Extramural Res, NCCAM, Bethesda, MD 20892 USA. RP Ianuzzi, A (reprint author), 1302 Wrights Lane E, W Chester, PA 19380 USA. EM allyson_ianuzzi@yahoo.com FU National Institute of Health National Center for Complementary and Alternative Medicine [U19AT001701]; Ruth L. Kirschstein National Research Service Award [F31AT 002666] FX This study was supported by funds from the National Institute of Health National Center for Complementary and Alternative Medicine (U19AT001701) and Ruth L. Kirschstein National Research Service Award (F31AT 002666). No conflicts of interest were reported for this study. NR 34 TC 4 Z9 5 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-4754 J9 J MANIP PHYSIOL THER JI J. Manip. Physiol. Ther. PD SEP PY 2011 VL 34 IS 7 BP 420 EP 431 DI 10.1016/j.jmpt.2011.05.005 PG 12 WC Health Care Sciences & Services; Integrative & Complementary Medicine; Rehabilitation SC Health Care Sciences & Services; Integrative & Complementary Medicine; Rehabilitation GA 822GX UT WOS:000295033100001 PM 21875516 ER PT J AU Kobilo, T Liu, QR Gandhi, K Mughal, M Shaham, Y van Praag, H AF Kobilo, Tali Liu, Qing-Rong Gandhi, Kriti Mughal, Mohammed Shaham, Yavin van Praag, Henriette TI Running is the neurogenic and neurotrophic stimulus in environmental enrichment SO LEARNING & MEMORY LA English DT Article ID VOLUNTARY EXERCISE; DENTATE GYRUS; HIPPOCAMPAL NEUROGENESIS; CELL-PROLIFERATION; SPATIAL MEMORY; BRAIN; MICE; PLASTICITY; RATS; BDNF AB Environmental enrichment (EE) increases dentate gyrus (DG) neurogenesis and brain-derived neurotrophic factor ( BDNF) levels. However, running is considered an element of EE. To dissociate effects of physical activity and enrichment on hippocampal neurogenesis and BDNF levels, young female C57BI/6 mice were housed under control, running, enrichment, or enrichment plus running conditions, and injected with bromodeoxyuridine. Cell genesis was assessed after 12 d and differentiation was analyzed 1 mo later. In addition, locomotor activity in the open field and hippocampal mature BDNF peptide levels were measured. Open-field adaptation was improved in all groups, compared to controls, but more so with running. New cell proliferation, survival, neuron number, and neurotrophin levels were enhanced only when running was accessible. We conclude that exercise is the critical factor mediating increased BDNF levels and adult hippocampal neurogenesis. C1 [Kobilo, Tali; Gandhi, Kriti; van Praag, Henriette] NIA, Neuroplast & Behav Unit, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Liu, Qing-Rong; Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Mughal, Mohammed] NIA, Cellular & Mol Neurosci Sect, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RP van Praag, H (reprint author), NIA, Neuroplast & Behav Unit, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM vanpraagh@mail.nih.gov RI shaham, yavin/G-1306-2014; van Praag, Henriette/F-3939-2015; Liu, Qing-Rong/A-3059-2012 OI van Praag, Henriette/0000-0002-5727-434X; Liu, Qing-Rong/0000-0001-8477-6452 FU NIH of the National Institute on Aging (NIA); National Institute on Drug Abuse (NIDA), NIH FX This research was supported by the Intramural Research Program of the NIH of the National Institute on Aging (NIA) and National Institute on Drug Abuse (NIDA), NIH. We thank Linda R. Kitabayashi for expert assistance with preparation of the figures. We thank Mike Still for animal care and technical assistance. NR 30 TC 105 Z9 112 U1 3 U2 16 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1072-0502 J9 LEARN MEMORY JI Learn. Mem. PD SEP PY 2011 VL 18 IS 9 BP 605 EP 609 DI 10.1101/lm.2283011 PG 5 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 822WJ UT WOS:000295080700009 PM 21878528 ER PT J AU Saoulidis, S Simitsopoulou, M Dalakiouridou, M Walsh, TJ Wheat, LJ Papaioannidou, P Roilides, E AF Saoulidis, Stamatis Simitsopoulou, Maria Dalakiouridou, Maria Walsh, Thomas J. Wheat, L. Joseph Papaioannidou, Paraskevi Roilides, Emmanuel TI Antifungal activity of posaconazole and granulocyte colony-stimulating factor in the treatment of disseminated zygomycosis (mucormycosis) in a neutropaenic murine model SO MYCOSES LA English DT Article DE Murine zygomycosis; murine mucormycosis; cytokines; antifungal therapy; azoles; Rhizopus microsporus ID IN-VITRO ACTIVITIES; AMPHOTERICIN-B; DISSEMINATED INFECTION; ASPERGILLUS-FUMIGATUS; COMBINATION THERAPY; GAMMA-INTERFERON; AZOLE ANTIFUNGAL; SCH 56592; G-CSF; VORICONAZOLE AB The aim of this study was to evaluate the pharmacokinetics and efficacy of posaconazole (PSC) in combination with granulocyte colony-stimulating factor (G-CSF) in a neutropaenic murine model of disseminated zygomycosis (mucormycosis) due to Rhizopus microsporus. Male BALB/c mice were rendered neutropaenic with cyclophosphamide (200 mg kg(-1), intraperitoneally) administered on days -1 and +5 postinfection. Mice were infected with R. microsporus (5 x 10(4) spores ml(-1)) intravenously. Mice were treated with PSC (40 mg kg(-1) day(-1) by gavage) or G-CSF (300 mu g kg(-1) day(-1) subcutaneously) or with the combination of PSC and G-CSF. The fungal burden was assessed by culturing the brain, liver, kidneys and lungs. Blood levels of PSC were measured by high performance liquid chromatography. The survival rates were 33%, 27% and 31% for PSC-treated-. G-CSF-treated- and PSC + G-CSF-treated mice, respectively, as compared to 18% for the controls (P = NS). PSC monotherapy and combination therapy significantly reduced the fungal burden in the kidneys, but not in the rest of the organs. Combination therapy was not superior to PSC monotherapy in terms of either survival or reduction in fungal burden. Serum concentrations of PSC were well-above the MIC of PSC for the particular isolate. PSC monotherapy has a modest efficacy against R. microsporus in reducing fungal burden in neutropaenic mice. Combining G-CSF with PSC does not substantially affect the antifungal activity of PSC. C1 [Saoulidis, Stamatis; Simitsopoulou, Maria; Dalakiouridou, Maria; Roilides, Emmanuel] Hippokrateion Hosp, Dept Pediat 3, Infect Dis Lab, GR-54642 Thessaloniki, Greece. [Walsh, Thomas J.; Roilides, Emmanuel] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD USA. [Walsh, Thomas J.] Cornell Univ, Weill Cornell Med Coll, Transplantat Oncol Infect Dis Program, New York, NY 10021 USA. [Walsh, Thomas J.] New York Presbyterian Hosp, New York, NY USA. [Wheat, L. Joseph] MiraVista Diagnost, Indianapolis, IN USA. [Papaioannidou, Paraskevi] Aristotle Univ Thessaloniki, Dept Pharmacol, GR-54006 Thessaloniki, Greece. RP Roilides, E (reprint author), Hippokrateion Hosp, Dept Pediat 3, Infect Dis Lab, Konstantinoupoleos 49, GR-54642 Thessaloniki, Greece. EM roilides@med.auth.gr RI Papaioannidou, Paraskevi/D-9864-2011; OI Papaioannidou, Paraskevi/0000-0001-8880-0288 FU Schering and Plough FX This work was supported by Schering and Plough by grant of free posaconazole. NR 38 TC 7 Z9 8 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0933-7407 J9 MYCOSES JI Mycoses PD SEP PY 2011 VL 54 IS 5 BP E486 EP E492 DI 10.1111/j.1439-0507.2010.01958.x PG 7 WC Dermatology; Mycology SC Dermatology; Mycology GA 820AW UT WOS:000294878900123 PM 21039940 ER PT J AU Sacktor, N Miyahara, S Deng, L Evans, S Schifitto, G Cohen, BA Paul, R Robertson, K Jarocki, B Scarsi, K Coombs, RW Zink, MC Nath, A Smith, E Ellis, RJ Singer, E Weihe, J McCarthy, S Hosey, L Clifford, DB AF Sacktor, N. Miyahara, S. Deng, L. Evans, S. Schifitto, G. Cohen, B. A. Paul, R. Robertson, K. Jarocki, B. Scarsi, K. Coombs, R. W. Zink, M. C. Nath, A. Smith, E. Ellis, R. J. Singer, E. Weihe, J. McCarthy, S. Hosey, L. Clifford, D. B. CA ACTG A5235 Team TI Minocycline treatment for HIV-associated cognitive impairment Results from a randomized trial SO NEUROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; AIDS DEMENTIA COMPLEX; PHARMACOKINETIC PROPERTIES; ANTIRETROVIRAL THERAPY; MULTIPLE-SCLEROSIS; HOMOSEXUAL-MEN; NERVOUS-SYSTEM; DOUBLE-BLIND; DISEASE; INFECTION AB Objective: We conducted a study of minocycline to assess its safety, tolerability, and efficacy for the treatment of HIV-associated cognitive impairment. Methods: HIV-1-infected individuals with progressive neurocognitive decline were enrolled in a double-blind, placebo-controlled study of minocycline. Participants were randomized to receive minocycline 100 mg or matching placebo orally every 12 hours. The primary efficacy measure was change in a neuropsychological test composite z score (NPZ-8) from baseline to week 24. Measures of safety included the frequency of adverse events and changes over time in laboratory tests. After 50% of participants completed the double-blind phase, an interim analysis of futility for the primary outcome measure was performed, and our Data and Safety Monitoring Board recommended early study termination. Results: A total of 107 HIV-1-infected individuals with cognitive impairment were enrolled. The minocycline group did not show improvement in the primary outcome measure (NPZ-8) (mean 24-week change = 0.12) compared to placebo (mean 24-week change = 0.17) (95% confidence interval = [-0.26, 0.39], p = 0.70). There were few severe adverse events or laboratory abnormalities in either treatment group. Conclusion: Minocycline was safe and well-tolerated in individuals with HIV-associated cognitive impairment, but cognitive improvement was not observed. Classification of evidence. This interventional study provides Class II evidence for the safety, tolerability, and efficacy of minocycline for the treatment of HIV-associated cognitive impairment. Neurology (R) 2011;77:1135-1142 C1 [Sacktor, N.; Zink, M. C.; Nath, A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Miyahara, S.; Deng, L.; Evans, S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Schifitto, G.] Univ Rochester, Rochester, NY USA. [Cohen, B. A.; Scarsi, K.] Northwestern Univ, Chicago, IL 60611 USA. [Paul, R.] Univ Missouri, St Louis, MO 63121 USA. [Robertson, K.] Univ N Carolina, Chapel Hill, NC USA. [Jarocki, B.] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Coombs, R. W.] Univ Washington, Seattle, WA 98195 USA. [Smith, E.] NIAID, HIV Res Branch, DAIDS, NIH, Bethesda, MD 20892 USA. [Ellis, R. J.] Univ Calif San Diego, San Diego, CA 92103 USA. [Singer, E.] Univ Calif Los Angeles, Los Angeles, CA USA. [Miyahara, S.; Hosey, L.] AIDS Clin Trials Grp ACTG Operat Ctr, Silver Spring, MD USA. [Clifford, D. B.] Washington Univ, St Louis, MO USA. RP Sacktor, N (reprint author), Johns Hopkins Bayview Med Ctr, Dept Neurol, 4940 Eastern Ave,301 Bldg,Suite 2100, Baltimore, MD 21224 USA. EM sacktor@jhmi.edu RI Ellis, Ronald/K-3543-2015 OI Ellis, Ronald/0000-0003-4931-752X FU AIDS Clinical Trials Group (ACTG); NIAID [AI38858, AI38855, AI27670, AI27668, AI27658, AI34853, AI127660, AI27664, AI27659, AI25903, AI25915, AI046376, AI46370, AI46381, AI50410, AI25868, AI46386, CFAR AI 127757]; Neurologic AIDS Research Consortium [NS32228]; National Institute of Mental Health [MH71150, MH64409, AI 068634]; National Center for Research Resources (NCRR) [RR00052, RR00044, RR00046]; University of California, San Diego Antiviral Research [AI069432]; Johns Hopkins University [AI069465]; CTSA [UL1 RR025005]; UCLA School of Medicine [AI069424]; Washington University (St. Louis) [AI069495]; The Research & Education Group-Portland CRS [AI069503]; Henry Ford Hospital CRS [AI069503]; Massachusetts General Hospital [AI069472]; NYU/NYC HHC at Bellevue [AI069532]; University of Colorado Hospital [AI069450]; Northwestern University [AI069471]; Virginia Commonwealth University Medical Center CRS [AI069503]; University of Washington (Seattle) [AI069434]; University of North Carolina [AI069423]; University of Rochester Medical Center [AI069511]; Emory University; The Ponce de Leon Center [AI069452]; University of Pennsylvania, Philadelphia [AI069467-04]; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [N01-AI-05414]; National Institute of Allergy and Infectious Diseases [AI068636]; National Institute of Mental Health (NIMH); National Institute of Dental and Craniofacial Research (NIDCR); Neurologic AIDS Research Consortium; Statistical and Data Management Center of the Adult AIDS Clinical Trials Group; Oral HIV/AIDS Research Alliance; Biogen Idec; Bristol-Myers Squibb; EMD Serono, Inc.; Novartis; sanofi-aventis; GlaxoSmithKline; Abbott; Tibotec Therapeutics; NIH (NIAID and Fogarty International Center); Department of Health and Human Services; Ralph and Marion Falk; Society of Infectious Diseases Pharmacists; NIH (NIAID/DAIDS); NIH (NINDS, NIMH); Pfizer Inc; Millennium Pharmaceuticals, Inc.; Genentech Inc.; Schering-Plough Corp.; Bavarian Nordic; NeurogesX; Boehringer Ingelheim; Gilead Sciences, Inc. FX Supported in part by the AIDS Clinical Trials Group (ACTG) (full protocol available from the ACTG upon request) funded by: NIAID, AI38858, AI38855, AI27670, AI27668, AI27658, AI34853, AI127660, AI27664, AI27659, AI25903, AI25915, AI046376, AI46370, AI46381, AI50410, AI25868, AI46386, CFAR AI 127757, the Neurologic AIDS Research Consortium, NS32228, the National Institute of Mental Health, MH71150, MH64409, AI 068634, and GCRC Units funded by the National Center for Research Resources (NCRR), RR00052, RR00044, RR00046. The NCT number for this study is NCT 00361257. This study is registered in Clinical Trials.gov. Participating site ACTG Clinical Trials Unit (CTU) grant numbers include the following: University of California, San Diego Antiviral Research CTU Grant AI069432, Johns Hopkins University CTU Grant AI069465, CTSA Grant UL1 RR025005, UCLA School of Medicine CTU Grant AI069424, Washington University (St. Louis) CTU Grant AI069495, The Research & Education Group-Portland CRS CTU Grant AI069503, Henry Ford Hospital CRS CTU Grant AI069503, Massachusetts General Hospital CTU Grant AI069472, NYU/NYC HHC at Bellevue CTU Grant AI069532, University of Colorado Hospital CTU Grant AI069450, Northwestern University CTU Grant AI069471, Virginia Commonwealth University Medical Center CRS CTU Grant AI069503, University of Washington (Seattle) CTU Grant AI069434, University of North Carolina CTU Grant AI069423, University of Rochester Medical Center CTU Grant AI069511, Emory University, The Ponce de Leon Center CTU Grant AI069452, University of Pennsylvania, Philadelphia CTU Grant AI069467-04. Manufacture of the minocycline and matching placebo was funded with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract no. N01-AI-05414. The project described was supported by Award AI068636 from the National Institute of Allergy and Infectious Diseases, National Institute of Mental Health (NIMH), and National Institute of Dental and Craniofacial Research (NIDCR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.; Dr. Sacktor receives support from the NIH (NIMH, NINDS, NIA, NIDA, Fogerty Institute, NIAID). Dr. Miyahara receives support from the NIH (NINDS, NIAID). L. Deng is supported by grants for the Neurologic AIDS Research Consortium (NINDS, NIH), the Statistical and Data Management Center of the Adult AIDS Clinical Trials Group (NIAID, NIH), and the Oral HIV/AIDS Research Alliance (NIDCR, NIH). Dr. Evans serves on data monitoring committees/scientific advisory boards for the FDA, NIH (NIAID and NICHD), Massachusetts General Hospital, Boston University, HIV Neurobehavioral Research Center (University of California at San Diego), Pfizer Inc, Genentech, Inc., Roche, CIS Biotech, Inc., InterMune, FzioMed, Inc., Alcon, Millennium Pharmaceuticals, Inc., and Averion International Corp.; and receives research support from the NIH (NINDS, NIAID, NIAID, NIMH, and NIDCR). Dr. Schifitto served as a consultant for Pfizer, Novartis, and Tibotec Therapeutics; received funding for travel from Biogen Idec; and receives research support from NIH. Dr. Cohen served as a consultant for Acorda Therapeutics Inc., Genzyme Corporation, Novartis, Pfizer Inc, and Astellas Pharma Inc.; served on speakers' bureaus for Bayer Schering Pharma, EMD Serono, Inc., and Teva Pharmaceutical Industries Ltd.; and received research support from Biogen Idec, Bristol-Myers Squibb, EMD Serono, Inc., Novartis, sanofi-aventis, and the NIH (NINDS, NIAID). Dr. Paul receives research support from the NIH. Dr. Robertson serves on scientific advisory boards for and has received funding for travel or speaker honoraria from GlaxoSmithKline, Abbott, and Tibotec Therapeutics; and receives research support from the NIH (NIMH, NIAID, and NINDS). B. Jarocki reports no disclosures. Dr. Scarsi receives research and salary support from the NIH (NIAID and Fogarty International Center) and the Department of Health and Human Services; and receives research support from the Ralph and Marion Falk and the Society of Infectious Diseases Pharmacists. Dr. Coombs received an honorarium for serving as an adjudicator for a Merck-sponsored study; served on a scientific advisory board for Abbott; serves as a consultant for NexBio, Inc.; and receives research support from the NIH (NIAID/DAIDS). Dr. Zink serves on the editorial board of the Journal of Neurovirology; serves as a consultant for AkaRx, Inc.; and receives research support from the NIH. Dr. Nath serves on scientific advisory boards for Biogen Idec and DioGenix, Inc.; serves as an Associate Editor for the Journal of Neurovirology; may accrue revenue on patents re: Tat as an immunogen; Diosgenin for treatment of neurodegenerative diseases; Role of Kv channels in neuroregeneration and protection; Role of limonoid compounds as neuroprotective agents; and Tat ELISA; has served as a consultant for N DioGenix, Inc. and Elan Corporation; receives research support from the NIH (NINDS, NIMH); and has provided expert advice in medico-legal cases. Dr. Smith is employed by NIAID, NIH, and DHHS and has no other disclosure. Dr. Ellis has served on the speakers' bureaus for and received speaker honoraria from Abbott and GlaxoSmithKline; served on the editorial board of the Journal of Neuroimmune Pharmacology; has received research support from the NIH; and his spouse holds stock in Abbott. Dr. Singer has received funding for travel from Biogen Idec and Pfizer Inc; and receives research support from Pfizer Inc and the NIH (NIMH, NCI, NINDS, NIDA). Dr. Weihe, S. McCarthy, and L. Hosey report no disclosures. Dr.; Clifford serves/has served on scientific advisory boards forBiogen Idec, Elan Corporation, Roche, Forest Laboratories, Inc., Genentech, Inc., GlaxoSmithKline, Millennium Pharmaceuticals, Inc., Schering-Plough Corp., Bristol-Meyers Squibb, and Genzyme Corporation; received speaker honoraria and funding for travel from GlaxoSmithKline, Millennium Pharmaceuticals, Inc., and Genentech Inc.; has received research support from Pfizer Inc, Schering-Plough Corp., Bavarian Nordic, NeurogesX, GlaxoSmithKline, Tibotec Therapeutics, Boehringer Ingelheim, and Gilead Sciences, Inc.; and receives research support from the NIH (NIMH, NINDS, NIAID, and Fogarty Institutes). NR 40 TC 33 Z9 34 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP PY 2011 VL 77 IS 12 BP 1135 EP 1142 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 822EX UT WOS:000295027800010 PM 21900636 ER PT J AU Colloca, L Miller, FG AF Colloca, Luana Miller, Franklin G. TI The Nocebo Effect and Its Relevance for Clinical Practice SO PSYCHOSOMATIC MEDICINE LA English DT Article DE disclosure; expectation; ethics; side effects; framing information ID PLACEBO GROUPS; ERECTILE DYSFUNCTION; CONDITIONED NAUSEA; PATIENT OUTCOMES; ADVANCED CANCER; ADVERSE EVENTS; DOUBLE-BLIND; PAIN; TRIALS; EXPECTATIONS AB Negative expectations deriving from the clinical encounter can produce negative outcomes, known as nocebo effects. Specifically, research on the nocebo effect indicates that information disclosure about potential side effects can itself contribute to producing adverse effects. Neurobiological processes play a role in the nocebo effect, and this article provides a selective review of mechanistic research on the nocebo effect. Comparatively little attention has been directed to clinical studies and their implications for daily clinical practice. The nocebo response is influenced by the content and the way information is presented to patients in clinical trials in both the placebo and active treatment conditions. Nocebo effects adversely influence quality of life and therapy adherence, emphasizing the need for minimizing these responses to the extent possible. Evidence further indicates that the informed consent process in clinical trials may induce nocebo effects. This article concludes with ethical directions for future patient-oriented research and routine practice. C1 [Colloca, Luana; Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Colloca, Luana] NIH, Natl Ctr Complementary & Alternat Med, Ctr Clin, Bethesda, MD 20892 USA. RP Colloca, L (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM luana.colloca@nih.gov OI Colloca, Luana/0000-0002-6503-4709 FU Intramural NIH HHS [Z99 AT999999] NR 59 TC 82 Z9 84 U1 6 U2 40 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD SEP PY 2011 VL 73 IS 7 BP 598 EP 603 DI 10.1097/PSY.0b013e3182294a50 PG 6 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 823KX UT WOS:000295122300011 PM 21862825 ER PT J AU Hu, KN AF Hu, Kan-Nian TI Polarizing agents and mechanisms for high-field dynamic nuclear polarization of frozen dielectric solids SO SOLID STATE NUCLEAR MAGNETIC RESONANCE LA English DT Article DE Dynamic nuclear polarization; NMR signal enhancement; Cross Effect (CE); Thermal Mixing (TM); Biradical; Nitroxide; BDPA; Trityl; Cryogenic magic-angle-spinning (MAS); Millimeter waves; Cross polarization (CP); 2,2,6,6-Tetramethylpiperidin-1-ol (TEMPO); 1,3-bis(diphenylene)-2-phenylallyl (BDPA) ID C-13 NMR-SPECTROSCOPY; LIQUID-STATE NMR; C-13-C-13 CORRELATION SPECTROSCOPY; POLYSTYRENE HETEROGENEOUS BLENDS; MAGNETIC-RESONANCE-SPECTROSCOPY; OVERHAUSER-ENHANCED MRI; CW GYROTRON OSCILLATOR; LOCAL WATER DYNAMICS; AQUEOUS-SOLUTION; SIGNAL ENHANCEMENT AB This article provides an overview of polarizing mechanisms involved in high-frequency dynamic nuclear polarization (DNP) of frozen biological samples at temperatures maintained using liquid nitrogen, compatible with contemporary magic-angle spinning (MAS) nuclear magnetic resonance (NMR). Typical DNP experiments require unpaired electrons that are usually exogenous in samples via paramagnetic doping with polarizing agents. Thus, the resulting nuclear polarization mechanism depends on the electron and nuclear spin interactions induced by the paramagnetic species. The Overhauser Effect (OE) DNP, which relies on time-dependent spin-spin interactions, is excluded from our discussion due the lack of conducting electrons in frozen aqueous solutions containing biological entities. DNP of particular interest to us relies primarily on time-independent, spin-spin interactions for significant electron-nucleus polarization transfer through mechanisms such as the Solid Effect (SE), the Cross Effect (CE) or Thermal Mixing (TM), involving one, two or multiple electron spins, respectively. Derived from monomeric radicals initially used in high-field DNP experiments, bi- or multiple-radical polarizing agents facilitate CE/TM to generate significant NMR signal enhancements in dielectric solids at low temperatures (< 100 K). For example, large DNP enhancements (similar to 300 times at 5 T) from a biologically compatible biradical, 1-(TEMPO-4-oxy)-3-(TEMPO-4-amino)propan-2-ol (TOTAPOL), have enabled high-resolution MAS NMR in sample systems existing in submicron domains or embedded in larger biomolecular complexes. The scope of this review is focused on recently developed DNP polarizing agents for high-field applications and leads up to future developments per the CE DNP mechanism. Because DNP experiments are feasible with a solid-state microwave source when performed at <20 K, nuclear polarization using lower microwave power (<100 mW) is possible by forcing a high proportion of biradicals to fulfill the frequency matching condition of CE (two EPR frequencies separated by the NMR frequency) using the strategies involving hetero-radical moieties and/or molecular alignment. In addition, the combination of an excited triplet and a stable radical might provide alternative DNP mechanisms without the microwave requirement. Published by Elsevier Inc. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hu, KN (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM knhu@alum.mit.edu FU National Institute of Diabetes, Digestive and Kidney Diseases FX The author thanks Prof. Griffin for guidance and support in acquiring extensive experience with DNP experiments. The author is also thankful for the collaborations and intellectual exchanges on DNP projects with colleagues in the Francis Bitter Magnet Laboratory at the Massachusetts Institute of Technology. He appreciates the opportunity to participate in the 9 T/20 K DNP projects in Dr. Robert Tycko's laboratory at NIH. This work was supported by a postdoctoral fellowship in the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases. NR 151 TC 32 Z9 32 U1 9 U2 79 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0926-2040 J9 SOLID STATE NUCL MAG JI Solid State Nucl. Magn. Reson. PD SEP PY 2011 VL 40 IS 2 BP 31 EP 41 DI 10.1016/j.ssnmr.2011.08.001 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical; Physics, Condensed Matter; Spectroscopy SC Chemistry; Physics; Spectroscopy GA 822CG UT WOS:000295020700001 PM 21855299 ER PT J AU Ghoreschi, K Laurence, A Yang, XP Hirahara, K O'Shea, JJ AF Ghoreschi, Kamran Laurence, Arian Yang, Xiang-Ping Hirahara, Kiyoshi O'Shea, John J. TI T helper 17 cell heterogeneity and pathogenicity in autoimmune disease SO TRENDS IN IMMUNOLOGY LA English DT Review ID GROWTH-FACTOR-BETA; ROR-GAMMA-T; GENOME-WIDE ASSOCIATION; HUMAN TH17 CELLS; CENTRAL-NERVOUS-SYSTEM; HYPER-IGE SYNDROME; TGF-BETA; T(H)17 CELLS; IN-VIVO; T-H-17 CELLS AB T helper (Th)17 cells have been proposed to represent a new CD4(+) T cell lineage that is important for host defense against fungi and extracellular bacteria, and the development of autoimmune diseases. Precisely how these cells arise has been the subject of some debate, with apparent species-specific differences in mice and humans. Here, we describe evolving views of Th17 specification, highlighting the contribution of transforming growth factor-beta and the opposing roles of signal transducer and activator of transcription (STAT)3 and STAT5. Increasing evidence points to heterogeneity and inherent phenotypic instability in this subset. Ideally, better understanding of expression and action of key transcription factors and the epigenetic landscape of Th17 can help explain the flexibility and diversity of interleukin-17-producing cells. C1 [Ghoreschi, Kamran; Laurence, Arian; Yang, Xiang-Ping; Hirahara, Kiyoshi; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov RI Laurence, Arian/A-8770-2009; Hirahara, Kiyoshi/E-2460-2017 OI Laurence, Arian/0000-0003-0942-8292; Hirahara, Kiyoshi/0000-0002-9128-9449 FU Intramural NIH HHS [Z99 AR999999] NR 107 TC 88 Z9 93 U1 0 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD SEP PY 2011 VL 32 IS 9 BP 395 EP 401 DI 10.1016/j.it.2011.06.007 PG 7 WC Immunology SC Immunology GA 820XT UT WOS:000294940100001 PM 21782512 ER PT J AU Donnelly, RP Dickensheets, H O'Brien, TR AF Donnelly, Raymond P. Dickensheets, Harold O'Brien, Thomas R. TI Interferon-lambda and therapy for chronic hepatitis C virus infection SO TRENDS IN IMMUNOLOGY LA English DT Review ID REGULATORY FACTOR FAMILY; IFN-LAMBDA; GENETIC-VARIATION; DENDRITIC CELLS; DIFFERENTIAL EXPRESSION; ANTIVIRAL RESPONSES; VIRAL-INFECTION; INTERLEUKIN 28B; III IFN; NON-A AB Interferon (IFN)-alpha, a type-I IFN, is widely used to treat chronic hepatitis C virus infection, but the broad expression of IFN-alpha receptors often leads to adverse reactions in many organs. Here, we examine IFN-lambda, a type-III IFN, as a therapeutic alternative to IFN-alpha. Like IFN-alpha, IFN-lambda also induces antiviral activity in hepatocytes, but might induce fewer adverse reactions because its receptor is largely restricted to cells of epithelial origin. We also discuss the recent discovery of single nucleotide polymorphisms (SNPs) near the human IFN-lambda 3 gene, IL28B, that correlate strongly with the ability to achieve a sustained virological response to therapy with pegylated IFN-alpha plus ribavirin in patients with chronic hepatitis C. C1 [Donnelly, Raymond P.; Dickensheets, Harold] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [O'Brien, Thomas R.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Donnelly, RP (reprint author), US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. EM Raymond.Donnelly@fda.hhs.gov FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. 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 64 TC 37 Z9 39 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD SEP PY 2011 VL 32 IS 9 BP 443 EP 450 DI 10.1016/j.it.2011.07.002 PG 8 WC Immunology SC Immunology GA 820XT UT WOS:000294940100007 PM 21820962 ER PT J AU Westbroek, W Gustafson, AM Sidransky, E AF Westbroek, Wendy Gustafson, Ann Marie Sidransky, Ellen TI Exploring the link between glucocerebrosidase mutations and parkinsonism SO TRENDS IN MOLECULAR MEDICINE LA English DT Review ID CHAPERONE-MEDIATED AUTOPHAGY; LEWY BODY DISORDERS; NEURONOPATHIC GAUCHER-DISEASE; SAPOSIN C DEFICIENCY; ALPHA-SYNUCLEIN; RISK-FACTOR; IN-VIVO; EARLY-ONSET; COMPLEX-I; GENE AB Clinical, genetic and pathological studies demonstrate that mutations in glucocerebrosidase (GBA), which encodes the lysosomal enzyme deficient in Gaucher disease (GD), are risk factors for Parkinson disease (PD) and related disorders. Some patients with GD and Gaucher carriers develop parkinsonism. Furthermore, subjects with PD have an increased frequency of GBA mutations. GBA-mutation carriers exhibit diverse parkinsonian phenotypes and have glucocerebrosidase-positive Lewy bodies. Although the mechanism for this association is unknown, we present several theories, including protein aggregation, prion transmission, lipid accumulation and impaired autophagy, mitophagy or trafficking. Each model has inherent limitations, and a second-hit mutation might be essential. Elucidation of the basis for this link will have important consequences for studying these diseases and should provide insights into lysosomal pathways and potential treatment strategies. C1 [Westbroek, Wendy; Gustafson, Ann Marie; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU National Human Genome Research Institute; National Institutes of Health FX We thank Dr Jim Gruschus and Dr Grisel Lopez for critically reading the manuscript. Dr Ehud Goldin designed Figure 3, and Darryl Leja assisted in drafting of the figures. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health. NR 89 TC 69 Z9 70 U1 1 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 J9 TRENDS MOL MED JI Trends Mol. Med PD SEP PY 2011 VL 17 IS 9 BP 485 EP 493 DI 10.1016/j.molmed.2011.05.003 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 820YC UT WOS:000294941000003 PM 21723784 ER PT J AU Singh, A Seavey, C Horvath, K Mohiuddin, M AF Singh, Avneesh Seavey, Caleb Horvath, Keith Mohiuddin, Muhammad TI Induced T regulatory (iTreg) cells suppress T and B cell immune responses SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint International Congress of the Cell-Transplant-Society(CTS)/International-Xenotransplantation-Associati on (IXA) CY OCT 23-26, 2011 CL Miami, FL SP Cell Transplant Soc, Int Xenotransplantat Assoc C1 [Singh, Avneesh; Seavey, Caleb; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP-OCT PY 2011 VL 18 IS 5 SI SI BP 271 EP 272 PG 3 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 823AJ UT WOS:000295092900013 ER PT J AU Azimzadeh, A Burdorf, L Singh, A Zhang, TS Rybak, E Kelishadi, S Stoddard, T Welty, E Avon, C Laaris, A Horvath, K Vanhove, B Ayares, D Mohiuddin, M Pierson, R AF Azimzadeh, Agnes Burdorf, Lars Singh, Avneesh Zhang, Tianshu Rybak, Elana Kelishadi, Sean Stoddard, Tiffany Welty, Emily Avon, Chris Laaris, Amal Horvath, Keith Vanhove, Bernard Ayares, David Mohiuddin, Muhammad Pierson, Richard, III TI Induction B-cell depletion, but not CD28/B7-directed costimulation blockade, prevents induced anti-non-Gal antibody responses after GalTKO.hCD46 cardiac xenotransplantation SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint International Congress of the Cell-Transplant-Society(CTS)/International-Xenotransplantation-Associati on (IXA) CY OCT 23-26, 2011 CL Miami, FL SP Cell Transplant Soc, Int Xenotransplantat Assoc C1 [Azimzadeh, Agnes; Burdorf, Lars; Zhang, Tianshu; Rybak, Elana; Kelishadi, Sean; Stoddard, Tiffany; Welty, Emily; Avon, Chris; Laaris, Amal; Pierson, Richard, III] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Singh, Avneesh; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, CSRP, NIH, Bethesda, MD 20892 USA. [Vanhove, Bernard] INSERM, U643, Nantes, France. [Ayares, David] Revivicor, Blacksburg, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP-OCT PY 2011 VL 18 IS 5 SI SI BP 281 EP 282 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 823AJ UT WOS:000295092900047 ER PT J AU Singh, A Corcoran, P Thomas, M Hoyt, R Ayares, D Horvath, K Mohiuddin, M AF Singh, Avneesh Corcoran, Philip Thomas, Marvin Hoyt, Robert Ayares, David Horvath, Keith Mohiuddin, Muhammad TI Long-term cardiac xenograft (pig to baboon) survival is correlated with presence of increased percentage of CD4+CD25HiFoxP3+T regulatory cells SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint International Congress of the Cell-Transplant-Society(CTS)/International-Xenotransplantation-Associati on (IXA) CY OCT 23-26, 2011 CL Miami, FL SP Cell Transplant Soc, Int Xenotransplantat Assoc C1 [Singh, Avneesh; Corcoran, Philip; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. [Hoyt, Robert] NHLBI, LAMS, Bethesda, MD 20892 USA. [Thomas, Marvin] ORS, DVR, NIH, Bethesda, MD USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP-OCT PY 2011 VL 18 IS 5 SI SI BP 281 EP 281 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 823AJ UT WOS:000295092900044 ER PT J AU Waldman, J Goding, L Rees, M AF Waldman, Joshua Goding, Linda Rees, Michael TI Nonhuman primates may fail to serve as an adequate model for studying extracorporeal porcine liver perfusion SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint International Congress of the Cell-Transplant-Society(CTS)/International-Xenotransplantation-Associati on (IXA) CY OCT 23-26, 2011 CL Miami, FL SP Cell Transplant Soc, Int Xenotransplantat Assoc C1 [Waldman, Joshua; Rees, Michael] Univ Toledo, Med Ctr, Toledo, MI USA. [Goding, Linda] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP-OCT PY 2011 VL 18 IS 5 SI SI BP 285 EP 285 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 823AJ UT WOS:000295092900057 ER PT J AU Mohiuddin, M Corcoran, P Singh, A Azimzadeh, A Hoyt, R Thomas, M Eckhaus, M Ayares, D Pierson, R Horvath, K AF Mohiuddin, Muhammad Corcoran, Philip Singh, Avneesh Azimzadeh, Agnes Hoyt, Robert Thomas, Marvin Eckhaus, Michael Ayares, David Pierson, Richard, III Horvath, Keith TI Rituxan and co stimulation blockade based immunosuppression effectively prevents pig cardiac xenograft rejection in baboon for up to 8 months SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint International Congress of the Cell-Transplant-Society(CTS)/International-Xenotransplantation-Associati on (IXA) CY OCT 23-26, 2011 CL Miami, FL SP Cell Transplant Soc, Int Xenotransplantat Assoc C1 [Mohiuddin, Muhammad; Corcoran, Philip; Singh, Avneesh; Horvath, Keith] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Hoyt, Robert] NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. [Thomas, Marvin; Eckhaus, Michael] ORS, DVR, NIH, Bethesda, MD USA. [Azimzadeh, Agnes; Pierson, Richard, III] Univ Maryland, Med Ctr, Dept Surg, Bethesda, MD USA. [Ayares, David] Revivicor Inc, Blacksburg, MD USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP-OCT PY 2011 VL 18 IS 5 SI SI BP 286 EP 287 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 823AJ UT WOS:000295092900063 ER PT J AU Mohiuddin, M Corcoran, P Singh, A Hoyt, R Thomas, M Eckhaus, M Ayares, D Horvath, K AF Mohiuddin, Muhammad Corcoran, Philip Singh, Avneesh Hoyt, Robert Thomas, Marvin Eckhaus, Michael Ayares, David Horvath, Keith TI Absence of thrombotic complication is a major advantage of murine anti CD40 over anti CD154 in heterotopic cardiac xenotransplantation studies SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint International Congress of the Cell-Transplant-Society(CTS)/International-Xenotransplantation-Associati on (IXA) CY OCT 23-26, 2011 CL Miami, FL SP Cell Transplant Soc, Int Xenotransplantat Assoc C1 [Hoyt, Robert] NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. [Thomas, Marvin; Eckhaus, Michael] ORS, DVR, NIH, Bethesda, MD USA. [Ayares, David] Revivicor Inc, Bethesda, MD USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP-OCT PY 2011 VL 18 IS 5 SI SI BP 294 EP 294 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 823AJ UT WOS:000295092900089 ER PT J AU Corcoran, P Horvath, K Singh, A Hoyt, R Keeran, K Zywicke, G Jeffries, K Zetts, A Mohiuddin, M AF Corcoran, Philip Horvath, Keith Singh, Avneesh Hoyt, Robert Keeran, Karen Zywicke, Gayle Jeffries, Kenneth Zetts, Arthur Mohiuddin, Muhammad TI Early graft function of heterotopic cardiac xenografts: Lessons learned from a large animal cardiac xenotransplantation program SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint International Congress of the Cell-Transplant-Society(CTS)/International-Xenotransplantation-Associati on (IXA) CY OCT 23-26, 2011 CL Miami, FL SP Cell Transplant Soc, Int Xenotransplantat Assoc C1 [Corcoran, Philip; Horvath, Keith; Singh, Avneesh; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Hoyt, Robert; Keeran, Karen; Zywicke, Gayle; Jeffries, Kenneth; Zetts, Arthur] NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP-OCT PY 2011 VL 18 IS 5 SI SI BP 297 EP 297 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 823AJ UT WOS:000295092900098 ER PT J AU Mohiuddin, M Singh, A Lewis, B Kozlov, S Thomas, M Hunt, T Clevenger, R Hoyt, R Corcoran, P Horvath, K AF Mohiuddin, Muhammad Singh, Avneesh Lewis, Billeta Kozlov, Shawn Thomas, Marvin Hunt, Timothy Clevenger, Randy Hoyt, Robert Corcoran, Philip Horvath, Keith TI Combined telemetry and video monitoring offers the most accurate assessment of transplanted xenograft function and recipient baboons health status SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint International Congress of the Cell-Transplant-Society(CTS)/International-Xenotransplantation-Associati on (IXA) CY OCT 23-26, 2011 CL Miami, FL SP Cell Transplant Soc, Int Xenotransplantat Assoc C1 [Mohiuddin, Muhammad; Singh, Avneesh; Corcoran, Philip; Horvath, Keith] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Thomas, Marvin] ORS, DVR, NIH, Bethesda, MD USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP-OCT PY 2011 VL 18 IS 5 SI SI BP 297 EP 297 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 823AJ UT WOS:000295092900099 ER PT J AU Mohiuddin, M Singh, A Lewis, B Corcoran, P Kozlov, S Thomas, M Hoyt, R Horvath, K AF Mohiuddin, Muhammad Singh, Avneesh Lewis, Billeta Corcoran, Philip Kozlov, Shawn Thomas, Marvin Hoyt, Robert Horvath, Keith TI Post operative management of heterotopic xenograft recipient baboons plays a significant role in survival of both the recipient and the cardiac xenografts SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint International Congress of the Cell-Transplant-Society(CTS)/International-Xenotransplantation-Associati on (IXA) CY OCT 23-26, 2011 CL Miami, FL SP Cell Transplant Soc, Int Xenotransplantat Assoc C1 [Mohiuddin, Muhammad; Singh, Avneesh; Corcoran, Philip; Horvath, Keith] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Kozlov, Shawn; Hoyt, Robert] NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. [Lewis, Billeta; Thomas, Marvin] NIH, DVR, ORS, Bethesda, MD 20892 USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP-OCT PY 2011 VL 18 IS 5 SI SI BP 303 EP 303 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 823AJ UT WOS:000295092900119 ER PT J AU Emaminia, A Singh, A Lewis, B Thomas, M Kozlov, S Corcoran, P Horvath, K Mohiuddin, M AF Emaminia, Abbas Singh, Avneesh Lewis, Billeta Thomas, Marvin Kozlov, Shawn Corcoran, Philip Horvath, Keith Mohiuddin, Muhammad TI Large-volume blood transfusion incurs superior hematologic outcome compared to multiple small-volume transfusion in recipients of cardiac xenotransplantation SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint International Congress of the Cell-Transplant-Society(CTS)/International-Xenotransplantation-Associati on (IXA) CY OCT 23-26, 2011 CL Miami, FL SP Cell Transplant Soc, Int Xenotransplantat Assoc C1 [Emaminia, Abbas; Singh, Avneesh; Corcoran, Philip; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Kozlov, Shawn] NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. [Lewis, Billeta; Thomas, Marvin] NIH, DVR, ORS, Bethesda, MD 20892 USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP-OCT PY 2011 VL 18 IS 5 SI SI BP 307 EP 308 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 823AJ UT WOS:000295092900133 ER PT J AU Castranova, D Lawton, A Lawrence, C Baumann, DP Best, J Coscolla, J Doherty, A Ramos, J Hakkesteeg, J Wang, CM Wilson, C Malley, J Weinstein, BM AF Castranova, Daniel Lawton, Angela Lawrence, Christian Baumann, Diana P. Best, Jason Coscolla, Jordi Doherty, Amy Ramos, Juan Hakkesteeg, Jenna Wang, Chongmin Wilson, Carole Malley, James Weinstein, Brant M. TI The Effect of Stocking Densities on Reproductive Performance in Laboratory Zebrafish (Danio rerio) SO ZEBRAFISH LA English DT Article ID SALVELINUS-ALPINUS; CROWDING STRESS; ARCTIC CHARR; GROWTH; JUVENILES AB Despite the growing popularity of the zebrafish model system, the optimal husbandry conditions for this animal are not well defined. The aim of this study was to examine the effect of stocking density on reproductive performance in zebrafish. In this study, undertaken by eight different zebrafish facilities, clutches of at least 200 wild-type zebrafish embryos from a single pairwise mating were produced at each participating institution and subsequently reared according to "in-house protocols'' until they were 14 weeks old. Fish were then randomly assigned into treatment groups with balanced sex ratios and densities of 3, 6, or 12 fish/L. After a 1-month acclimation period, fish were spawned in pair crosses every 2 weeks for 3 months, for a total of six spawning dates. The number of viable and nonviable embryos produced in each clutch were counted at 1 day post-fertilization. Although there was a great deal of variability in clutch size and percent spawning success among laboratories, there were no significant differences in average clutch size, spawning success, or percent viable among the treatment densities. These data suggest that using stocking densities as high as 12 fish/L does not have a negative impact on performance, when measured by reproductive performance. C1 [Castranova, Daniel; Wang, Chongmin; Weinstein, Brant M.] NICHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Lawton, Angela] Univ Queensland, Brisbane, Qld 4072, Australia. [Lawrence, Christian; Best, Jason] Childrens Hosp Boston, Boston, MA USA. [Baumann, Diana P.] Stowers Inst Med Res, Kansas City, MO USA. [Coscolla, Jordi; Ramos, Juan] Barcelona Biomed Res Pk, Barcelona, Spain. [Doherty, Amy] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hakkesteeg, Jenna; Wilson, Carole] UCL, London, England. [Malley, James] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHD, Program Genom Differentiat, NIH, Bldg 6B,Room 413,6 Ctr Dr, Bethesda, MD 20892 USA. EM castrand@mail.nih.gov; flyingfish2@nih.gov RI Zebrafish, UCL/A-3125-2009 NR 16 TC 11 Z9 11 U1 1 U2 17 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1545-8547 J9 ZEBRAFISH JI Zebrafish PD SEP PY 2011 VL 8 IS 3 BP 141 EP 146 DI 10.1089/zeb.2011.0688 PG 6 WC Developmental Biology; Zoology SC Developmental Biology; Zoology GA 822GL UT WOS:000295031900006 PM 21854208 ER PT J AU Mansour, AY Drummond, JL Evans, CA Bakhsh, Z AF Mansour, Ameerah Yousef Drummond, James L. Evans, Carla A. Bakhsh, Zuhair TI In vitro evaluation of self-etch bonding in orthodontics using cyclic fatigue Part I, Shear testing methods SO ANGLE ORTHODONTIST LA English DT Article DE Bond strength; Self-etch; Total-etch; Shear testing; Cyclic fatigue ID STAINLESS-STEEL; STRENGTH; ENAMEL; BRACKETS; DENTIN; ADHESION; SYSTEM; PRIMER; MODE AB Objective: To evaluate the bond strength of a self-etch bonding system using static loading and cyclic fatigue with shear testing. This is a two-part evaluation; the first part will evaluate shear testing, the second part tensile testing. Materials and Methods: Bovine teeth (n = 82) were randomly distributed to either a self-etch (Transbond Plus) or total-etch (37% phosphoric-acid + Transbond XT) group. The static shear (SSBS) and cyclic shear (CSBS) bond strengths were measured 24 hours after the bonding of mesh-based brackets. The adhesive remnant index (ARI) and failure sites were evaluated. Results: The mean SSBS was 34.25 +/- 9.21 and 24.64 +/- 9.42 MPa for the total- and self-etch groups, respectively. CSBS was 24.07 +/- 0.65 MPa and 18.92 +/- 1.08 MPa for the total- and sel-fetch groups, respectively. Cyclic loading produced lower bond strengths compared to static testing for both adhesives; the difference was only statistically significant for the total-etch system. Comparison of the two materials showed a statistically significant difference between the two techniques. The total-etch had higher bond strengths than the self-etch bonding system. The samples showed a predominance of ARI scored of 2 and 1, and their bonding failure sites were cohesive within the composite. Conclusion: Cyclic loading, simulating occlusal forces, reduces the bond strength of both bonding systems. Even though the self-etch bonding system had lower shear bond strength than the totaletch system, both were still clinically acceptable. (Angle Orthod. 2011;81:783-787.) C1 [Mansour, Ameerah Yousef] King Abdulaziz Univ, Coll Dent, Dept Prevent Sci, Jeddah 21443, Saudi Arabia. [Drummond, James L.] Natl Inst Dent & Craniofacial Res, Dent Mat & Biomat Program, Integrat Biol & Infect Dis Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. [Evans, Carla A.] Univ Illinois, Dept Orthodont, Chicago, IL USA. [Bakhsh, Zuhair] King Abdulaziz Univ, Coll Dent, Dept Orthodont, Jeddah 21443, Saudi Arabia. RP Mansour, AY (reprint author), King Abdulaziz Univ, Coll Dent, Dept Prevent Sci, POB 10703, Jeddah 21443, Saudi Arabia. EM drmansoura@hotmail.com NR 26 TC 1 Z9 1 U1 1 U2 11 PU E H ANGLE EDUCATION RESEARCH FOUNDATION, INC PI NEWTON N PA 1615 BEACON ST, NEWTON N, MA 02468-1507 USA SN 0003-3219 J9 ANGLE ORTHOD JI Angle Orthod. PD SEP PY 2011 VL 81 IS 5 BP 783 EP 787 DI 10.2319/012811-59.1 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 820DV UT WOS:000294886600007 PM 21545301 ER PT J AU Zhou, HB Qin, GY Longnecker, MP AF Zhou, Haibo Qin, Guoyou Longnecker, Matthew P. TI A Partial Linear Model in the Outcome-Dependent Sampling Setting to Evaluate the Effect of Prenatal PCB Exposure on Cognitive Function in Children SO BIOMETRICS LA English DT Article DE Cost-effective designs; Empirical likelihood; Outcome-dependent sampling; Partial linear model; Polychlorinated biphenyls; P-spline ID EMPIRICAL LIKELIHOOD METHOD; POLYCHLORINATED-BIPHENYLS; LONGITUDINAL/CLUSTERED DATA; ESTIMATING EQUATIONS; IN-UTERO; REGRESSION; INFERENCE; AGE AB Outcome-dependent sampling (ODS) has been widely used in biomedical studies because it is a cost-effective way to improve study efficiency. However, in the setting of a continuous outcome, the representation of the exposure variable has been limited to the framework of linear models, due to the challenge in terms of both theory and computation. Partial linear models (PLM) are a powerful inference tool to nonparametrically model the relation between an outcome and the exposure variable. In this article, we consider a case study of a PLM for data from an ODS design. We propose a semiparametric maximum likelihood method to make inferences with a PLM. We develop the asymptotic properties and conduct simulation studies to show that the proposed ODS estimator can produce a more efficient estimate than that from a traditional simple random sampling design with the same sample size. Using this newly developed method, we were able to explore an open question in epidemiology: whether in utero exposure to background levels of polychlorinated biphenyls (PCBs) is associated with children's intellectual impairment. Our model provides further insights into the relation between low-level PCB exposure and children's cognitive function. The results shed new light on a body of inconsistent epidemiologic findings. C1 [Zhou, Haibo; Qin, Guoyou] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Qin, Guoyou] Fudan Univ, Sch Publ Hlth, Dept Biostat, Shanghai 200032, Peoples R China. [Qin, Guoyou] Fudan Univ, Minist Educ China, Key Lab Publ Hlth Safety, Shanghai 200032, Peoples R China. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Zhou, HB (reprint author), Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. EM zhou@bios.unc.edu OI Longnecker, Matthew/0000-0001-6073-5322 FU National Institutes of Health [CA 79949]; NIH, National Institute of Environmental Health Sciences; National Nature Science Fund of China [10801039] FX We thank the editor, the associate editor, and two referees for their constructive suggestions that largely improved the presentation of this article. This work is supported by National Institutes of Health grants CA 79949 (Zhou and Qin), the intramural research program of the NIH, National Institute of Environmental Health Sciences (Longnecker), and the National Nature Science Fund of China grants of China 10801039 (Qin). NR 27 TC 5 Z9 5 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2011 VL 67 IS 3 BP 876 EP 885 DI 10.1111/j.1541-0420.2010.01500.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 819XE UT WOS:000294866800021 PM 21039397 ER PT J AU Pfeiffer, RM Gail, MH AF Pfeiffer, R. M. Gail, M. H. TI Two Criteria for Evaluating Risk Prediction Models SO BIOMETRICS LA English DT Article DE Discrimination; Discriminatory accuracy; Lorenz curve; Risk models ID BINARY REGRESSION; PROSTATE-CANCER; BREAST-CANCER; CURVE; SUSCEPTIBILITY; INVERSES; MARKER AB We propose and study two criteria to assess the usefulness of models that predict risk of disease incidence for screening and prevention, or the usefulness of prognostic models for management following disease diagnosis. The first criterion, the proportion of cases followed PCF(q), is the proportion of individuals who will develop disease who are included in the proportion q of individuals in the population at highest risk. The second criterion is the proportion needed to follow-up, PNF(p), namely the proportion of the general population at highest risk that one needs to follow in order that a proportion p of those destined to become cases will be followed. PCF(q) assesses the effectiveness of a program that follows 100q% of the population at highest risk. PNF(p) assess the feasibility of covering 100p% of cases by indicating how much of the population at highest risk must be followed. We show the relationship of those two criteria to the Lorenz curve and its inverse, and present distribution theory for estimates of PCF and PNF. We develop new methods, based on influence functions, for inference for a single risk model, and also for comparing the PCFs and PNFs of two risk models, both of which were evaluated in the same validation data. C1 [Pfeiffer, R. M.; Gail, M. H.] NCI, Biostat Branch, Bethesda, MD 20892 USA. RP Pfeiffer, RM (reprint author), NCI, Biostat Branch, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM pfeiffer@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 FU Intramural NIH HHS [Z01 CP010188-03, ZIA CP010181-08] NR 25 TC 15 Z9 15 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD SEP PY 2011 VL 67 IS 3 BP 1057 EP 1065 DI 10.1111/j.1541-0420.2010.01523.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 819XE UT WOS:000294866800039 PM 21155746 ER PT J AU Dodd, LE Korn, EL Freidlin, B Gray, R Bhattacharya, S AF Dodd, Lori E. Korn, Edward L. Freidlin, Boris Gray, Robert Bhattacharya, Suman TI An Audit Strategy for Progression-Free Survival SO BIOMETRICS LA English DT Article DE Auxiliary variables; Blinded independent central review; Event adjudication committee; Measurement error; Randomized clinical trial; Regression estimator ID CLINICAL-TRIALS; TESTS AB In randomized clinical trials, the use of potentially subjective endpoints has led to frequent use of blinded independent central review (BICR) and event adjudication committees to reduce possible bias in treatment effect estimators based on local evaluations (LE). In oncology trials, progression-free survival (PFS) is one such endpoint. PFS requires image interpretation to determine whether a patient's cancer has progressed, and BICR has been advocated to reduce the potential for endpoints to be biased by knowledge of treatment assignment. There is current debate, however, about the value of such reviews with time-to-event outcomes such as PFS. We propose a BICR audit strategy as an alternative to a complete-case BICR to provide assurance of the presence of a treatment effect. We develop an auxiliary-variable estimator of the log-hazard ratio that is more efficient than simply using the audited (i.e., sampled) BICR data for estimation. Our estimator incorporates information from the LE on all the cases and the audited BICR cases, and is an asymptotically unbiased estimator of the log-hazard ratio from BICR. The estimator offers considerable efficiency gains that improve as the correlation between LE and BICR increases. A two-stage auditing strategy is also proposed and evaluated through simulation studies. The method is applied retrospectively to a large oncology trial that had a complete-case BICR, showing the potential for efficiency improvements. C1 [Dodd, Lori E.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Korn, Edward L.; Freidlin, Boris] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Gray, Robert] Harvard Univ, Dept Biostat, Boston, MA 02115 USA. [Bhattacharya, Suman] Genentech Inc, San Francisco, CA 94080 USA. RP Dodd, LE (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM doddl@mail.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 16 TC 15 Z9 15 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2011 VL 67 IS 3 BP 1092 EP 1099 DI 10.1111/j.1541-0420.2010.01539.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 819XE UT WOS:000294866800043 PM 21210772 ER PT J AU Follmann, D Nason, M AF Follmann, Dean Nason, Martha TI An Augmented Probit Model for Missing Predictable Covariates in Quantal Bioassay with Small Sample Size SO BIOMETRICS LA English DT Article DE Assay; Errors-in-variables; HIV vaccine; ID(50); Measurement error; Probit regression; Regression calibration; Validation set ID NEUTRALIZING ANTIBODIES; LIKELIHOOD ESTIMATION; REGRESSION; ERROR; PROTECTION; BINARY AB Quantal bioassay experiments relate the amount or potency of some compound; for example, poison, antibody, or drug to a binary outcome such as death or infection in animals. For infectious diseases, probit regression is commonly used for inference and a key measure of potency is given by the ID(P), the amount that results in P% of the animals being infected. In some experiments, a validation set may be used where both direct and proxy measures of the dose are available on a subset of animals with the proxy being available on all. The proxy variable can be viewed as a messy reflection of the direct variable, leading to an errors-in-variables problem. We develop a model for the validation set and use a constrained seemingly unrelated regression (SUR) model to obtain the distribution of the direct measure conditional on the proxy. We use the conditional distribution to derive a pseudo-likelihood based on probit regression and use the parametric bootstrap for statistical inference. We re-evaluate an old experiment in 21 monkeys where neutralizing antibodies (nABs) to HIV were measured using an old (proxy) assay in all monkeys and with a new (direct) assay in a validation set of 11 who had sufficient stored plasma. Using our methods, we obtain an estimate of the ID(1) for the new assay, an important target for HIV vaccine candidates. In simulations, we compare the pseudo-likelihood estimates with regression calibration and a full joint likelihood approach. C1 [Follmann, Dean; Nason, Martha] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. RP Follmann, D (reprint author), NIAID, Biostat Res Branch, 6700B Rockledge Dr,MSC 7609, Bethesda, MD 20892 USA. EM dfollmann@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 22 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2011 VL 67 IS 3 BP 1127 EP 1134 DI 10.1111/j.1541-0420.2010.01536.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 819XE UT WOS:000294866800047 PM 21210769 ER PT J AU Proschan, M Brittain, E Kammerman, L AF Proschan, Michael Brittain, Erica Kammerman, Lisa TI Minimize the Use of Minimization with Unequal Allocation SO BIOMETRICS LA English DT Article DE Adaptive randomization; Analyze as you randomize; Asymptotics; Minimization; Permuted block randomization; Permutation test; Randomization; Rerandomization test; Temporal trend; Unequal allocation ID CLINICAL-TRIALS; RANDOMIZATION AB Minimization as an alternative to randomization is gaining popularity for small clinical trials. In response to critics' questions about the proper analysis of such a trial, proponents have argued that a rerandomization approach, akin to a permutation test with conventional randomization, can be used. However, they add that this computationally intensive approach is not necessary because its results are very similar to those of a t-test or test of proportions unless the sample size is very small. We show that minimization applied with unequal allocation causes problems that challenge this conventional wisdom. C1 [Proschan, Michael; Brittain, Erica] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Kammerman, Lisa] US FDA, Div Biometr 3, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Proschan, M (reprint author), NIAID, Biostat Res Branch, 6700A Rockledge Dr,Room 5140, Bethesda, MD 20892 USA. EM ProschaM@niaid.nih.gov NR 14 TC 15 Z9 15 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2011 VL 67 IS 3 BP 1135 EP 1141 DI 10.1111/j.1541-0420.2010.01545.x PG 7 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 819XE UT WOS:000294866800048 PM 21281276 ER PT J AU Lamont, RF Sobel, JD Carrington, D Mazaki-Tovi, S Kusanovic, JP Vaisbuch, E Romero, R AF Lamont, Ronald F. Sobel, Jack D. Carrington, D. Mazaki-Tovi, Shali Kusanovic, Juan Pedro Vaisbuch, Edi Romero, Roberto TI Varicella-zoster virus (chickenpox) infection in pregnancy SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Review DE Chickenpox; infection; pregnancy; varicella; virus; zoster ID UK ADVISORY GROUP; PNEUMONIA COMPLICATING PREGNANCY; TRANS-PLACENTAL PASSAGE; CONGENITAL VARICELLA; HERPES-SIMPLEX; INTRAUTERINE INFECTION; MATERNAL VARICELLA; BRITISH SOCIETY; NEONATAL VARICELLA; NATURAL-HISTORY AB Congenital varicella syndrome, maternal varicella-zoster virus pneumonia and neonatal varicella infection are associated with serious fetomaternal morbidity and, not infrequently, mortality. Vaccination against varicella-zoster virus can prevent the disease, and outbreak control limits the exposure of pregnant women to the infectious agent. Maternal varicella-zoster immunoglobulin administration before rash development, with or without antiviral medication, can modify the progression of the disease. C1 [Lamont, Ronald F.; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Vaisbuch, Edi; Romero, Roberto] NICHD, Perinatol Res Branch, DHHS, NIH, Detroit, MI USA. [Lamont, Ronald F.; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Vaisbuch, Edi; Romero, Roberto] NICHD, Perinatol Res Branch, DHHS, NIH, Bethesda, MD USA. [Lamont, Ronald F.; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Vaisbuch, Edi; Romero, Roberto] Wayne State Univ, Sch Med, Dept Obstet & Gynaecol, Detroit, MI 48201 USA. [Lamont, Ronald F.] Univ So Denmark, Dept Obstet & Gynaecol, Odense, Denmark. [Sobel, Jack D.] Wayne State Univ, Sch Med, Dept Infect Dis, Detroit, MI 48201 USA. [Carrington, D.] Hlth Protect Agcy SW, Dept Virol, Bristol, Avon, England. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. RP Lamont, RF (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD, DHHS,NIH, 3990 John R,Box 4, Detroit, MI 48201 USA. EM rlamont@med.wayne.edu; prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX This research was supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 115 TC 30 Z9 31 U1 1 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1470-0328 EI 1471-0528 J9 BJOG-INT J OBSTET GY JI BJOG PD SEP PY 2011 VL 118 IS 10 BP 1155 EP 1162 DI 10.1111/j.1471-0528.2011.02983.x PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 820RP UT WOS:000294923400001 PM 21585641 ER PT J AU Blumberg, PM Pearce, LV Lee, J AF Blumberg, Peter M. Pearce, Larry V. Lee, Jeewoo TI TRPV1 Activation is Not An All-Or-None Event: TRPV1 Partial Agonism/Antagonism and Its Regulatory Modulation SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review DE Resiniferatoxin; capsaicin; partial agonist; partial antagonist; TRPV1; efficacy; signaling pathway ID VANILLOID RECEPTOR TRPV1; CAPSAICIN RECEPTOR; BODY-TEMPERATURE; ANALGESIC AGENTS; AGONIST ACTIVITY; POTENTIAL VANILLOID-1; CALCIUM RESPONSE; SENSORY NEURONS; MICE LACKING; SPINAL-CORD AB TRPV1 has emerged as a promising therapeutic target for pain as well as a broad range of other conditions such as asthma or urge incontinence. The identification of resiniferatoxin as an ultrapotent ligand partially able to dissect the acute activation of TRPV1 from subsequent desensitization and the subsequent intense efforts in medicinal chemistry have revealed that TRPV1 affords a dramatic landscape of opportunities for pharmacological manipulation. While agonism and antagonism have represented the primary directions for drug development, the pharmacological complexity of TRPV1 affords additional opportunities. Partial agonism/partial antagonism, its modulation by signaling pathways, variable desensitization, and slow kinetics of action can all be exploited through drug design. C1 [Blumberg, Peter M.; Pearce, Larry V.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Lee, Jeewoo] Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Seoul 151742, South Korea. RP Blumberg, PM (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bldg 37,Room 4048,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov FU NIH, Center for Cancer Research, National Cancer Institute; National Research Foundation of Korea [R11-2007-107-02001-0] FX This work was supported in part through the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute and in part by Grants R11-2007-107-02001-0 from the National Research Foundation of Korea. NR 73 TC 9 Z9 9 U1 1 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PD SEP PY 2011 VL 11 IS 17 BP 2151 EP 2158 PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 820GH UT WOS:000294893100004 PM 21671879 ER PT J AU Iadarola, MJ Mannes, AJ AF Iadarola, Michael J. Mannes, Andrew J. TI The Vanilloid Agonist Resiniferatoxin for Interventional-Based Pain Control SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review DE Analgesia; hyperalgesia; cancer pain; osteosarcoma; canine; capsaicin; intrathecal; cerebrospinal fluid; spinal cord; dorsal root ganglion; proprioceptor; C-fiber; A-delta fiber; vanilloid receptor; calcium cytotoxicity; ion channel ID CONCENTRATION CAPSAICIN PATCH; SPINAL-CORD NEURONS; CANINE BONE CANCER; C-FOS; PERIPHERAL INFLAMMATION; INTRATHECAL CAPSAICIN; GENE-EXPRESSION; RECEPTOR TRPV1; RAT MODEL; HYPERALGESIA AB The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophysical conductance properties and its expression in inflammation-sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chemical and pharmacological investigation, for TRPV1 agonists nature has provided an optimized compound in RTX. RTX is not suitable for systemic administration, but it is highly adaptable to a variety of pain problems when used by local administration. This can include routes as diverse as subcutaneous, intraganglionic or intrathecal (CSF space around the spinal cord). The present review focuses on the molecular and preclinical animal experiments that form the underpinnings of our clinical trial of intrathecal RTX for pain in advanced cancer. As such this represents a new approach to pain control that emerges from a long line of research on capsaicin and other vanilloids, their physiological actions, and the molecular biology of the capsaicin receptor TRPV1. C1 [Iadarola, Michael J.; Mannes, Andrew J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. RP Iadarola, MJ (reprint author), Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. EM miadarola@dir.nidcr.nih.gov; amannes@mail.nih.gov OI Mannes, Andrew/0000-0001-5834-5667 FU Division of Intramural Research, NIDCR; National Institute of Drug Abuse FX The authors would like to thank Laszlo Karai, Zoltan Olah, and Jason Keller, from NIDCR; John Neubert and Robert Caudle now at University of Florida, Gainesville; and James Terrill, Nathan Appel, Robert Walsh, Marta De Santis, Roberta Kahn, Moo Park and Nora Chiang from the Division of Pharmacotherapies & Medical Consequences of Drug Abuse, NIDA; George Grimes and Judith Starling from the Pharmaceutical Development Section of the NIH Clinical Center; and Dorothy Cimino Brown from University of Pennsylvania for their intensive involvement in the various phases of this project over the years. This research was supported by the Division of Intramural Research, NIDCR, and in part, the National Institute of Drug Abuse. NR 47 TC 28 Z9 30 U1 1 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PD SEP PY 2011 VL 11 IS 17 BP 2171 EP 2179 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 820GH UT WOS:000294893100006 PM 21671877 ER PT J AU Hodics, T Upreti, B Alex, A Xu, B Hidler, J Kowalske, K Hart, J Dromerick, A Pezzullo, J Cohen, L AF Hodics, T. Upreti, B. Alex, A. Xu, B. Hidler, J. Kowalske, K. Hart, J. Dromerick, A. Pezzullo, J. Cohen, L. TI TRANSCRANIAL DIRECT CURRENT STIMULATION (tDCS) ENHANCED STROKE RECOVERY AND CORTICAL REORGANIZATION - AN ONGOING CLINICAL TRIAL SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 15th Congress of the European-Federation-of-Neurological-Societies (EFNS) CY SEP 10-13, 2011 CL Budapest, HUNGARY SP European Federat Neurol Soc C1 [Kowalske, K.] Univ Texas SW, PM&R, Dallas, TX USA. [Hodics, T.; Xu, B.; Cohen, L.] NINDS, HCPS, NIH, Bethesda, MD 20892 USA. [Hodics, T.; Xu, B.; Cohen, L.] NINDS, SRS, NIH, Bethesda, MD 20892 USA. [Hidler, J.] Natl Rehabil Hosp, Washington, DC USA. [Dromerick, A.; Pezzullo, J.] Georgetown Univ, Washington, DC USA. NR 0 TC 3 Z9 3 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD SEP PY 2011 VL 18 SU 2 SI SI BP 127 EP 127 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 819DW UT WOS:000294806600251 ER PT J AU Kranz, G Ejaz, SA Peter, LT Kranz, GS Hallett, M AF Kranz, G. Ejaz, S. A. Peter, L. T. Kranz, G. S. Hallett, M. TI LTD-LIKE PLASTICITY OF THE TRIGEMINAL BLINK REFLEX FOR THE TREATMENT OF BLEPHAROSPASM SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 15th Congress of the European-Federation-of-Neurological-Societies (EFNS) CY SEP 10-13, 2011 CL Budapest, HUNGARY SP European Federat Neurol Soc C1 [Kranz, G.] Med Univ Vienna, Dept Neurol, Vienna, Austria. [Kranz, G.; Ejaz, S. A.; Peter, L. T.; Hallett, M.] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD USA. [Kranz, G. S.] Med Univ Vienna, Dept Biol Psychiat, Vienna, Austria. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD SEP PY 2011 VL 18 SU 2 SI SI BP 245 EP 245 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 819DW UT WOS:000294806600449 ER PT J AU Tasca, G Odgerel, Z Monforte, M Aurino, S Clarke, NF Ricci, E Goldfarb, LG AF Tasca, G. Odgerel, Z. Monforte, M. Aurino, S. Clarke, N. F. Ricci, E. Goldfarb, L. G. TI FILAMINOPATHY WITH A COMPLICATED PHENOTYPE SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 15th Congress of the European-Federation-of-Neurological-Societies (EFNS) CY SEP 10-13, 2011 CL Budapest, HUNGARY SP European Federat Neurol Soc C1 [Tasca, G.; Monforte, M.; Ricci, E.] Univ Cattolica Sacro Cuore, Sch Med, Inst Neurol, I-00168 Rome, Italy. [Odgerel, Z.; Goldfarb, L. G.] NINDS, Bethesda, MD 20892 USA. [Aurino, S.] Univ Naples 2, Dipartimento Patol Gen, Naples, Italy. [Clarke, N. F.] Univ Sydney, Inst Neurosci & Muscle Res, Childrens Hosp Westmead, Discipline Paediat & Child Hlth, Sydney, NSW, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD SEP PY 2011 VL 18 SU 2 SI SI BP 285 EP 285 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 819DW UT WOS:000294806600521 ER PT J AU Sailer, A Scholz, SW Gibbs, JR Johnson, JO Wood, NW Hernandez, D Hardy, J Federoff, H Traynor, BJ Singleton, AB Houlden, H AF Sailer, A. Scholz, S. W. Gibbs, J. R. Johnson, J. O. Wood, N. W. Hernandez, D. Hardy, J. Federoff, H. Traynor, B. J. Singleton, A. B. Houlden, H. TI EXOME SEQUENCING AS A RAPID AND COST EFFICIENT DIAGNOSTIC METHOD IN NEUROGENETIC DISORDERS SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 15th Congress of the European-Federation-of-Neurological-Societies (EFNS) CY SEP 10-13, 2011 CL Budapest, HUNGARY SP European Federat Neurol Soc C1 [Sailer, A.; Wood, N. W.; Hardy, J.; Houlden, H.] UCL Inst Neurol, London, England. [Scholz, S. W.; Gibbs, J. R.; Johnson, J. O.; Hernandez, D.; Traynor, B. J.; Singleton, A. B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Scholz, S. W.; Federoff, H.] Georgetown Univ, Dept Neurosci, Washington, DC USA. RI Singleton, Andrew/C-3010-2009; Houlden, Henry/C-1532-2008 OI Houlden, Henry/0000-0002-2866-7777 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD SEP PY 2011 VL 18 SU 2 SI SI BP 552 EP 552 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 819DW UT WOS:000294806601368 ER PT J AU Ferrer, RA Hall, KL Portnoy, DB Ling, BS Han, PKJ Klein, WMP AF Ferrer, Rebecca A. Hall, Kara L. Portnoy, David B. Ling, Bruce S. Han, Paul K. J. Klein, William M. P. TI Relationships Among Health Perceptions Vary Depending on Stage of Readiness for Colorectal Cancer Screening SO HEALTH PSYCHOLOGY LA English DT Article DE health perceptions; stage of readiness; risk perceptions; worry; ambiguity; fatalism ID FECAL-OCCULT-BLOOD; SOCIAL-COMPARISON INFORMATION; TRENDS SURVEY HINTS; BEHAVIOR-CHANGE; TRANSTHEORETICAL MODEL; RISK PERCEPTIONS; WORRY; AMBIGUITY; PREDICTORS; PREVENTION AB Objective: We explored whether relationships among health perceptions differ depending on individuals' stage of readiness for colorectal cancer screening (CRCS). Methods: Data from the National Cancer Institute's Health Information National Trends Survey (HINTS) were used to stage adults over 50 years of age (N = 2324) using a modified version of the Precaution Adoption Process Model (PAPM) staging algorithm. Health perceptions examined included perceived risk of cancer, worry about cancer, fatalism, and beliefs about ambiguity of cancer prevention recommendations. Results: Meaningful differences in patterns of relationships among health perceptions by stage were found. Conclusions: The nonlinear patterns that emerged indicate support for the role of these health perceptions in screening, the idea that behavioral readiness may moderate the relationship between important health perceptions, and the use of the stage construct in this context. C1 [Ferrer, Rebecca A.; Hall, Kara L.; Portnoy, David B.; Klein, William M. P.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20852 USA. [Portnoy, David B.] NIH, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Ling, Bruce S.] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. [Han, Paul K. J.] Maine Med Ctr Res Inst, Ctr Outcomes Res & Evaluat, Scarborough, ME USA. [Klein, William M. P.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. RP Ferrer, RA (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7326,Room 4083, Bethesda, MD 20852 USA. EM ferrerra@mail.nih.gov OI Portnoy, David/0000-0003-2175-9457; Han, Paul/0000-0003-0165-1940 NR 56 TC 18 Z9 18 U1 2 U2 14 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 J9 HEALTH PSYCHOL JI Health Psychol. PD SEP PY 2011 VL 30 IS 5 BP 525 EP 535 DI 10.1037/a0023583 PG 11 WC Psychology, Clinical; Psychology SC Psychology GA 819ZU UT WOS:000294876100004 PM 21534672 ER PT J AU Ferrer, RA Fisher, JD Buck, R Amico, KR AF Ferrer, Rebecca A. Fisher, Jeffrey D. Buck, Ross Amico, K. Rivet TI Pilot Test of an Emotional Education Intervention Component for Sexual Risk Reduction SO HEALTH PSYCHOLOGY LA English DT Article DE emotion; intervention; sexual risk reduction; HIV prevention; emotional education ID METAANALYTIC EVIDENCE; BEHAVIORAL SKILLS; DECISION-MAKING; YOUNG-ADULTS; HIV; ADOLESCENTS; INFORMATION; MOTIVATION; REASON; MODEL AB Objective: Emotions are key predictors of sexual risk behavior but have been largely ignored in theory-based intervention development. The present study aims to evaluate whether the addition of an emotional education intervention component to a traditional social cognitive safer sex intervention increases intervention efficacy, compared with both a social cognitive only intervention and a no intervention control condition. Methods: Young adults were randomized in small groups to receive the social cognitive emotional (SCE) intervention, the social cognitive (SC) intervention, or standard of care. Results: Analyses of data from 176 participants indicated that intervention arms reported similar increased condom use compared with the no intervention control arm at 3 months' postintervention (beta = = .41, d = 0.08). However, at 6 months' postintervention, individuals in the SCE intervention arm reported increased condom use compared with both the SC intervention (beta = .27, p = .04, d = 0.38) and control arms (beta =.37, p < .01; d = 0.56), demonstrating preliminary evidence that the addition of an emotional education component may facilitate sustained behavior change. Conclusions: An emotional education intervention module has the potential to facilitate sustained behavior change at delayed follow-up. Additional research is necessary to replicate findings in a larger sample and to determine the mediators of emotional education intervention efficacy. C1 [Ferrer, Rebecca A.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Ferrer, Rebecca A.; Fisher, Jeffrey D.; Buck, Ross; Amico, K. Rivet] Univ Connecticut, Ctr Hlth Intervent & Prevent, Storrs, CT 06269 USA. [Fisher, Jeffrey D.; Buck, Ross] Univ Connecticut, Dept Psychol, Storrs, CT 06269 USA. [Buck, Ross] Univ Connecticut, Dept Commun Sci, Storrs, CT 06269 USA. RP Ferrer, RA (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 4083, Rockville, MD 20852 USA. EM ferrerra@mail.nih.gov FU NIH [F31MH080626] FX This research was supported by NIH Grant F31MH080626 to Rebecca A. Ferrer (mentor: Jeffrey D. Fisher). NR 39 TC 12 Z9 12 U1 0 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 J9 HEALTH PSYCHOL JI Health Psychol. PD SEP PY 2011 VL 30 IS 5 BP 656 EP 660 DI 10.1037/a0023438 PG 5 WC Psychology, Clinical; Psychology SC Psychology GA 819ZU UT WOS:000294876100017 PM 21534680 ER PT J AU Egger, HL Pine, DS Nelson, E Leibenluft, E Ernst, M Towbin, KE Angold, A AF Egger, Helen Link Pine, Daniel S. Nelson, Eric Leibenluft, Ellen Ernst, Monique Towbin, Kenneth E. Angold, Adrian TI The NIMH Child Emotional Faces Picture Set (NIMH-ChEFS): a new set of children's facial emotion stimuli SO INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH LA English DT Article DE face processing; emotion perception; face stimuli sets; developmental psychopathology; methodology ID IMPAIRED RECOGNITION; LABELING DEFICITS; BIPOLAR DISORDER; HUMAN AMYGDALA; EXPRESSIONS; AUTISM; PHOTOGRAPHS; SERIES; DAMAGE AB With the emergence of new technologies, there has been an explosion of basic and clinical research on the affective and cognitive neuroscience of face processing and emotion perception. Adult emotional face stimuli are commonly used in these studies. For developmental research, there is a need for a validated set of child emotional faces. This paper describes the development of the National Institute of Mental Health Child Emotional Faces Picture Set (NIMH-ChEFS), a relatively large stimulus set with high quality, color images of the emotional faces of children. The set includes 482 photographs of fearful, angry, happy, sad and neutral child faces with two gaze conditions: direct and averted gaze. In this paper we describe the development of the NIMH-ChEFS and data on the set's validity based on ratings by 20 healthy adult raters. Agreement between the a priori emotion designation and the raters' labels was high and comparable with values reported for commonly used adult picture sets. Intensity, representativeness, and composite "goodness" ratings are also presented to guide researchers in their choice of specific stimuli for their studies. These data should give researchers confidence in the NIMH-ChEFS's validity for use in affective and social neuroscience research. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Egger, Helen Link; Angold, Adrian] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Ctr Dev Epidemiol, Durham, NC 27710 USA. [Pine, Daniel S.; Nelson, Eric; Ernst, Monique] NIMH, Sect Dev & Affect Neurosci, Mood & Anxiety Disorders Program, Intramural Res Program, Bethesda, MD 20892 USA. [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Mood & Anxiety Disorders Program, Intramural Res Program, Bethesda, MD 20892 USA. [Towbin, Kenneth E.] NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, Bethesda, MD 20892 USA. RP Egger, HL (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Ctr Dev Epidemiol, DUMC Box 3454, Durham, NC 27710 USA. EM helen.egger@duke.edu OI Nelson, Eric/0000-0002-3376-2453; Egger, Helen/0000-0001-8447-5350 FU National Institute of Mental Health [R01 MH081025]; National Institute on Drug Abuse (NIDA); Center for Disease Control (CDC); National Alliance for Research on Schizophrenia and Depression (NARSAD); Autism Speaks FX This work was supported by the National Institute of Mental Health Grant # R01 MH081025. Tim Blitchington at the Center for Developmental Epidemiology developed the electronic rating program used in this study. The NIMH-ChEFS can be downloaded at http://devepi.duhs.duke.edu/instruments.html.; Dr Egger receives grant funding from the National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), Center for Disease Control (CDC), National Alliance for Research on Schizophrenia and Depression (NARSAD), and Autism Speaks. Dr Angold receives grant funding from the National Institute of Mental Health (NIMH) and National Institute on Drug Abuse (NIDA). Drs Pine, Nelson, Leibenluft, Ernst, and Towbin have no disclosures. The authors have no competing interests. NR 30 TC 37 Z9 37 U1 0 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1049-8931 J9 INT J METH PSYCH RES JI Int. J. Methods Psychiatr. Res. PD SEP PY 2011 VL 20 IS 3 BP 145 EP 156 DI 10.1002/mpr.343 PG 12 WC Psychiatry SC Psychiatry GA 820QC UT WOS:000294919500004 PM 22547297 ER PT J AU Rohde, K Klein, DC Moller, M Rath, MF AF Rohde, Kristian Klein, David C. Moller, Morten Rath, Martin F. TI Rax: developmental and daily expression patterns in the rat pineal gland and retina SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE circadian biology; developmental biology; pineal gland; Rax; retina; Rx ID HYDROXYINDOLE-O-METHYLTRANSFERASE; ARYLALKYLAMINE-N-ACETYLTRANSFERASE; VERTEBRATE EYE DEVELOPMENT; OTX2 HOMEOBOX GENE; RX; CRX; CELLS; PAX6; ANOPHTHALMIA; EVOLUTION AB Retina and anterior neural fold homeobox (Rax) gene encodes a transcription factor essential for vertebrate eye development. Recent microarray studies indicate that Rax is expressed in the adult rat pineal gland and retina. The present study reveals that Rax expression levels in the rat change significantly during retinal development with a peak occurring at embryonic day 18, whereas Rax expression in the pineal is relatively delayed and not detectable until embryonic day 20. In both tissues, Rax is expressed throughout postnatal development into adulthood. In the mature rat pineal gland, the abundance of Rax transcripts increases 2-fold during the light period with a peak occurring at dusk. These findings are consistent with the evidence that Rax is of functional importance in eye development and suggest a role of Rax in the developing pineal gland. In addition, it would appear possible that Rax contributes to phenotype maintenance in the mature retina and pineal gland and may facilitate 24-h changes in the pineal transcriptome. C1 [Rohde, Kristian; Moller, Morten; Rath, Martin F.] Univ Copenhagen, Panum Inst, Dept Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark. [Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Sect Neuroendocrinol, NIH, Bethesda, MD USA. RP Rath, MF (reprint author), Univ Copenhagen, Panum Inst 24 3, Dept Neurosci & Pharmacol, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. EM mrath@sund.ku.dk OI Rath, Martin/0000-0002-4047-6324 FU Novo Nordisk Foundation; Danish Medical Research Council; Lundbeck Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX This study was supported by the Novo Nordisk Foundation, the Danish Medical Research Council, the Lundbeck Foundation and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. We wish to thank Ms Tine Thorup Mellergaard for expert histological assistance. The authors declare no conflicts of interest. NR 41 TC 9 Z9 9 U1 2 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD SEP PY 2011 VL 118 IS 6 BP 999 EP 1007 DI 10.1111/j.1471-4159.2011.07385.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 820JB UT WOS:000294900600006 PM 21749377 ER PT J AU Baratz, R Tweedie, D Rubovitch, V Luo, WM Yoon, JS Hoffer, BJ Greig, NH Pick, CG AF Baratz, Renana Tweedie, David Rubovitch, Vardit Luo, Weiming Yoon, Jeong Seon Hoffer, Barry J. Greig, Nigel H. Pick, Chaim G. TI Tumor necrosis factor-alpha synthesis inhibitor, 3,6 '-dithiothalidomide, reverses behavioral impairments induced by minimal traumatic brain injury in mice SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE etanercept; neuroinflammation; thalidomide; thiothalidomide; TNF-alpha; traumatic brain injury ID CLOSED-HEAD INJURY; CELL-DEATH MECHANISMS; SPINAL-CORD-INJURY; TNF-ALPHA; NEURODEGENERATIVE DISEASES; MESSENGER-RNA; INFLAMMATORY DISEASES; COGNITIVE DEFICITS; FACTOR RECEPTORS; RAT-BRAIN AB Mild traumatic brain injury (mTBI) patients do not show clear structural brain defects and, in general, do not require hospitalization, but frequently suffer from long-lasting cognitive, behavioral and emotional difficulties. Although there is no current effective treatment or cure for mTBI, tumor necrosis factor-alpha (TNF-alpha), a cytokine fundamental in the systemic inflammatory process, represents a potential drug target. TNF-alpha levels increase after mTBI and may induce or exacerbate secondary damage to brain tissue. The present study evaluated the efficacy of the experimental TNF-alpha synthesis inhibitor, 3,6'-dithiothalidomide, on recovery of mice from mTBI in a closed head weight-drop model that induces an acute elevation in brain TNF-alpha and an impairment in cognitive performance, as assessed by the Y-maze, by novel object recognition and by passive avoidance paradigms at 72 h and 7 days after injury. These impairments were fully ameliorated in mice that received a one time administration of 3,6'-dithiothalidomide at either a low (28 mg/kg) or high (56 mg/kg) dose provided either 1 h prior to injury, or at 1 or 12 h post-injury. Together, these results implicate TNF-alpha as a drug target for mTBI and suggests that 3,6'-dithiothalidomide may act as a neuroprotective drug to minimize impairment. C1 [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Baratz, Renana; Rubovitch, Vardit; Pick, Chaim G.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. [Hoffer, Barry J.] Natl Inst Drug Abuse, Cellular Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD USA. [Hoffer, Barry J.] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH USA. RP Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, BRC Room 05C220,251 Bayview Blvd, Baltimore, MD 21224 USA. EM greign@grc.nia.nih.gov FU Sackler School of Medicine, Tel-Aviv University; National Institute on Aging; National Institute on Drug Abuse, National Institutes of Health FX This research was supported in part by the Sackler School of Medicine, Tel-Aviv University, and the Intramural Research Programs of both the National Institute on Aging and National Institute on Drug Abuse, National Institutes of Health. This work was performed in partial fulfillment of the requirements for a Ph.D. degree of Renana Baratz, Sackler Faculty of Medicine, Tel Aviv University, Israel. NR 71 TC 45 Z9 45 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD SEP PY 2011 VL 118 IS 6 BP 1032 EP 1042 DI 10.1111/j.1471-4159.2011.07377.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 820JB UT WOS:000294900600009 PM 21740439 ER PT J AU Simone, CB Lonser, RR Ondos, J Oldfield, EH Camphausen, K Simone, NL AF Simone, Charles B., II Lonser, Russell R. Ondos, John Oldfield, Edward H. Camphausen, Kevin Simone, Nicole L. TI Infratentorial craniospinal irradiation for von Hippel-Lindau: a retrospective study supporting a new treatment for patients with CNS hemangioblastomas SO NEURO-ONCOLOGY LA English DT Article DE central nervous system; craniospinal irradiation; hemangioblastoma; tumor volume; von Hippel-Lindau (VHL) ID CENTRAL-NERVOUS-SYSTEM; SURGICAL-MANAGEMENT; NATURAL-HISTORY; CEREBELLAR HEMANGIOBLASTOMAS; SPINAL-CORD; DISEASE; RADIOSURGERY AB Patients with von Hippel-Lindau (VHL) syndrome with diffuse CNS hemangioblastomas have morbidity related to their disease and require a lifetime of surgical resections. Ninety-seven percent of tumors progress, and 5-year surgery rates are 20%-60%. Stereotactic radiosurgery and fractionated radiotherapy have had limited success. For the first time, we have used infratentorial craniospinal radiation therapy (ICSRT) for VHL patients with CNS hemangioblastomas. Consecutive VHL patients treated at the National Institutes of Health with radiographic evidence of hemangioblastomas were included if they received ICSRT. Patients underwent neurologic examinations and imaging at 3- to 12-month intervals. Seven patients with 84 hemangioblastomas met eligibility criteria. ICSRT was commonly administered to 43.2 Gy in 24 fractions. Mean pre-ICSRT tumor volume was 5.48 cm(3). At a mean follow-up of 73.8 months, mean post-ICSRT tumor volume was 6.87 cm(3), and 91 tumors were identified. Complete radiographic resolution was achieved in 17.9% of lesions. Although many patients were no longer optimal surgical candidates, only 4 surgeries were needed for symptomatic lesions after ICSRT, compared with 33 prior. Acute toxicity was mild and no patient developed grade >= 1 late spinal cord toxicity according to the criteria of the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer, despite the high dose that the entire spinal cord received. Clinical and radiographic stability or resolution was demonstrated in the majority of tumors. Tumor growth rate in this study was less than reported in natural history studies, and the rate of surgical intervention was reduced. ICSRT was well tolerated, can decrease hemangioblastoma growth rate, and is a potential therapeutic option for VHL patients that warrants further investigation. C1 [Simone, Charles B., II; Ondos, John; Camphausen, Kevin; Simone, Nicole L.] NCI, NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Lonser, Russell R.; Oldfield, Edward H.] Natl Inst Neurol Disorders & Stroke, NIH, Surg Neurol Branch, Bethesda, MD 20892 USA. RP Simone, NL (reprint author), Bldg 10-CRC,Room B2-3500,10 Ctr Dr, Bethesda, MD 20892 USA. EM simonen@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the intramural research program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 21 TC 8 Z9 8 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD SEP PY 2011 VL 13 IS 9 BP 1030 EP 1036 DI 10.1093/neuonc/nor085 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 819YT UT WOS:000294872400011 PM 21798886 ER PT J AU Cao, XG Shen, DF Patel, MM Tuo, JS Johnson, TM Olsen, TW Chan, CC AF Cao, Xiaoguang Shen, Defen Patel, Mrinali M. Tuo, Jingsheng Johnson, T. Mark Olsen, Timothy W. Chan, Chi-Chao TI Macrophage polarization in the maculae of age-related macular degeneration: A pilot study SO PATHOLOGY INTERNATIONAL LA English DT Article DE age-related macular degeneration (AMD); chemokine; choroidal neovascularization; M1 macrophage; M2 macrophage ID CHOROIDAL NEOVASCULARIZATION; BRUCHS MEMBRANE; ACTIVATION; ANGIOGENESIS; INFLAMMATION; INVOLVEMENT; EXPRESSION; PHENOTYPE; GROWTH; SYSTEM AB Macrophages can be polarized to exhibit either proinflammatory M1 or pro-angiogenic M2 phenotypes, but have high phenotypic plasticity. This pilot study investigated macrophage polarization in the macular retina and choroid of age-related macular degeneration (AMD) and non-AMD subjects, as well as in AMD choroidal neovascular membranes (CNVM). All specimens were evaluated for routine histopathology. Quantitative real-time polymerase chain reaction for representative M1 (CXCL11) and M2 (CCL22) transcripts were performed on macular choroidal trephines (MCT) of 19 AMD and nine non-AMD eye bank eyes, on the microdissected macular retinal cells from the archived slides of five geographic atrophic AMD, five exudative/neovascular AMD, and eight normal autopsied eyes, and on microdissected inflammatory cells from two surgically removed CNVM that did not respond to anti-vascular endothelial growth factor (VEGF) therapy. High M2-chemokine transcript and a low ratio of M1 to M2 chemokine transcript were found in aging non-AMD MCT. Advanced AMD maculae had a higher M1 to M2 chemokine transcript ratio compared to normal autopsied eyes. Macrophages in the two CNVM of patients unresponsive to anti-VEGF therapy were polarized toward either M1 or M2 phenotypes. The number of M2 macrophages was increased compared to M1 macrophages in normal aging eyes. A pathological shift of macrophage polarization may play a potential role in AMD pathogenesis. C1 [Cao, Xiaoguang; Shen, Defen; Patel, Mrinali M.; Tuo, Jingsheng; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Johnson, T. Mark] Natl Retina Inst, Chevy Chase, MD USA. [Patel, Mrinali M.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Olsen, Timothy W.] Emory Univ, Emory Eye Ctr, Atlanta, GA 30322 USA. [Cao, Xiaoguang] Peking Univ, Peoples Hosp, Dept Ophthalmol, Beijing 100871, Peoples R China. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov RI du, zhao jiang/F-6229-2011; OI Tuo, Jingsheng/0000-0002-1372-7810 FU NEI FX The NEI Intramural Research program supported the study. NR 33 TC 72 Z9 78 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1320-5463 J9 PATHOL INT JI Pathol. Int. PD SEP PY 2011 VL 61 IS 9 BP 528 EP 535 DI 10.1111/j.1440-1827.2011.02695.x PG 8 WC Pathology SC Pathology GA 821LO UT WOS:000294976700004 PM 21884302 ER PT J AU Morens, DM Taubenberger, JK AF Morens, David M. Taubenberger, Jeffery K. TI Pandemic influenza: certain uncertainties SO REVIEWS IN MEDICAL VIROLOGY LA English DT Review ID HONG-KONG INFLUENZA; A H1N1 VIRUSES; SWINE INFLUENZA; BACTERIAL PNEUMONIA; EQUINE INFLUENZA; UNITED-STATES; ASIAN STRAIN; TRANSMISSION; EPIDEMIC; NEURAMINIDASE AB For at least five centuries, major epidemics and pandemics of influenza have occurred unexpectedly and at irregular intervals. Despite the modern notion that pandemic influenza is a distinct phenomenon obeying such constant (if incompletely understood) rules such as dramatic genetic change, cyclicity, "wave" patterning, virus replacement, and predictable epidemic behavior, much evidence suggests the opposite. Although there is much that we know about pandemic influenza, there appears to be much more that we do not know. Pandemics arise as a result of various genetic mechanisms, have no predictable patterns of mortality among different age groups, and vary greatly in how and when they arise and recur. Some are followed by new pandemics, whereas others fade gradually or abruptly into long-term endemicity. Human influenza pandemics have been caused by viruses that evolved singly or in co-circulation with other pandemic virus descendants and often have involved significant transmission between, or establishment of, viral reservoirs within other animal hosts. In recent decades, pandemic influenza has continued to produce numerous unanticipated events that expose fundamental gaps in scientific knowledge. Influenza pandemics appear to be not a single phenomenon but a heterogeneous collection of viral evolutionary events whose similarities are overshadowed by important differences, the determinants of which remain poorly understood. These uncertainties make it difficult to predict influenza pandemics and, therefore, to adequately plan to prevent them. Published 2011. This article is a US Government work and is in the public domain in the USA. C1 [Morens, David M.; Taubenberger, Jeffery K.] NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, Bldg 31,Room 7A-03, Bethesda, MD 20892 USA. EM dm270q@nih.gov FU Intramural NIH HHS [ZIA AI000995-04] NR 241 TC 23 Z9 23 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1052-9276 EI 1099-1654 J9 REV MED VIROL JI Rev. Med. Virol. PD SEP PY 2011 VL 21 IS 5 BP 262 EP 284 DI 10.1002/rmv.689 PG 23 WC Virology SC Virology GA 819WJ UT WOS:000294863500002 PM 21706672 ER PT J AU Bevilacqua, L Goldman, D AF Bevilacqua, Laura Goldman, David TI Genetics of emotion SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID CATECHOL-O-METHYLTRANSFERASE; TRANSPORTER PROMOTER POLYMORPHISM; SEROTONIN TRANSPORTER; INDIVIDUAL-DIFFERENCES; BEHAVIORAL-INHIBITION; PREFRONTAL COGNITION; VAL(158)MET GENOTYPE; ANXIOUS TEMPERAMENT; PSYCHOSOCIAL STRESS; PERSONALITY-TRAITS AB Emotion is critical to most aspects of human behavior, and individual differences in systems recruited to process emotional stimuli, expressed as variation in emotionality, are characteristic of several neuropsychiatric disorders. We examine the genetic origins of individual differences in emotion processing by focusing on functional variants at five genes: catechol-O-methyltransferase (COMT), serotonin transporter (SLC6A4), neuropeptide Y (NPY), a glucocorticoid receptor-regulating co-chaperone of stress proteins (FKBP5) and pituitary adenylate cyclase-activating polypeptide receptor (ADCYAP1R1). These represent a range of effects of genes on emotion as well as the variety of mechanisms and factors, such as stress, that modify these effects. The new genomic era of genome-wide association studies (GWAS) and deep sequencing may yield a wealth of new loci modulating emotion. The effects of these genes can be validated by neuroimaging, neuroendocrine and other studies accessing intermediate phenotypes, deepening our understanding of mechanisms of emotion and variation in emotionality. C1 [Bevilacqua, Laura; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. EM davidgoldman@mail.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z01 AA000301-09, Z01 AA000301-10, Z99 AA999999] NR 89 TC 30 Z9 31 U1 5 U2 25 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD SEP PY 2011 VL 15 IS 9 SI SI BP 401 EP 408 DI 10.1016/j.tics.2011.07.009 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 820CD UT WOS:000294882200006 PM 21835681 ER PT J AU Perry, GJ Ahmed, MI Desai, RV Mujib, M Zile, M Sui, XM Aban, IB Zhang, Y Tallaj, J Allman, RM Aronow, WS Fleg, JL Ahmed, A AF Perry, Gilbert J. Ahmed, Mustafa I. Desai, Ravi V. Mujib, Marjan Zile, Michael Sui, Xuemei Aban, Inmaculada B. Zhang, Yan Tallaj, Jose Allman, Richard M. Aronow, Wilbert S. Fleg, Jerome L. Ahmed, Ali TI Left Ventricular Diastolic Function and Exercise Capacity in Community-Dwelling Adults >= 65 Years of Age Without Heart Failure SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID 6-MINUTE WALK TEST; ECHOCARDIOGRAPHY; DECLINE; RECOMMENDATIONS; RELAXATION; GUIDELINES; DISEASE; GENDER AB Left ventricular diastolic dysfunction (LVDD) has been reported to have strong correlation with exercise capacity. However, this relationship has not been studied extensively in community-dwelling older adults. Data on pulse and tissue Doppler echocardiographic estimates of resting early (E) and atrial (A) transmitral peak inflow and early (Em) mitral annular velocities, and six-minute walk test were obtained from 89 community-dwelling older adults (mean age, 74; range, 65-93 years; 54% women), without a history of heart failure. Overall, 47% had cardiovascular morbidity and 60% had normal diastolic function (E/A 0.75-1.5 and E:Em <10). Among the 36 individuals with LVDD, 83%, 14% and 3% had grade I (E/A <0.75, regardless of E/E(m)), II (E/A 0.75-1.5 and E/E(m) >= 10) and III (E/A >1.5 and E/E(m) >= 10) LVDD, respectively. Those with LVDD were older (77 versus 73 years; p = 0.001) and had a trend for higher prevalence of cardiovascular morbidity (58% versus 40%; p = 0.083). LVDD negatively correlated with six-minute walk distance (1013 versus 1128 feet; R = -0.25; p = 0.017). This association remained significant despite adjustment for cardiovascular morbidity (R = -0.35; p = 0.048), but lost significance when adjusted for age (R = -0.32; p = 0.105), age and cardiovascular morbidity (R = -0.38; p = 0.161), and additional adjustment for sex, race, body mass index, and systolic blood pressure (R = -0.44; p = 0.365). In conclusion, most community-dwelling older adults without heart failure had normal left ventricular diastolic function or grade-I LVDD. Although LVDD was associated with decreased performance on a six-minute walk test, that association was no longer evident after adjustment for age, body mass index and cardiovascular morbidity. Published by Elsevier Inc. (Am J Cardiol 2011;108:735-740) C1 [Perry, Gilbert J.; Tallaj, Jose; Allman, Richard M.; Ahmed, Ali] VA Med Ctr, Birmingham, AL USA. [Perry, Gilbert J.; Ahmed, Mustafa I.; Mujib, Marjan; Aban, Inmaculada B.; Zhang, Yan; Tallaj, Jose; Allman, Richard M.; Ahmed, Ali] Univ Alabama, Birmingham, AL USA. [Desai, Ravi V.] Lehigh Valley Hosp, Allentown, PA USA. [Zile, Michael] Med Univ S Carolina, Charleston, SC 29425 USA. [Sui, Xuemei] Univ S Carolina, Columbia, SC 29208 USA. [Aronow, Wilbert S.] New York Med Coll, Valhalla, NY 10595 USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. RP Ahmed, A (reprint author), VA Med Ctr, Birmingham, AL USA. EM aahmed@uab.edu RI Mujib, Marjan/J-2709-2013 OI Mujib, Marjan/0000-0002-3261-8599 FU National Heart, Lung, and Blood Institute/National Institutes of Health, Bethesda, Maryland [R01-HL085561, R01-HL097047] FX Dr. Ahmed is supported by Grants R01-HL085561 and R01-HL097047 from the National Heart, Lung, and Blood Institute/National Institutes of Health, Bethesda, Maryland and a generous gift from Ms. Jean B. Morris, Birmingham, Alabama. NR 26 TC 6 Z9 6 U1 0 U2 4 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 SEP 1 PY 2011 VL 108 IS 5 BP 735 EP 740 DI 10.1016/j.amjcard.2011.04.025 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 818KQ UT WOS:000294751000021 PM 21704282 ER PT J AU Ooi, WW Wijemanne, S Thomas, CB Quezado, M Brown, CR Nash, TE AF Ooi, Winnie W. Wijemanne, Subhashie Thomas, Christine B. Quezado, Martha Brown, Charles R. Nash, Theodore E. TI Short Report: A Calcified Taenia solium Granuloma Associated with Recurrent Perilesional Edema Causing Refractory Seizures: Histopathological Features SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID NEUROCYSTICERCOSIS LESIONS; EPILEPSY; CALCIFICATIONS; INFLAMMATION AB We describe the first detailed histological description of an excised calcified Taenia solium granuloma from a patient who developed recurrent seizures associated with perilesional edema surrounding a calcified cysticercus (PEC). The capsule, around a degenerated cysticercus, contained marked mononuclear infiltrates that extended to adjacent brain, which showed marked astrocytosis, microgliosis, and inflammatory perivascular infiltrates. The presence of large numbers of mononuclear cells supports an inflammatory cause of PEC. Immunosuppression or anti-inflammatory measures may be able to treat and prevent PEC and recurrent seizures. C1 [Nash, Theodore E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Ooi, Winnie W.] Laicy Clin, Dept Infect Dis, Burlington, MA USA. [Wijemanne, Subhashie] Lahey Clin Fdn, Dept Neurol, Burlington, MA USA. [Thomas, Christine B.] Lahey Clin Fdn, Dept Clin Pathol, Burlington, MA USA. [Quezado, Martha] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Brown, Charles R.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Nash, TE (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4, Bethesda, MD 20892 USA. EM Winnie.W.Ooi@lahey.org; tnash@niaid.nih.gov FU Lahey Clinic; National Institutes of Allergy and Infectious Diseases at the National Institutes of Health FX The authors would like to thank Dr. Grace Lee of Lahey Clinic for her help and support in preparing this manuscript.; Support for this study was received from the intramural National Institutes of Allergy and Infectious Diseases at the National Institutes of Health. NR 30 TC 18 Z9 19 U1 0 U2 4 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD SEP PY 2011 VL 85 IS 3 BP 460 EP 463 DI 10.4269/ajtmh.2011.11-0221 PG 4 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 816EL UT WOS:000294581400014 PM 21896805 ER PT J AU Hendler, RW Meuse, CW Braiman, MS Smith, PD Kakareka, JW AF Hendler, Richard W. Meuse, Curtis W. Braiman, Mark S. Smith, Paul D. Kakareka, John W. TI Infrared and Visible Absolute and Difference Spectra of Bacteriorhodopsin Photocycle Intermediates SO APPLIED SPECTROSCOPY LA English DT Article DE Kinetic analysis; Reversible homogeneous model; Parallel cycles; Arginine 82 deprotonation; Proton release group; PRG; Flash photolysis; Purple membrane; Infrared spectroscopy ID RESONANCE RAMAN-SPECTRA; PROTON-RELEASE GROUP; ACID SIDE-CHAINS; PURPLE MEMBRANE; HALOBACTERIUM-SALINARIUM; CHROMOPHORE STRUCTURE; PARALLEL PHOTOCYCLES; AQUEOUS-SOLUTIONS; N-INTERMEDIATE; KINETIC-MODELS AB We have used new kinetic fitting procedures to obtain infrared (IR) absolute spectra for intermediates of the main bacteriorhodopsin (bR) photocycle(s). The linear-algebra-based procedures of Hendler et al. (J. Phys. Chem. B, 105,3319-3228(2001)) for obtaining clean absolute visible spectra of bR photocycle intermediates were adapted for use with IR data. This led to isolation, for the first time, of corresponding clean absolute IR spectra, including the separation of the M intermediate into its M-F and M-S components from parallel photocycles. This in turn permitted the computation of clean IR difference spectra between pairs of successive intermediates, allowing for the most rigorous analysis to date of changes occurring at each step of the photocycle. The statistical accuracy of the spectral calculation methods allows us to identify, with great confidence, new spectral features. One of these is a very strong differential IR band at 1650 cm(-1) for the L intermediate at room temperature that is not present in analogous L spectra measured at cryogenic temperatures. This band, in one of the noisiest spectral regions, has not been identified in any previous time-resolved ER papers, although retrospectively it is apparent as one of the strongest L absorbance changes in their raw data, considered collectively. Additionally, our results are most consistent with Arg82 as the primary proton-release group (PRG), rather than a protonated water cluster or H-bonded grouping of carboxylic residues. Notably, the Arg82 deprotonation occurs exclusively in the M-F pathway of the parallel cycles model of the photocycle. C1 [Hendler, Richard W.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Hendler, Richard W.; Meuse, Curtis W.] NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. [Braiman, Mark S.] Syracuse Univ, Dept Chem, Syracuse, NY 13244 USA. [Smith, Paul D.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Kakareka, John W.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Hendler, RW (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM rwh@helix.nih.gov; mbraiman@syr.edu OI Kakareka, John/0000-0003-0072-0035 FU Intramural NIH HHS [ZIA HL000518-10] NR 60 TC 4 Z9 4 U1 1 U2 17 PU SOC APPLIED SPECTROSCOPY PI FREDERICK PA 5320 SPECTRUM DRIVE SUITE C, FREDERICK, MD 21703 USA SN 0003-7028 J9 APPL SPECTROSC JI Appl. Spectrosc. PD SEP PY 2011 VL 65 IS 9 BP 1029 EP 1045 DI 10.1366/11-06302 PG 17 WC Instruments & Instrumentation; Spectroscopy SC Instruments & Instrumentation; Spectroscopy GA 819MV UT WOS:000294831900010 PM 21929858 ER PT J AU Campbell, NRC Gilbert, RE Leiter, LA Larochelle, P Tobe, S Chockalingam, A Ward, R Morris, D Tsuyuki, RT Harris, SB AF Campbell, Norm R. C. Gilbert, Richard E. Leiter, Lawrence A. Larochelle, Pierre Tobe, Sheldon Chockalingam, Arun Ward, Richard Morris, Dorothy Tsuyuki, Ross T. Harris, Stewart B. TI Hypertension in people with type 2 diabetes Update on pharmacologic management SO CANADIAN FAMILY PHYSICIAN LA English DT Review ID BLOOD-PRESSURE CONTROL; RANDOMIZED CONTROLLED-TRIAL; HIGH-RISK PATIENTS; LOW-DOSE ASPIRIN; CARDIOVASCULAR EVENTS; EDUCATION-PROGRAM; MICROVASCULAR COMPLICATIONS; SYSTOLIC HYPERTENSION; OUTCOMES; MELLITUS AB Objective To summarize the evidence for the need to improve pharmacologic management of hypertension in people with type 2 diabetes and to provide expert advice on how blood pressure (BP) treatment can be improved in primary care. Sources of information Studies were obtained by performing a systematic review of the literature on hypertension and diabetes, from which management recommendations were developed, reviewed, and voted on by a group of experts selected by the Canadian Hypertension Education Program and the Canadian Diabetes Association; authors' expert opinions on optimal pharmacologic management were also considered during this process. Main message The pathogenesis of hypertension in patients with diabetes is complex, involving a range of biological and environmental factors and genetic predisposition; as a result, hypertension in people with diabetes incurs higher associated risks and adverse events. Mortality and morbidity are heightened in diabetes patients who do not achieve BP control (ie, a target value of less than 130/80 mm Hg). Large randomized controlled trials and meta-analyses of randomized controlled trials have shown that reducing BP pharmacologically is single-handedly the most effective way to reduce rates of death and disability in patients with diabetes, particularly associated cardiovascular risks. Often, combinations of 2 or more drugs (diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, angiotensin receptor blockers, calcium channel blockers, spironolactone, etc) are required for pharmacotherapy to be effective, particularly for patients in whom BP is difficult to control. However, the health care costs associated with extensively lowering BP are substantially less than the costs associated with treating the complications that can be prevented by lowering BP. Conclusion Detecting and managing hypertension in people with diabetes is one of the most effective measures to prevent adverse events, and pharmacotherapy is one of the most effective ways to maintain target BP levels in primary care. C1 [Campbell, Norm R. C.] Univ Calgary, Libin Cardiovasc Inst Alberta, Fac Med, Calgary, AB T2N 4Z6, Canada. [Gilbert, Richard E.; Leiter, Lawrence A.; Tobe, Sheldon] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Larochelle, Pierre] Ctr Hosp Univ Montreal, Quebec City, PQ, Canada. [Larochelle, Pierre] Inst Rech Clin Montreal, Montreal, PQ, Canada. [Chockalingam, Arun] NHLBI, Off Global Hlth, NIH, Bethesda, MD 20892 USA. [Ward, Richard] Univ Calgary, Dept Family Med, Calgary, AB T2N 1N4, Canada. [Morris, Dorothy] Vancouver Isl Hlth Author, Canadian Council Cardiovasc Nurses, Victoria, BC, Canada. [Tsuyuki, Ross T.] Univ Alberta, Div Cardiol, Fac Med & Dent, EPICORE Ctr, Edmonton, AB, Canada. [Harris, Stewart B.] Univ Western Ontario, Schulich Sch Med & Dent, London, ON N6A 3K7, Canada. RP Campbell, NRC (reprint author), Univ Calgary, Libin Cardiovasc Inst Alberta, Fac Med, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM hyperten@ucalgary.ca RI Tsuyuki, Ross/E-2462-2016 OI Tsuyuki, Ross/0000-0002-3724-598X FU Pfizer; Merck; Boehringer Ingelheim; Servier; AstraZeneca; Abbott Laboratories; Bayer; Bristol-Myers Squibb; Janssen; Novartis; Sanofi-Aventis; Novo Nordisk FX Dr Gilbert has served on advisory boards, received research grant funding, and given lectures for AstraZeneca, Bristol-Myers Squibb, and Novartis. Dr Leiter has received research funding from, has provided continuing medical education on behalf of, or has acted as a consultant to Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Novo Nordisk, Roche, Sanofi-Aventis, and Servier. Dr Larochelle has received support for continuing education and research grants from Pfizer, Merck, Boehringer Ingelheim, Servier, and AstraZeneca. Dr Tobe has received research grants and speaker's honoraria from Abbott Laboratories, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, Pfizer, Sanofi-Aventis, and Servier. Dr Ward has received funding from AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi-Aventis, and Pfizer. None of the other authors has any competing interests to declare. NR 43 TC 21 Z9 21 U1 1 U2 4 PU COLL FAMILY PHYSICIANS CANADA PI MISSISSAUGA PA 2630 SKYMARK AVE, MISSISSAUGA, ONTARIO L4W 5A4, CANADA SN 0008-350X J9 CAN FAM PHYSICIAN JI Can. Fam. Phys. PD SEP PY 2011 VL 57 IS 9 BP 997 EP 1002 PG 6 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 819RL UT WOS:000294847200013 PM 21918140 ER PT J AU Qin, J Zhang, B AF Qin, Jing Zhang, Biao TI Optimal estimating functions in incomplete data and length biased sampling data problems SO CANADIAN JOURNAL OF STATISTICS-REVUE CANADIENNE DE STATISTIQUE LA English DT Article DE Covariate-missing; length biased sampling; likelihood; missing at random; mis-specification; robustness ID NONPARAMETRIC-ESTIMATION; PARAMETERS; MODELS AB It is well known that the score function is the optimal estimating function among all regular unbiased estimating functions (Godambe, 1960). In the presence of incomplete data such as missing data or length biased sampling data, Horvitz and Thompson's (1952) method is an effective way of eliminating the possible bias induced by using complete data only. In this article, we show that the inverse weighted Horvitz and Thompson score estimating function is not optimal in the presence of incomplete data. By using Godambe's estimating function theory, we can identify the optimal estimating function in this situation. In the case of the accelerated failure time model with length bias sampling data, the optimal estimating function can produce an unbiased estimator for the slope parameter even when the underlying density function is misspecified. Simulation studies show that the estimate derived from the optimal estimating function can be substantially better than the estimate derived from the inverse weighted score estimating function. The Canadian Journal of Statistics 39: 510-518; 2011 (C) 2011 Statistical Society of Canada C1 [Qin, Jing] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Zhang, Biao] Univ Toledo, Dept Math, Toledo, OH 43606 USA. RP Qin, J (reprint author), NIAID, Biostat Res Branch, NIH, 6700B Rockledge Dr,MSC 7609, Bethesda, MD 20892 USA. EM jingqin@niaid.nih.gov NR 18 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0319-5724 J9 CAN J STAT JI Can. J. Stat.-Rev. Can. Stat. PD SEP PY 2011 VL 39 IS 3 SI SI BP 510 EP 518 PG 9 WC Statistics & Probability SC Mathematics GA 816GV UT WOS:000294587600010 ER PT J AU Albanes, D Mondul, AM Yu, K Parisi, D Horst, RL Virtamo, J Weinstein, SJ AF Albanes, Demetrius Mondul, Alison M. Yu, Kai Parisi, Dominick Horst, Ronald L. Virtamo, Jarmo Weinstein, Stephanie J. TI Serum 25-Hydroxy Vitamin D and Prostate Cancer Risk in a Large Nested Case-Control Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; MALE SMOKERS; PANCREATIC-CANCER; UNITED-STATES; INSULIN-RESISTANCE; SUBSEQUENT RISK; BETA-CAROTENE; TRIAL; CALCIUM; 1,25-DIHYDROXYVITAMIN-D AB Background: Vitamin D compounds inhibit prostate tumorigenesis experimentally, but epidemiologic data are inconsistent with respect to prostate cancer risk, with some studies suggesting nonsignificant positive associations. Methods: The 25-hydroxy vitamin D [25(OH)D]-prostate cancer relation was examined in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 50- to 69-year-old Finnish men. We matched 1,000 controls to 1,000 cases diagnosed during up to 20 years of follow-up on the basis of age (+/- 1 year) and fasting blood collection date (+/- 30 days). Conditional multivariate logistic regression models estimated ORs and 95% CIs. All statistical significance testing was 2-sided. Results: Cases had nonsignificantly 3% higher serum 25(OH)D levels (P = 0.19). ORs (95% CIs) for increasing season-specific quintiles of 25(OH)D concentrations were 1.00 (reference), 1.29 (0.95-1.74), 1.34 (1.00-1.80), 1.26 (0.93-1.72), and 1.56 (1.15-2.12), with P(trend) = 0.01. Analyses based on prespecified clinical categories and season-adjusted values yielded similar results. These findings seemed stronger for aggressive disease [OR (95% CI) for fifth quintile of serum 25(OH)D [1.70 (1.05-2.76), P(trend) = 0.02], among men with greater physical activity [1.85 (1.26-2.72), P(trend) = 0.002], higher concentrations of serum total cholesterol [2.09 (1.36-3.21), P(trend) = 0.003] or alpha-tocopherol [2.00 (1.30-3.07), P(trend) = 0.01] and higher intakes of total calcium [1.82 (1.20-2.76), P(trend) = 0.01] or vitamin D [1.69 (1.04-2.75), P(trend) = 0.08], or among those who had received the trial a-tocopherol supplements [1.74 (1.15-2.64), P(trend) = 0.006]. Conclusion: Our findings indicate that men with higher vitamin D blood levels are at increased risk of developing prostate cancer. Impact: Greater caution is warranted with respect to recommendations for high-dose vitamin D supplementation and higher population target blood levels. Cancer Epidemiol Biomarkers Prev; 20(9); 1850-60. (C)2011 AACR. C1 [Albanes, Demetrius; Mondul, Alison M.; Weinstein, Stephanie J.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20982 USA. [Yu, Kai] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20982 USA. [Parisi, Dominick] Informat Management Serv Inc, Silver Spring, MD USA. [Horst, Ronald L.] Heartland Assays Inc, Ames, IA USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Albanes, D (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Suite 320, Bethesda, MD 20982 USA. EM daa@nih.gov RI Albanes, Demetrius/B-9749-2015; OI Mondul, Alison/0000-0002-8843-1416 FU U.S. Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; National Cancer Institute, Department of Health and Human Services; National Cancer Institute FX The ATBC Study was supported in part by U.S. Public Health Service (contract numbers N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute, Department of Health and Human Services, and Intramural Research Program of the National Cancer Institute. NR 50 TC 53 Z9 54 U1 1 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2011 VL 20 IS 9 BP 1850 EP 1860 DI 10.1158/1055-9965.EPI-11-0403 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 816NN UT WOS:000294609200006 PM 21784952 ER PT J AU Chaturvedi, AK Kemp, TJ Pfeiffer, RM Biancotto, A Williams, M Munuo, S Purdue, MP Hsing, AW Pinto, L McCoy, JP Hildesheim, A AF Chaturvedi, Anil K. Kemp, Troy J. Pfeiffer, Ruth M. Biancotto, Angelique Williams, Marcus Munuo, Stella Purdue, Mark P. Hsing, Ann W. Pinto, Ligia McCoy, J. Philip Hildesheim, Allan TI Evaluation of Multiplexed Cytokine and Inflammation Marker Measurements: a Methodologic Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BEAD ARRAY ASSAYS; CANCER; REPRODUCIBILITY; SENSITIVITY; PLATFORMS; PLASMA; ELISA; SERUM; KITS AB Background: Chronic inflammation is etiologically related to several cancers. We evaluated the performance [ability to detect concentrations above the assay's lower limit of detection, coefficients of variation (CV), and intraclass correlation coefficients (ICC)] of 116 inflammation, immune, and metabolic markers across two Luminex bead-based commercial kits and three specimen types. Methods: From 100 cancer-free participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Trial, serum, heparin plasma, and EDTA plasma samples were utilized. We measured levels of 67 and 97 markers using Bio-Rad and Millipore kits, respectively. Reproducibility was assessed using 40 blinded duplicates (20 within-batches and 20 across-batches) for each specimen type. Results: A majority of markers were detectable in more than 25% of individuals on all specimen types/kits. Of the 67 Bio-Rad markers, 51, 52, and 47 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs of less than 20%. Likewise, of 97 Millipore markers, 75, 69, and 78 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs of less than 20%. When results were combined across specimen types, 45 Bio-Rad and 71 Millipore markers had acceptable performance (>25% detectability on all three specimen types and across-batch CVs <20% on at least two of three specimen types). Median concentrations and ICCs differed to a small extent across specimen types and to a large extent between Bio-Rad and Millipore. Conclusions: Inflammation and immune markers can be measured reliably in serum and plasma samples using multiplexed Luminex-based methods. Impact: Multiplexed assays can be utilized for epidemiologic investigations into the role of inflammation in cancer etiology. Cancer Epidemiol Biomarkers Prev; 20(9); 1902-11. (C)2011 AACR. C1 [Chaturvedi, Anil K.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Munuo, Stella] Informat Management Serv Inc, Rockville, MD USA. [Kemp, Troy J.; Williams, Marcus; Pinto, Ligia] NCI, HPV Immunol Lab, SAIC, Frederick, MD 21701 USA. [Biancotto, Angelique; McCoy, J. Philip] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. RP Chaturvedi, AK (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7072, Rockville, MD 20852 USA. EM chaturva@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Hildesheim, Allan/B-9760-2015; Purdue, Mark/C-9228-2016; Chaturvedi, Anil/J-2024-2015 OI Hildesheim, Allan/0000-0003-0257-2363; Purdue, Mark/0000-0003-1177-3108; Chaturvedi, Anil/0000-0003-2696-8899 FU Intramural NIH HHS [Z99 HL999999, ZIC HL005905-02, ZIC HL005905-03, ZIC HL005905-04] NR 22 TC 44 Z9 44 U1 3 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 SEP PY 2011 VL 20 IS 9 BP 1902 EP 1911 DI 10.1158/1055-9965.EPI-11-0221 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 816NN UT WOS:000294609200012 PM 21715603 ER PT J AU Vermeulen, R Hosnijeh, FS Portengen, L Krogh, V Palli, D Panico, S Tumino, R Sacredote, C Purdue, M Lan, Q Rothman, N Vineis, P AF Vermeulen, Roel Hosnijeh, Fatemeh Saberi Portengen, Luetzen Krogh, Vittorio Palli, Domenico Panico, Salvatore Tumino, Rosario Sacredote, Carlotta Purdue, Mark Lan, Qing Rothman, Nathaniel Vineis, Paolo TI Circulating Soluble CD30 and Future Risk of Lymphoma; Evidence from Two Prospective Studies in the General Population SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NON-HODGKIN-LYMPHOMA; NUTRITION; CANCER AB Background: Elevated circulating soluble CD30 (sCD30) has been previously associated with AIDS-related non-Hodgkin lymphoma (NHL) risk. This finding was recently extended to the general population where elevated levels of sCD30 were reported in prediagnostic serum among subjects that developed NHL later in life. Methods: We carried out a replication study within the Italian European Prospective Investigation into Cancer and Nutrition cohort. Plasma sCD30 concentration was measured by ELISA in prospectively collected blood of 35 B-cell lymphoma cases and 36 matched controls. Results: We observed significantly increased relative risks for lymphoma with increasing sCD30 levels [OR (95% CI) for second and third tertiles vs. first tertile: 5.5 (1.5-20.2), 4.0 (1.1-13.9), respectively]. In addition, spline analyses showed that the dose-response curve of sCD30 and lymphoma risk was monotonic and quite similar to the risks reported in the previous study. Conclusion: This replication study adds to the evidence that sCD30 is related to future lymphoma risk in a concentration-dependent manner in the general population. Impact: The results of this study strengthen the observation that chronic sustained B-cell activation plays an important role in lymphomagenesis. Cancer Epidemiol Biomarkers Prev; 20(9); 1925-7. (C)2011 AACR. C1 [Vermeulen, Roel; Hosnijeh, Fatemeh Saberi; Portengen, Luetzen] Univ Utrecht, Div Environm Epidemiol, Inst Risk Assessment Sci, NL-3584 CK Utrecht, Netherlands. [Hosnijeh, Fatemeh Saberi] Zanjan Univ Med Sci, Zanjan, Iran. [Krogh, Vittorio] Natl Canc Inst, Nutr Epidemiol Unit, I-20133 Milan, Italy. [Palli, Domenico] Sci Inst Tuscany, Canc Res & Prevent Ctr, Mol & Nutr Epidemiol Unit, Florence, Italy. [Panico, Salvatore] Univ Naples Federico 2, Dept Clin & Expt Med, Naples, Italy. [Tumino, Rosario] Ragusa Canc Registry, Ragusa, Italy. [Sacredote, Carlotta; Vineis, Paolo] Human Genet Fdn, Turin, Italy. [Purdue, Mark; Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. RP Vermeulen, R (reprint author), Univ Utrecht, Div Environm Epidemiol, Inst Risk Assessment Sci, Jenalaan 18D, NL-3584 CK Utrecht, Netherlands. EM R.C.H.Vermeulen@uu.nl RI Vermeulen, Roel/F-8037-2011; Krogh, Vittorio/K-2628-2016; Panico, Salvatore/K-6506-2016; Saberi Hosnijeh, Fatemeh/N-6684-2013; OI Vermeulen, Roel/0000-0003-4082-8163; Krogh, Vittorio/0000-0003-0122-8624; Panico, Salvatore/0000-0002-5498-8312; PALLI, Domenico/0000-0002-5558-2437 NR 12 TC 10 Z9 10 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2011 VL 20 IS 9 BP 1925 EP 1927 DI 10.1158/1055-9965.EPI-11-0396 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 816NN UT WOS:000294609200015 PM 21784955 ER PT J AU Lin, DW FitzGerald, LM Fu, R Kwon, EM Zheng, SL Kolb, S Wiklund, F Stattin, P Isaacs, WB Xu, JF Ostrander, EA Feng, ZD Gronberg, H Stanford, JL AF Lin, Daniel W. FitzGerald, Liesel M. Fu, Rong Kwon, Erika M. Zheng, Siqun Lilly Kolb, Suzanne Wiklund, Fredrik Stattin, Paer Isaacs, William B. Xu, Jianfeng Ostrander, Elaine A. Feng, Ziding Groenberg, Henrik Stanford, Janet L. TI Genetic Variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF Genes Are Prognostic Markers of Prostate Cancer-Specific Mortality SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; POPULATION-BASED COHORT; RADICAL PROSTATECTOMY; SUSCEPTIBILITY VARIANTS; METASTATIC PROGRESSION; PREOPERATIVE NOMOGRAM; SIGNALING PATHWAY; TUMOR-SUPPRESSOR; CARCINOMA-CELLS; BONE METASTASIS AB Background: Prostate cancer is the second leading cause of cancer-related deaths in men, accounting for more than 30,000 deaths annually. The purpose of this study was to test whether variation in selected candidate genes in biological pathways of interest for prostate cancer progression could help distinguish patients at higher risk for fatal prostate cancer. Methods: In this hypothesis-driven study, we genotyped 937 single nucleotide polymorphisms (SNPs) in 156 candidate genes in a population-based cohort of 1,309 prostate cancer patients. We identified 22 top-ranking SNPs (P <= 0.01, FDR <= 0.70) associated with prostate cancer-specific mortality (PCSM). A subsequent validation study was completed in an independent population-based cohort of 2,875 prostate cancer patients. Results: Five SNPs were validated (P <= 0.05) as being significantly associated with PCSM, one each in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes. Compared with patients with 0 to 2 of the at-risk genotypes those with 4 to 5 at-risk genotypes had a 50% (95% CI, 1.2-1.9) higher risk of PCSM and risk increased with the number of at-risk genotypes carried (P(trend) = 0.001), adjusting for clinicopathologic factors known to influence prognosis. Conclusion: Five genetic markers were validated to be associated with lethal prostate cancer. Impact: This is the first population-based study to show that germline genetic variants provide prognostic information for prostate cancer-specific survival. The clinical utility of this five-SNP panel to stratify patients at higher risk for adverse outcomes should be evaluated. Cancer Epidemiol Biomarkers Prev; 20(9); 1928-36. (C)2011 AACR. C1 [Lin, Daniel W.; FitzGerald, Liesel M.; Fu, Rong; Kolb, Suzanne; Feng, Ziding; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Lin, Daniel W.] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Fu, Rong; Feng, Ziding] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Kwon, Erika M.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Zheng, Siqun Lilly; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Zheng, Siqun Lilly; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. [Wiklund, Fredrik; Groenberg, Henrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Stattin, Paer] Umea Univ, Dept Surg & Preoperat Sci Urol & Androl, Umea, Sweden. [Isaacs, William B.] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Stanford, JL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Mailstop M4-B874,POB 19024, Seattle, WA 98109 USA. EM jstanfor@fhcrc.org OI Ostrander, Elaine/0000-0001-6075-9738 FU National Cancer Institute at the NIH [RO1 CA056678, R01 CA092579, R03 CA121871, RO3 CA137799, RO1 CA133009, RO1 CA129684, P50 CA097186]; Fred Hutchinson Cancer Research Center; National Human Genome Research Institute; Cancer Risk Prediction Center (CRisP); Linneus Centre [70867902]; Swedish Research Council [K2010-70X-20430-04-3]; Swedish Cancer Foundation [09-0677]; Hedlund Foundation; Soderberg Foundation; Enqvist Foundation; Stockholm County Council FX This work was supported by grants RO1 CA056678 (J.L. Stanford), R01 CA092579 (J.L. Stanford), R03 CA121871 (J.L. Stanford), RO3 CA137799 (J.L. Stanford), RO1 CA133009 (S.L. Zheng), RO1 CA129684 (J. Xu) and P50 CA097186 from the National Cancer Institute at the NIH. Additional support was provided by the Fred Hutchinson Cancer Research Center, the Intramural Program of the National Human Genome Research Institute, the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linneus Centre (contract 70867902) financed by the Swedish Research Council, the Swedish Research Council (grant K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant 09-0677), the Hedlund Foundation, the Soderberg Foundation, the Enqvist Foundation, and ALF funds from the Stockholm County Council. NR 72 TC 40 Z9 41 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 SEP PY 2011 VL 20 IS 9 BP 1928 EP 1936 DI 10.1158/1055-9965.EPI-11-0236 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 816NN UT WOS:000294609200016 PM 21846818 ER PT J AU Liao, LM Baccarelli, A Shu, XO Gao, YT Ji, BT Yang, G Li, HL Hoxha, M Dioni, L Rothman, N Zheng, W Chow, WH AF Liao, Linda M. Baccarelli, Andrea Shu, Xiao-Ou Gao, Yu-Tang Ji, Bu-Tian Yang, Gong Li, Hong-Lan Hoxha, Mirjam Dioni, Laura Rothman, Nathaniel Zheng, Wei Chow, Wong-Ho TI Mitochondrial DNA Copy Number and Risk of Gastric Cancer: a Report from the Shanghai Women's Health Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN-DISEASE; GENETIC INSTABILITY; SOMATIC MUTATIONS; OXIDATIVE STRESS; CARCINOMA; DEPLETION; GENOME; CELLS AB Background: Mitochondrial DNA (mtDNA) is an approximately 16,000-bp circular double-stranded DNA molecule that is a prime target of oxidative damage. Several somatic mutations in mtDNA have been observed in gastric tumors, suggesting an involvement in gastric cancer risk and progression. mtDNA copy number in leukocyte DNA has also been linked to several other cancers, although the temporal relationship between mtDNA and cancer has not been adequately explored. Methods: Using a nested case-control study design, we examined the association between mtDNA copy number in 162 gastric cancer cases and 299 matched controls within the Shanghai Women's Health Study, a large population-based prospective cohort. Relative mtDNA copy number was measured in triplicate by a quantitative real-time PCR assay in peripheral leukocytes. Results: mtDNA copy number levels were comparable among cases and controls, with a median of 1.04 [interquartile range (IQR), 0.87-1.25] and 1.06 (IQR, 0.88-1.29), respectively. Overall, mtDNA was not associated with gastric cancer risk. However, the association differed when stratified by the time between sample collection and cancer diagnosis. An association between low levels of mtDNA copy number (100 (41% versus 34%, P = 0.03) and CAC >400 (26% versus 19%, P = 0.02). However, after adjusting for sociodemographic factors, these differences were no longer significant. In adjusted analyses, Hispanics had a higher odds of LVH compared with non-Hispanic Caucasians (odds ratio 1.97, 95% confidence interval, 1.22 to 3.17, P = 0.005), and a higher odds of CAC >400 compared with non-Hispanic African Americans (odds ratio, 2.49, 95% confidence interval, 1.11 to 5.58, P = 0.03). Hispanic ethnicity was not independently associated with any other CVD measures. Conclusions Prevalent LVH was more common among Hispanics than non-Hispanic Caucasians, and elevated CAC score was more common among Hispanics than non-Hispanic African Americans. Understanding reasons for these racial/ethnic differences and their association with long-term clinical outcomes is needed. Clin J Am Soc Nephrol 6: 2121-2131, 2011. doi:10.2215/CJN.11341210 C1 [Lash, James P.] Univ Illinois, Dept Med, Sect Nephrol MC 793, Chicago, IL 60612 USA. [Fischer, Michael J.] Jesse Brown VAMC, Ctr Management Complex Chron Care, Chicago, IL USA. [Budoff, Matthew] Harbor UCLA, Los Angels Biomed Res Inst, Torrance, CA USA. [Keane, Martin G.; Feldman, Harold I.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Kusek, John W.] NIDDK, NIH, Bethesda, MD USA. [Nessel, Lisa; Yang, Wei; Feldman, Harold I.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Ojo, Akinlolu] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Rahman, Mahboob] Case Western Univ, Dept Med, Cleveland, OH USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol, Div Publ Hlth Sci, Winston Salem, NC USA. [Go, Alan S.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Fischer, Michael J.] Edward Hines VA, Chicago, IL USA. RP Lash, JP (reprint author), Univ Illinois, Dept Med, Sect Nephrol MC 793, 820 S Wood St,Room 416W, Chicago, IL 60612 USA. EM jplash@uic.edu RI Yang, Wei/A-9223-2009 OI Yang, Wei/0000-0001-8984-4389 FU National Institute of Digestive, Diabetes and Kidney Diseases [R01 DK072231, U01 DK060980, U01 DK060902, R01DK072231, U01DK082223]; University of Illinois at Chicago (UIC) Center for Clinical and Translational Science (CCTS), National Center for Research Resources [UL1RR029879]; Department of Veterans Affairs (VA); National Heart, Lung and Blood Institute [U19HL091179] FX James P. Lash received relevant support from the National Institute of Digestive, Diabetes and Kidney Diseases (R01 DK072231, U01 DK060980). Ana C. Ricardo received research support from the University of Illinois at Chicago (UIC) Center for Clinical and Translational Science (CCTS), Award Number UL1RR029879 from the National Center for Research Resources. Claudia Lora received research support from the University of Illinois at Chicago (UIC) Center for Clinical and Translational Science (CCTS) KL2 Scholars Program, Award Number UL1RR029879 from the National Center for Research Resources. Michael Fischer received support from a Department of Veterans Affairs (VA) Health Services Research and Development (HSR&D) Career Development Award. Alan S. Go received relevant support from the National Institute of Digestive, Diabetes and Kidney Diseases (U01 DK060902, R01DK072231, U01DK082223), and the National Heart, Lung and Blood Institute (U19HL091179). NR 43 TC 10 Z9 11 U1 0 U2 6 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 SEP PY 2011 VL 6 IS 9 BP 2121 EP 2131 DI 10.2215/CJN.11341210 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 817EN UT WOS:000294654200006 PM 21896829 ER PT J AU Furth, SL Abraham, AG Jerry-Fluker, J Schwartz, GJ Benfield, M Kaskel, F Wong, C Mak, RH Moxey-Mims, M Warady, BA AF Furth, Susan L. Abraham, Alison G. Jerry-Fluker, Judith Schwartz, George J. Benfield, Mark Kaskel, Frederick Wong, Craig Mak, Robert H. Moxey-Mims, Marva Warady, Bradley A. TI Metabolic Abnormalities, Cardiovascular Disease Risk Factors, and GFR Decline in Children with Chronic Kidney Disease SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; LEFT-VENTRICULAR MASS; PROSPECTIVE COHORT; DIALYSIS PATIENTS; ADOLESCENTS; CKD; HOSPITALIZATION; ASSOCIATION AB Background and objectives Metabolic abnormalities and cardiovascular disease (CVD) risk factors have rarely been systematically assessed in children with chronic kidney disease (CKD). We examined the prevalence of various CKD sequelae across the GFR spectrum. Design, setting, participants, & measurements Data were used from 586 children participating in the Chronic Kidney Disease in Children (CKiD) study (United States and Canada) with GFR measured by iohexol plasma disappearance. Laboratory values and CVD risk factors were compared across GFR categories and with an age-, gender-, and race-matched community sample. Results CKiD participants were 62% male, 66% Caucasian, 23% African American, and 15% Hispanic with a median age of 11 years and a median GFR of 44 ml/min per 1.73 m(2). Compared with those with a GFR 50 ml/min per 1.73 m(2), having a GFR <30 ml/min per 1.73 m(2) was associated with a three-fold higher risk of acidosis and growth failure and a four- to five-fold higher risk of anemia and elevated potassium and phosphate. Median GFR change was 4.3 ml/min per 1.73 m(2) and 1.5 ml/min per 1.73 m(2) per year in children with glomerular and nonglomerular diagnoses, respectively. Despite medication and access to nephrology care, uncontrolled systolic hypertension was present in 14%, and 16% had left ventricular hypertrophy. Children with CKD frequently were also shorter and had lower birth weight, on average, compared with norms. Conclusions Growth failure, metabolic abnormalities, and CVD risk factors are present at GFR >50 ml/min per 1.73 m(2) in children with CKD and, despite therapy, increase in prevalence two- to four-fold with decreasing GFR. Clin J Am Soc Nephrol 6: 2132-2140, 2011. doi:10.2215/CJN.07100810 C1 [Furth, Susan L.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Furth, Susan L.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Abraham, Alison G.; Jerry-Fluker, Judith] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Schwartz, George J.] Univ Rochester, Med Ctr, Dept Pediat, Rochester, NY 14642 USA. [Benfield, Mark] Univ Alabama, Birmingham, AL USA. [Kaskel, Frederick] Albert Einstein Yeshiva Univ, Montefiore Med Ctr, Bronx, NY USA. [Wong, Craig] Univ New Mexico, Albuquerque, NM 87131 USA. [Mak, Robert H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Moxey-Mims, Marva] NIDDK, NIH, Bethesda, MD USA. [Warady, Bradley A.] Univ Missouri, Childrens Mercy Hosp, Dept Pediat, Kansas City, MO 64108 USA. RP Furth, SL (reprint author), Childrens Hosp Philadelphia, Dept Pediat, 34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM Furths@email.chop.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; National institute of Neurologic Disorders and Stroke; National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute FX The CKiD prospective cohort study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases, with additional funding from the National institute of Neurologic Disorders and Stroke; the National Institute of Child Health and Human Development; and the National Heart, Lung, and Blood Institute. The CKiD prospective cohort study has clinical coordinating centers (principal investigators) at Children's Mercy Hospital and the University of Missouri Kansas City (Bradley Warady, MD) and Children's Hospital of Philadelphia and the University of Pennsylvania (Susan Furth, MD, PhD), a Central Biochemistry Laboratory at the University of Rochester (George Schwartz, MD), and a data coordinating center at the Johns Hopkins Bloomberg School of Public Health (Alvaro Munoz, PhD) (U01-DK-66143, U01-DK-66174, U01-DK-082194, and U01-DK-66116). NR 29 TC 43 Z9 47 U1 0 U2 14 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 SEP PY 2011 VL 6 IS 9 BP 2132 EP 2140 DI 10.2215/CJN.07100810 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 817EN UT WOS:000294654200007 PM 21841064 ER PT J AU Belyakov, IM Ahlers, JD AF Belyakov, I. M. Ahlers, J. D. TI Simultaneous Approach Using Systemic, Mucosal and Transcutaneous Routes of Immunization For Development of Protective HIV-1 Vaccines SO CURRENT MEDICINAL CHEMISTRY LA English DT Review DE HIV-1; AIDS; vaccine; mucosal immunity; systemic immunity; T lymphocyte; CTL; innate immunity; dendritic cells; TLR ligands; cytokines; chemokines; adjuvant; epitope; peptide ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL RESPONSES; PRIME-BOOST IMMUNIZATION; ADAPTIVE IMMUNE-RESPONSES; SMALL-INTESTINAL MUCOSA; ADENOVIRUS SEROTYPE 5; TUMOR-NECROSIS-FACTOR; TRANS-RETINOIC ACID; TOLL-LIKE RECEPTORS; HIGH-AVIDITY AB Mucosal tissues are major sites of HIV entry and initial infection. Induction of a local mucosal cytotoxic T lymphocyte response is considered an important goal in developing an effective HIV vaccine. In addition, activation and recruitment of memory CD4(+) and CD8(+) T cells in systemic lymphoid circulation to mucosal effector sites might provide the firewall needed to prevent virus spread. Therefore a vaccine that generates CD4(+) and CD8(+) responses in both mucosal and systemic tissues might be required for protection against HIV. However, optimal routes and number of vaccinations required for the generation of long lasting CD4(+) and CD8(+) CTL effector and memory responses are not well understood especially for mucosal T cells. A number of studies looking at protective immune responses against diverse mucosal pathogens have shown that mucosal vaccination is necessary to induce a compartmentalized immune response including maximum levels of mucosal high-avidity CD8(+) CTL, antigen specific mucosal antibodies titers (especially sIgA), as well as induction of innate anti-viral factors in mucosa tissue. Immune responses are detectable at mucosal sites after systemic delivery of vaccine, and prime boost regimens can amplify the magnitude of immune responses in mucosal sites and in systemic lymphoid tissues. We believe that the most optimal mucosal and systemic HIV/SIV specific protective immune responses and innate factors might best be achieved by simultaneous mucosal and systemic prime and boost vaccinations. Similar principals of vaccination may be applied for vaccine development against cancer and highly invasive pathogens that lead to chronic infection. C1 [Belyakov, I. M.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Belyakov, I. M.] Univ Michigan, Sch Med, Michigan Nanotechnol Inst Med & Biol Sci, Ann Arbor, MI 48109 USA. [Ahlers, J. D.] NIAID, NIH, Rockville, MD USA. RP Belyakov, IM (reprint author), Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. EM igorbelyakov@yahoo.com NR 159 TC 8 Z9 8 U1 1 U2 6 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8673 EI 1875-533X J9 CURR MED CHEM JI Curr. Med. Chem. PD SEP PY 2011 VL 18 IS 26 BP 3953 EP 3962 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 820JG UT WOS:000294901100002 PM 21824096 ER PT J AU Patterson, LJ AF Patterson, L. J. TI The "STEP-Wise" Future of Adenovirus-Based HIV Vaccines SO CURRENT MEDICINAL CHEMISTRY LA English DT Review DE Adenovirus vectors; HIV vaccines; mucosal immunity; non-neutralizing antibodies ID IMMUNODEFICIENCY-VIRUS TYPE-1; RHESUS-MONKEYS; T-CELLS; IMMUNE-RESPONSES; SEROTYPE 5; DNA; INFECTION; REPLICATION; VACCINATION; CHALLENGE AB The HIV pandemic continues to be a public health crisis with over 30 million people currently living with the disease and, depending on the estimate, another 2 - 2.8 million infected annually. The disappointing results of the first Phase II study of a highly immunogenic adenovirus-vectored vaccine, named the STEP trial, was a wake up call to both the clinical and preclinical HIV vaccine fields. A vaccine designed only to elicit T cells and including a single HIV gene insert, will not be sufficient to reduce transmission or lower viremia in people. Additionally, future use of adenovirus-based vectored vaccines needs to be carefully planned with respect to vector type, gene inserts, route of immunization and risk factors among subject volunteers. The initial observation of a transient, increased risk of infection in Ad5 seropositive, uncircumcised men who have sex with men (MSM) is still unexplained, and may yet be considered simply a random event. The vaccine field has not given up on adenoviruses and there is continued interest in pursuing these highly immunogenic vectors, either in combination approaches with DNA, use of rare serotypes with low seroprevalence, or those derived from simian origin. Finally, evaluation of replicating adenovirus vectors known to be capable of inducing potent cellular, humoral, and mucosal immunity will be vital to meeting our future goal of an effective HIV vaccine. C1 NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. RP Patterson, LJ (reprint author), NCI, Vaccine Branch, NIH, 41 Medlars Dr,Bldg 41,Room D310, Bethesda, MD 20892 USA. EM pattersj@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX Thanks to Dr. Marjorie Robert-Guroff for critical review of this manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 47 TC 4 Z9 4 U1 1 U2 4 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD SEP PY 2011 VL 18 IS 26 BP 3981 EP 3986 PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 820JG UT WOS:000294901100005 PM 21824093 ER PT J AU Degheidy, HA Venzon, DJ Farooqui, MZH Abbasi, F Arthur, DC Wilson, WH Wiestner, A Stetler-Stevenson, MA Marti, GE AF Degheidy, Heba A. Venzon, David J. Farooqui, Mohammed Z. H. Abbasi, Fatima Arthur, Diane C. Wilson, Wyndham H. Wiestner, Adrian Stetler-Stevenson, M. A. Marti, Gerald E. TI Methodological Comparison of Two Anti-ZAP-70 Antibodies SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE chronic lymphocytic leukemia; ZAP-70 score; flow cytometry; 1E7.2/AF488; SBZAP/PE ID CHRONIC LYMPHOCYTIC-LEUKEMIA; FLOW-CYTOMETRIC MEASUREMENT; ZAP-70 PROTEIN EXPRESSION; GENE MUTATION STATUS; CELLS; CD38 AB Background: ZAP-70 expression is a stage independent prognostic marker in CLL. However, interlaboratory variation is large, and there is neither a consensus nor a regulatory approved methodology. Methods: Two anti-ZAP70 clones (1E7.2 and SBZAP) were compared in 45 untreated CLL patients. Nine different methods for ZAP-70 expression analysis were evaluated: M1, isotype control to determine negative; M2, internal residual T-cell to determine positive; M3, normal donor (ND) T-cell to determine positive; M4, internal T-cell/clone ratio; M5, ND residual T-cell/clone ratio; M6, clone/normal remaining B-cell ratio; M7, clone/ND B-cell ratio; M8, CLL-Z score; M9, modified CLL-Z score. A scoring system was designed integrating both 1E7.2 and SBZAP clones to assign ZAP-70 expression. Results: The correlation coefficients for the four selected highest statistically significant methods were as follows (M1 = 0.71, M3 = 0.72, M7 = 0.67, and M9 = 0.64). These four methods were used to generate a combined score. The two reagents showed agreement using the designed scoring system for 37/45 samples (82%), and 8/45 (18%) showed equivocal result with one of the two clones. Seven of the eight equivocal samples were resolved using the scoring system. Conclusions: Four of the nine methods of analysis were compared for each reagent. The use of two independent ZAP-70 reagents increases analytical certitude and the scoring method aids in the resolution of equivocal results. The combined use of two reagents, four methods of analysis, and a scoring method allowed for assignment of ZAP-70 expression in 44/45 samples (98%) tested and improved performance of this important prognostic assay. Published 2011 Wiley-Liss, Inc.(dagger) C1 [Marti, Gerald E.] US FDA, Cellular & Tissue Therapy Branch, Div Cell & Gene Therapies, Off Cellular Tissues & Gene Therapies,CBER,NIH, Bethesda, MD 20892 USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, NIH, Bethesda, MD 20892 USA. [Arthur, Diane C.; Stetler-Stevenson, M. A.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Metab Branch, Bethesda, MD 20892 USA. RP Marti, GE (reprint author), US FDA, Cellular & Tissue Therapy Branch, Div Cell & Gene Therapies, Off Cellular Tissues & Gene Therapies,CBER,NIH, Bdg 29B,Rm 1NN010,8800 Rockville Pike, Bethesda, MD 20892 USA. EM gemarti@mac.com FU NHLBI, NIH FX The authors acknowledge the nursing and data management skills of Susan Soto and Therese White in this study. In addition, we acknowledge the friendly support provided by the Phlebotomy Service (Department of Transfusion Medicine, NIH). This research was supported in part, by the Intramural Research Program of the NHLBI, NIH. NR 22 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD SEP PY 2011 VL 80B IS 5 BP 300 EP 308 DI 10.1002/cyto.b.20591 PG 9 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 817OX UT WOS:000294684800004 PM 21472849 ER PT J AU Degheidy, HA Venzon, DJ Farooqui, MZH Abbasi, F Arthur, DC Wilson, WW Wiestner, A Stetler-Stevenson, MA Marti, GE AF Degheidy, Heba A. Venzon, David J. Farooqui, Mohammed Z. H. Abbasi, Fatima Arthur, Diane C. Wilson, Wyndham W. Wiestner, Adrian Stetler-Stevenson, M. A. Marti, Gerald E. TI Improved ZAP-70 Assay Using Two Clones, Multiple Methods of Analysis and Clinical Correlation SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE chronic lymphocytic leukemia; ZAP-70; CLL score system; flow cytometry; prognostic marker ID CHRONIC LYMPHOCYTIC-LEUKEMIA; GENE MUTATION STATUS; CD38 EXPRESSION; DISEASE PROGRESSION; FLOW-CYTOMETRY; FLUDARABINE; DIAGNOSIS; CLL; CHEMOIMMUNOTHERAPY; CYCLOPHOSPHAMIDE AB Introduction: In a companion methodological study, we compared two anti-ZAP-70 clones (1E7.2 AF 488 and SBZAP PE) and four selected methods of analysis. Clinical correlations are required for validation. Methods: Multicolor flow-cytometric evaluation of ZAP-70, CD38, CD69, CD26, CD49d, and CD27 was tested in 45 untreated-CLL patients. Four methods of ZAP-70 expression analysis and a scoring system were designed. A correlation analysis between ZAP-70 score, immunoglobulin heavy chain variable (IGHV) mutational status, fluorescence in situ hybridization, and these biomarkers was undertaken. Results: There is a strong correlation between ZAP-70 expression and IGHV mutational status. The scoring system for a single reagent (P = 0.0006 or 0.0002) favors the use of multiple methods of analysis. The combined score was substantially equivalent (P = 0.0003). There was also a correlation with del 13q14 (P = 0.017) and trisomy12 (P = 0.011). A correlation for CD38 and ZAP-70 score was seen using both 1E7.2 AF488 and SBZAP PE when >= 20% or >= 7% cutoff was used. A positive correlation was seen for CD49d expression using both reagents. CD26 showed a correlation with ZAP-70 expression, but it was dependent upon the method of analysis. CD69 and CD27 showed no statistically significant correlation. Conclusion: In our study population, ZAP-70 expression is the better predictor of the IGHV mutational status. The correlation analysis confirms that the use of four methods of analysis with a single reagent or both reagents is superior to the use of a single method of analysis. The routine use of CD38, CD49d, and CD26 will require standardization. Published 2011 Wiley-Liss, Inc.(dagger) C1 [Degheidy, Heba A.; Abbasi, Fatima; Marti, Gerald E.] US FDA, Div Cellular Tissue & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, NIH, Bethesda, MD 20892 USA. [Arthur, Diane C.; Stetler-Stevenson, M. A.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wilson, Wyndham W.] NCI, Metab Branch, Bethesda, MD 20892 USA. RP Marti, GE (reprint author), US FDA, Cellular & Tissue Therapy Branch, Div Cell & Gene Therapies, Off Cellular Tissues & Gene Therapies,CBER,NIH, Bdg 29B,Room 1NN010,8800 Rockville Pike, Bethesda, MD 20892 USA. EM gemarti@mac.com FU NHLBI, NIH FX This research was supported in part, by the Intramural Research Program of the NHLBI, NIH. NR 31 TC 4 Z9 4 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD SEP PY 2011 VL 80B IS 5 BP 309 EP 317 DI 10.1002/cyto.b.20593 PG 9 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 817OX UT WOS:000294684800005 PM 21472850 ER PT J AU Ali, AH Koutsari, C Mundi, M Stegall, MD Heimbach, JK Taler, SJ Nygren, J Thorell, A Bogachus, LD Turcotte, LP Bernlohr, D Jensen, MD AF Ali, Asem H. Koutsari, Christina Mundi, Manpreet Stegall, Mark D. Heimbach, Julie K. Taler, Sandra J. Nygren, Jonas Thorell, Anders Bogachus, Lindsey D. Turcotte, Lorraine P. Bernlohr, David Jensen, Michael D. TI Free Fatty Acid Storage in Human Visceral and Subcutaneous Adipose Tissue Role of Adipocyte Proteins SO DIABETES LA English DT Article ID IN-VIVO; BODY-FAT; MEAL; METABOLISM; MUSCLE; LIPOLYSIS; WOMEN; MEN; TRIGLYCERIDES; INSULIN AB OBJECTIVE-Because direct adipose tissue free fatty acid (FFA) storage may contribute to body fat distribution, we measured FFA (palmitate) storage rates and fatty acid (FA) storage enzymes/proteins in omental and abdominal subcutaneous fat. RESEARCH DESIGN AND METHODS-Elective surgery patients received a bolus of [1-C-14]palmitate followed by mental and abdominal subcutaneous fat biopsies to measure direct FFA storage. Long chain acyl-CoA synthetase (ACS) and diacylglycerol acyltransferase activities, CD36, fatty acid-binding protein, and fatty acid transport protein 1 were measured. RESULTS-Palmitate tracer storage (dpm/g adipose lipid) and calculated palmitate storage rates were greater in omental than abdominal subcutaneous fat in women (1.2 +/- 0.8 vs. 0.7 +/- 0.4 mu mol . kg adipose lipid(-1) . min(-1), P = 0.005) and men (0.7 +/- 0.2 vs. 0.2 +/- 0.1, P < 0.001), and both were greater in women than men (P < 0.0001). Abdominal subcutaneous adipose tissue palmitate storage rates correlated with ACS activity (women: r = 0.66, P = 0.001; men: r = 0.70, P = 0.007); in men, CD36 was also independently related to palmitate storage rates. The content/activity of FA storage enzymes/proteins in ()mental fat was dramatically lower in those with more visceral fat. In women, only omental palmitate storage rates were correlated (r = 0.54, P = 0.03) with ACS activity. CONCLUSIONS-Some adipocyte FA storage factors correlate with direct FFA storage, but sex differences in this process in visceral fat do not account for sex differences in visceral fatness. The reduced storage proteins in those with greater visceral fat suggest that the storage factors we measured are not a predominant cause of visceral adipose tissue accumulation. Diabetes 60:2300-2307, 2011 C1 [Ali, Asem H.; Koutsari, Christina; Mundi, Manpreet; Jensen, Michael D.] Mayo Clin, Endocrine Res Unit, Rochester, MN 55905 USA. [Ali, Asem H.] NIDDK, Bethesda, MD USA. [Ali, Asem H.] NICHHD, Bethesda, MD 20892 USA. [Stegall, Mark D.; Heimbach, Julie K.] Mayo Clin, Div Transplantat Surg, Dept Surg, Rochester, MN USA. [Stegall, Mark D.; Heimbach, Julie K.] Mayo Clin, William J von Liebig Transplant Ctr, Rochester, MN USA. [Taler, Sandra J.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. [Nygren, Jonas; Thorell, Anders] Ersta Hosp, Dept Surg, Stockholm, Sweden. [Nygren, Jonas; Thorell, Anders] Karolinska Inst, Danderyds Hosp, Dept Clin Sci, Stockholm, Sweden. [Bogachus, Lindsey D.; Turcotte, Lorraine P.] Univ So Calif, Dept Biol Sci, Coll Letters Arts & Sci, Los Angeles, CA 90089 USA. [Bernlohr, David] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN USA. RP Jensen, MD (reprint author), Mayo Clin, Endocrine Res Unit, Rochester, MN 55905 USA. EM jensen@mayo.edu FU National Institutes of Health [DK-40484, DK-45343, DK-50456]; National Center for Research Resources [1 UL1 RR024150]; University of Southern California; Mayo Foundation; Stockholm County Council; Erling-Persson Family Foundation FX This study was funded by National Institutes of Health grants DK-40484, DK-45343, and DK-50456; Grant 1 UL1 RR024150 from the National Center for Research Resources; the Women in Science and Engineering Program and Integrative and Evolutionary Biology Program, the University of Southern California; and the Mayo Foundation. Financial support was provided for clinical research by Stockholm County Council and the Erling-Persson Family Foundation. NR 35 TC 20 Z9 24 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD SEP PY 2011 VL 60 IS 9 BP 2300 EP 2307 DI 10.2337/db11-0219 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817TN UT WOS:000294699600012 PM 21810594 ER PT J AU Kanoni, S Nettleton, JA Hivert, MF Ye, Z van Rooij, FJA Shungin, D Sonestedt, E Ngwa, JS Wojczynski, MK Lemaitre, RN Gustafsson, S Anderson, JS Tanaka, T Hindy, G Saylor, G Renstrom, F Bennett, AJ van Duijn, CM Florez, JC Fox, CS Hofman, A Hoogeveen, RC Houston, DK Hu, FB Jacques, PF Johansson, I Lind, L Liu, YM McKeown, N Ordovas, J Pankow, JS Sijbrands, EJG Syvanen, AC Uitterlinden, AG Yannakoulia, M Zillikens, MC Wareham, NJ Prokopenko, I Bandinelli, S Forouhi, NG Cupples, LA Loos, RJ Hallmans, G Dupuis, J Langenberg, C Ferrucci, L Kritchevsky, SB McCarthy, MI Ingelsson, E Borecki, IB Witteman, JCM Orho-Melander, M Siscovick, DS Meigs, JB Franks, PW Dedoussis, GV AF Kanoni, Stavroula Nettleton, Jennifer A. Hivert, Marie-France Ye, Zheng van Rooij, Frank J. A. Shungin, Dmitry Sonestedt, Emily Ngwa, Julius S. Wojczynski, Mary K. Lemaitre, Rozenn N. Gustafsson, Stefan Anderson, Jennifer S. Tanaka, Toshiko Hindy, George Saylor, Georgia Renstrom, Frida Bennett, Amanda J. van Duijn, Cornelia M. Florez, Jose C. Fox, Caroline S. Hofman, Albert Hoogeveen, Ron C. Houston, Denise K. Hu, Frank B. Jacques, Paul F. Johansson, Ingegerd Lind, Lars Liu, Yongmei McKeown, Nicola Ordovas, Jose Pankow, James S. Sijbrands, Eric J. G. Syvanen, Ann-Christine Uitterlinden, Andre G. Yannakoulia, Mary Zillikens, M. Carola Wareham, Nick J. Prokopenko, Inga Bandinelli, Stefania Forouhi, Nita G. Cupples, L. Adrienne Loos, Ruth J. Hallmans, Goran Dupuis, Josee Langenberg, Claudia Ferrucci, Luigi Kritchevsky, Stephen B. McCarthy, Mark I. Ingelsson, Erik Borecki, Ingrid B. Witteman, Jacqueline C. M. Orho-Melander, Marju Siscovick, David S. Meigs, James B. Franks, Paul W. Dedoussis, George V. CA MAGIC Investigators TI Total Zinc Intake May Modify the Glucose-Raising Effect of a Zinc Transporter (SLC30A8) Variant A 14-Cohort Meta-analysis SO DIABETES LA English DT Article ID GENOME-WIDE ASSOCIATION; GENE-ENVIRONMENT INTERACTIONS; RISK LOCI; INSULIN-RESISTANCE; CELL-FUNCTION; HOMEOSTASIS; SUPPLEMENTATION; ZNT8; POLYMORPHISMS; EXPRESSION AB OBJECTIVE-Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for beta-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants. RESEARCH DESIGN AND METHODS-We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes. RESULTS-We observed a significant association of total zinc intake with lower fasting glucose levels (beta-coefficient +/- SE per 1 mg/day of zinc intake: -0.0012 +/- 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (beta-coefficient +/- SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 +/- 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant. CONCLUSIONS Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels. Diabetes 60:2407-2416, 2011 C1 [Kanoni, Stavroula; Yannakoulia, Mary; Dedoussis, George V.] Harokopio Univ, Dept Nutr Dietet, Athens, Greece. [Kanoni, Stavroula] Wellcome Trust Sanger Inst, Hinxton, England. [Nettleton, Jennifer A.] Univ Texas Hlth Sci Ctr, Div Epidemiol Htunan Genet & Environm Sci, Houston, TX USA. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Div Endocrinol, Sherbrooke, PQ J1K 2R1, Canada. [Ye, Zheng; Wareham, Nick J.; Forouhi, Nita G.; Loos, Ruth J.; Langenberg, Claudia] Addenbrookes Hosp, MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England. [van Rooij, Frank J. A.; van Duijn, Cornelia M.; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Rooij, Frank J. A.; van Duijn, Cornelia M.; Hofman, Albert; Sijbrands, Eric J. G.; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.] NGI NCHA, Leiden, Netherlands. [Shungin, Dmitry; Renstrom, Frida; Hallmans, Goran; Franks, Paul W.] Umea Univ Hosp, Dept Publ Hlth & Clin Med, Med Sect, Genet Epidemiol & Clin Res Grp, S-90185 Umea, Sweden. [Shungin, Dmitry; Sonestedt, Emily; Hindy, George; Renstrom, Frida; Orho-Melander, Marju; Franks, Paul W.] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Shungin, Dmitry; Johansson, Ingegerd] Umea Univ, Dept Odontol, Umea, Sweden. [Ngwa, Julius S.; Cupples, L. Adrienne; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Wojczynski, Mary K.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Lemaitre, Rozenn N.; Siscovick, David S.] Univ Washington, Dept Med & Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Gustafsson, Stefan; Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Anderson, Jennifer S.; Saylor, Georgia] Wake Forest Univ, Baptist Med Ctr, Winston Salem, NC 27109 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Renstrom, Frida; Hu, Frank B.; Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Bennett, Amanda J.; Prokopenko, Inga; McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Fox, Caroline S.; Cupples, L. Adrienne; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Hoogeveen, Ron C.] Baylor Coll Med, Dept Med, Sect Atherosclerosis & Vasc Med, Houston, TX 77030 USA. [Hoogeveen, Ron C.] Methodist DeBakey Heart Ctr, Ctr Cardiovasc Dis Prevent, Houston, TX USA. [Houston, Denise K.; Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Sect Gerontol & Geriatr Med,Sticht Ctr Aging, Winston Salem, NC 27103 USA. [Jacques, Paul F.; McKeown, Nicola] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Nutr Epidemiol Program, Boston, MA 02111 USA. [Lind, Lars; Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Liu, Yongmei] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. [McKeown, Nicola] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Ordovas, Jose] Tufts Univ, Jean Mayer USDA HNRCA, Nutr & Genom Lab, Boston, MA 02111 USA. [Pankow, James S.] Univ Minnesota, Dept Epidemiol, Minneapolis, MN USA. [Sijbrands, Eric J. G.; Uitterlinden, Andre G.; Zillikens, M. Carola] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Prokopenko, Inga; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [McCarthy, Mark I.] Churchill Hosp, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Oxford OX3 7LJ, England. [Meigs, James B.] Massachusetts Gen Hosp, Clin Epidemiol Unit, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Diabet Res Unit, Boston, MA 02114 USA. RP Kanoni, S (reprint author), Harokopio Univ, Dept Nutr Dietet, Athens, Greece. EM stavroula.kanoni@sanger.ac.uk; paul.franks@med.lu.se; dedousi@hua.gr RI Prokopenko, Inga/H-3241-2014; Sonestedt, Emily/I-3814-2016; Hindy, George/H-1864-2016; OI Prokopenko, Inga/0000-0003-1624-7457; Sonestedt, Emily/0000-0002-0747-4562; Ordovas, Jose/0000-0002-7581-5680; Cupples, L. Adrienne/0000-0003-0273-7965; Shungin, Dmitry/0000-0001-7900-5856; Hindy, George/0000-0002-7257-9299; Sijbrands, Eric/0000-0001-8857-7389; Dupuis, Josee/0000-0003-2871-3603; Kritchevsky, Stephen/0000-0003-3336-6781; Forouhi, Nita/0000-0002-5041-248X FU Medical Research Council [G0701863, MC_U106179471, MC_U106188470, MC_UP_A100_1003]; NHLBI NIH HHS [R01 HL087700]; Wellcome Trust [090532] NR 48 TC 39 Z9 41 U1 0 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD SEP PY 2011 VL 60 IS 9 BP 2407 EP 2416 DI 10.2337/db11-0176 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817TN UT WOS:000294699600024 PM 21810599 ER PT J AU Yeh, S Lombardi, L Fahle, G Lauer, AK AF Yeh, S. Lombardi, L. Fahle, G. Lauer, A. K. TI A therapeutic challenge in AIDS-associated viral retinitis SO EYE LA English DT Letter ID OUTER RETINAL NECROSIS; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; ACTIVE ANTIRETROVIRAL THERAPY; MANAGEMENT C1 [Yeh, S.] Emory Univ, Sch Med, Emory Eye Ctr, Atlanta, GA 30322 USA. [Lombardi, L.; Lauer, A. K.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Fahle, G.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Yeh, S (reprint author), Emory Univ, Sch Med, Emory Eye Ctr, Atlanta, GA 30322 USA. EM lauera@ohsu.edu NR 8 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-222X J9 EYE JI Eye PD SEP PY 2011 VL 25 IS 9 BP 1241 EP 1242 DI 10.1038/eye.2011.135 PG 2 WC Ophthalmology SC Ophthalmology GA 818NW UT WOS:000294760300027 PM 21681217 ER PT J AU Mukherjee, T Boshoff, H AF Mukherjee, Tathagata Boshoff, Helena TI Nitroimidazoles for the treatment of TB: past, present and future SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID NONREPLICATING MYCOBACTERIUM-TUBERCULOSIS; HELICOBACTER-PYLORI; BACTERICIDAL ACTIVITY; MURINE MODEL; METRONIDAZOLE-RESISTANCE; ANTITUBERCULAR ACTIVITY; BIOLOGICAL-ACTIVITY; DRUG-RESISTANCE; NITRIC-OXIDE; ANTIBACTERIAL ACTIVITY AB Tuberculosis remains a leading cause of death resulting from an infectious agent, and the spread of multi-and extensively drug-resistant strains of Mycobacterium tuberculosis poses a threat to management of global health. New drugs that effectively shorten the duration of treatment and are active against drug-resistant strains of this pathogen are urgently required to develop effective chemotherapies to combat this disease. Two nitroimidazoles, PA-824 and OPC-67683, are currently in Phase II clinical trials for the treatment of TB and the outcome of these may determine the future directions of drug development for anti-tubercular nitroimidazoles. In this review we summarize the development of these nitroimidazoles and alternative analogs in these series that may offer attractive alternatives to PA-824 and OPC-67683 for further development in the drug-discovery pipeline. Lastly, the potential pitfalls in the development of nitroimidazoles as drugs for TB are discussed. C1 [Mukherjee, Tathagata; Boshoff, Helena] NIAID, TB Res Sect, LCID, NIH, Bethesda, MD 20892 USA. RP Boshoff, H (reprint author), NIAID, TB Res Sect, LCID, NIH, Room 2W20G,Bldg 33,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hboshoff@niaid.nih.gov FU Bill and Melinda Gates Foundation; Wellcome Trust through the Grand Challenges in Global Health Initiative; NIH National Institute of Allergy and Infectious Diseases FX This work was funded by a grant from the Bill and Melinda Gates Foundation and the Wellcome Trust through the Grand Challenges in Global Health Initiative and by the intramural research program of the NIH National Institute of Allergy and Infectious Diseases. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 126 TC 31 Z9 31 U1 1 U2 17 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 J9 FUTURE MED CHEM JI Future Med. Chem. PD SEP PY 2011 VL 3 IS 11 SI SI BP 1427 EP 1454 DI 10.4155/FMC.11.90 PG 28 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 815RI UT WOS:000294544900014 PM 21879846 ER PT J AU Choy, JS Acuna, R Au, WC Basrai, MA AF Choy, John S. Acuna, Rachel Au, Wei-Chun Basrai, Munira A. TI A Role for Histone H4K 16 Hypoacetylation in Saccharomyces cerevisiae Kinetochore Function SO GENETICS LA English DT Article ID BUDDING YEAST; CHROMOSOME LOSS; ACETYLTRANSFERASE COMPLEX; PERICENTRIC CHROMATIN; CENTROMERIC CHROMATIN; MITOTIC SPINDLE; PROTEIN; ACETYLATION; NUCLEOSOME; SIR2 AB Hypoacetylated H4 is present at regional centromeres; however, its role in kinetochore function is poorly understood. We characterized H4 acetylation at point centromeres in Saccharomyces cerevisiae and determined the consequences of altered H4 acetylation on chromosome segregation. We observed low levels of tetra-acetylated and K16 acetylated histone H4 (H4K16Ac) at centromeres. Low levels of H4K16Ac were also observed at noncentromeric regions associated with Cse4p. Inhibition of histone deacetylases (HDAC) using nicotinamide (NAM) caused lethality in cse4 and hhf1-20 kinetochore mutants and increased centromeric H4K16Ac. Overexpression of Sas2-mediated H4K16 acetylation activity in wild-type cells led to increased rates of chromosome loss and synthetic dosage lethality in kinetochore mutants. Consistent with increased H4K16 acetylation as a cause of the phenotypes, deletion of the H4K16 deacetylase SIR2 or a sir2-H364Y catalytic mutant resulted in higher rates of chromosome loss compared to wild-type cells. Moreover, H4K16Q acetylmimic mutants displayed increased rates of chromosome loss compared to H4K16R nonacetylatable mutants and wild-type cells. Our work shows that hypoacetylated centromeric H4 is conserved across eukaryotic centromeres and hypoacetylation of H4K16 at centromeres plays an important role in accurate chromosome segregation. C1 [Choy, John S.; Acuna, Rachel; Au, Wei-Chun; Basrai, Munira A.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Basrai, MA (reprint author), NCI Genet, NIH, Bldg 41,Room C629,41 Ctr Dr, Bethesda, MD 20892 USA. EM basraim@nih.gov FU National Cancer Institute, National Institutes of Health FX The authors thank S. Biggins, C. Chan, Danesh Moazed, J. Gerton, P. Megee, V. Measday, M. Smith, L. Pillus, and J. Workman for strains and plasmids. We are grateful to members of the Basrai lab, R. Baker, and D. Clarke for critical discussions and comments on the manuscript. This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 53 TC 21 Z9 21 U1 0 U2 3 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD SEP PY 2011 VL 189 IS 1 BP 11 EP U595 DI 10.1534/genetics.111.130781 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA 818AQ UT WOS:000294721600003 PM 21652526 ER PT J AU Kuo, CL Zaykin, DV AF Kuo, Chia-Ling Zaykin, Dmitri V. TI Novel Rank-Based Approaches for Discovery and Replication in Genome-Wide Association Studies SO GENETICS LA English DT Article ID GENE-DISEASE ASSOCIATION; FALSE DISCOVERY; 2-STAGE DESIGNS; COMPLEX TRAITS; P-VALUES; PROBABILITY; LINKAGE; EPIDEMIOLOGY; DISSECTION; VARIANTS AB In recent years, genome-wide association studies (GWAS) have uncovered a large number of susceptibility variants. Nevertheless, GWAS findings provide only tentative evidence of association, and replication studies are required to establish their validity. Due to this uncertainty, researchers often focus on top-ranking SNPs, instead of considering strict significance thresholds to guide replication efforts. The number of SNPs for replication is often determined ad hoc. We show how the rank-based approach can be used for sample size allocation in GWAS as well as for deciding on a number of SNPs for replication. The basis of this approach is the "ranking probability": chances that at least j true associations will rank among top u SNPs, when SNPs are sorted by P-value. By employing simple but accurate approximations for ranking probabilities, we accommodate linkage disequilibrium (LD) and evaluate consequences of ignoring LD. Further, we relate ranking probabilities to the proportion of false discoveries among top u SNPs. A study-specific proportion can be estimated from P-values, and its expected value can be predicted for study design applications. C1 [Kuo, Chia-Ling; Zaykin, Dmitri V.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Zaykin, DV (reprint author), NIEHS, NIH, South Campus 101,MD A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. EM zaykind@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences FX We benefited from discussion with Shyamal Peddada and David Umbach and from useful comments by Gary Churchill and two anonymous reviewers. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 32 TC 10 Z9 10 U1 0 U2 4 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD SEP PY 2011 VL 189 IS 1 BP 329 EP 340 DI 10.1534/genetics.111.130542 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 818AQ UT WOS:000294721600025 PM 21705758 ER PT J AU Miller, AM Wang, H Bertola, A Park, O Horiguchi, N Ki, SH Yin, S Lafdil, F Gao, B AF Miller, Andrew M. Wang, Hua Bertola, Adeline Park, Ogyi Horiguchi, Norio Ki, Sung Hwan Yin, Shi Lafdil, Fouad Gao, Bin TI Inflammation-Associated Interleukin-6/Signal Transducer and Activator of Transcription 3 Activation Ameliorates Alcoholic and Nonalcoholic Fatty Liver Diseases in Interleukin-10-Deficient Mice SO HEPATOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; HEPATIC INFLAMMATION; INSULIN-RESISTANCE; SIGNALING PATHWAYS; INJURY; LIPOTOXICITY; HEPATOCYTES; STEATOSIS; STEATOHEPATITIS; POLYMORPHISMS AB Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, whereas inflammation in turn aggregates steatosis. Thus, we hypothesized the deletion of interleukin (IL)-10, a key anti-inflammatory cytokine, exacerbates liver inflammation, steatosis, and hepatocellular damage in alcoholic and nonalcoholic fatty liver disease models that were achieved via feeding mice with a liquid diet containing 5% ethanol for 4 weeks or a high-fat diet (HFD) for 12 weeks, respectively. IL-10 knockout (IL-10(-/-)) mice and several other strains of genetically modified mice were generated and used. Compared with wild-type mice, IL-10(-/-) mice had greater liver inflammatory response with higher levels of IL-6 and hepatic signal transducer and activator of transcription 3 (STAT3) activation, but less steatosis and hepatocellular damage after alcohol or HFD feeding. An additional deletion of IL-6 or hepatic STAT3 restored steatosis and hepatocellular damage but further enhanced liver inflammatory response in IL-10(-/-) mice. In addition, the hepatic expression of sterol regulatory element-binding protein 1 and key downstream lipogenic proteins and enzymes in fatty acid synthesis were down-regulated in IL-10(-/-) mice. Conversely, IL-10(-/-) mice displayed enhanced levels of phosphorylated adenosine monophosphate-activated protein kinase and its downstream targets including phosphorylated acetyl-coenzyme A carboxylase and carnitine palmitoyltransferase 1 in the liver. Such dysregulations were corrected in IL-10(-/-) IL-6 or IL-10(-/-) STAT3(Hep-/-) double knockout mice. Conclusion: IL-10(-/-) mice are prone to liver inflammatory response but are resistant to steatosis and hepatocellular damage induced by ethanol or HFD feeding. Resistance to steatosis in these mice is attributable to elevation of inflammation-associated hepatic IL-6/STAT3 activation that subsequently down-regulates lipogenic genes but up-regulates fatty acid oxidation-associated genes in the liver. (HEPATOLOGY 2011;54:846-856) C1 [Miller, Andrew M.; Wang, Hua; Bertola, Adeline; Park, Ogyi; Horiguchi, Norio; Ki, Sung Hwan; Yin, Shi; Lafdil, Fouad; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Horiguchi, Norio] Gunma Univ, Grad Sch Med, Dept Med & Mol Sci, Gunma, Japan. [Ki, Sung Hwan] Chosun Univ, Coll Pharm, Toxicol Lab, Kwangju, South Korea. [Yin, Shi] Anhui Med Univ, Inst Clin Pharmacol, Hefei, Anhui, Peoples R China. [Lafdil, Fouad] Hop Henri Mondor, INSERM, U955, F-94010 Creteil, France. [Lafdil, Fouad] Univ Paris, E Creteil, France. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov OI Bertola, Adeline/0000-0002-4885-8423 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX Supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 44 TC 35 Z9 37 U1 1 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD SEP PY 2011 VL 54 IS 3 BP 846 EP 856 DI 10.1002/hep.24517 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 818FZ UT WOS:000294738300013 PM 21725996 ER PT J AU Suzuki, A Brunt, EM Kleiner, DE Miquel, R Smyrk, TC Andrade, RJ Lucena, MI Castiella, A Lindor, K Bjornsson, E AF Suzuki, Ayako Brunt, Elizabeth M. Kleiner, David E. Miquel, Rosa Smyrk, Thomas C. Andrade, Raul J. Isabel Lucena, M. Castiella, Agustin Lindor, Keith Bjoernsson, Einar TI The Use of Liver Biopsy Evaluation in Discrimination of Idiopathic Autoimmune Hepatitis Versus Drug-Induced Liver Injury SO HEPATOLOGY LA English DT Article ID PROGNOSIS; CRITERIA AB Distinguishing drug-induced liver injury (DILI) from idiopathic autoimmune hepatitis (AIH) can be challenging. We performed a standardized histologic evaluation to explore potential hallmarks to differentiate AIH versus DILI. Biopsies from patients with clinically well-characterized DILI [n = 35, including 19 hepatocellular injury (HC) and 16 cholestatic/mixed injury (CS)] and AIH (n = 28) were evaluated for Ishak scores, prominent inflammatory cell types in portal and intra-acinar areas, the presence or absence of emperipolesis, rosette formation, and cholestasis in a blinded fashion by four experienced hepatopathologists. Histologic diagnosis was concordant with clinical diagnosis in 65% of cases; but agreement on final diagnosis among the four pathologists was complete in only 46% of cases. Interface hepatitis, focal necrosis, and portal inflammation were present in all evaluated cases, but were more severe in AIH (P < 0.05) than DILI (HC). Portal and intra-acinar plasma cells, rosette formation, and emperiopolesis were features that favored AIH (P < 0.02). A model combining portal inflammation, portal plasma cells, intra-acinar lymphocytes and eosinophils, rosette formation, and canalicular cholestasis yielded an area under the receiver operating characteristic curve (AUROC) of 0.90 in predicting DILI (HC) versus AIH. All Ishak inflammation scores were more severe in AIH than DILI (CS) (P < 0.05). The four AIH-favoring features listed above were consistently more prevalent in AIH, whereas portal neutrophils and intracellular (hepatocellular) cholestasis were more prevalent in DILI (CS) (P < 0.02). The combination of portal inflammation, fibrosis, portal neutrophils and plasma cells, and intracellular (hepatocellular) cholestasis yielded an AUC of 0.91 in predicting DILI (CS) versus AIH. Conclusion: Although an overlap of histologic findings exists for AIH and DILI, sufficient differences exist so that pathologists can use the pattern of injury to suggest the correct diagnosis. (HEPATOLOGY 2011;54:931-939) C1 [Suzuki, Ayako] Duke Univ, Med Ctr, Div Gastroenterol, Durham, NC 27710 USA. [Brunt, Elizabeth M.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Dept Hlth, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Dept Hlth Serv, Bethesda, MD 20892 USA. [Miquel, Rosa] Univ Barcelona, Hosp Clin, Dept Pathol, Barcelona, Spain. [Smyrk, Thomas C.] Mayo Clin, Dept Anat Pathol, Rochester, MN USA. [Smyrk, Thomas C.] Mayo Clin, Dept Clin Pathol, Rochester, MN USA. [Andrade, Raul J.] Univ Hosp Virgen de la Victoria, Sch Med, Liver Unit, Malaga, Spain. [Andrade, Raul J.; Isabel Lucena, M.] CIBERehd, Barcelona, Spain. [Isabel Lucena, M.] Univ Hosp Virgen de la Victoria, Sch Med, Clin Pharmacol Serv, Malaga, Spain. [Castiella, Agustin] Hosp Mendaro, Digest Serv, Guipuzcoa, Spain. [Lindor, Keith] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Bjoernsson, Einar] Univ Iceland, Dept Gastroenterol, Reykjavik, Iceland. RP Suzuki, A (reprint author), Duke Univ, Med Ctr, Div Gastroenterol, Room 0340,POB 3913, Durham, NC 27710 USA. EM suzuk004@mc.duke.edu OI Andrade Bellido, Raul Jesus/0000-0002-1565-0757; Kleiner, David/0000-0003-3442-4453 FU Agencia Espanola del Medicament; Fondo de Investigacion Sanitaria [PS 09/01384]; National Iinstitues of Health, National Cancer Institute FX The Spanish DILI Registry is supported, in part, by research grants from the Agencia Espanola del Medicament and Fondo de Investigacion Sanitaria (PS 09/01384). This research was also supported, in part, by the Intramural Research Program of the National Iinstitues of Health, National Cancer Institute. NR 17 TC 77 Z9 88 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD SEP PY 2011 VL 54 IS 3 BP 931 EP 939 DI 10.1002/hep.24481 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 818FZ UT WOS:000294738300021 PM 21674554 ER PT J AU Marquardt, JU Raggi, C Andersen, JB Seo, D Avital, I Geller, D Lee, YH Kitade, M Holczbauer, A Gillen, MC Conner, EA Factor, VM Thorgeirsson, SS AF Marquardt, Jens U. Raggi, Chiara Andersen, Jesper B. Seo, Daekwan Avital, Itzhak Geller, David Lee, Yun-Han Kitade, Mitsuteru Holczbauer, Agnes Gillen, Matthew C. Conner, Elizabeth A. Factor, Valentina M. Thorgeirsson, Snorri S. TI Human Hepatic Cancer Stem Cells Are Characterized by Common Stemness Traits and Diverse Oncogenic Pathways SO HEPATOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA CELLS; INITIATING CELLS; GENE-EXPRESSION; PROGENITOR CELLS; SIDE POPULATION; LIVER-CANCER; IDENTIFICATION; TUMORS; LUNG; HEPATOCARCINOGENESIS AB Epigenetic mechanisms play critical roles in stem cell biology by maintaining pluripotency of stem cells and promoting differentiation of more mature derivatives. If similar mechanisms are relevant for the cancer stem cell (CSC) model, then epigenetic modulation might enrich the CSC population, thereby facilitating CSC isolation and rigorous evaluation. To test this hypothesis, primary human cancer cells and liver cancer cell lines were treated with zebularine (ZEB), a potent DNA methyltransferase-1 inhibitor, and putative CSCs were isolated using the side population (SP) approach. The CSC properties of ZEB-treated and untreated subpopulations were tested using standard in vitro and in vivo assays. Whole transcriptome profiling of isolated CSCs was performed to generate CSC signatures. Clinical relevance of the CSC signatures was evaluated in diverse primary human cancers. Epigenetic modulation increased frequency of cells with CSC properties in the SP fraction isolated from human cancer cells as judged by self-renewal, superior tumor-initiating capacity in serial transplantations, and direct cell tracking experiments. Integrative transcriptome analysis revealed common traits enriched for sternness-associated genes, although each individual CSC gene expression signature exhibited activation of different oncogenic pathways (e.g., EGFR, SRC, and MYC). The common CSC signature was associated with malignant progression, which is enriched in poorly differentiated tumors, and was highly predictive of prognosis in liver and other cancers. Conclusion: Epigenetic modulation may provide a tool for prospective isolation and in-depth analysis of CSC. The liver CSC gene signatures are defined by a pernicious interaction of unique oncogene-specific and common sternness traits. These data should facilitate the identifications of therapeutic tools targeting both unique and common features of CSCs. (HEPATOLOGY 2011;54:1031-1042) C1 [Marquardt, Jens U.; Raggi, Chiara; Andersen, Jesper B.; Seo, Daekwan; Lee, Yun-Han; Kitade, Mitsuteru; Holczbauer, Agnes; Gillen, Matthew C.; Conner, Elizabeth A.; Factor, Valentina M.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Avital, Itzhak] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Geller, David] Univ Pittsburgh, Med Ctr, Liver Canc Ctr, Pittsburgh, PA USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 4146A, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov OI Andersen , Jesper B/0000-0003-1760-5244; RAGGI, Chiara/0000-0003-2473-3535 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Transcript profiling: GEO accession number. GSE24520. NR 39 TC 41 Z9 43 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD SEP PY 2011 VL 54 IS 3 BP 1031 EP 1042 DI 10.1002/hep.24454 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 818FZ UT WOS:000294738300031 PM 21618577 ER PT J AU Shao, BM Kitchens, RL Munford, RS Rogers, TE Rockey, DC Varley, AW AF Shao, Baomei Kitchens, Richard L. Munford, Robert S. Rogers, Thomas E. Rockey, Don C. Varley, Alan W. TI Prolonged Hepatomegaly in Mice That Cannot Inactivate Bacterial Endotoxin SO HEPATOLOGY LA English DT Article ID LIVER-INJURY; HEPATIC-INJURY; LIPOPOLYSACCHARIDE; ACTIVATION; TOLERANCE; CELLS; DEACYLATION; DISEASE; SEPSIS; RATS AB Transient hepatomegaly often accompanies acute bacterial infections. Reversible, dose-dependent hepatomegaly also occurs when animals are given intravenous infusions of bacterial lipopolysaccharide (LPS). We found that recovery from LPS-induced hepatomegaly requires a host enzyme, acyloxyacyl hydrolase (AOAH), that inactivates LPS. When we challenged Aoah(-/-) mice with low doses of LPS or Gram-negative bacteria, their livers remained enlarged (as much as 80% above normal) many weeks longer than did the livers of Aoah(+/+) animals. When compared with livers from LPS-primed Aoah(+/+) mice, LPS-primed Aoah(-/-) livers had (1) more numerous and larger Kupffer cells, (2) intrasinusoidal leukocyte aggregates and activated sinusoidal endothelial cells, and (3) sustained production of interleukin (IL)-10 and messenger RNAs (mRNAs) for tumor necrosis factor (TNF), IL-10, and IRAK-M. Depleting Kupffer cells decreased the liver enlargement by approximate to 40%, whereas depletion of neutrophils, dendritic cells, natural killer (NK) cells, NK-T cells, or B cells had no effect. Pretreatment with dexamethasone almost completely prevented prolonged hepatomegaly in Aoah(-/-) mice, whereas neutralizing TNF or interleukin-1 beta was only partially effective. In contrast, an antagonistic antibody to the IL-10 receptor increased LPS-induced hepatomegaly by as much as 50%. Conclusion: our findings suggest that persistently active LPS induces Kupffer cells to elaborate mediators that promote the accumulation of leukocytes within enlarged sinusoids. Large increases in IL-10 and several other modulatory molecules are unable to prevent prolonged hepatomegaly in mice that cannot inactivate LPS. The striking findings in this mouse model should encourage studies to find out how AOAH contributes to human liver physiology and disease. (HEPATOLOGY 2011;54:1051-1062) C1 [Shao, Baomei; Kitchens, Richard L.; Munford, Robert S.; Varley, Alan W.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Infect Dis, Dallas, TX 75390 USA. [Rockey, Don C.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Digest Dis, Dallas, TX 75390 USA. [Rogers, Thomas E.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Munford, Robert S.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Munford, RS (reprint author), 9000 Rockville Pike, Bethesda, MD 20892 USA. EM munfordrs@niaid.nih.gov FU National Institute for Allergy and Infectious Diseases [AI18188]; Jan and Henri Bromberg Chair in Internal Medicine (UT Southwestern); Division of Intramural Research, NIAID, NIH FX Supported by extramural grant AI18188 from the National Institute for Allergy and Infectious Diseases, the Jan and Henri Bromberg Chair in Internal Medicine (UT Southwestern), and the Division of Intramural Research, NIAID, NIH. NR 31 TC 6 Z9 6 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD SEP PY 2011 VL 54 IS 3 BP 1051 EP 1062 DI 10.1002/hep.24488 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 818FZ UT WOS:000294738300033 PM 21674560 ER PT J AU Jager, J AF Jager, Justin TI A developmental shift in Black-White differences in depressive affect across adolescence and early adulthood: The influence of early adult social roles and socio-economic status SO INTERNATIONAL JOURNAL OF BEHAVIORAL DEVELOPMENT LA English DT Article DE cumulative risk; early adulthood; mental health; piece-wise growth curve modeling; race ID STRESSFUL LIFE EVENTS; QUALITY-OF-LIFE; MENTAL-HEALTH; SELF-ESTEEM; EMERGING ADULTHOOD; GENDER-DIFFERENCES; RACIAL-DIFFERENCES; YOUNG ADULTHOOD; UNITED-STATES; SYMPTOMS AB This study examined Black-White differences in growth of depressive affect using a longitudinal sample of middle-class, suburban U.S. subjects (n = 956) that spanned from adolescence to early adulthood. Specifically, this study examined whether Black-White differences in growth of depressive affect shift over time, and the extent to which that shift, if any, was associated with racial differences in the rate and ental health consequences of early adult social roles (e.g., living arrangements, work/college status, and single parenthood) and socio-economic status (SES). As expected, growth in depressive affect pivoted around the onset of early adulthood, with the trajectory pivoting upward for Black Americans and downward for White Americans. Due to deficits in SES, the relation between challenging early adult social roles-under/unemployment in particular-and growth in depressive affect was more positive for Black Americans. This differential "vulnerability'' appears to underlie racial differences in early adult growth (and by connection contribute to racial differences in growth pivot). The extent to which Black Americans were at a greater risk (relative to White Americans) for an upward pivot increased as the number of challenging roles increased. Black Americans facing only optimal early adult social roles were not at a greater risk, while those facing only challenging social roles were at the greatest risk. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Jager, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM jagerjo@mail.nih.gov FU Intramural NIH HHS [Z01 HD001119-20, Z99 HD999999]; NICHD NIH HHS [R01 HD033437, R01 HD033437-05S1] NR 87 TC 9 Z9 9 U1 3 U2 10 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0165-0254 J9 INT J BEHAV DEV JI Int. J. Behav. Dev. PD SEP PY 2011 VL 35 IS 5 BP 457 EP 469 DI 10.1177/0165025411417504 PG 13 WC Psychology, Developmental SC Psychology GA 816LK UT WOS:000294601100012 PM 22282639 ER PT J AU Agwu, AL Fleishman, JA Korthuis, PT Siberry, GK Ellen, JM Gaur, AH Rutstein, R Gebo, KA AF Agwu, Allison L. Fleishman, John A. Korthuis, P. Todd Siberry, George K. Ellen, Jonathan M. Gaur, Aditya H. Rutstein, Richard Gebo, Kelly A. CA HIV Res Network TI Disparities in Antiretroviral Treatment: A Comparison of Behaviorally HIV-Infected Youth and Adults in the HIV Research Network SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; youth; adolescent; HAART; disparities ID HUMAN-IMMUNODEFICIENCY-VIRUS; UNITED-STATES; YOUNG-ADULTS; THERAPY; ADOLESCENTS; CARE; ADHERENCE; HAART; AGE; ASSOCIATION AB Objectives: Increasing numbers of youth are becoming HIV-infected and need highly active antiretroviral therapy (HAART). We hypothesized that behaviorally HIV-infected youth (BIY) ages 18 to 24 years are less likely than adults (25 years or older) to receive HAART and, once initiated, more likely to discontinue their first HAART regimen. Methods: Longitudinal analysis of treatment-naive patients (age 18 years or older) meeting criteria for HAART and followed at HIV Research Network sites (2002-2008). Time from meeting criteria to HAART initiation and duration on first regimen were assessed using Cox proportional hazards regression. Results: A total of 3127 (268 youth, 2859 adult) treatment-naive, HIV-infected patients met criteria. BIY were more likely to be black 66.8% vs 51.1%; P < 0.01) and less likely to identify injection drug use HIV risk (1.1% vs 8.8%; P < 0.01) than adults 25 years of age or older. Nearly 69% of BIY started HAART versus 79% of adults (P < 0.001). Adults 25 to 29 years of age (adjusted hazards ratio [AHR], 1.39; 95% confidence interval [CI], 1.12-1.73) and 50 years of age or older (AHR, 1.24; 95% CI, 1.00-1.54), but not 30 to 49 years (AHR, 1.19; 95% CI, 0.99-1.44) were more likely to initiate HAART than BIY. Attending four or more HIV provider visits within 1 year of meeting criteria was associated with HAART initiation (AHR, 1.91; 1.70-2.14). CD4 200 to 350 versus less than 200 cells/mm(3) (AHR, 0.57; 95% CI, 0.52-0.63), and injection drug use (AHR, 0.80; 95% CI, 0.69-0.92) were associated with a lower likelihood of HAART initiation. There were no age-related differences in duration of the first regimen. Conclusion: BIY are less likely to start HAART when meeting treatment criteria. Addressing factors associated with this disparity is critical to improving care for youth. C1 [Agwu, Allison L.] Johns Hopkins Sch Med, Dept Pediat, Div Pediat Infect Dis, Baltimore, MD USA. [Agwu, Allison L.; Gebo, Kelly A.] Johns Hopkins Sch Med, Dept Med, Div Infect Dis, Baltimore, MD USA. [Ellen, Jonathan M.] Johns Hopkins Sch Med, Dept Pediat, Div Adolescent Med, Baltimore, MD USA. [Fleishman, John A.] Agcy Hlth Care Res & Qual, Ctr Financing Access & Cost Trends, Rockville, MD USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Internal Med, Portland, OR 97201 USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD USA. [Gaur, Aditya H.] St Jude Childrens Hosp, Dept Infect Dis, Memphis, TN USA. [Rutstein, Richard] Childrens Hosp Philadelphia, Div Gen Pediat, Philadelphia, PA 19104 USA. RP Agwu, AL (reprint author), 200 N Wolfe St,Room 3145, Baltimore, MD 21287 USA. EM ageorg10@jhmi.edu FU Agency for Healthcare Research and Quality [290-01-0012]; National Institute on Aging [R01 AG026250]; National Center for Research Resources (NCCR) of the National Institute of Health (NIH) Roadmap for Medical Research [1KL2RR025006-01]; National Institutes of Allergy and Infectious Diseases [1K23 AI084549]; National Institute on Drug Abuse [K23 DA019809]; Agency for Healthcare Research and Quality, Rockville, MD; Health Resources and Services Administration, Rockville, MD; Data Coordinating Center: Johns Hopkins University, Baltimore, MD FX Supported by the Agency for Healthcare Research and Quality (grant 290-01-0012) and the National Institute on Aging (R01 AG026250) (K. A. G.). A. L. A. was supported by the National Center for Research Resources (NCCR), a component of the National Institute of Health (NIH) Roadmap for Medical Research (1KL2RR025006-01) and the National Institutes of Allergy and Infectious Diseases (1K23 AI084549). P. T. K. was supported by the National Institute on Drug Abuse (K23 DA019809).; The sponsoring agencies are the Agency for Healthcare Research and Quality, Rockville, MD; Health Resources and Services Administration, Rockville, MD; and the Data Coordinating Center: Johns Hopkins University, Baltimore, MD (Kelly Gebo, MD). NR 41 TC 11 Z9 11 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD SEP 1 PY 2011 VL 58 IS 1 BP 100 EP 107 DI 10.1097/QAI.0b013e31822327df PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 816OA UT WOS:000294610600019 PM 21637114 ER PT J AU Veetil, BMA Whitt, I AF Veetil, Bharath Manu Akkara Whitt, Irene TI Amyopathic Dermatomyositis Presenting as Skin Necrosis SO JCR-JOURNAL OF CLINICAL RHEUMATOLOGY LA English DT Article ID INTERSTITIAL LUNG-DISEASE; MANIFESTATIONS; INFUSIONS; LESIONS C1 [Veetil, Bharath Manu Akkara] Mayo Clin, Div Rheumatol, Rochester, MN 55905 USA. [Whitt, Irene] NIEHS, NIH, Environm Autoimmun Grp, Bethesda, MD USA. RP Veetil, BMA (reprint author), Mayo Clin, Div Rheumatol, 200 1st St SW, Rochester, MN 55905 USA. EM bharathmanu@yahoo.co.in NR 13 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-1608 J9 JCR-J CLIN RHEUMATOL JI JCR-J. Clin. Rheumatol. PD SEP PY 2011 VL 17 IS 6 BP 332 EP 333 DI 10.1097/RHU.0b013e318230962c PG 2 WC Rheumatology SC Rheumatology GA 814UR UT WOS:000294483200010 PM 21869704 ER PT J AU Skloot, G Schechter, C Desai, A Togias, A AF Skloot, Gwen Schechter, Clyde Desai, Alpa Togias, Alkis TI Impaired response to deep inspiration in obesity SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE airway responsiveness; lung inflation; bronchodilation; bronchoprotection ID BODY-MASS INDEX; AIRWAY HYPERRESPONSIVENESS; LUNG-FUNCTION; RESPIRATORY RESISTANCE; ASTHMATIC SUBJECTS; PULMONARY-FUNCTION; SMOOTH-MUSCLE; NONASTHMATIC SUBJECTS; COLD-AIR; METHACHOLINE AB Skloot G, Schechter C, Desai A, Togias A. Impaired response to deep inspiration in obesity. J Appl Physiol 111: 726-734, 2011. First published June 23, 2011; doi: 10.1152/japplphysiol.01155.2010.-Deep inspirations modulate airway caliber and airway closure and their effects are impaired in asthma. The association between asthma and obesity raises the question whether the deep inspiration (DI) effect is also impaired in the latter condition. We assessed the DI effects in obese and nonobese nonasthmatics. Thirty-six subjects (17 obese, 19 nonobese) underwent routine methacholine (Mch) challenge and 30 of them also had a modified bronchoprovocation in the absence of DIs. Lung function was monitored with spirometry and forced oscillation (FO) [resistance (R) at 5 Hz (R5), at 20 Hz (R20), R5-R20 and the integrated area of low-frequency reactance (AX)]. The response to Mch, assessed with area under the dose-response curves (AUC), was consistently greater in the routine challenge in the obese (mean +/- SE, obese vs. nonobese AUC: R5: 15.7 +/- 2.3 vs. 2.4 +/- 2.0, P < 0.0005; R20: 5.6 +/- 1.4 vs. 1.4 +/- 1.2, P = 0.027; R5-R20: 10.2 +/- 1.6 vs. 0.9 +/- 0.1.4, P < 0.0005; AX: 115.6 +/- 22.0 vs. 1.5 +/- 18.9, P < 0.0005), but differences between groups in the modified challenge were smaller, indicating reduced DI effects in obesity. Given that DI has bronchodilatory and bronchoprotective effects, we further assessed these components separately. In the obese subjects, DI prior to Mch enhanced Mch-induced bronchoconstriction, but DI after Mch resulted in bronchodilation that was of similar magnitude as in the nonobese. We conclude that obesity is characterized by increased Mch responsiveness, predominantly of the small airways, due to a DI effect that renders the airways more sensitive to the stimulus. C1 [Skloot, Gwen; Desai, Alpa] Mt Sinai Med Ctr, Mt Sinai Sch Med, Dept Med, Div Pulm Crit Care & Sleep Med, New York, NY 10029 USA. [Schechter, Clyde] Albert Einstein Coll Med, Dept Family & Social Med, Bronx, NY 10467 USA. [Togias, Alkis] NIAID, NIH, Bethesda, MD 20892 USA. RP Skloot, G (reprint author), Mt Sinai Med Ctr, Mt Sinai Sch Med, Dept Med, Div Pulm Crit Care & Sleep Med, 1 Gustave L Levy Pl,Box 1232, New York, NY 10029 USA. EM gwen.skloot@mssm.edu FU Mount Sinai Pulmonary Divisional Fund FX This work was supported by the Mount Sinai Pulmonary Divisional Fund. NR 72 TC 16 Z9 16 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD SEP PY 2011 VL 111 IS 3 BP 726 EP 734 DI 10.1152/japplphysiol.01155.2010 PG 9 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 817QM UT WOS:000294688900012 PM 21700888 ER PT J AU Feng, HZ Chen, M Weinstein, LS Jin, JP AF Feng, Han-Zhong Chen, Min Weinstein, Lee S. Jin, J. -P. TI Improved fatigue resistance in G(s)alpha-deficient and aging mouse skeletal muscles due to adaptive increases in slow fibers SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE G(s)alpha deficiency; aging; skeletal muscle adaptation; myosin and troponin isoforms ID INSULIN-RESISTANCE; TROPONIN-T; GLUCOSE-INTOLERANCE; DIABETES-MELLITUS; NEMALINE MYOPATHY; BETA; CLENBUTEROL; METABOLISM; ADAPTATION; ISOFORMS AB Feng HZ, Chen M, Weinstein LS, Jin JP. Improved fatigue resistance in G(s)alpha-deficient and aging mouse skeletal muscles due to adaptive increases in slow fibers. J Appl Physiol 111: 834-843, 2011. First published June 16, 2011; doi: 10.1152/japplphysiol.00031.2011.-Genetically modified mice with deficiency of the G protein alpha-subunit (G(s)alpha) in skeletal muscle showed metabolic abnormality with reduced glucose tolerance, low muscle mass, and low contractile force, along with a fast-to-slow-fiber-type switch (Chen M, Feng HZ, Gupta D, Kelleher J, Dickerson KE, Wang J, Hunt D, Jou W, Gavrilova O, Jin JP, Weinstein LS. Am J Physiol Cell Physiol 296: C930-C940, 2009). Here we investigated a hypothesis that the switching to more slow fibers is an adaptive response with specific benefit. The results showed that, corresponding to the switch of myosin isoforms, the thin-filament regulatory proteins troponin T and troponin I both switched to their slow isoforms in the atrophic soleus muscle of 3-mo-old G(s)alpha-deficient mice. This fiber-type switch involving coordinated changes of both thick-and thin-myofilament proteins progressed in the G(s)alpha-deficient soleus muscles of 18- to 24-mo-old mice, as reflected by the expression of solely slow isoforms of myosin and troponin. Compared with age-matched controls, G(s)alpha-deficient soleus muscles with higher proportion of slow fibers exhibited slower contractile and relaxation kinetics and lower developed force, but significantly increased resistance to fatigue, followed by a better recovery. G(s)alpha-deficient soleus muscles of neonatal and 3-wk-old mice did not show the increase in slow fibers. Therefore, the fast-to-slow-fiber-type switch in G(s)alpha deficiency at older ages was likely an adaptive response. The benefit of higher fatigue resistance in adaption to metabolic deficiency and aging provides a mechanism to sustain skeletal muscle function in diabetic patients and elderly individuals. C1 [Feng, Han-Zhong; Jin, J. -P.] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA. [Chen, Min; Weinstein, Lee S.] NIDDK, Metab Dis Branch, Bethesda, MD USA. RP Jin, JP (reprint author), Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA. EM jjin@med.wayne.edu FU National Institutes of Health (NIH) [AR048816, HL098945]; National Institute of Diabetes and Digestive and Kidney Diseases, NIH, US Department of Health and Human Services FX This study was supported by National Institutes of Health (NIH) Grants AR048816 and HL098945 to J.-P. Jin and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, US Department of Health and Human Services. NR 47 TC 6 Z9 6 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD SEP PY 2011 VL 111 IS 3 BP 834 EP 843 DI 10.1152/japplphysiol.00031.2011 PG 10 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 817QM UT WOS:000294688900025 PM 21680879 ER PT J AU Buchanan, IM Scott, T Tandle, AT Burgan, WE Burgess, TL Tofilon, PJ Camphausen, K AF Buchanan, Ian M. Scott, Tamalee Tandle, Anita T. Burgan, William E. Burgess, Teresa L. Tofilon, Philip J. Camphausen, Kevin TI Radiosensitization of glioma cells by modulation of Met signalling with the hepatocyte growth factor neutralizing antibody, AMG102 SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE glioblastoma; AMG102; radiation; HGF; Met ID SCATTER FACTOR EXPRESSION; DOUBLE-STRAND BREAKS; C-MET; MONOCLONAL-ANTIBODY; IONIZING-RADIATION; MOLECULAR-CLONING; HISTONE H2AX; TUMOR-CELLS; DNA-REPAIR; KINASE AB The hepatocyte growth factor (HGF)/Met signalling pathway is up-regulated in many cancers, with downstream mediators playing a role in DNA double strand break repair. Previous studies have shown increased radiosensitization of tumours through modulation of Met signalling by genetic methods. We investigated the effects of the anti-HGF monoclonal antibody, AMG102, on the response to ionizing radiation in a model of glioblastoma multiforme in vitro and in vivo. Radiosensitivity was evaluated in vitro in the U-87 MG human glioma cell line. Met activation was measured by Western blot, and the effect on survival following radiation was evaluated by clonogenic assay. Mechanism of cell death was evaluated by apoptosis and mitotic catastrophe assays. DNA damage was quantitated by gamma H2AX foci and neutral comet assay. Growth kinetics of subcutaneous tumours was used to assess the effects of AMG102 on in vivo tumour radiosensitivity. AMG102 inhibited Met activation after irradiation. An enhancement of radiation cell killing was shown with no toxicity using drug alone. Retention of gamma H2AX foci at 6 and 24 hrs following the drug/radiation combination indicated an inhibition of DNA repair following radiation, and comet assay confirmed DNA damage persisting over the same duration. At 48 and 72 hrs following radiation, a significant increase of cells undergoing mitotic catastrophe was seen in the drug/radiation treated cells. Growth of subcutaneous tumours was slowed in combination treated mice, with an effect that was greater than additive for each modality individually. Modulation of Met signalling with AMG102 may prove a novel radiation sensitizing strategy. Our data indicate that DNA repair processes downstream of Met are impaired leading to increased cell death through mitotic catastrophe. C1 [Buchanan, Ian M.; Scott, Tamalee; Tandle, Anita T.; Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Buchanan, Ian M.] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. [Buchanan, Ian M.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Burgess, Teresa L.] NCI, Mol Radiat Therapeut Branch, Frederick, MD 21701 USA. [Burgess, Teresa L.] NCI, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. [Tofilon, Philip J.] Univ S Florida, H Lee Moffitt Canc Ctr, Drug Discovery Program, Tampa, FL 33682 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr B2-3561, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov FU National Institutes of Health, National Cancer Institute; Howard Hughes Medical Institute through the Howard Hughes Medical Institute-National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and by the Howard Hughes Medical Institute through the Howard Hughes Medical Institute-National Institutes of Health, Research Scholar Program. NR 49 TC 19 Z9 22 U1 5 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD SEP PY 2011 VL 15 IS 9 BP 1999 EP 2006 DI 10.1111/j.1582-4934.2010.01122.x PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 816KI UT WOS:000294597400019 PM 20629992 ER PT J AU King, KS Chen, CC Alexopoulos, DK Whatley, MA Reynolds, JC Patronas, N Ling, A Adams, KT Xekouki, P Lando, H Stratakis, CA Pacak, K AF King, Kathryn S. Chen, Clara C. Alexopoulos, Dimitrios K. Whatley, Millie A. Reynolds, James C. Patronas, Nicholas Ling, Alexander Adams, Karen T. Xekouki, Paraskevi Lando, Howard Stratakis, Constantine A. Pacak, Karel TI Functional Imaging of SDHx-Related Head and Neck Paragangliomas: Comparison of F-18-Fluorodihydroxyphenylalanine, F-18-Fluorodopamine, F-18-Fluoro-2-Deoxy-D-Glucose PET, I-123-Metaiodobenzylguanidine Scintigraphy, and In-111-Pentetreotide Scintigraphy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; MALIGNANT PHEOCHROMOCYTOMA; I-123-MIBG SCINTIGRAPHY; OCTREOTIDE SCINTIGRAPHY; METAIODOBENZYLGUANIDINE; DIAGNOSIS; SUPERIOR; BENIGN; TUMORS; LOCALIZATION AB Rationale: Accurate diagnosis of head and neck paragangliomas is often complicated by biochemical silence and lack of catecholamine-associated symptoms, making accurate anatomical and functional imaging techniques essential to the diagnostic process. Methods: Ten patients (seven SDHD, three SDHB), with a total of 26 head and neck paragangliomas, were evaluated with anatomical and functional imaging. This study compares five different functional imaging techniques [F-18-fluorodihydroxyphenylalanine (F-18-FDOPA) positron emission tomography (PET), F-18-fluorodopamine (F-18-FDA) PET/computed tomography (CT), F-18-fluoro-2-deoxy-D-glucose (F-18-FDG) PET/CT, I-123-metaiodobenzylguanidine (I-123-MIBG) scintigraphy, and In-111-pentetreotide scintigraphy] in the localization of head and neck paragangliomas. Results: Prospectively F-18-FDOPA PET localized 26 of 26 lesions in the 10 patients, CT/magnetic resonance imaging localized 21 of 26 lesions, F-18-FDG PET/CT localized 20 of 26 lesions, (111)-Inpentetreotide scintigraphy localized 16 of 25 lesions, F-18-FDA PET/CT localized 12 of 26 lesions, and 123I-MIBG scintigraphy localized eight of 26 lesions. Differences in imaging efficacy related to genetic phenotype, even in the present small sample size, included the negativity of 18F-FDA PET/CT and 123I-MIBG scintigraphy in patients with SDHB mutations and the accuracy of 18F-FDG PET/CT in all patients with SDHD mutations, as compared with the accuracy of 18F-FDG PET/CT in only one patient with an SDHB mutation. Conclusion: Overall, F-18-FDOPA PET proved to be the most efficacious functional imaging modality in the localization of SDHx-related head and neck paragangliomas and may be a potential first-line functional imaging agent for the localization of these tumors. (J Clin Endocrinol Metab 96: 2779-2785, 2011) C1 [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Med Neuroendocrinol, Reprod & Adult Endocrinol Program, Bethesda, MD 20892 USA. [Chen, Clara C.; Whatley, Millie A.; Reynolds, James C.; Xekouki, Paraskevi; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet,Nucl Med Div,Dept, Bethesda, MD 20892 USA. [Alexopoulos, Dimitrios K.; Patronas, Nicholas; Ling, Alexander] NIH, Ctr Clin, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Xekouki, Paraskevi; Stratakis, Constantine A.] NIH, Pediat Endocrinol Inter Inst Training Program, Bethesda, MD 20892 USA. [Lando, Howard] Med Specialists No Virginia, Alexandria, VA 22306 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Med Neuroendocrinol, Reprod & Adult Endocrinol Program, Bldg 10,CRC,1-E,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported, in part, by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 39 TC 59 Z9 59 U1 1 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2011 VL 96 IS 9 BP 2779 EP 2785 DI 10.1210/jc.2011-0333 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 815VR UT WOS:000294558600049 PM 21752889 ER PT J AU Wu, JY Aarnisalo, P Bastepe, M Sinha, P Fulzele, K Selig, MK Chen, M Poulton, IJ Purton, LE Sims, NA Weinstein, LS Kronenberg, HM AF Wu, Joy Y. Aarnisalo, Piia Bastepe, Murat Sinha, Partha Fulzele, Keertik Selig, Martin K. Chen, Min Poulton, Ingrid J. Purton, Louise E. Sims, Natalie A. Weinstein, Lee S. Kronenberg, Henry M. TI G(s)alpha enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteoblast differentiation in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID PARATHYROID-HORMONE; BONE-FORMATION; BETA-CATENIN; CHONDROCYTE DIFFERENTIATION; INTERMITTENT PTH; PROTEIN-KINASE; CELL-LINE; GS-ALPHA; RECEPTOR; OSTEOCYTES AB The heterotrimeric G protein subunit G(s)alpha stimulates cAMP-dependent signaling downstream of G protein-coupled receptors. In this study, we set out to determine the role of G(s)alpha signaling in cells of the early osteoblast lineage in vivo by conditionally deleting G(s)alpha from osterix-expressing cells. This led to severe osteoporosis with fractures at birth, a phenotype that was found to be the consequence of impaired bone formation rather than increased resorption. Osteoblast number was markedly decreased and osteogenic differentiation was accelerated, resulting in the formation of woven bone. Rapid differentiation of mature osteoblasts into matrix-embedded osteocytes likely contributed to depletion of the osteoblast pool. In addition, the number of committed osteoblast progenitors was diminished in both bone marrow stromal cells (BMSCs) and calvarial cells of mutant mice. In the absence of G(s)alpha, expression of sclerostin and dickkopf1 (Dkk1), inhibitors of canonical Wnt signaling, was markedly increased; this was accompanied by reduced Wnt signaling in the osteoblast lineage. In summary, we have shown that G(s)alpha regulates bone formation by at least two distinct mechanisms: facilitating the commitment of mesenchymal progenitors to the osteoblast lineage in association with enhanced Wnt signaling; and restraining the differentiation of committed osteoblasts to enable production of bone of optimal mass, quality, and strength. C1 [Wu, Joy Y.; Aarnisalo, Piia; Bastepe, Murat; Sinha, Partha; Fulzele, Keertik; Kronenberg, Henry M.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Aarnisalo, Piia] Univ Helsinki, Biomedicum Helsinki, Inst Biomed Physiol, Helsinki, Finland. [Aarnisalo, Piia] Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland. [Aarnisalo, Piia] Helsinki Univ Cent Hosp, Helsinki, Finland. [Selig, Martin K.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Chen, Min; Weinstein, Lee S.] NIDDKD, Metab Dis Branch, Bethesda, MD 20892 USA. [Poulton, Ingrid J.; Purton, Louise E.; Sims, Natalie A.] Univ Melbourne, St Vincents Inst, Fitzroy, Vic 3065, Australia. [Poulton, Ingrid J.; Purton, Louise E.; Sims, Natalie A.] Univ Melbourne, St Vincents Hosp, Dept Med, Fitzroy, Vic 3065, Australia. RP Wu, JY (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1101, Boston, MA 02114 USA. EM jywu@partners.org; hkronenberg@partners.org FU NIH [AR053781, DK117940]; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank David Rowe for providing the Col2.3::GFP transgenic mice; Mark Horowitz for providing the ALP antibody; James Oh, Jackie McConnell, and Rhiannon Chubb for technical assistance; the MGH Center for Comparative Medicine staff for care of the mice; and the Dana Farber Cancer Institute and Harvard Stem Cell Institute flow cytometry cores. This work was supported in part by NIH grants AR053781 (to J.Y. Wu) and DK117940 (to H.M. Kronenberg) and by the National Institute of Diabetes and Digestive and Kidney Diseases' Intramural Research Program (to M. Chen and L.S. Weinstein). NR 67 TC 36 Z9 39 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 SEP PY 2011 VL 121 IS 9 BP 3492 EP 3504 DI 10.1172/JCI46406 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 818LR UT WOS:000294753700017 PM 21804192 ER PT J AU Kim, KY Stevens, MV Akter, MH Rusk, SE Huang, RJ Cohen, A Noguchi, A Springer, D Bocharov, AV Eggerman, TL Suen, DF Youle, RJ Amar, M Remaley, AT Sack, MN AF Kim, Kye-Young Stevens, Mark V. Akter, M. Hasina Rusk, Sarah E. Huang, Robert J. Cohen, Alexandra Noguchi, Audrey Springer, Danielle Bocharov, Alexander V. Eggerman, Tomas L. Suen, Der-Fen Youle, Richard J. Amar, Marcelo Remaley, Alan T. Sack, Michael N. TI Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID RECESSIVE JUVENILE PARKINSONISM; UBIQUITIN-PROTEIN LIGASE; DISEASE GENE-PRODUCT; DEFICIENT MICE; INDEPENDENT UBIQUITINATION; ENERGY-EXPENDITURE; INSULIN ACTION; ACID UPTAKE; MUTATIONS; CHOLESTEROL AB It has long been hypothesized that abnormalities in lipid biology contribute to degenerative brain diseases. Consistent with this, emerging epidemiologic evidence links lipid alterations with Parkinson disease (PD), and disruption of lipid metabolism has been found to predispose to cc-synuclein toxicity. We therefore investigated whether Parkin, an E3 ubiquitin ligase found to be defective in patients with early onset PD, regulates systemic lipid metabolism. We perturbed lipid levels by exposing Parkin(+/+) and Parkin(-/-) mice to a high-fat and -cholesterol diet (HFD). Parkin(-/-) mice resisted weight gain, steatohepatitis, and insulin resistance. In wild-type mice, the HFD markedly increased hepatic Parkin levels in parallel with lipid transport proteins, including CD 36, Sr-B1, and FABP. These lipid transport proteins were not induced in Parkin(-/-) mice. The role of Parkin in fat uptake was confirmed by increased oleate accumulation in hepatocytes overexpressing Parkin and decreased uptake in Parkin(-/-) mouse embryonic fibroblasts and patient cells harboring complex heterozygous mutations in the Parkin-encoding gene PARK2. Parkin conferred this effect, in part, via ubiquitin-mediated stabilization of the lipid transporter CD36. Reconstitution of Parkin restored hepatic fat uptake and CD36 levels in Parkin(-/-) mice, and Parkin augmented fat accumulation during adipocyte differentiation. These results demonstrate that Parkin is regulated in a lipid-dependent trimmer and modulates systemic fat uptake via ubiquitin ligase-dependent effects. Whether this metabolic regulation contributes to premature Parkinsonism warrants investigation. C1 [Kim, Kye-Young; Stevens, Mark V.; Akter, M. Hasina; Rusk, Sarah E.; Huang, Robert J.; Cohen, Alexandra; Sack, Michael N.] NHLBI, Ctr Mol Med, Bethesda, MD 20892 USA. [Bocharov, Alexander V.; Eggerman, Tomas L.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Suen, Der-Fen; Youle, Richard J.] Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, Bethesda, MD USA. [Amar, Marcelo; Remaley, Alan T.] NHLBI, Cardiopulm Med Branch, Bethesda, MD 20892 USA. RP Sack, MN (reprint author), NHLBI, Ctr Mol Med, Bldg 10-CRC,Room 5-3150,10 Ctr Dr, Bethesda, MD 20892 USA. EM sackm@nhlbi.nih.gov FU Division of Intramural Research program of the NHLBI; Howard Hughes Medical Institute/NIH; NIH/Pfizer FX We thank Paul Hwang, Mark Knepper, Joe Chou, and Jay Chung, all of the NHLBI, for the generous use of their metabolic analysis equipment. We acknowledge the technical assistance of Jie Liu, Ilsa Rovira, and Liu Cao (NHLBI). We also thank Sonja Scholz (NIA) for helpful discussions about the human B cell lines; Bob Shamburek (NHLBI) and Oksana Gavrilova (NIDDK) for helpful suggestions regarding lipid biology; and Toren Finkel for helpful discussion about the manuscript. Finally, we thank Olga Corti from Pitie-Salpetriere Hospital (France) for the pcDNA-Parkin/Delta Ubi constructs. This research was funded by the Division of Intramural Research program of the NHLBI. S. Rusk and R. Huang were supported by the Howard Hughes Medical Institute/NIH research Fellowship and the NIH/Pfizer Clinical Research Training Program, respectively. NR 47 TC 65 Z9 65 U1 0 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2011 VL 121 IS 9 BP 3701 EP 3712 DI 10.1172/JCI44736 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 818LR UT WOS:000294753700035 PM 21865652 ER PT J AU Chennamsetty, I Claudel, T Kostner, KM Baghdasaryan, A Kratky, D Levak-Frank, S Frank, S Gonzalez, FJ Trauner, M Kostner, GM AF Chennamsetty, Indumathi Claudel, Thierry Kostner, Karam M. Baghdasaryan, Anna Kratky, Dagmar Levak-Frank, Sanja Frank, Sasa Gonzalez, Frank J. Trauner, Michael Kostner, Gert M. TI Farnesoid X receptor represses hepatic human APOA gene expression SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID BILE-ACID-HOMEOSTASIS; CORONARY HEART-DISEASE; NUCLEAR RECEPTOR; MYOCARDIAL-INFARCTION; TRANSGENIC MICE; DNA-BINDING; APOLIPOPROTEIN(A) GENE; PLASMA LIPOPROTEIN(A); HETERODIMER PARTNER; CARDIOVASCULAR RISK AB High plasma concentrations of lipoprotein(a) [Lp(a), which is encoded by the APOA gene] increase an individual's risk of developing diseases, such as coronary artery diseases, restenosis, and stroke. Unfortunately, increased Lp(a) levels are minimally influenced by dietary changes or drug treatment. Further, the development of Lp(a)-specific medications has been hampered by limited knowledge of Lp(a) metabolism. In this study, we identified patients suffering from biliary obstructions with very low plasma Lp(a) concentrations that rise substantially after surgical intervention. Consistent with this, common bile duct ligation in mice transgenic for human APOA (tg-APOA mice) lowered plasma concentrations and hepatic expression of APOA. To test whether farnesoid X receptor (FXR), which is activated by bile acids, was responsible for the low plasma Lp(a) levels in cholestatic patients and mice, we treated tg-APOA and tg-APOA/Fxr(-/-) mice with cholic acid. FXR activation markedly reduced plasma concentrations and hepatic expression of human APOA in tg-APOA mice but not in tg-APOA/Fxr(-/-) mice. Incubation of primary hepatocytes from tg-APOA mice with bile acids dose dependently downregulated APOA expression. Further analysis determined that the direct repeat 1 element between nucleotides -826 and -814 of the APOA promoter functioned as a negative FXR response element. This motif is also bound by hepatocyte nuclear factor 4 alpha (HNF4 alpha), which promotes APOA transcription, and FXR was shown to compete with HNF4a for binding to this motif. These findings may have important implications in the development of Lp(a)-lowering medications. C1 [Chennamsetty, Indumathi; Kratky, Dagmar; Levak-Frank, Sanja; Frank, Sasa; Kostner, Gert M.] Med Univ Graz, Inst Mol Biol & Biochem, Ctr Mol Med, A-8010 Graz, Austria. [Claudel, Thierry; Baghdasaryan, Anna; Trauner, Michael] Med Univ Graz, Lab Expt & Mol Hepatol, Div Gastroenterol & Hepatol, Dept Internal Med, A-8010 Graz, Austria. [Kostner, Karam M.] Univ Queensland, Mater Adult Hosp, Dept Cardiol, Brisbane, Qld, Australia. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Trauner, Michael] Med Univ Vienna, Div Gastroenterol & Hepatol, Dept Internal Med 3, Vienna, Austria. RP Kostner, GM (reprint author), Med Univ Graz, Inst Mol Biol & Biochem, Ctr Mol Med, Harrachgasse 21, A-8010 Graz, Austria. EM Gerhard.kostner@medunigraz.at RI Kostner, Karam/F-5167-2010; Chennamsetty, Indumathi/E-3034-2015; OI Kratky, Dagmar/0000-0003-1357-7573 FU Medical University of Graz; Molecular Medicine; Austrian Science Fund FWF [SFB-LIPOTOX F3004, F3008, P19186]; Austrian Federal Ministry of Science and Research FX This work was supported by the Medical University of Graz (I. Chennamsetty and A. Baghdasaryan are funded by the PhD program "Molecular Medicine"), the Austrian Science Fund FWF (SFB-LIPOTOX F3004, F3008, and P19186), and the Austrian Federal Ministry of Science and Research (GEN-AU project Genomics of Lipid-associated Disorders GOLD). The authors thank A. Ibovnik for excellent technical assistance. NR 66 TC 38 Z9 44 U1 0 U2 2 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 SEP PY 2011 VL 121 IS 9 BP 3724 EP 3734 DI 10.1172/JCI45277 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 818LR UT WOS:000294753700037 PM 21804189 ER PT J AU Torchia, DA AF Torchia, Dennis A. TI Dynamics of biomolecules from picoseconds to seconds at atomic resolution SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Protein; Dynamics; Spectral density; Labeling; Spin; Order parameter; Relaxation; RDC; Dispersion; Exchange; TROSY ID NUCLEAR-MAGNETIC-RESONANCE; SOLID-STATE NMR; CHEMICAL-SHIFT ANISOTROPY; RESIDUAL DIPOLAR COUPLINGS; SPIN-LATTICE-RELAXATION; SIDE-CHAIN DYNAMICS; MODEL-FREE APPROACH; LIQUID-CRYSTAL NMR; PANCREATIC TRYPSIN-INHIBITOR; FIELD-CYCLING NMR AB Although biomolecular dynamics has been investigated using NMR for at least 40 years, only in the past 20 years have internal motions been characterized at atomic resolution throughout proteins and nucleic acids. This development was made possible by multidimensional heteronuclear NMR approaches that provide near complete sequential signal assignments of uniformly labeled biomolecules. Recent methodological advances have enabled characterization of internal dynamics on timescales ranging from picoseconds to seconds, both in solution and in the solid state. The size, complexity and functional significance of biomolecules investigated by NMR continue to grow, as do the insights that have been obtained about function. In this article I review a number of recent advances that have made such studies possible, and provide a few examples of where NMR either by itself or in combination with other approaches has paved the way to a better understanding of the complex relationship between dynamics and biomolecular function. Finally. I discuss prospects for further advances in this field. (C) 2011 Elsevier Inc. All rights reserved. C1 NIH, Bethesda, MD 20892 USA. RP Torchia, DA (reprint author), NIH, Bldg 5,Room 128, Bethesda, MD 20892 USA. EM dtorchia@dir.nidcr.nih.gov NR 112 TC 25 Z9 25 U1 0 U2 31 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD SEP PY 2011 VL 212 IS 1 BP 1 EP 10 DI 10.1016/j.jmr.2011.07.010 PG 10 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 818KL UT WOS:000294750500001 PM 21840740 ER PT J AU Joiner, WM Cavanaugh, J Wurtz, RH AF Joiner, Wilsaan M. Cavanaugh, James Wurtz, Robert H. TI Modulation of shifting receptive field activity in frontal eye field by visual salience SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE exogenous attention; onset attention ID LATERAL INTRAPARIETAL AREA; ATTENTIONAL CONTROL; PARIETAL CORTEX; NEURAL BASIS; TIME-COURSE; REPRESENTATION; SEARCH; MONKEY; MAP; STABILITY AB Joiner WM, Cavanaugh J, Wurtz RH. Modulation of shifting receptive field activity in frontal eye field by visual salience. J Neurophysiol 106: 1179-1190, 2011. First published June 8, 2011; doi:10.1152/jn.01054.2010.-In the monkey frontal eye field (FEF), the sensitivity of some neurons to visual stimulation changes just before a saccade. Sensitivity shifts from the spatial location of its current receptive field (RF) to the location of that field after the saccade is completed (the future field, FF). These shifting RFs are thought to contribute to the stability of visual perception across saccades, and in this study we investigated whether the salience of the FF stimulus alters the magnitude of FF activity. We reduced the salience of the usually single flashed stimulus by adding other visual stimuli. We isolated 171 neurons in the FEF of 2 monkeys and did experiments on 50 that had FF activity. In 30% of these, that activity was higher before salience was reduced by adding stimuli. The mean magnitude reduction was 16%. We then determined whether the shifting RFs were more frequent in the central visual field, which would be expected if vision across saccades were only stabilized for the visual field near the fovea. We found no evidence of any skewing of the frequency of shifting receptive fields (or the effects of salience) toward the central visual field. We conclude that the salience of the FF stimulus makes a substantial contribution to the magnitude of FF activity in FEF. In so far as FF activity contributes to visual stability, the salience of the stimulus is probably more important than the region of the visual field in which it falls for determining which objects remain perceptually stable across saccades. C1 [Joiner, Wilsaan M.; Cavanaugh, James; Wurtz, Robert H.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20982 USA. RP Joiner, WM (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Rm 2A50,49 Convent Dr, Bethesda, MD 20982 USA. EM joinerw@nei.nih.gov FU National Eye Institute, National Institutes of Health FX This work was supported by the National Eye Institute Intramural Research Program at the National Institutes of Health. NR 37 TC 18 Z9 18 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD SEP PY 2011 VL 106 IS 3 BP 1179 EP 1190 DI 10.1152/jn.01054.2010 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 818SM UT WOS:000294775500009 PM 21653709 ER PT J AU Asthagiri, AR Walbridge, S Heiss, JD Lonser, RR AF Asthagiri, Ashok R. Walbridge, Stuart Heiss, John D. Lonser, Russell R. TI Convection-enhanced delivery Response SO JOURNAL OF NEUROSURGERY LA English DT Editorial Material ID BRAIN-STEM; MACROMOLECULES; INFUSION; SIZE; TIME C1 [Asthagiri, Ashok R.; Walbridge, Stuart; Heiss, John D.; Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD USA. RP Asthagiri, AR (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2011 VL 115 IS 3 BP 465 EP 466 DI 10.3171/2010.11.JNS101801 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 816FG UT WOS:000294583500002 ER PT J AU Asthagiri, AR Walbridge, S Heiss, JD Lonser, RR AF Asthagiri, Ashok R. Walbridge, Stuart Heiss, Joon D. Lonser, Russell R. TI Effect of concentration on the accuracy of convective imaging distribution of a gadolinium-based surrogate tracer Laboratory investigation SO JOURNAL OF NEUROSURGERY LA English DT Article DE convection-enhanced delivery; gadolinium; oncology; magnetic resonance imaging; surrogate tracer; volume of distribution ID VIRUS-SIZED PARTICLES; ENHANCED DELIVERY; PRIMATE BRAIN; MACROMOLECULES; INFUSION; STEM; PERFUSION; DISEASE AB Object. Accurate real-time imaging of coinfused surrogate tracers can be used to determine the convective distribution of therapeutic agents. To assess the effect that a concentration of a Gd-based surrogate tracer has on the accuracy of determining the convective distribution, the authors infused different concentrations of Gd-diethylenetriamine pentaacetic acid (DTPA) in primates during MR imaging. Methods. Five nonhuman primates underwent convective infusion (1 or 5 mM, 21-65 mu l) of Gd-DTPA alone, Gd-DTPA and (14)C-sucrose, or Gd-DTPA and (14)C-dextran into the bilateral striata. Animals underwent real-time MR imaging during infusion (5 animals) and autoradiographic analysis (2 animals). Results. Gadolinium-DTPA could be seen filling the striata at either concentration (1 or 5 mM) on real-time MR imaging. While the volume of distribution (Vd) increased linearly with the volume of infusion (Vi) for both concentrations of tracer (1 mM: R(2) = 0.83; 5 mM: R(2) = 0.96), the Vd/Vi ratio was significantly (p < 0.0001) less for the 1-mM (2.3 +/- 1.0) as compared with the 5-mM (7.4 +/- 1.9) concentration. Autoradiographic and MR volumetric analysis revealed that the 5-mM concentration most accurately estimated the Vd for both small (sucrose [359 D], 12% difference between imaging and autoradiographic distribution) and large (dextran [70 kD], 0.2% difference) molecules compared with the 1-mM concentration (sucrose, 65% difference; dextran, 68% difference). Conclusions. The concentration of infused Gd-DTPA plays a critical role in accurately assessing the distribution of molecules delivered by CED. A 5-mM concentration of Gd-DTPA most accurately estimated the Vd over a wide range of molecular sizes. (DOI: 10.3171/2011.3.JNS101381) C1 [Asthagiri, Ashok R.; Walbridge, Stuart; Heiss, Joon D.; Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Asthagiri, AR (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, 10 Ctr Dr,Room 3D20, Bethesda, MD 20892 USA. EM asthagiria@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX This work was supported by the intramural research program at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. NR 23 TC 20 Z9 20 U1 0 U2 3 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2011 VL 115 IS 3 BP 467 EP 473 DI 10.3171/2011.3.JNS101381 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 816FG UT WOS:000294583500003 PM 21619409 ER PT J AU Iyer, RR Butman, JA Walbridge, S Gai, ND Heiss, JD Lonser, RR AF Iyer, Rajiv R. Butman, John A. Walbridge, Stuart Gai, Neville D. Heiss, John D. Lonser, Russell R. TI Tracking accuracy of T2-and diffusion-weighted magnetic resonance imaging for infusate distribution by convection-enhanced delivery Laboratory investigation SO JOURNAL OF NEUROSURGERY LA English DT Article DE accuracy; convection-enhanced delivery; drug distribution; imaging; magnetic resonance imaging; volume of distribution; oncology ID BRAIN; MACROMOLECULES; INFUSION; LIPOSOMES; PERFUSION AB Object. Because convection-enhanced delivery relies on bulk flow of fluid in the interstitial spaces, MR imaging techniques that detect extracellular fluid and fluid movement may be useful for tracking convective drug distribution. To determine the tracking accuracy of T2-weighted and diffusion-weighted MR imaging sequences, the authors followed convective distribution of radiolabeled compounds using these imaging sequences in nonhuman primates. Methods. Three nonhuman primates underwent thalamic convective infusions (5 infusions) with (14)C-sucrose (MW 342 D) or (14)C-dextran (MW 70,000 D) during serial MR imaging (T2- and diffusion-weighted imaging). Imaging, histological, and autoradiographic findings were analyzed. Results. Real-time T2- and diffusion-weighted imaging clearly demonstrated the region of infusion, and serial images revealed progressive filling of the bilateral thalami during infusion. Imaging analysis for T2- and diffusion-weighted sequences revealed that the tissue volume of distribution (Vd) increased linearly with volume of infusion (Vi; R(2) = 0.94, R(2) = 0.91). Magnetic resonance imaging analysis demonstrated that the mean +/- SD Vd/Vi ratios for T2-weighted (3.6 +/- 0.5) and diffusion-weighted (3.3 +/- 0.4) imaging were similar (p = 0.5). While (14)C-sucrose and (14)C-dextran were homogeneously distributed over the infused region, autoradiographic analysis revealed that T2-weighted and diffusion-weighted imaging significantly underestimated the Vd of both (14)C-sucrose (mean differences 51.3% and 52.3%, respectively; p = 0.02) and (14)C-dextran (mean differences 49.3% and 59.6%; respectively, p = 0.001). Conclusions. Real-time T2- and diffusion-weighted MR imaging significantly underestimate tissue Vd during convection-enhanced delivery over a wide range of molecular sizes. Application of these imaging modalities may lead to inaccurate estimation of convective drug distribution. (DOI: 10.3171/2011.5.JNS11246) C1 [Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Butman, John A.; Gai, Neville D.] NIH, Neuroradiol Sect, Dept Radiol, NIH Clin Ctr, Bethesda, MD 20892 USA. RP Lonser, RR (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bldg 10,Room 3D20, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX This work was supported by the intramural research program at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. NR 16 TC 12 Z9 12 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2011 VL 115 IS 3 BP 474 EP 480 DI 10.3171/2011.5.JNS11246 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 816FG UT WOS:000294583500004 PM 21663409 ER PT J AU Merrill, MJ Edwards, NA Lonser, RR AF Merrill, Marsha J. Edwards, Nancy A. Lonser, Russell R. TI Notch receptor and effector expression in von Hippel-Lindau disease associated central nervous system hemangioblastomas Laboratory investigation SO JOURNAL OF NEUROSURGERY LA English DT Article DE notch; von Hippel-Lindau disease; hemangioblastoma; HES; vasculature; oncology ID BRAIN ARTERIOVENOUS-MALFORMATIONS; GAMMA-SECRETASE INHIBITOR; HYPOXIA-INDUCIBLE FACTORS; RENAL-CELL CARCINOMA; STEM-CELLS; CANCER-THERAPY; ANGIOGENESIS; DIFFERENTIATION; TRANSCRIPTION; TARGETS AB Object. Central nervous system hemangioblastomas are the most common manifestation of von Hippel-Lindau (VHL) disease, an autosomal dominant tumor suppressor syndrome that results in loss of VHL protein function and continuous upregulation of hypoxia-inducible factors. These tumors are composed of neoplastic stromal cells and abundant vasculature. Stromal cells express markers consistent with multipotent embryonically arrested hemangioblasts, which are precursors for hematopoietic and vascular lineages. Notch receptors are transmembrane signaling molecules that regulate multiple developmental processes including hematopoiesis and vasculogenesis. To investigate the importance of notch signaling in the development of VHL disease associated CNS hemangioblastomas, the authors examined the presence of the four notch receptors and downstream notch effectors in this setting. Methods. The authors used surgical specimens obtained from confirmed VHL-associated hemangioblastomas. Immunohistochemical analysis for the four notch receptors and the downstream effectors was performed on formalin-fixed paraffin-embedded sections. Western blot analysis for HES1 was performed on frozen specimens. Results. All four notch receptors are present in hemangioblastomas. NOTCH1 and NOTCH4 receptors were widely and prominently expressed in both the stromal and vascular cells, NOTCH2 receptor expression was limited to primarily stromal cells, and NOTCH3 receptor expression was limited to vascular cells. All 4 receptors displayed a nuclear presence. Immunohistochemical analysis also demonstrated that downstream notch effectors, HES1 and HES5, were uniformly expressed in tumor stromal and vascular cells, but HES3. HEY1, and HEY2 were not. Strong HES1 expression was confirmed by Western blot analysis. Conclusions. The presence of all four notch receptors and downstream effector molecules suggests that the notch signaling pathway plays a critical role in the maintenance of the undifferentiated pluripotent phenotype of these tumors and in the associated vascular response. Moreover, the prominent expression of notch receptors in VHL-associated CNS hemangioblastomas reveals a new and possibly potent therapeutic target. (DO!: 10.3171/2011.5.JNS11271) C1 [Merrill, Marsha J.; Edwards, Nancy A.; Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD USA. RP Merrill, MJ (reprint author), 10 Ctr Dr,MSC 1414,Bldg 10,Room 3D-20, Bethesda, MD 20892 USA. EM merrillm@ninds.nih.gov FU National Institutes of Health, National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. NR 43 TC 3 Z9 3 U1 0 U2 4 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2011 VL 115 IS 3 BP 512 EP 517 DI 10.3171/2011.5.JNS11271 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 816FG UT WOS:000294583500011 PM 21663414 ER PT J AU Heiss, JD Oldfield, EH AF Heiss, John D. Oldfield, Edward H. TI Syringomyelia RESPONSE SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Letter ID THECOPERITONEAL SHUNT; PATHOPHYSIOLOGY C1 [Heiss, John D.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Oldfield, Edward H.] Univ Virginia Hlth Syst, Charlottesville, VA USA. RP Heiss, JD (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD SEP PY 2011 VL 15 IS 3 BP 341 EP 342 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 816FF UT WOS:000294583400022 ER PT J AU Virzi, L Pemberton, V Ohye, RG Tabbutt, S Lu, MM Atz, TC Barnard, T Dunbar-Masterson, C Ghanayem, NS Jacobs, JP Lambert, LM Lewis, A Pike, N Pizarro, C Radojewski, E Teitel, D Xu, MF Pearson, GD AF Virzi, Lisa Pemberton, Victoria Ohye, Richard G. Tabbutt, Sarah Lu, Minmin Atz, Teresa C. Barnard, Teresa Dunbar-Masterson, Carolyn Ghanayem, Nancy S. Jacobs, Jeffrey P. Lambert, Linda M. Lewis, Alan Pike, Nancy Pizarro, Christian Radojewski, Elizabeth Teitel, David Xu, Mingfen Pearson, Gail D. TI Reporting adverse events in a surgical trial for complex congenital heart disease: The Pediatric Heart Network experience SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID PULMONARY-ARTERY CONDUIT; BLALOCK-TAUSSIG SHUNT; RANDOMIZED-TRIAL; DATABASE-TASKFORCE; SINGLE VENTRICLE; INFANTS; MULTICENTER; OUTCOMES; CHILDREN; SAFETY AB Objective: The purpose of this analysis was to evaluate a novel strategy for reporting adverse events in the Pediatric Heart Network's randomized surgical trial of systemic-pulmonary artery shunt versus right ventricle-pulmonary artery conduit in infants with hypoplastic left heart syndrome. The strategy was developed to align the reporting process with the needs of a surgical trial while maintaining participant safety. Methods: Adverse event reporting was analyzed for 2 groups of study subjects: those randomized to a trial arm during a period in which a standard adverse event reporting system was used (period 1) and those randomized after institution of a system that focused serious adverse event reporting on 6 sentinel events (period 2). The analysis encompassed the period from randomization (Norwood surgery) to hospital discharge from stage II surgery. Adverse event rates were compared using a Poisson regression model for the number of events per subject. Results: From period 1 to period 2, the rate of serious adverse events requiring expedited reporting decreased as expected (0.42 vs 0.14/subject/month of follow-up; P < .001). Subjects with a serious (sentinel) adverse event in period 2 had a significantly higher rate of death and cardiac transplantation. Conclusions: The new adverse event reporting system successfully targeted subjects at highest risk, while decreasing the administrative burden associated with adverse event reports. This methodology may be of benefit in trials evaluating surgical or device-based interventions and in critically ill populations where many common clinical events would qualify as serious adverse events in the context of a drug trial. (J Thorac Cardiovasc Surg 2011;142:531-7) C1 [Virzi, Lisa; Lu, Minmin] New England Res Inst, Watertown, MA 02172 USA. [Pemberton, Victoria; Pearson, Gail D.] NHLBI, NIH, Bethesda, MD 20892 USA. [Ohye, Richard G.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Tabbutt, Sarah] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Atz, Teresa C.] Med Univ S Carolina, Charleston, SC 29425 USA. [Barnard, Teresa] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Dunbar-Masterson, Carolyn] Childrens Hosp, Boston, MA 02115 USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Ghanayem, Nancy S.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Jacobs, Jeffrey P.] Univ S Florida, Coll Med, Tampa, FL USA. [Lambert, Linda M.] Primary Childrens Med Ctr, Salt Lake City, UT USA. [Lewis, Alan] Univ So Calif, Los Angeles, CA USA. [Pike, Nancy] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Pizarro, Christian] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Radojewski, Elizabeth] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Teitel, David] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Xu, Mingfen] Duke Univ, Med Ctr, Durham, NC USA. RP Pemberton, V (reprint author), 6701 Rockledge Dr,Room 8102, Bethesda, MD 20892 USA. EM pembertonv@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057] FX Supported by U01 grants from the National Heart, Lung, and Blood Institute (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057). NR 23 TC 7 Z9 7 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2011 VL 142 IS 3 BP 531 EP 537 DI 10.1016/j.jtcvs.2010.11.052 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 807FQ UT WOS:000293882100024 PM 21397260 ER PT J AU Merims, S Li, X Joe, B Dokouhaki, P Han, M Childs, RW Wang, ZY Gupta, V Minden, MD Zhang, L AF Merims, S. Li, X. Joe, B. Dokouhaki, P. Han, M. Childs, R. W. Wang, Z-Y Gupta, V. Minden, M. D. Zhang, L. TI Anti-leukemia effect of ex vivo expanded DNT cells from AML patients: a potential novel autologous T-cell adoptive immunotherapy SO LEUKEMIA LA English DT Article DE acute myeloid leukemia (AML); double negative T (DNT) cells; adoptive immunotherapy ID ACUTE MYELOID-LEUKEMIA; TUMOR-INFILTRATING LYMPHOCYTES; INDUCED KILLER-CELLS; ACUTE MYELOBLASTIC-LEUKEMIA; DONOR LEUKOCYTE INFUSIONS; IN-VITRO; METASTATIC MELANOMA; MYELODYSPLASTIC SYNDROME; TRANSPLANTATION; THERAPY AB CD3(+)CD56(-), CD4 and CD8 double negative T (DNT) cells comprise 1-3% of peripheral blood (PB) mononuclear cells. Their role in tumor immunity remains largely unknown due to their limited numbers and lack of effective methods to expand them. Here we developed a novel protocol by which DNT cells can be expanded ex vivo to therapeutic levels in 2 weeks from 13 of 16 acute myeloid leukemia (AML) patients during chemotherapy-induced complete remission. The expanded DNT cells expressed similar or higher levels of interferon-gamma and tumor necrosis factor-alpha and Granzyme B as that seen in bulk activated CD8T cells from the same patient but significantly higher levels of perforin. The expanded DNT cells could effectively kill both allogeneic and autologous primary CD34(+) leukemic blasts isolated from PB of AML patients in a perforindependant manner. These results demonstrate, for the first time, that DNT cells from AML patients can be expanded ex vivo even after intensive chemotherapy, and are effective at killing both allogeneic and autologous primary leukemic blasts. These findings warrant studies further exploring the potential of DNT cells as a novel adjuvant immunotherapy to decrease the risk of relapse in patients with AML and, perhaps, other cancers. Leukemia (2011) 25, 1415-1422; doi: 10.1038/leu.2011.99; published online 13 May 2011 C1 [Zhang, L.] Univ Toronto, Toronto Gen Res Inst, Dept Lab Med & Pathobiol, TMDT, Toronto, ON M5G 1L7, Canada. [Merims, S.; Li, X.; Joe, B.; Dokouhaki, P.; Han, M.; Zhang, L.] Toronto Gen Res Inst, Dept Immunol, Toronto, ON, Canada. [Childs, R. W.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wang, Z-Y] Rui Jin Hosp, Shanghai Inst Hematol, Shanghai, Peoples R China. [Gupta, V.; Minden, M. D.] Princess Margaret Hosp, Dept Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. [Zhang, L.] Univ Toronto, Dept Immunol, Toronto, ON M5G 1L7, Canada. RP Zhang, L (reprint author), Univ Toronto, Toronto Gen Res Inst, Dept Lab Med & Pathobiol, TMDT, Room 2-807,101 Coll St, Toronto, ON M5G 1L7, Canada. EM lzhang@uhnresearch.ca FU Ontario Institute for Cancer Research through Government of Ontario; Canadian Cancer Society [020516] FX This study was funded by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario and the Canadian Cancer Society (grant 020516) to LZ. LZ is a Maria H Bacardi Chair in Transplantation. We would like to thank Dr Andre Schuh for his insightful comments. NR 40 TC 5 Z9 6 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD SEP PY 2011 VL 25 IS 9 BP 1415 EP 1422 DI 10.1038/leu.2011.99 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 817IM UT WOS:000294665400005 PM 21566657 ER PT J AU Lanasa, MC Allgood, SD Slager, SL Dave, SS Love, C Marti, GE Kay, NE Hanson, CA Rabe, KG Achenbach, SJ Goldin, LR Camp, NJ Goodman, BK Vachon, CM Spector, LG Rassenti, LZ Leis, JF Gockerman, JP Strom, SS Call, TG Glenn, M Cerhan, JR Levesque, MC Weinberg, JB Caporaso, NE AF Lanasa, M. C. Allgood, S. D. Slager, S. L. Dave, S. S. Love, C. Marti, G. E. Kay, N. E. Hanson, C. A. Rabe, K. G. Achenbach, S. J. Goldin, L. R. Camp, N. J. Goodman, B. K. Vachon, C. M. Spector, L. G. Rassenti, L. Z. Leis, J. F. Gockerman, J. P. Strom, S. S. Call, T. G. Glenn, M. Cerhan, J. R. Levesque, M. C. Weinberg, J. B. Caporaso, N. E. TI Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL SO LEUKEMIA LA English DT Article DE chronic lymphocytic leukemia; monoclonal B lymphocytosis; immunophenotype; B-cell immunology; gene expression profiling ID VARIABLE-REGION MUTATIONS; CD38 EXPRESSION; ZAP-70 EXPRESSION; PERIPHERAL-BLOOD; NATURAL-HISTORY; FLOW-CYTOMETRY; LEUKEMIA; SURVIVAL; RECEPTOR; DISEASE AB Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and 'CLL-like' MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders. Leukemia (2011) 25, 1459-1466; doi: 10.1038/leu.2011.117; published online 27 May 2011 C1 [Lanasa, M. C.; Allgood, S. D.; Dave, S. S.; Love, C.; Gockerman, J. P.; Weinberg, J. B.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Slager, S. L.; Rabe, K. G.; Achenbach, S. J.; Vachon, C. M.; Cerhan, J. R.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Marti, G. E.] US FDA, Cellular & Tissue Therapy Branch, CBER, OCTGC, Rockville, MD 20857 USA. [Kay, N. E.; Call, T. G.] Mayo Clin, Coll Med, Dept Med, Rochester, MN USA. [Hanson, C. A.] Mayo Clin, Coll Med, Dept Pathol, Rochester, MN USA. [Goldin, L. R.] NCI, Genet Epidemiol Branch, Bethesda, MD USA. [Camp, N. J.] Univ Utah, Dept Biomed Informat, Salt Lake City, UT USA. [Goodman, B. K.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Spector, L. G.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Rassenti, L. Z.; Weinberg, J. B.] Moores UCSD Canc Ctr, Dept Med, La Jolla, CA USA. [Leis, J. F.] Mayo Clin, Coll Med, Dept Med, Scottsdale, AZ USA. [Strom, S. S.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Glenn, M.] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. [Levesque, M. C.] Univ Pittsburgh, Med Ctr, Dept Med, Pittsburgh, PA USA. [Caporaso, N. E.] Durham Vet Affairs Med Ctr, Dept Med, Durham, NC USA. RP Lanasa, MC (reprint author), Duke Univ, Med Ctr, Dept Med, DUMC Box 3872,1 Trent Dr,Morris Bldg,Room 25152, Durham, NC 27710 USA. EM mark.lanasa@duke.edu OI Cerhan, James/0000-0002-7482-178X; Spector, Logan/0000-0003-2516-0222 FU Duke Clinical Oncology Research Clinical Development Program [K12]; Leukemia and Lymphoma Society of America; Harold Bernstein Family Fund; VA Research Service; National Institutes of Health [NCI R03 CA128030, NCI R01 CA95241, NCI U01 CA118444, AI-51445] FX MC Lanasa is supported by the Duke Clinical Oncology Research Clinical Development Program (K12) and is a fellow of the Leukemia and Lymphoma Society of America. This research is supported by the Leukemia and Lymphoma Society of America, the Harold Bernstein Family Fund, the VA Research Service and grants from the National Institutes of Health (NCI R03 CA128030, NCI R01 CA95241 and NCI U01 CA118444). We thank the study research subjects for their willingness to participate in this study and the hematology-oncology nurses and physician assistants for their special help. Flow Cytometry was performed in the Duke Human Vaccine Institute Flow Cytometry Core Facility that is supported by the National Institutes of Health award AI-51445. NR 42 TC 19 Z9 21 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD SEP PY 2011 VL 25 IS 9 BP 1459 EP 1466 DI 10.1038/leu.2011.117 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 817IM UT WOS:000294665400011 PM 21617698 ER PT J AU Shufelt, CL Johnson, BD Berga, SL Braunstein, GD Reis, SE Bittner, V Yang, YC Pepine, CJ Sharaf, BL Sopko, G Kelsey, SF Merz, CNB AF Shufelt, Chrisandra L. Johnson, B. Delia Berga, Sarah L. Braunstein, Glenn D. Reis, Steven E. Bittner, Vera Yang, YuChing Pepine, Carl J. Sharaf, Barry L. Sopko, George Kelsey, Sheryl F. Merz, C. Noel Bairey CA Women's Ischemia Syndrome TI Timing of hormone therapy, type of menopause, and coronary disease in women: data from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Cardiovascular disease; Menopause; Hormone therapy; Atherosclerosis ID SYNDROME EVALUATION WISE; ESTROGEN-REPLACEMENT THERAPY; CONJUGATED EQUINE ESTROGENS; RANDOMIZED CONTROLLED TRIAL; POSTMENOPAUSAL WOMEN; ARTERY ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; SECONDARY PREVENTION; PLUS PROGESTIN; OLDER WOMEN AB Objective: The aim of this study was to assess the relationship of the timing of hormone therapy (HT) use with angiographic coronary artery disease (CAD) and cardiovascular disease (CVD) events in women with natural versus surgical menopause. Methods: We studied 654 postmenopausal women undergoing coronary angiography for the evaluation of suspected ischemia. Timing and type of menopause, HT use, and quantitative angiographic evaluations were obtained at baseline, and the women were followed for a median of 6 years for CVD events. Results: Ever users of HT had a significantly lower prevalence of obstructive CAD compared with never users (age-adjusted odds ratio, 0.41 [0.28-0.60]). Women with natural menopause initiating HT before age 55 years had lower CAD severity compared with never users (age-adjusted A [SE] = -6.23 [1.50], P < 0.0001), whereas those initiating HT at age 55 years or more did not differ statistically from never users (-3.34 [2.13], P = 0.12). HT use remained a significant predictor of obstructive CAD when adjusted for a "healthy user" model (odds ratio, 0.44 [0.30-0.73]; P = 0.002). An association between HT and fewer CVD events was observed only in the natural menopause group (hazard ratio [95% CI], 0.60 [0.41-0.88]; P = 0.009) but became nonsignificant when adjusted for the presence or severity of obstructive CAD. Conclusions: Using the quantitative measurements of the timing and type of menopause and HT use, earlier initiation of HT was associated with less angiographic CAD in women with natural but not surgical menopause. Our data suggest that the effect of HT use on reduced cardiovascular event rates is mediated by the presence or absence of angiographic obstructive atherosclerosis. C1 [Shufelt, Chrisandra L.; Braunstein, Glenn D.; Yang, YuChing; Merz, C. Noel Bairey] Cedars Sinai Med Ctr, Womens Heart Ctr, Inst Heart, Div Cardiol, Los Angeles, CA 90048 USA. [Shufelt, Chrisandra L.; Braunstein, Glenn D.; Yang, YuChing; Merz, C. Noel Bairey] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Johnson, B. Delia; Kelsey, Sheryl F.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Berga, Sarah L.] Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA USA. [Reis, Steven E.] Univ Pittsburgh, Cardiovasc Inst, Pittsburgh, PA USA. [Bittner, Vera] Univ Alabama Birmingham, Dept Med, Div Cardiol, Birmingham, AL 35294 USA. [Pepine, Carl J.] Univ Florida, Div Cardiol, Dept Med, Gainesville, FL USA. [Sharaf, Barry L.] Rhode Isl Hosp, Providence, RI USA. [Sopko, George] NHLBI, Div Heart & Vasc Dis, NIH, Bethesda, MD 20892 USA. RP Shufelt, CL (reprint author), Cedars Sinai Med Ctr, Womens Heart Ctr, Inst Heart, Div Cardiol, 444 S San Vicente Blvd,Suite 600, Los Angeles, CA 90048 USA. EM shufeltc@cshs.org RI Reis, Steven/J-3957-2014; OI Bittner, Vera/0000-0001-9456-850X FU National Heart, Lung, and Blood Institutes [N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164]; National Center for Research Resources [M01-RR00425]; Gustavus and Louis Pfeiffer Research Foundation, Denville, NJ; Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA; Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA; Edythe L. Broad Women's Heart Research Fellowship; Cedars-Sinai Medical Center, Los Angeles, CA; Barbra Streisand Women's Cardiovascular Research and Education Program; National Institutes of Health, National Heart, Lung, and Blood Institute FX This work was supported by contracts from the National Heart, Lung, and Blood Institutes (N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164), a General Clinical Research Center Grant M01-RR00425 from the National Center for Research Resources, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Denville, NJ; The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA; The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA; the Edythe L. Broad Women's Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, CA; and the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, CA. This study was also funded by the National Institutes of Health, National Heart, Lung, and Blood Institute, which was involved in the Women's Ischemia Syndrome Evaluation study design, conduct, and reporting. NR 35 TC 13 Z9 14 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD SEP PY 2011 VL 18 IS 9 BP 943 EP 950 DI 10.1097/gme.0b013e3182113672 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 812HA UT WOS:000294280500005 PM 21532511 ER PT J AU Rosenthal, ME Dever, LL Moucha, CS Chavda, KD Otto, M Kreiswirth, BN AF Rosenthal, Marnie E. Dever, Lisa L. Moucha, Calin S. Chavda, Kalyan D. Otto, Michael Kreiswirth, Barry N. TI Molecular Characterization of an Early Invasive Staphylococcus epidermidis Prosthetic Joint Infection SO MICROBIAL DRUG RESISTANCE LA English DT Article ID SEQUENCE ELEMENT IS256; BIOFILM FORMATION; AUREUS; VIRULENCE; INSERTION; RESISTANCE; USA300; CLONE; MEC AB Historically regarded as a skin commensal, Staphylococcus epidermidis has been increasingly implicated in invasive foreign body infections such as catheter-related bloodstream infections, indwelling device infections, and prosthetic joint infections. We report a case of an aggressive, difficult-to-eradicate, invasive prosthetic hip infection occurring early after hardware implant and associated with a high-grade bacteremia and assess its salient molecular characteristics. The clinical and molecular characteristics of this isolate mirror the pathogenesis and persistence commonly seen with invasive methicillin-resistant S. aureus and may be attributed to the combination of resistance genes (SCCmec type IV), putative virulence factors (arcA and opp3a), cytolytic peptide production (alpha-type phenol-soluble modulins), and biofilm adhesion, interaction, and maturation (bhp, aap, and beta-type phenol-soluble modulins). C1 [Rosenthal, Marnie E.; Chavda, Kalyan D.; Kreiswirth, Barry N.] Univ Med & Dent New Jersey, Publ Hlth Res Inst, Newark, NJ 07103 USA. [Rosenthal, Marnie E.] Jersey Shore Univ, Med Ctr, Dept Internal Med, Infect Dis Sect, Neptune, NJ USA. [Dever, Lisa L.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Internal Med & Infect Dis, Newark, NJ 07103 USA. [Moucha, Calin S.] Mt Sinai Sch Med, Dept Orthopaed Surg, New York, NY USA. [Otto, Michael] NIAID, Pathogen Mol Genet Sect, NIH, Bethesda, MD 20892 USA. RP Kreiswirth, BN (reprint author), Univ Med & Dent New Jersey, Publ Hlth Res Inst, 225 Warren St, Newark, NJ 07103 USA. EM kreiswba@umdnj.edu RI Chavda, Kalyan/L-4311-2014; OI Otto, Michael/0000-0002-2222-4115 FU Ruth Kirschstein T-32 training grant [T32-AI-7329-16] FX M.E.R. was supported by Ruth Kirschstein T-32 training grant (T32-AI-7329-16). NR 23 TC 6 Z9 7 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1076-6294 J9 MICROB DRUG RESIST JI Microb. Drug Resist. PD SEP PY 2011 VL 17 IS 3 BP 345 EP 350 DI 10.1089/mdr.2010.0157 PG 6 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 818RL UT WOS:000294772600002 PM 21510745 ER PT J AU Zhao, Q Feng, Y Zhu, ZY Dimitrov, DS AF Zhao, Qi Feng, Yang Zhu, Zhongyu Dimitrov, Dimiter S. TI Human Monoclonal Antibody Fragments Binding to Insulin-like Growth Factors I and II with Picomolar Affinity SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID CROSS-REACTIVE NEUTRALIZATION; PROSTATE-CANCER CELLS; YEAST SURFACE DISPLAY; DIRECTED EVOLUTION; IGF SYSTEM; RECEPTOR; LIBRARIES; CONSTRUCTION; METASTASIS; INHIBITION AB The type 1 insulin-like growth factor receptor (IGF1R) and its ligands (IGF-I and IGF-II) have been implicated in a variety of physiologic processes and in diseases such as cancer. In addition to IGF1R, IGF-II also activates the insulin receptor (IR) isoform A, and therefore, antibodies against IGF-II can inhibit cell proliferation mediated by the signaling through both IGF1R and IR triggered by IGF-II. We identified a new human monoclonal antibody (mAb), m708.2, which is bound to IGF-I and IGF-II but not to insulin. m708.2 potently inhibited signal transduction mediated by the interaction of IGF-I or IGF-II with the IGF1R and IGF-II with the IR. It also inhibited the growth of the breast cancer cell line MCF-7. An affinity-matured derivative of m708.2, m708.5, bound to IGF-I with equilibrium dissociation constant, K(D)-200 pmol/L and to IGF-II with K(D)-60 pmol/L. m708.5 inhibited signal transduction mediated by IGF-I and IGF-II and cancer cell growth more potently than m708.2. These results suggest that m708.5 could have potential as a candidate therapeutic for cancers driven by the IGF-I and IGF-II interactions with IGF1R and IR. Mol Cancer Ther; 10(9); 1677-85. (C)2011 AACR. C1 [Zhao, Qi; Feng, Yang; Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Bldg 469,Rm 150B, Frederick, MD 21702 USA. EM dimiter.dimitrov@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 38 TC 15 Z9 15 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP PY 2011 VL 10 IS 9 BP 1677 EP 1685 DI 10.1158/1535-7163.MCT-11-0281 PG 9 WC Oncology SC Oncology GA 817JR UT WOS:000294668900015 PM 21750218 ER PT J AU Huff, J Infante, PF AF Huff, James Infante, Peter F. TI Styrene exposure and risk of cancer SO MUTAGENESIS LA English DT Editorial Material ID RODENT CARCINOGENICITY TESTS; PRIMARY PREVENTION; ENVIRONMENTAL CANCER; CHEMICALS; BIOASSAYS; ANIMALS; WORKERS AB Styrene is widely used in the manufacture of synthetic rubber, resins, polyesters and plastics. Styrene and the primary metabolite styrene-7,8-oxide are genotoxic and carcinogenic. Long-term chemical carcinogenesis bioassays showed that styrene caused lung cancers in several strains of mice and mammary cancers in rats and styrene-7,8-oxide caused tumours of the forestomach in rats and mice and of the liver in mice. Subsequent epidemiologic studies found styrene workers had increased mortality or incidences of lymphohematopoietic cancers (leukaemia or lymphoma or all), with suggestive evidence for pancreatic and esophageal tumours. No adequate human studies are available for styrene-7,8-oxide although this is the primary and active epoxide metabolite of styrene. Both are genotoxic and form DNA adducts in humans. C1 [Huff, James] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Infante, Peter F.] George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC 20037 USA. RP Huff, J (reprint author), Natl Inst Environm Hlth Sci, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM huff1@niehs.nih.gov NR 27 TC 4 Z9 4 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 EI 1464-3804 J9 MUTAGENESIS JI Mutagenesis PD SEP PY 2011 VL 26 IS 5 BP 583 EP 584 DI 10.1093/mutage/ger033 PG 2 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 815UF UT WOS:000294554600001 PM 21724974 ER PT J AU Lindeman, TE Poirier, MC Divi, RL AF Lindeman, Tracey Einem Poirier, Miriam C. Divi, Rao L. TI The resveratrol analogue, 2,3',4,5'-tetramethoxystilbene, does not inhibit CYP gene expression, enzyme activity and benzo[a]pyrene-DNA adduct formation in MCF-7 cells exposed to benzo[a]pyrene SO MUTAGENESIS LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; HUMAN CYTOCHROME P4501B1; ESTROGEN-DNA ADDUCTS; UNIFYING MECHANISM; ORTHO-QUINONES; CANCER; ACTIVATION; RECEPTOR; 1B1; VALIDATION AB Exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs) induces cytochrome P450 (CYP) 1A1 and 1B1 enzymes, which biotransform PAHs resulting in the formation of DNA adducts. We hypothesised that 2,3',4,5'-tetramethoxystilbene (TMS), an analogue of resveratrol and a potent CYP1B1 inhibitor, may inhibit r7, t8, t9-trihydroxy-c-10-(N(2)deoxyguanosyl)-7,8,9,10-tetrahydro-benzo[a]pyrene (BPdG) adduct formation in cells exposed to benzo[a]pyrene (BP). To address this, MCF-7 cells were cultured for 96 h in the presence of 1 mu M BP, 1 mu M BP + 1 mu M TMS or 1 mu M BP + 4 mu M TMS. Cells were assayed at 2-12 h intervals for: BPdG adducts by r7, t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA chemiluminescence immunoassay; CYP1A1 and 1B1 gene expression changes by relative real-time polymerase chain reaction; and CYP1A1/1B1 enzyme activity by ethoxyresorufin-O-deethylase (EROD) assay. Whereas maximal BPdG levels were similar for all exposure groups, the times at which the maxima were reached increased by 16 and 24 h with the addition of 1 and 4 mu M TMS, respectively. The maximal expression of CYP1A1 and CYP1B1 occurred at 16, 24 and 48 h, but the maximal level for EROD-specific activity was reached at 24, 48 and 60 h, in cells exposed to 1 mu M BP, 1 mu M BP + 1 mu M TMS or 1 mu M BP + 4 mu M TMS, respectively. The area under the curve from 4 to 96 h of exposure (AUC(4-96 h)) for BPdG adduct formation was not increased in the presence of TMS, but for CYP1A1 and CYP1B1 expression fold increase AUC(4-96 h) and EROD-specific activity AUC(4-96 h), there were significant (P < 0.05) increases in the presence of 4 mu M TMS. Therefore, during 96 h of exposure in MCF-7 cells, the combination of BP plus TMS caused a slowing of BP biotransformation, with an increase in CYP1A1 and CYP1B1 expression and EROD activity, and a slowing, but no change in magnitude of BPdG formation. C1 [Lindeman, Tracey Einem; Poirier, Miriam C.; Divi, Rao L.] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bldg 37,Room 4032,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. EM poirierm@exchange.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institute of Health FX Intramural program of the Center for Cancer Research, National Cancer Institute, National Institute of Health NR 39 TC 5 Z9 5 U1 2 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 J9 MUTAGENESIS JI Mutagenesis PD SEP PY 2011 VL 26 IS 5 BP 629 EP 635 DI 10.1093/mutage/ger024 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 815UF UT WOS:000294554600006 ER PT J AU Tan, IL McArthur, JC Clifford, DB Major, EO Nath, A AF Tan, I. L. McArthur, J. C. Clifford, D. B. Major, E. O. Nath, A. TI Immune reconstitution inflammatory syndrome in natalizumab-associated PML SO NEUROLOGY LA English DT Article ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; ADVERSE DRUG EVENTS; MULTIPLE-SCLEROSIS; T-CELLS; RITUXIMAB; INTEGRIN; THERAPY; PROJECT AB Objective: To study the outcome of patients with multiple sclerosis (MS) and with natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution inflammatory syndrome (IRIS). Methods: MedWatch reports from Biogen-Idec (manufacturer of natalizumab, Tysabri (R)) were reviewed which comprised all 42 cases of natalizumab-related PML cases since its reintroduction until March 2010. Results: All except 2 patients with natalizumab-related PML were managed by discontinuation of natalizumab and plasmapheresis/immunoadsorption (PLEX/IA). Seventeen patients had contrast enhancement of PML lesions on neuroimaging at the time of diagnosis before withdrawal/removal of natalizumab (early-PML-IRIS) and 23 patients developed contrast enhancement only after withdrawal/removal of natalizumab (late-PML-IRIS). All patients developed IRIS. IRIS was defined as worsening of neurologic deficits during the immune reconstitution following discontinuation of natalizumab, corroborated by inflammatory changes on neuroimaging. Following PLEX/IA, JC viral load in CSF increased by >10 fold in those with early-PML-IRIS but <2 fold in late-PML-IRIS. IRIS developed earlier and was more severe in early-PML-IRIS (p < 0.05). At the last follow-up, all patients had worse EDSS scores but this was higher in patients with early-PML-IRIS compared to those with late-PML-IRIS (p > 0.05). Mortality was comparable between the 2 groups, 29.4 +/- 11% vs 21.7 +/- 8.8%. Corticosteroid therapy during IRIS was associated with better Expanded Disability Status Scale outcome, p < 0.05. Conclusion: Early immunologic rebound in natalizumab-associated PML has worse survival and neurologic outcome. PLEX/IA may accelerate IRIS and its impact on the final outcome is unclear. Corticosteroid therapy provides a modest benefit and needs to be systemically studied in a controlled manner in the management of natalizumab-associated PML-IRIS. Neurology (R) 2011; 77: 1061-1067 C1 [Major, E. O.; Nath, A.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. [Tan, I. L.; McArthur, J. C.; Nath, A.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Clifford, D. B.] Washington Univ, Dept Neurol, St Louis, MO USA. RP Nath, A (reprint author), NINDS, Lab Mol Med & Neurosci, NIH, Bldg 10-7C-103,10 Ctr Dr, Bethesda, MD 20892 USA. EM natha@ninds.nih.gov FU NIH [1P30MH075673, UL1RR025005, R01NS056884]; Biogen Idec; Pfizer Inc.; National Multiple Sclerosis Society; Foundation for Peripheral Neuropathy; Schering-Plough Corp.; Bavarian Nordic; NeurogesX; GlaxoSmithKline; Tibotec Therapeutics; Boehringer Ingelheim; Gilead Sciences, Inc.; NIH (NIMH, NINDS, NIAID, and Fogarty Institutes); NIH/NINDS FX Supported in part by NIH grants: 1P30MH075673, UL1RR025005, R01NS056884.; Dr. Tan reports no disclosures. Dr. McArthur serves on a scientific advisory board for CNS Bio Services; receives publishing royalties for Current Therapy in Neurologic Disease, 7th Edition (Mosby, 2006); is an author on patents re: Device for thermal stimulation of small neural fibers and Immunophilin ligand treatment of antiretroviral toxic neuropathy; and receives research support from Biogen Idec, Pfizer Inc., the NIH, the National Multiple Sclerosis Society, and the Foundation for Peripheral Neuropathy. Dr. Clifford serves/has served on scientific advisory boards for Biogen Idec, Elan Corporation, Roche, Forest Laboratories, Inc., Genentech, Inc., GlaxoSmithKline, Millennium Pharmaceuticals, Inc., Schering-Plough Corp., Bristol-Meyers Squibb, and Genzyme Corporation; received speaker honoraria and funding for travel from GlaxoSmithKline, Millennium Pharmaceuticals, Inc., and Genentech Inc.; has received research support from Pfizer Inc, Schering-Plough Corp., Bavarian Nordic, NeurogesX, GlaxoSmithKline, Tibotec Therapeutics, Boehringer Ingelheim, and Gilead Sciences, Inc.; and receives research support from the NIH (NIMH, NINDS, NIAID, and Fogarty Institutes). Dr. Major receives research support from the NIH/NINDS. Dr. Nath serves on scientific advisory boards for Biogen Idec and DioGenix, Inc.; serves as an Associate Editor for the Journal of Neurovirology; may accrue revenue on patents re: Tat as an immunogen, Diosgenin for treatment of neurodegenerative diseases, Role of Kv channels in neuroregeneration and protection, Role of lominoid compounds as neuroprotective agents, and Tat ELISA; has served as a consultant for Nerveda Inc. and Elan Corporation; receives research support from the NIH; and has served as an expert advice in medico-legal cases. NR 19 TC 92 Z9 93 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP PY 2011 VL 77 IS 11 BP 1061 EP 1067 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 819CE UT WOS:000294802200011 PM 21832229 ER PT J AU Wong, JB Coates, PM Russell, RM Dwyer, JT Schuttinga, JA Bowman, BA Peterson, SA AF Wong, John B. Coates, Paul M. Russell, Robert M. Dwyer, Johanna T. Schuttinga, James A. Bowman, Barbara A. Peterson, Sarah A. TI Economic analysis of nutrition interventions for chronic disease prevention: methods, research, and policy SO NUTRITION REVIEWS LA English DT Review DE cost-benefit analysis; medical economics; nutrition policy; nutrition therapy; primary prevention ID COST-EFFECTIVENESS ANALYSIS; FOLIC-ACID FORTIFICATION; POLYUNSATURATED FATTY-ACIDS; UNITED-STATES; HEALTH-CARE; MULTIMINERAL SUPPLEMENTS; MYOCARDIAL-INFARCTION; CONTROLLED-TRIAL; VITAMIN THERAPY; ADULTS AB Increased interest in the potential societal benefit of incorporating health economics as a part of clinical translational science, particularly nutrition interventions, led the Office of Dietary Supplements at the National Institutes of Health to sponsor a conference to address key questions about the economic analysis of nutrition interventions to enhance communication among health economic methodologists, researchers, reimbursement policy makers, and regulators. Issues discussed included the state of the science, such as what health economic methods are currently used to judge the burden of illness, interventions, or healthcare policies, and what new research methodologies are available or needed to address knowledge and methodological gaps or barriers. Research applications included existing evidence-based health economic research activities in nutrition that are ongoing or planned at federal agencies. International and US regulatory, policy, and clinical practice perspectives included a discussion of how research results can help regulators and policy makers within government make nutrition policy decisions, and how economics affects clinical guideline development. (C) 2011 International Life Sciences Institute C1 [Wong, John B.] Tufts Univ, Tufts Med Ctr, Sch Med, Div Clin Decis Making, Boston, MA 02111 USA. [Coates, Paul M.; Russell, Robert M.; Dwyer, Johanna T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Dwyer, Johanna T.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Dwyer, Johanna T.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Schuttinga, James A.] NIH, Div Program Coordinat Planning & Strateg Initiat, Bethesda, MD 20892 USA. [Bowman, Barbara A.] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Wong, JB (reprint author), Tufts Univ, Tufts Med Ctr, Sch Med, Div Clin Decis Making, 800 Washington St 302, Boston, MA 02111 USA. EM jwong@tuftsmedicalcenter.org OI Dwyer, Johanna/0000-0002-0783-1769 FU Office of Dietary Supplements; National Center for Complementary and Alternative Medicine; National Cancer Institute; National Institute for Nursing Research, National Institutes of Health FX The workshop was jointly sponsored by the Office of Dietary Supplements, the National Center for Complementary and Alternative Medicine, the National Cancer Institute, and the National Institute for Nursing Research, which belong to the National Institutes of Health. NR 53 TC 3 Z9 4 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD SEP PY 2011 VL 69 IS 9 BP 533 EP 549 DI 10.1111/j.1753-4887.2011.00412.x PG 17 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 815TH UT WOS:000294551900004 PM 21884133 ER PT J AU Shoham, V Insel, TR AF Shoham, Varda Insel, Thomas R. TI Rebooting for Whom? Portfolios, Technology, and Personalized Intervention SO PERSPECTIVES ON PSYCHOLOGICAL SCIENCE LA English DT Article DE treatment; mental illness; personalized intervention ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE THERAPY; PSYCHOTHERAPY-RESEARCH; RECURRENT DEPRESSION; MENTAL-DISORDERS; CHRONIC FORMS; HETEROGENEITY; ALCOHOLISM; MEDIATORS; SYSTEM AB We share Kazdin and Blase's (2011) sense of urgency about finding better ways to reduce the burden of mental illness. Although effective psychosocial treatments exist, they do not often reach the patients who need them most. Kazdin and Blase's portfolio approach aims to cast a wider net through increased use of technology, media, self-help, nonprofessional providers, and collaborations with other disciplines. It is unclear, however, whether reaching more people would suffice to reduce the burden of mental illness, much less offset the small effect sizes of simplified, scaled-down interventions such a portfolio approach would likely entail. We focus here on an underdeveloped theme in Kazdin and Blase's essay-that bending the curve of mental illness will require better knowledge of for whom simplified intervention and prevention strategies will suffice and for whom more intensive intervention is necessary. Such "for whom" questions deserve a central place on the national research agenda as we move toward individualized or personalized health care. In the absence of such knowledge, we risk treatment decisions guided by accessibility to resources rather than patient needs-the very problem Kazdin and Blase aim to solve. C1 [Shoham, Varda] Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. [Shoham, Varda; Insel, Thomas R.] NIMH, Bethesda, MD 20892 USA. RP Shoham, V (reprint author), Univ Arizona, Dept Psychol, 1503 E Univ Blvd, Tucson, AZ 85721 USA. EM varda@email.arizona.edu NR 34 TC 12 Z9 12 U1 3 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1745-6916 EI 1745-6924 J9 PERSPECT PSYCHOL SCI JI Perspect. Psychol. Sci. PD SEP PY 2011 VL 6 IS 5 BP 478 EP 482 DI 10.1177/1745691611418526 PG 5 WC Psychology, Multidisciplinary SC Psychology GA 815ZH UT WOS:000294568000006 PM 26168199 ER PT J AU Jourdain, E van Riel, D Munster, VJ Kuiken, T Waldenstrom, J Olsen, B Ellstrom, P AF Jourdain, Elsa van Riel, Debby Munster, Vincent J. Kuiken, Thijs Waldenstrom, Jonas Olsen, Bjorn Ellstrom, Patrik TI The Pattern of Influenza Virus Attachment Varies among Wild Bird Species SO PLOS ONE LA English DT Article ID LOWER RESPIRATORY-TRACT; SIALIC-ACID RECEPTORS; A VIRUS; BINDING-SITES; HEMAGGLUTININ; DUCKS; HOST; REPLICATION; SPECIFICITY; INFECTION AB The ability to attach to host cells is one of the main determinants of the host range of influenza A viruses. By using virus histochemistry, we investigate the pattern of virus attachment of both a human and an avian influenza virus in colon and trachea sections from 12 wild bird species. We show that significant variations exist, even between closely related avian species, which suggests that the ability of wild birds to serve as hosts for influenza viruses strongly varies among species. These results will prove valuable to assess the possibilities of interspecies transmission of influenza viruses in natural environments and better understand the ecology of influenza. C1 [Jourdain, Elsa] INRA, UR 346, F-63122 St Genes Champanelle, France. [van Riel, Debby; Kuiken, Thijs] Erasmus MC, Dept Virol, Rotterdam, Netherlands. [Munster, Vincent J.] NIAID, Virol Lab, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Waldenstrom, Jonas; Olsen, Bjorn] Linnaeus Univ, Sch Nat Sci, Sect Zoonot Ecol & Epidemiol, Kalmar, Sweden. [Olsen, Bjorn; Ellstrom, Patrik] Uppsala Univ, Dept Med Sci, Infect Dis Sect, Uppsala, Sweden. RP Jourdain, E (reprint author), INRA, UR 346, F-63122 St Genes Champanelle, France. EM elsa.jourdain@clermont.inra.fr RI Waldenstrom, Jonas/E-4460-2013; OI Waldenstrom, Jonas/0000-0002-1152-4235; Olsen, Bjorn/0000-0002-4646-691X; Munster, Vincent/0000-0002-2288-3196 FU Swedish Research Council (VR); Swedish Research Council Formas; French Fondation pour la Recherche Medicale [SPE20070709608]; National Institutes of Health FX This study was financially supported by the Swedish Research Council (VR) and the Swedish Research Council Formas, the French Fondation pour la Recherche Medicale (reference SPE20070709608) and the Intramural Research Program of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 12 Z9 12 U1 0 U2 10 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 SEP 1 PY 2011 VL 6 IS 9 AR e24155 DI 10.1371/journal.pone.0024155 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817OO UT WOS:000294683900034 PM 21909418 ER PT J AU Mashiach-Farkash, E Nussinov, R Wolfson, HJ AF Mashiach-Farkash, Efrat Nussinov, Ruth Wolfson, Haim J. TI SymmRef: A flexible refinement method for symmetric multimers SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE protein docking; symmetric complexes; docking refinement; side-chain optimization; backbone refinement; symmetric refinement ID PROTEIN-PROTEIN COMPLEXES; FIT BACKBONE REFINEMENT; MOLECULAR DOCKING; GEOMETRIC FIT; C-N; PREDICTION; ASSEMBLIES; INTERFACE; RECOGNITION; ALGORITHMS AB Symmetric protein complexes are abundant in the living cell. Predicting their atomic structure can shed light on the mechanism of many important biological processes. Symmetric docking methods aim to predict the structure of these complexes given the unbound structure of a single monomer, or its model. Symmetry constraints reduce the search-space of these methods and make the prediction easier compared to asymmetric protein-protein docking. However, the challenge of modeling the conformational changes that the monomer might undergo is a major obstacle. In this article, we present SymmRef, a novel method for refinement and reranking of symmetric docking solutions. The method models backbone and side-chain movements and optimizes the rigid-body orientations of the monomers. The backbone movements are modeled by normal modes minimization and the conformations of the side-chains are modeled by selecting optimal rotamers. Since solved structures of symmetric multimers show asymmetric side-chain conformations, we do not use symmetry constraints in the side-chain optimization procedure. The refined models are re-ranked according to an energy score. We tested the method on a benchmark of unbound docking challenges. The results show that the method significantly improves the accuracy and the ranking of symmetric rigid docking solutions. SymmRef is available for download at http://bioinfo3d.cs.tau.ac.il/SymmRef/download.html. C1 [Mashiach-Farkash, Efrat; Wolfson, Haim J.] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Blavatnik Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Wolfson, HJ (reprint author), Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. EM wolfson@tau.ac.il FU Israel Science Foundation [1403/09]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Israel Academy of Sciences and Humanities; Hermann Minkowski-Minerva Center for Geometry, Tel Aviv University; NIH, National Cancer Institute, Center for Cancer Research FX Grant sponsor: The Israel Science Foundation; Grant number: 1403/09; Grant sponsor: The National Cancer Institute, National Institutes of Health; Grant number: HHSN261200800001E; Grant sponsor: The Adams Fellowship Program of the Israel Academy of Sciences and Humanities; Grant sponsor: The Hermann Minkowski-Minerva Center for Geometry, Tel Aviv University; Grant sponsor: The Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 43 TC 9 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-3585 J9 PROTEINS JI Proteins PD SEP PY 2011 VL 79 IS 9 BP 2607 EP 2623 DI 10.1002/prot.23082 PG 17 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 816OE UT WOS:000294611100002 PM 21721046 ER PT J AU Jacobson, KA Deflorian, F Mishra, S Costanzi, S AF Jacobson, Kenneth A. Deflorian, Francesca Mishra, Shilpi Costanzi, Stefano TI Pharmacochemistry of the platelet purinergic receptors SO PURINERGIC SIGNALLING LA English DT Article DE Purines; GPCR; Ion channel; Structure-activity relationship; Molecular modeling; Mutagenesis ID HUMAN P2Y(1) RECEPTOR; A(2A) ADENOSINE RECEPTOR; ADENINE-NUCLEOTIDE ANALOGS; NORTHERN RING CONFORMATION; SITE-DIRECTED MUTAGENESIS; RAT P2X RECEPTORS; ACTIVE METABOLITE; BIOLOGICAL-ACTIVITY; DIADENOSINE POLYPHOSPHATES; P-2Y-PURINOCEPTOR AGONISTS AB Platelets contain at least five purinergic G protein-coupled receptors, e.g., the pro-aggregatory P2Y(1) and P2Y(12) receptors, a P2Y(14) receptor (GPR105) of unknown function, and anti-aggregatory A(2A) and A(2B) adenosine receptor (ARs), in addition to the ligand-gated P2X1 ion channel. Probing the structure-activity relationships (SARs) of the P2X and P2Y receptors for extracellular nucleotides has resulted in numerous new agonist and antagonist ligands. Selective agents derived from known ligands and novel chemotypes can be used to help define the subtypes pharmacologically. Some of these agents have entered into clinical trials in spite of the challenges of drug development for these classes of receptors. The functional architecture of P2 receptors was extensively explored using mutagenesis and molecular modeling, which are useful tools in drug discovery. In general, novel drug delivery methods, prodrug approaches, allosteric modulation, and biased agonism would be desirable to overcome side effects that tend to occur even with receptor subtype-selective ligands. Detailed SAR analyses have been constructed for nucleotide and non-nucleotide ligands at the P2Y(1), P2Y(12), and P2Y(14) receptors. The thienopyridine antithrombotic drugs Clopidogrel and Prasugrel require enzymatic pre-activation in vivo and react irreversibly with the P2Y(12) receptor. There is much pharmaceutical development activity aimed at identifying reversible P2Y(12) receptor antagonists. The screening of chemically diverse compound libraries has identified novel chemotypes that act as competitive, non-nucleotide antagonists of the P2Y(1) receptor or the P2Y(12) receptor, and antithrombotic properties of the structurally optimized analogues were demonstrated. In silico screening at the A(2A) AR has identified antagonist molecules having novel chemotypes. Fluorescent and other reporter groups incorporated into ligands can enable new technology for receptor assays and imaging. The A(2A) agonist CGS21680 and the P2Y(1) receptor antagonist MRS2500 were derivatized for covalent attachment to polyamidoamine dendrimeric carriers of MW 20,000, and the resulting multivalent conjugates inhibited ADP-promoted platelet aggregation. In conclusion, a wide range of new pharmacological tools is available to control platelet function by interacting with cell surface purine receptors. C1 [Jacobson, Kenneth A.; Deflorian, Francesca; Mishra, Shilpi] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Costanzi, Stefano] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, 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; Costanzi, Stefano/G-8990-2013; OI Jacobson, Kenneth/0000-0001-8104-1493; Costanzi, Stefano/0000-0003-3183-7332 FU NIDDK of NIH FX Support from the NIDDK Intramural Research Program of NIH is acknowledged. NR 152 TC 24 Z9 24 U1 1 U2 15 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 EI 1573-9546 J9 PURINERG SIGNAL JI Purinergic Signal. PD SEP PY 2011 VL 7 IS 3 SI SI BP 305 EP 324 DI 10.1007/s11302-011-9216-0 PG 20 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 817ZM UT WOS:000294717400004 PM 21484092 ER PT J AU Glazer, PM Le, QT Bristow, R Helleday, T Pelroy, R Bernhard, EJ AF Glazer, Peter M. Quynh-Thu Le Bristow, Rob Helleday, Thomas Pelroy, Richard Bernhard, Eric J. TI New Translational Possibilities for Microenvironmental Modulation of Radiosensitivity SO RADIATION RESEARCH LA English DT Editorial Material ID CHRONIC HYPOXIA; RADIATION; CELLS; INHIBITION; PATHWAY; ANGIOGENESIS; ACTIVATION; STRATEGIES; GROWTH; RAD51 C1 [Glazer, Peter M.] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06510 USA. [Quynh-Thu Le] Stanford Univ, Dept Radiat Oncol, Sch Med, Stanford, CA 94305 USA. [Bristow, Rob] Ontario Canc Inst, Div Appl Mol Oncol, Toronto, ON M4X 1K9, Canada. [Helleday, Thomas] Univ Oxford, Gray Inst Radiat Oncol & Biol, Oxford, England. [Pelroy, Richard] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. [Bernhard, Eric J.] NCI, Div Canc Treatment & Diag, Radiat Res Program, Bethesda, MD 20892 USA. RP Glazer, PM (reprint author), Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06510 USA. EM peter.glazer@yale.edu RI Helleday, Thomas/D-5224-2013; OI Helleday, Thomas/0000-0002-7384-092X NR 21 TC 3 Z9 3 U1 0 U2 1 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD SEP PY 2011 VL 176 IS 3 BP 412 EP 414 DI 10.1667/RRXX33.1 PG 3 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 816HY UT WOS:000294590500015 PM 21867431 ER PT J AU Vikram, B AF Vikram, B. TI Grand challenges in imaging for radiation oncology and some opportunities for transatlantic cooperation SO STRAHLENTHERAPIE UND ONKOLOGIE LA English DT Meeting Abstract CT 4th Langendorff-Symposium on Pros and Cons on Imaging in Radiotherapy CY SEP 09-10, 2011 CL Freiburg I. Breisgau, GERMANY C1 [Vikram, B.] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU URBAN & VOGEL PI MUNICH PA NEUMARKTER STRASSE 43, D-81673 MUNICH, GERMANY SN 0179-7158 J9 STRAHLENTHER ONKOL JI Strahlenther. Onkol. PD SEP PY 2011 VL 187 IS 9 BP 600 EP 600 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 815WB UT WOS:000294559600038 ER PT J AU Aschebrook-Kilfoy, B Sabra, MM Brenner, A Moore, SC Ron, E Schatzkin, A Hollenbeck, A Ward, MH AF Aschebrook-Kilfoy, Briseis Sabra, Mona M. Brenner, Alina Moore, Steven C. Ron, Elaine Schatzkin, Arthur Hollenbeck, Albert Ward, Mary H. TI Diabetes and Thyroid Cancer Risk in the National Institutes of Health-AARP Diet and Health Study SO THYROID LA English DT Article ID POPULATION-BASED COHORT; BODY-MASS INDEX; GROWTH-FACTOR-I; IODOTHYRONINE DEIODINASE; VITAMIN-D; COLORECTAL-CANCER; BREAST-CANCER; MELLITUS; HORMONE; EXPRESSION AB Background: We hypothesized that diabetes may play a role in thyroid cancer risk due to the parallel secular rise in diabetes prevalence and morbidity in the United States, the higher prevalence of thyroid disorders among diabetics compared with the general population, and the potential roles of metabolic syndrome, obesity, and diabetes as precipitating factors in cancer development. Methods: We assessed the association between self-reported diabetes and the risk of differentiated thyroid cancer in the NIH-AARP Diet and Health Study, a prospective cohort of 200,556 women and 295,992 men, 50-71 years of age, in 1995-1996. Diabetes status and information on potential confounders was ascertained using a self-administered questionnaire. During an average of 10 years of follow-up, 585 thyroid cancer cases were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer and thyroid cancer subtypes in men and women according to diabetes status. Results: Nine percent of the total baseline cohort reported a history of diabetes (7% of women, 10% of men). A nonsignificant 25% increase in thyroid cancer risk (HR-1.25; 95% CI: 0.95-1.64) was associated with diabetes. Among women, the risk was significantly increased (HR-1.46, 95% CI: 1.01-2.10). The risk was not elevated among men (HR-1.04, 95% CI: 0.69-1.58). In this cohort, diabetic women with differentiated thyroid cancer were at somewhat higher risk of follicular thyroid cancer (HR-1.92; 95% CI: 0.86-4.27) than papillary thyroid cancer (HR-1.25; 95% CI: 0.80-1.97). Conclusion: This study lends support to the hypothesis that diabetes increases the risk of differentiated thyroid cancer. C1 [Aschebrook-Kilfoy, Briseis; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Sabra, Mona M.] Mem Sloan Kettering Canc Ctr, Dept Med, Endocrine Serv, New York, NY 10021 USA. [Brenner, Alina; Ron, Elaine] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Moore, Steven C.; Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Aschebrook-Kilfoy, B (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8111, Bethesda, MD 20892 USA. EM kilfoyb@mail.nih.gov RI Aschebrook-Kilfoy, Briseis/A-2537-2012; Moore, Steven/D-8760-2016 OI Moore, Steven/0000-0002-8169-1661 FU National Cancer Institute (NCI) FX This research was supported by the Intramural Research Program of the National Cancer Institute (NCI). The investigators are indebted to all participants for providing the data and for their commitment to the NIH-AARP Diet and Health Study. NR 65 TC 32 Z9 34 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD SEP PY 2011 VL 21 IS 9 BP 957 EP 963 DI 10.1089/thy.2010.0396 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 818QI UT WOS:000294768800004 PM 21767143 ER PT J AU Hannas, BR Lambright, CS Furr, J Howdeshell, KL Wilson, VS Gray, LE AF Hannas, Bethany R. Lambright, Christy S. Furr, Johnathan Howdeshell, Kembra L. Wilson, Vickie S. Gray, Leon E., Jr. TI Dose-Response Assessment of Fetal Testosterone Production and Gene Expression Levels in Rat Testes Following In Utero Exposure to Diethylhexyl Phthalate, Diisobutyl Phthalate, Diisoheptyl Phthalate, and Diisononyl Phthalate SO TOXICOLOGICAL SCIENCES LA English DT Article DE endocrine disruptors; endocrine toxicology; testis; endocrine toxicology; reproductive and developmental toxicology; developmental toxicity; prenatal; reproductive and developmental toxicology ID ALTERS SEXUAL-DIFFERENTIATION; NUTRITION EXAMINATION SURVEY; MALE SPRAGUE-DAWLEY; N-BUTYL PHTHALATE; REPRODUCTIVE DEVELOPMENT; DI(N-BUTYL) PHTHALATE; DIBUTYL PHTHALATE; TESTICULAR DYSGENESIS; POSTNATAL-DEVELOPMENT; PROGRAMMING WINDOW AB Several phthalate esters have been linked to the Phthalate Syndrome, affecting male reproductive development when administered to pregnant rats during in utero sexual differentiation. The goal of the current study was to enhance understanding of this class of compounds in the Sprague Dawley (SD) fetal rat following exposure on gestational days (GDs) 14-18 by determining the relative potency factors for several phthalates on fetal testes endpoints, the effects of a nine phthalate mixture on fetal testosterone (T) production, and differences in SD and Wistar (W) strain responses of fetal T production and testicular gene expression to di(2-ethylhexyl) phthalate (DEHP). We determined that diisobutyl phthalate (DIBP) and diisoheptyl phthalate (DIHP) reduced fetal testicular T production with similar potency to DEHP, whereas diisononyl phthalate (DINP) was 2.3-fold less potent. DINP was also less potent at reducing StAR and Cyp11a gene expression levels, whereas DIBP was slightly more potent than DEHP. We observed that administration of dilutions of a mixture of nine phthalates (DEHP, DIHP, DIBP, dibutyl-, benzyl butyl-, dicyclohexyl-, diheptyl-, dihexyl-, and dipentyl phthalate) reduced fetal T production in a dose-dependent manner best predicted by dose addition. Finally, we found that the differential effects of in utero DEHP treatment on epididymal and gubernacular differentiation in male SD and W rats (0, 100, 300, 500, 625, 750, or 875 mg DEHP/kg/day) are likely due to tissue-specific strain differences in the androgen and insl3 signaling pathways rather than differential effects of DEHP on fetal testis T and insl3 production. C1 [Hannas, Bethany R.; Lambright, Christy S.; Furr, Johnathan; Howdeshell, Kembra L.; Wilson, Vickie S.; Gray, Leon E., Jr.] US EPA, Natl Hlth & Environm Effects Res Lab, Toxicol Assessment Div, Reprod Toxicol Branch, Res Triangle Pk, NC 27711 USA. [Howdeshell, Kembra L.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Gray, LE (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, Toxicol Assessment Div, Reprod Toxicol Branch, Mail Drop 72, Res Triangle Pk, NC 27711 USA. EM gray.earl@epa.gov OI Wilson, Vickie/0000-0003-1661-8481 FU U.S. EPA [RW-75-92285501-1]; National Research Council [CR833232] FX U.S. EPA/National Toxicology Program Interagency Cooperative Agreement (RW-75-92285501-1); National Research Council Research Postdoctoral Associate Fellowship (CR833232 to B.R.H.). NR 49 TC 64 Z9 67 U1 6 U2 41 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2011 VL 123 IS 1 BP 206 EP 216 DI 10.1093/toxsci/kfr146 PG 11 WC Toxicology SC Toxicology GA 815VG UT WOS:000294557500019 PM 21633115 ER PT J AU Zheng, CY Voutetakis, A Goldstein, B Afione, S Rivera, VM Clackson, T Wenk, ML Boyle, M Nyska, A Chiorini, JA Vallant, M Irwin, RD Baum, BJ AF Zheng, Changyu Voutetakis, Antonis Goldstein, Benjamin Afione, Sandra Rivera, Victor M. Clackson, Tim Wenk, Martin L. Boyle, Molly Nyska, Abraham Chiorini, John A. Vallant, Molly Irwin, Richard D. Baum, Bruce J. TI Assessment of the Safety and Biodistribution of a Regulated AAV2 Gene Transfer Vector after Delivery to Murine Submandibular Glands SO TOXICOLOGICAL SCIENCES LA English DT Article DE AAV2 vector; safety; salivary gland; rapamycin; regulated gene expression ID RECOMBINANT ADENOASSOCIATED VIRUS; MOUSE SALIVARY-GLANDS; PAROTID-GLANDS; NONHUMAN-PRIMATES; FACTOR-IX; IN-VIVO; TRANSGENE EXPRESSION; ADENOVIRAL VECTOR; SYSTEMIC DELIVERY; RAPAMYCIN CONTROL AB Clinical gene transfer holds promise for the treatment of many inherited and acquired disorders. A key consideration for all clinical gene transfer applications is the tight control of transgene expression. We have examined the safety and biodistribution of a serotype 2, recombinant adeno-associated viral (AAV2) vector that encodes a rapamycin-responsive chimeric transcription factor, which regulates the expression of a therapeutic transgene (human erythropoietin [hEpo]). The vector, AAV2-TF2.3w-hEpo (2.5 x 10(7)-2.5 x 10(10) particles), was administered once to a single submandibular gland of male and female mice and mediated hEpo expression in vivo following a rapamycin injection but not in its absence. Control (saline treated) and vector-treated animals maintained their weight, and consumed food and water, similarly. Vector delivery led to no significant toxicological effects as judged by hematology, clinical chemistry, and gross and microscopic pathology evaluations. On day 3 after vector delivery, vector copies were not only abundant in the targeted right submandibular gland but also detected in multiple other tissues. Vector was cleared from the targeted gland much more rapidly in female mice than in male mice. Overall, our results are consistent with the notion that administration of the AAV2-TF2.3w-hEpo vector to salivary glands posed no significant risk in mice. C1 [Zheng, Changyu; Voutetakis, Antonis; Goldstein, Benjamin; Afione, Sandra; Chiorini, John A.; Baum, Bruce J.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Rivera, Victor M.; Clackson, Tim] ARIAD Pharmaceut Inc, Cambridge, MA 02139 USA. [Wenk, Martin L.] BioReliance Invitrogen Bioserv, Div Toxicol, Rockville, MD USA. [Boyle, Molly] Integrated Syst Lab, Comparat Mol Pathol Div, Res Triangle Pk, NC USA. [Nyska, Abraham; Vallant, Molly; Irwin, Richard D.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. RP Baum, BJ (reprint author), NIDCR, Mol Physiol & Therapeut Branch, NIH, Bldg 10,Room 1N113,MSC 1190, Bethesda, MD 20892 USA. EM bbaum@dir.nidcr.nih.gov FU Division of Intramural Research, National Institute of Dental and Craniofacial Research; National Institute of Environmental Health Sciences (Rockville, MD) [NO1-ES-75408] FX Division of Intramural Research, National Institute of Dental and Craniofacial Research; National Institute of Environmental Health Sciences to BioReliance Invitrogen Bioservices (Rockville, MD, contract NO1-ES-75408). NR 40 TC 1 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2011 VL 123 IS 1 BP 247 EP 255 DI 10.1093/toxsci/kfr144 PG 9 WC Toxicology SC Toxicology GA 815VG UT WOS:000294557500022 PM 21625005 ER PT J AU Szabo, DT Diliberto, JJ Huwe, JK Birnbaum, LS AF Szabo, David T. Diliberto, Janet J. Huwe, Janice K. Birnbaum, Linda S. TI Differences in Tissue Distribution of HBCD Alpha and Gamma between Adult and Developing Mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE mice; HBCD; stereoisomers; toxicokinetics; development; distribution; elimination age susceptibility ID FLAME-RETARDANT HEXABROMOCYCLODODECANE; MESSENGER-RNA EXPRESSION; THYROID-HORMONE ACTION; GASTROINTESTINAL ABSORPTION; PHARMACOKINETIC DIFFERENCES; REPEATED EXPOSURE; DRUG-METABOLISM; GENE-EXPRESSION; WISTAR RATS; BRAIN AB Hexabromocyclododecane (HBCD) is a mixture of three stereoisomers alpha (alpha), beta (beta), and gamma (gamma). gamma-HBCD dominates the mixture (similar to 70%), and despite alpha-HBCD's minor contribution to global HBCD production and usage (similar to 10%), it is the dominant congener found in most biotic samples worldwide. Evidence of toxicity and lack of stereoisomer studies drives the importance of understanding HBCD toxicokinetics in potentially susceptible populations. The majority of public health concern has focused on hazardous effects resulting from exposure of infants and young children to HBCD due to reports on adverse developmental effects in rodent studies, in combination with human exposure estimates suggesting that nursing infants and young children have the highest exposure to HBCD. This study was designed to investigate differences in the disposition of both gamma-HBCD and alpha-HBCD in infantile mice reported to be susceptible to the HBCD commercial mixture. The tissue distribution of alpha-[(14)C]HBCD- and gamma-[(14)C]HBCD-derived radioactivity was monitored in C57BL/6 mice following a single oral dose of either compound (3 mg/kg) after direct gavage at postnatal day 10. Mice were held up to 7 days in shoebox cages after which pups were sacrificed, tissue collected, and internal dosimetry was measured. Developing mice exposed to alpha-HBCD had an overall higher body burden than gamma-HBCD at every time point measured; at 4 days postexposure, they retained 22% of the alpha-HBCD administered dose, whereas pups exposed to gamma-HBCD retained 10%. Total body burden in infantile mice after exposure to gamma-HBCD was increased 10-fold as compared with adults. Similarly, after exposure to alpha-HBCD, infantile mice contained 2.5-fold higher levels than adult. These differences lead to higher concentrations of the HBCD diastereomers at target tissues during critical windows of development. The results indicate that the toxicokinetics of the two HBCD diastereomers differ between developing and adult mice; whereas distribution patterns are similar, concentrations of each HBCD diastereomer's-derived radioactivity are higher in the pup's liver, fat, kidney, brain, blood, muscle, and lungs than in the adult's. This study suggests that developmental stage may be a risk factor for the harmful effects of alpha-HBCD and gamma-HBCD, when developing animals may be more sensitive to effects and have increased body burden. C1 [Szabo, David T.] Univ N Carolina Chapel Hill Curriculum Toxicol, US EPA, Res Triangle Pk, NC 27711 USA. [Szabo, David T.; Diliberto, Janet J.] US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Integrated Syst Toxicol Div, Res Triangle Pk, NC 27711 USA. [Huwe, Janice K.] ARS, USDA, Biosci Res Lab, Fargo, ND 58102 USA. [Birnbaum, Linda S.] NCI, NIH, Res Triangle Pk, NC 27709 USA. RP Szabo, DT (reprint author), US EPA, Natl Ctr Environm Assessment, Off Res & Dev, 2733 S Crystal Dr,8623-P, Arlington, VA 22202 USA. EM Szabo.David@epa.gov FU University of North Carolina in Chapel Hill; Environmental Protection Agency [CR 833237] FX This work is funded in part by a cooperative agreement between the University of North Carolina in Chapel Hill and the Environmental Protection Agency (CR 833237 predoctoral training grants). NR 56 TC 13 Z9 13 U1 1 U2 30 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2011 VL 123 IS 1 BP 256 EP 263 DI 10.1093/toxsci/kfr161 PG 8 WC Toxicology SC Toxicology GA 815VG UT WOS:000294557500023 PM 21705717 ER PT J AU Cippitelli, A Rezvani, AH Robinson, JE Eisenberg, L Levin, ED Bonaventure, P Motley, ST Lovenberg, TW Heilig, M Thorsell, A AF Cippitelli, Andrea Rezvani, Amir H. Robinson, J. Elliott Eisenberg, Lindsay Levin, Edward D. Bonaventure, Pascal Motley, S. Timothy Lovenberg, Timothy W. Heilig, Markus Thorsell, Annika TI The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety SO ALCOHOL LA English DT Article DE Neuropeptide Y; Y2 receptor; Anxiety; Alcohol-preferring rats; Relapse; Alcohol drinking ID PREFERRING P-RATS; CORTICOTROPIN-RELEASING-FACTOR; SUPPRESSES ETHANOL DRINKING; MESSENGER-RNA EXPRESSION; ANXIOLYTIC-LIKE ACTION; NONPREFERRING NP RATS; ELEVATED PLUS-MAZE; WISTAR RATS; HIPPOCAMPAL SLICE; CENTRAL NUCLEUS AB Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety. Furthermore, we tested its effects on voluntary alcohol consumption in a genetic animal model of alcohol preference, the alcohol-preferring (P) rat. Neither systemic (0, 15, 30, and 40 mg/kg, subcutaneously [s.c.]) nor intracerebroventricular (0.0, 0.3, and 1.0 nmol/rat) administration of JNJ-31020028 affected alcohol-reinforced lever pressing or relapse to alcohol seeking behavior following stress exposure. Also, when its effects were tested on unlimited access to alcohol in P rats, preference for alcohol solution was transiently suppressed but without affecting voluntary alcohol intake. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism. Our data do not support Y2 antagonism as a mechanism for reducing alcohol consumption or relapse-like behavior, but the observed effects on withdrawal-induced anxiety suggest that NPY Y2 receptor antagonists may be a putative treatment for the negative affective states following alcohol withdrawal. Published by Elsevier Inc. C1 [Cippitelli, Andrea; Robinson, J. Elliott; Eisenberg, Lindsay; Heilig, Markus; Thorsell, Annika] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Rezvani, Amir H.; Levin, Edward D.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Bonaventure, Pascal; Motley, S. Timothy; Lovenberg, Timothy W.] Johnson & Johnson Pharmaceut Res & Dev LLC, Dept Neurosci, San Diego, CA 92121 USA. RP Cippitelli, A (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. EM cippitellia@mail.nih.gov RI Bonaventure, Pascal/K-3052-2015; OI Bonaventure, Pascal/0000-0003-2971-6152; Heilig, Markus/0000-0003-2706-2482; Robinson, J. Elliott/0000-0001-9417-3938; Thorsell, Annika/0000-0003-3535-3845 FU Johnson & Johnson Pharmaceuticals FX The authors thank Dr. Larry Lumeng of Indian University for providing alcohol-preferring rats. This research was partially supported by a contract from Johnson & Johnson Pharmaceuticals to A.H.R. NR 62 TC 23 Z9 23 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 J9 ALCOHOL JI Alcohol PD SEP PY 2011 VL 45 IS 6 BP 567 EP 576 DI 10.1016/j.alcohol.2010.09.003 PG 10 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 816EQ UT WOS:000294581900005 PM 21145691 ER PT J AU Bosworth, HB Granger, BB Mendys, P Brindis, R Burkholder, R Czajkowski, SM Daniel, JG Ekman, I Ho, M Johnson, M Kimmel, SE Liu, LZ Musaus, J Shrank, WH Buono, EW Weiss, K Granger, CB AF Bosworth, Hayden B. Granger, Bradi B. Mendys, Phil Brindis, Ralph Burkholder, Rebecca Czajkowski, Susan M. Daniel, Jodi G. Ekman, Inger Ho, Michael Johnson, Mimi Kimmel, Stephen E. Liu, Larry Z. Musaus, John Shrank, William H. Buono, Elizabeth Whalley Weiss, Karen Granger, Christopher B. TI Medication adherence: A call for action SO AMERICAN HEART JOURNAL LA English DT Article ID BLOOD-PRESSURE CONTROL; RANDOMIZED CONTROLLED-TRIAL; PRESCRIPTION DRUG LABELS; NURSE FOLLOW-UP; PHYSICIAN COMMUNICATION; TREATMENT OUTCOMES; PATIENT ADHERENCE; ELDERLY-PATIENTS; HEALTH LITERACY; AUTOMATED CALLS AB Poor adherence to efficacious cardiovascular-related medications has led to considerable morbidity, mortality, and avoidable health care costs. This article provides results of a recent think-tank meeting in which various stakeholder groups representing key experts from consumers, community health providers, the academic community, decision-making government officials (Food and Drug Administration, National Institutes of Health, etc), and industry scientists met to evaluate the current status of medication adherence and provide recommendations for improving outcomes. Below, we review the magnitude of the problem of medication adherence, prevalence, impact, and cost. We then summarize proven effective approaches and conclude with a discussion of recommendations to address this growing and significant public health issue of medication nonadherence. (Am Heart J 2011;162:412-24.) C1 [Bosworth, Hayden B.] Durham VAMC, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Bosworth, Hayden B.] Duke Univ, Sch Nursing, Dept Psychiat & Behav Sci, Durham, NC 27705 USA. [Mendys, Phil] UNC, Sch Pharm, Pfizer, US Med Affairs, Chapel Hill, NC USA. [Mendys, Phil] UNC, Sch Pharm, Div Cardiol, Chapel Hill, NC USA. [Brindis, Ralph] Oakland Kaiser Hosp, Amer Coll Cardiol, San Francisco, CA USA. [Brindis, Ralph] Oakland Kaiser Hosp, Dept Cardiol, San Francisco, CA USA. [Burkholder, Rebecca; Johnson, Mimi] Natl Consumers League, Washington, DC USA. [Czajkowski, Susan M.] Natl Inst Heart Lung & Blood Inst, NIH, Bethesda, MD USA. [Daniel, Jodi G.] US Dept HHS, Office Natl Coordinator Hlth Informat Technol, Washington, DC 20201 USA. [Ekman, Inger] Gothenburg Univ, Sahlgrenska Acad, Ctr Person Ctr Care Long Term Illness GPCC, S-41124 Gothenburg, Sweden. [Ho, Michael] Denver VA Med Ctr, Denver, CO USA. [Kimmel, Stephen E.] Univ Penn, Sch Med, Div Cardiol, Dept Med & Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Liu, Larry Z.] Pfizer Inc, New York, NY USA. [Liu, Larry Z.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Musaus, John; Buono, Elizabeth Whalley] MWV Healthcare, Richmond, VA USA. [Shrank, William H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol & Pharmacoecon,Dept Med, Boston, MA 02115 USA. [Weiss, Karen] US FDA, Washington, DC 20204 USA. [Granger, Christopher B.] Duke Univ, Div Cardiol, Dept Med, Durham, NC 27705 USA. [Bosworth, Hayden B.] Duke Univ, Med Ctr, Dept Med, Div Gen Internal Med, Durham, NC 27705 USA. RP Bosworth, HB (reprint author), Duke Univ, Med Ctr, Dept Med, Div Gen Internal Med, 2424 Erwin Rd,Suite 1105,Hock Plaza, Durham, NC 27705 USA. EM hayden.bosworth@duke.edu RI Granger, Christopher/D-3458-2014 OI Granger, Christopher/0000-0002-0045-3291 FU VA HSRD career scientist award [RCS 08-027]; American Heart Association; NIH [UL1RR024128] FX This research is supported by a VA HSRD career scientist award (RCS 08-027) and an Established Investigator Award from the American Heart Association to the first author (H. B. B.). Dr. B. Granger was supported by A NIH funded CTSA grant (UL1RR024128). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 84 TC 80 Z9 86 U1 7 U2 27 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2011 VL 162 IS 3 BP 412 EP 424 DI 10.1016/j.ahj.2011.06.007 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 814JU UT WOS:000294447400002 PM 21884856 ER PT J AU Rienstra, M Cheng, S Larson, MG McCabe, EL Booth, SL Jacques, PF Lubitz, SA Yin, XY Levy, D Magnani, JW Ellinor, PT Benjamin, EJ Wang, TJ AF Rienstra, Michiel Cheng, Susan Larson, Martin G. McCabe, Elizabeth L. Booth, Sarah L. Jacques, Paul F. Lubitz, Steven A. Yin, Xiaoyan Levy, Daniel Magnani, Jared W. Ellinor, Patrick T. Benjamin, Emelia J. Wang, Thomas J. TI Vitamin D status is not related to development of atrial fibrillation in the community SO AMERICAN HEART JOURNAL LA English DT Article ID NEGATIVE ENDOCRINE REGULATOR; CONGESTIVE-HEART-FAILURE; RENIN-ANGIOTENSIN SYSTEM; BLOOD-PRESSURE; 1,25-DIHYDROXYVITAMIN D-3; D DEFICIENCY; RISK; 25-HYDROXYVITAMIN-D; POPULATION; DISEASE AB Background Atrial fibrillation (AF) is common and is an important cause of cardiovascular morbidity and mortality. Vitamin D is an emerging risk factor in cardiovascular disease, and vitamin D status is modifiable. Thus, we sought to investigate whether vitamin D status predisposed to the development of AF in a community-based sample. Methods We evaluated the relation between vitamin D status and development of AF in 2,930 participants of the Framingham Heart Study, Massachusetts, USA, without prevalent AF. The mean age was 65 +/- 11 years, and 56% were women. Vitamin D status was assessed by measuring 25-hydroxyvitamin D (25[OH] D) concentrations. Multivariable Cox regression models were adjusted for AF risk factors and season. Results During a mean follow-up of 9.9 years, 425 participants (15%) developed AF. In Cox proportional hazards models, 25(OH) D was not associated with development of AF, with a multivariable-adjusted hazard ratio of 0.99 per SD increment in 25(OH) D levels (95% CI 0.88-1.10, P = .81). Also, no relation was found in models including 25(OH) D as a dichotomous variable (above and below the cohort-specific 20th percentile; P = .59). Conclusion In our community-based sample, vitamin D status was not related to incident AF. Our data suggest that vitamin D deficiency does not promote the development of AF in the ambulatory setting. (Am Heart J 2011;162:538-41.) C1 [Rienstra, Michiel; Ellinor, Patrick T.; Wang, Thomas J.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Rienstra, Michiel; Cheng, Susan; Larson, Martin G.; Yin, Xiaoyan; Levy, Daniel; Magnani, Jared W.; Benjamin, Emelia J.; Wang, Thomas J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Rienstra, Michiel; Cheng, Susan; Larson, Martin G.; Yin, Xiaoyan; Levy, Daniel; Magnani, Jared W.; Benjamin, Emelia J.; Wang, Thomas J.] NHLBI, Framingham, MA USA. [Cheng, Susan; McCabe, Elizabeth L.; Lubitz, Steven A.; Ellinor, Patrick T.; Wang, Thomas J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Cheng, Susan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med,Dept Med, Boston, MA 02114 USA. [Larson, Martin G.; Yin, Xiaoyan] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Booth, Sarah L.; Jacques, Paul F.] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Div Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA. RP Wang, TJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. EM tjwang@partners.org OI Larson, Martin/0000-0002-9631-1254; Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU National Institutes of Health [NO1-HC-25195, K23-HL-074077, R01-AG14759, K23-RR-017376-04, K24-HL-04334, 1R01HL092577, 1RC1HL101056, 1R01HL102214, 6R01-NS 17950, R01AG028321, 5R21DA027021, 5RO1HL104156, 1K24HL105780]; US Department of Agriculture [58-1950-4-401]; American Heart Association; Netherlands Organization for Scientific Research [825.09.020]; Ellison Foundation; American Heart Association [09FTF2190028]; Evans Center for Interdisciplinary Biomedical Research ARC at Boston University FX This work was supported by grants from the National Institutes of Health (NO1-HC-25195, K23-HL-074077, R01-AG14759, K23-RR-017376-04, and K24-HL-04334; 1R01HL092577; 1RC1HL101056; 1R01HL102214; 6R01-NS 17950; 1R01HL092577; R01AG028321; 5R21DA027021; 5RO1HL104156; 1K24HL105780), the US Department of Agriculture (agreement 58-1950-4-401), and the American Heart Association. Dr Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Rubicon Grant 825.09.020). Dr Cheng is supported by a grant from the Ellison Foundation. Dr Magnani is supported by American Heart Association Award 09FTF2190028. This work was partially supported by the Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation Initiative at Boston University. NR 31 TC 24 Z9 25 U1 0 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2011 VL 162 IS 3 BP 538 EP 541 DI 10.1016/j.ahj.2011.06.013 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 814JU UT WOS:000294447400019 PM 21884873 ER PT J AU Ames, NJ Sulima, P Yates, JM McCullagh, L Gollins, SL Soeken, K Wallen, GR AF Ames, Nancy J. Sulima, Pawel Yates, Jan M. McCullagh, Linda Gollins, Sherri L. Soeken, Karen Wallen, Gwenyth R. TI EFFECTS OF SYSTEMATIC ORAL CARE IN CRITICALLY ILL PATIENTS: A MULTICENTER STUDY SO AMERICAN JOURNAL OF CRITICAL CARE LA English DT Article ID VENTILATOR-ASSOCIATED PNEUMONIA; CHLORHEXIDINE GLUCONATE; MECHANICAL VENTILATION; NOSOCOMIAL INFECTIONS; RANDOMIZED-TRIAL; HEART-SURGERY; APACHE-II; PREVENTION; DECONTAMINATION; REDUCE AB Background No standard oral assessment tools are available for determining frequency of oral care in critical care patients, and the method of providing oral care is controversial. Objectives To examine the effects of a systematic program of oral care on oral assessment scores in critically ill intubated and nonintubated, patients. Methods Clinical data were collected 3 times during critical care admissions before and after institution of a systematic program of oral care in 3 different medical centers. The oral care education program consisted of instruction from a dentist or dental hygienist and a clear procedure outlining systematic oral care. The Beck Oral Assessment Scale and the mucosal-plaque score were used to assess the oral cavity. Data were analyzed by using linear mixed modeling with controls for severity of illness. Results Scores on the Beck Scale differed significantly (F = 4.79, P = .01) in the pattern of scores across the 3 days and between the control group (before oral education) and the systematic oral care group. Unlike the control group, the treatment group had decreasing scores on the Beck Scale from day 1 to day 5. The mucosal-plaque score and the Beck Scale scores had strong correlations throughout the study; the highest correlation was on day 5 (r = 0.798, P < .001, n = 43). Conclusions Oral assessment scores improved after nurses implemented a protocol for systematic oral care. Use of the Beck Scale and the mucosal-plaque score could standardize oral assessment and guide nurses in providing oral interventions. (American Journal of Critical Care. 2011;20:e103-e114) C1 [Ames, Nancy J.; Yates, Jan M.; Wallen, Gwenyth R.] NIH, Nursing Serv, Ctr Clin, Bethesda, MD 20892 USA. [Ames, Nancy J.; Yates, Jan M.; Wallen, Gwenyth R.] NIH, Patient Care Serv, Ctr Clin, Bethesda, MD 20892 USA. [Gollins, Sherri L.] NIH, Off Protocol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Sulima, Pawel] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. [McCullagh, Linda] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, Bethesda, MD USA. RP Ames, NJ (reprint author), NIH, Nursing Serv, Ctr Clin, Rm 3-5564,Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. EM names@nih.gov RI Sulima, Pawel/H-8649-2012 FU National Institute of Dental and Craniofacial Research; Clinical Center Nursing and Patient Care Services of the National Institutes of Health FX This research received support from the intramural program of the National Institute of Dental and Craniofacial Research and the Clinical Center Nursing and Patient Care Services of the National Institutes of Health. We thank the entire nursing staffs of the 4 critical care units that participated in this study. NR 42 TC 8 Z9 12 U1 0 U2 7 PU AMER ASSOC CRITICAL CARE NURSES PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1062-3264 J9 AM J CRIT CARE JI Am. J. Crit. Care PD SEP 1 PY 2011 VL 20 IS 5 BP E103 EP E114 DI 10.4037/ajcc2011359 PG 12 WC Critical Care Medicine; Nursing SC General & Internal Medicine; Nursing GA 814MV UT WOS:000294460500001 PM 21885453 ER PT J AU Duprez, DA Jacobs, DR Lutsey, PL Bluemke, DA Brumback, LC Polak, JF Peralta, CA Greenland, P Kronmal, RA AF Duprez, Daniel A. Jacobs, David R., Jr. Lutsey, Pamela L. Bluemke, David A. Brumback, Lyndia C. Polak, Joseph F. Peralta, Carmen A. Greenland, Philip Kronmal, Richard A. TI Association of Small Artery Elasticity With Incident Cardiovascular Disease in Older Adults The Multi-Ethnic Study of Atherosclerosis SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE arteries; cardiovascular diseases; elasticity; risk factors ID PULSE-WAVE VELOCITY; ALL-CAUSE MORTALITY; INTIMA-MEDIA THICKNESS; INDEPENDENT PREDICTOR; RATIONAL APPROACH; CONTOUR ANALYSIS; RISK-FACTOR; STIFFNESS; EVENTS; HYPERTENSION AB Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45-84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events. C1 [Duprez, Daniel A.] Univ Minnesota, Sch Med, Div Cardiovasc, Minneapolis, MN 55455 USA. [Jacobs, David R., Jr.; Lutsey, Pamela L.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN 55455 USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Brumback, Lyndia C.; Kronmal, Richard A.] Univ Washington, Dept Biostat, Sch Publ Hlth, Washington, DC USA. [Polak, Joseph F.] Tufts Med Ctr, Dept Radiol, Boston, MA USA. [Peralta, Carmen A.] Univ Calif San Francisco, Med Ctr, Dept Med, Div Nephrol, San Francisco, CA USA. [Greenland, Philip] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Jacobs, David R., Jr.] Univ Oslo, Sch Med, Dept Nutr, Oslo, Norway. RP Duprez, DA (reprint author), Univ Minnesota, Sch Med, Div Cardiovasc, VCRC Room 270,MMC 508,420 Delaware St SE, Minneapolis, MN 55455 USA. EM dupre007@umn.edu FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95169, R01-HL-098382]; National Center for Research Resources, National Institutes of Health [RR-024156] FX This research was supported by contracts N01-HC-95159 through N01-HC-95169 and grant R01-HL-098382 from the National Heart, Lung, and Blood Institute and by grant RR-024156 from the National Center for Research Resources, National Institutes of Health. NR 33 TC 49 Z9 50 U1 0 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 SEP 1 PY 2011 VL 174 IS 5 BP 528 EP 536 DI 10.1093/aje/kwr120 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 813HG UT WOS:000294356800005 PM 21709134 ER PT J AU Gao, X Chen, HL Schwarzschild, MA Ascherio, A AF Gao, Xiang Chen, Honglei Schwarzschild, Michael A. Ascherio, Alberto TI A Prospective Study of Bowel Movement Frequency and Risk of Parkinson's Disease SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE constipation; Parkinson disease; prospective studies ID BRAIN PATHOLOGY; NERVOUS-SYSTEM; LATE-LIFE; QUESTIONNAIRE; CONSTIPATION; CONSUMPTION AB The authors prospectively examined bowel movement frequency at baseline in relation to future Parkinson's disease risk in the Health Professionals Follow-up Study (HPFS) during 2000-2006 (33,901 men) and the Nurses' Health Study (NHS) during 1982-2006 (93,767 women). During the follow-up (6 years for the HPFS and 24 years for the NHS), the authors identified 156 incident male Parkinson's disease cases (HPFS) and 402 female cases (NHS). In the HPFS, compared with men with daily bowel movements, men with a bowel movement every 3 days or less had a multivariate-adjusted relative risk of 4.98 (95% confidence interval (CI): 2.59, 9.57) for developing Parkinson's disease in the next 6 years. In the NHS, the corresponding relative risk was 2.15 (95% CI: 0.76, 6.10), and the risk of Parkinson's disease was not elevated beyond 6 years of follow-up (relative risks = 1.25 for years 7-12, 0.54 for years 13-18, and 0.88 for years 19-24). When these 2 cohorts were combined, the pooled relative risks for Parkinson's disease in the next 6 years were 0.75, 1 (referent), 2.62, and 3.93 (95% CI: 2.26, 6.84) (P(trend) < 0.0001) across 4 bowel movement categories. In conclusion, infrequent bowel movements may antedate the onset of cardinal motor symptoms of Parkinson's disease and may contribute to the identification of populations with higher than average Parkinson's disease risk. C1 [Gao, Xiang; Ascherio, Alberto] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chen, Honglei] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Gao, X (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. EM xiang.gao@channing.harvard.edu OI Chen, Honglei/0000-0003-3446-7779 FU National Institutes of Health [R01 NS048517, R01 NS061858, K24NS060991]; National Institute of Environmental Health Sciences [Z01-ES-101986] FX The study was supported by National Institutes of Health grants R01 NS048517, R01 NS061858, and K24NS060991 and, in part, by grant Z01-ES-101986 from the intramural research program of the National Institute of Environmental Health Sciences. NR 24 TC 22 Z9 23 U1 0 U2 5 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 SEP 1 PY 2011 VL 174 IS 5 BP 546 EP 551 DI 10.1093/aje/kwr119 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 813HG UT WOS:000294356800007 PM 21719744 ER PT J AU Mihalopoulos, NL Phillips, TM Slater, H Thomson, JA Varner, MW Nanjee, MN Moyer-Mileur, LJ AF Mihalopoulos, Nicole L. Phillips, Terry M. Slater, Hillarie Thomson, J. Anne Varner, Michael W. Nanjee, M. Nazeem Moyer-Mileur, Laurie J. TI Validity and Reliability of Perinatal Biomarkers of Adiposity After Storage as Dried Blood Spots on Paper SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Article ID MINIMALLY INVASIVE METHOD; ADIPONECTIN CONCENTRATIONS; GESTATIONAL-AGE; SAMPLES; GROWTH; LEPTIN; ELECTROPHORESIS; APPROPRIATE; GHRELIN; INFANTS AB Objective: To validate use of chip-based immunoaffinity capillary electrophoresis on dried blood spot samples (DBSS) to measure obesity-related hormones. Methods: Chip-based immunoaffinity capillary electrophoresis was used to measure adiponectin, leptin and insulin in capillary serum and DBSS in pregnant women and infant heelstick at birth and six weeks. Concordance of measurements was determined with Pearson's correlation and Bland-Altman plots. Results: We report high concordance between results obtained from serum and DBSS. Conclusions: Ease of sample collection and storage makes DBSS an optimal method for use in studies involving neonates and young children, as well as studies conducted in areas where freezer storage is not available. Am. J. Hum. Biol. 23:717-719, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Slater, Hillarie; Thomson, J. Anne; Moyer-Mileur, Laurie J.] Univ Utah, Dept Pediat, Ctr Pediat Nutr Res, Salt Lake City, UT 84158 USA. [Phillips, Terry M.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Varner, Michael W.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Nanjee, M. Nazeem] Univ Utah, Dept Internal Med, Cardiovasc Genet Div, Salt Lake City, UT 84108 USA. RP Mihalopoulos, NL (reprint author), Div Adolescent Med, POB 581289, Salt Lake City, UT 84158 USA. EM Nicole.mihalopoulos@hsc.utah.edu RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Primary Children's Medical Center Foundation FX Grant sponsor: Primary Children's Medical Center Foundation. NR 14 TC 4 Z9 4 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD SEP-OCT PY 2011 VL 23 IS 5 BP 717 EP 719 DI 10.1002/ajhb.21199 PG 3 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 813TH UT WOS:000294392600018 PM 21735507 ER PT J AU Lamont, RF Nhan-Chang, CL Sobel, JD Workowski, K Conde-Agudelo, A Romero, R AF Lamont, Ronald F. Nhan-Chang, Chia-Ling Sobel, Jack D. Workowski, Kimberly Conde-Agudelo, Agustin Romero, Roberto TI Treatment of abnormal vaginal flora in early pregnancy with clindamycin for the prevention of spontaneous preterm birth: a systematic review and metaanalysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Review DE antibiotic; bacterial vaginosis; clindamycin; late miscarriage; preterm birth ID RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; INFLAMMATORY RESPONSE SYNDROME; GROUP-B STREPTOCOCCUS; TUMOR-NECROSIS-FACTOR; ASYMPTOMATIC BACTERIAL VAGINOSIS; ULTRASONOGRAPHIC CERVICAL LENGTH; DISEASES TREATMENT GUIDELINES; AMNIOTIC-FLUID INFECTION; GENITAL-TRACT FLORA AB The purpose of this study was to determine whether the administration of clindamycin to women with abnormal vaginal flora at < 22 weeks of gestation reduces the risk of preterm birth and late miscarriage. We conducted a systematic review and metaanalysis of randomized controlled trials of the early administration of clindamycin to women with abnormal vaginal flora at < 22 weeks of gestation. Five trials that comprised 2346 women were included. Clindamycin that was administered at < 22 weeks of gestation was associated with a significantly reduced risk of preterm birth at < 37 weeks of gestation and late miscarriage. There were no overall differences in the risk of preterm birth at < 33 weeks of gestation, low birthweight, very low birthweight, admission to neonatal intensive care unit, stillbirth, peripartum infection, and adverse effects. Clindamycin in early pregnancy in women with abnormal vaginal flora reduces the risk of spontaneous preterm birth at < 37 weeks of gestation and late miscarriage. There is evidence to justify further randomized controlled trials of clindamycin for the prevention of preterm birth. However, a deeper understanding of the vaginal microbiome, mucosal immunity, and the biology of bacterial vaginosis will be needed to inform the design of such trials. C1 [Lamont, Ronald F.; Nhan-Chang, Chia-Ling; Conde-Agudelo, Agustin; Romero, Roberto] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, Detroit, MI 48201 USA. [Lamont, Ronald F.; Nhan-Chang, Chia-Ling; Conde-Agudelo, Agustin; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Lamont, Ronald F.; Nhan-Chang, Chia-Ling] Wayne State Univ, Dept Obstet & Gynecol, Hutzel Hosp, Detroit, MI 48201 USA. [Sobel, Jack D.] Wayne State Univ, Dept Infect Dis, Hutzel Hosp, Detroit, MI 48201 USA. [Workowski, Kimberly] Emory Univ, Atlanta, GA 30322 USA. [Workowski, Kimberly] Ctr Dis Control & Prevent, Div STD Prevent, Atlanta, GA USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX Supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 175 TC 56 Z9 59 U1 1 U2 14 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2011 VL 205 IS 3 BP 177 EP 190 DI 10.1016/j.ajog.2011.03.047 PG 14 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 812YF UT WOS:000294330000016 PM 22071048 ER PT J AU Kominiarek, MA Zhang, J VanVeldhuisen, P Troendle, J Beaver, J Hibbard, JU AF Kominiarek, Michelle A. Zhang, Jun VanVeldhuisen, Paul Troendle, James Beaver, Julie Hibbard, Judith U. TI Contemporary labor patterns: the impact of maternal body mass index SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 31st Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 07-12, 2011 CL San Francisco, CA SP Soc Maternal Fetal Med DE body mass index; labor curves; obesity; pregnancy ID CESAREAN DELIVERY; NULLIPAROUS WOMEN; OBESE WOMEN; OUTCOMES; RISK; PROGRESSION; PREGNANCY; INDUCTION; WEIGHT; TERM AB OBJECTIVE: We sought to compare labor patterns by body mass index (BMI). STUDY DESIGN: A total of 118,978 gravidas with a singleton term cephalic gestation were studied. Repeated-measures analysis constructed mean labor curves by parity and BMI categories for those who reached 10 cm. Interval-censored regression analysis determined median traverse times, adjusting for covariates in vaginal deliveries and intrapartum cesareans. RESULTS: In the labor curves, the time difference to reach 10 cm was 1.2 hours from the lowest to highest BMI category for nulliparas. Multiparas entered active phase by 6 cm, but reaching this point took longer for BMI >= 40.0 (3.4 hours) compared to BMI <25.0 (2.4 hours). Progression by centimeter (P < .001 for nulliparas) and from 4-10 cm (P < .001 for nulliparas and multiparas) increased as BMI increased. Second stage length, with and without an epidural, was similar among BMI categories for nulliparas (P > .05) but decreased as BMI increased for multiparas (P < .001). CONCLUSION: Labor proceeds more slowly as BMI increases, suggesting that labor management be altered to allow longer time for these differences. C1 [Kominiarek, Michelle A.; Hibbard, Judith U.] Univ Illinois, Dept Obstet & Gynecol, Div Maternal Fetal Med, Chicago, IL 60612 USA. [Kominiarek, Michelle A.] Indiana Univ Sch Med Clarian Hlth, Dept Obstet & Gynecol, Div Maternal Fetal Med, Indianapolis, IN USA. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Shanghai Key Lab Childrens Environm Hlth, Shanghai 200030, Peoples R China. [Troendle, James] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [VanVeldhuisen, Paul] EMMES Corp, Rockville, MD USA. RP Kominiarek, MA (reprint author), Univ Illinois, Dept Obstet & Gynecol, Div Maternal Fetal Med, 820 S Wood St,M-C 808, Chicago, IL 60612 USA. EM Mkomin1@uic.edu FU Intramural NIH HHS; NICHD NIH HHS [HHSN267200603425C, K12 HD055892, K12HD055892]; PHS HHS [HHSN267200603425C] NR 35 TC 12 Z9 12 U1 0 U2 6 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 SEP PY 2011 VL 205 IS 3 AR 244.e1 DI 10.1016/j.ajog.2011.06.014 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 812YF UT WOS:000294330000042 PM 21798510 ER PT J AU Lum, KJ Sundaram, R Louis, GMB AF Lum, Kirsten J. Sundaram, Rajeshwari Louis, Germaine M. Buck TI Women's lifestyle behaviors while trying to become pregnant: evidence supporting preconception guidance SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 1st European Congress on Preconception Care and Preconception Health CY OCT 06-09, 2010 CL Brussels, BELGIUM DE alcohol; caffeine; cigarettes; cohort; preconception ID LONGITUDINAL DATA-ANALYSIS; 1ST PREGNANCY; CARE; RECOMMENDATIONS; CONCEPTION; SMOKING; FECUNDITY; ALCOHOL; HEALTH; COHORT AB OBJECTIVE: We sought to prospectively measure women's daily cigarette, alcohol, and caffeine use, while attempting pregnancy in relation to intentions to change. STUDY DESIGN: This was a cohort comprising 90 women enrolled upon discontinuing contraception and followed up prospectively until pregnant. Women reported number of daily cigarettes, and alcoholic and caffeinated beverages for 459 menstrual cycles while attempting pregnancy. RESULTS: A significant mean reduction in daily caffeinated drinks (estimate [EST] = -0.52; 95% confidence interval [CI], -0.70 to -0.33) was observed when compared to baseline usage. Intention to change was associated with a reduction in caffeinated drinks (EST = -0.32; 95% CI, -0.64 to 0.00), and with alcohol and cigarette usage from the first menstrual cycle (EST = -0.15; 95% CI, -0.28 to -0.02 and EST = -1.65; 95% CI, -3.12 to -0.19, respectively). CONCLUSION: A reduction in daily caffeine intake while attempting pregnancy was observed, but not in alcohol or cigarette use, underscoring the need for preconception guidance. C1 [Lum, Kirsten J.; Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, NIH, Bethesda, MD 20892 USA. [Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Lum, KJ (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, 615 N Wolfe St, Baltimore, MD 21205 USA. EM klum@jhsph.edu OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural NIH HHS [Z01 HD008729-07]; PHS HHS [H751 ATH298338] NR 28 TC 1 Z9 1 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2011 VL 205 IS 3 AR 203.e1 DI 10.1016/j.ajog.2011.04.030 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 812YF UT WOS:000294330000020 PM 21658667 ER PT J AU Ohayon, J Gharib, AM Garcia, A Heroux, J Yazdani, SK Malve, M Tracqui, P Martinez, MA Doblare, M Finet, G Pettigrew, RI AF Ohayon, Jacques Gharib, Ahmed M. Garcia, Alberto Heroux, Julie Yazdani, Saami K. Malve, Mauro Tracqui, Philippe Martinez, Miguel-Angel Doblare, Manuel Finet, Gerard Pettigrew, Roderic I. TI Is arterial wall-strain stiffening an additional process responsible for atherosclerosis in coronary bifurcations?: an in vivo study based on dynamic CT and MRI SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE atherosclerosis; coronary disease; wall stiffness; wall stress; biomechanics; computed tomography; magnetic resonance imaging ID THIN-CAP FIBROATHEROMA; SUBSTRATE RIGIDITY; PLAQUE RUPTURE; COMPUTED-TOMOGRAPHY; VASCULAR-RESPONSES; STIFFNESS; DISEASE; STRESS; RISK; CELLS AB Ohayon J, Gharib AM, Garcia A, Heroux J, Yazdani SK, Malve M, Tracqui P, Martinez MA, Doblare M, Finet G, Pettigrew RI. Is arterial wall-strain stiffening an additional process responsible for atherosclerosis in coronary bifurcations?: an in vivo study based on dynamic CT and MRI. Am J Physiol Heart Circ Physiol 301: H1097-H1106, 2011. First published June 17, 2011; doi:10.1152/ajpheart.01120.2010.-Coronary bifurcations represent specific regions of the arterial tree that are susceptible to atherosclerotic lesions. While the effects of vessel compliance, curvature, pulsatile blood flow, and cardiac motion on coronary endothelial shear stress have been widely explored, the effects of myocardial contraction on arterial wall stress/strain (WS/S) and vessel stiffness distributions remain unclear. Local increase of vessel stiffness resulting from wall-strain stiffening phenomenon (a local process due to the nonlinear mechanical properties of the arterial wall) may be critical in the development of atherosclerotic lesions. Therefore, the aim of this study was to quantify WS/S and stiffness in coronary bifurcations and to investigate correlations with plaque sites. Anatomic coronary geometry and cardiac motion were generated based on both computed tomography and MRI examinations of eight patients with minimal coronary disease. Computational structural analyses using the finite element method were subsequently performed, and spatial luminal arterial wall stretch (LW(Stretch)) and stiffness (LW(Stiff)) distributions in the left main coronary bifurcations were calculated. Our results show that all plaque sites were concomitantly subject to high LW(Stretch) and high LW(Stiff), with mean amplitudes of 34.7 +/- 1.6% and 442.4 +/- 113.0 kPa, respectively. The mean LW(Stiff) amplitude was found slightly greater at the plaque sites on the left main coronary artery (mean value: 482.2 +/- 88.1 kPa) compared with those computed on the left anterior descending and left circumflex coronary arteries (416.3 +/- 61.5 and 428.7 +/- 181.8 kPa, respectively). These findings suggest that local wall stiffness plays a role in the initiation of atherosclerotic lesions. C1 [Ohayon, Jacques; Gharib, Ahmed M.; Heroux, Julie; Pettigrew, Roderic I.] Natl Inst Diabet Digest & Kidney Dis, Lab Integrat Cardiovasc Imaging Sci, NIH, Bethesda, MD USA. [Ohayon, Jacques; Tracqui, Philippe] Univ Grenoble 1, Lab TIMC IMAG DyCTiM, CNRS, Unite Mixte Rech 5525,In3S, Grenoble, France. [Ohayon, Jacques] Univ Savoie, Polytech Annecy Chambery, Savoie, France. [Garcia, Alberto; Malve, Mauro; Martinez, Miguel-Angel; Doblare, Manuel] Univ Zaragoza, Grp Struct Mech & Mat Modeling, Aragon Inst Engn Res I3A, Dept Mech Engn, Zaragoza, Spain. [Garcia, Alberto; Malve, Mauro; Martinez, Miguel-Angel; Doblare, Manuel] Ctr Invest Biomed Red Bioingn Biomat & Nanomed, Zaragoza, Spain. [Yazdani, Saami K.] CVPath Inst, Gaithersburg, MD USA. [Finet, Gerard] Hosp Civils Lyon, Dept Hemodynam & Intervent Cardiol, Lyon, France. [Finet, Gerard] Univ Lyon 1, Inst Natl Sante & Rech Med, Unit 886, F-69365 Lyon, France. RP Ohayon, J (reprint author), Univ Grenoble 1, Lab TIMC DyCTiM, CNRS, Unite Mixte Rech 5525,In3S, Grenoble, France. EM jacques.ohayon@imag.fr RI Gharib, Ahmed/O-2629-2016; Doblare Castellano, Manuel/M-9028-2015; Martinez, Miguel Angel/F-5903-2011; Malve, Mauro/A-5516-2013; Ohayon, Jacques/M-6576-2014 OI Gharib, Ahmed/0000-0002-2476-481X; Doblare Castellano, Manuel/0000-0001-8741-6452; Martinez, Miguel Angel/0000-0002-8375-0354; Malve, Mauro/0000-0002-0116-2736; FU Rhone-Alpes (France); Spanish Instituto de Salud Carlos III (CIBER initiative); Ministerio de Ciencia e Innovacion [DPI2007-63254]; Ministerio de Sanidad [FIS PI06-0406] FX This work was supported in part by an appointment (J. Ohayon) to the Senior Fellow Program at the National Institutes of Health (National Institutes of Health). This program was administered by Oak Ridge Institute for Science and Education through an interagency agreement between NIH and the United States Department of Energy. J. Ohayon and G. Finet were supported by grants from the Rhone-Alpes (France) research cluster (I3M: Medical Images and Multiscale Models). M. Doblare, A. Garcia, M. Malve, and MA. Martinez were supported by the Spanish Instituto de Salud Carlos III (CIBER initiative), Ministerio de Ciencia e Innovacion Project DPI2007-63254, and Ministerio de Sanidad Project FIS PI06-0406. NR 46 TC 13 Z9 14 U1 1 U2 12 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 2011 VL 301 IS 3 BP H1097 EP H1106 DI 10.1152/ajpheart.01120.2010 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 814EX UT WOS:000294431400051 PM 21685261 ER PT J AU Dmitrieva, NI Malide, D Burg, MB AF Dmitrieva, Natalia I. Malide, Daniela Burg, Maurice B. TI Mre11 is expressed in mammalian mitochondria where it binds to mitochondrial DNA SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE mitochondrial DNA damage; osmotic stress; NaCl; bleomycin ID DOUBLE-STRAND BREAKS; HIGH NACL; IN-VIVO; ATAXIA-TELANGIECTASIA; HUMAN-CELLS; REPAIR; DAMAGE; COMPLEX; MRE11-RAD50-NBS1; NUCLEUS AB Dmitrieva NI, Malide D, Burg MB. Mre11 is expressed in mammalian mitochondria where it binds to mitochondrial DNA. Am J Physiol Regul Integr Comp Physiol 301: R632-R640, 2011. First published June 15, 2011; doi:10.1152/ajpregu.00853.2010.-Mre11 is a critical participant in upkeep of nuclear DNA, its repair, replication, meiosis, and maintenance of telomeres. The upkeep of mitochondrial DNA (mtDNA) is less well characterized, and whether Mre11 participates has been unknown. We previously found that high NaCl causes some of the Mre11 to leave the nucleus, but we did not then attempt to localize it within the cytoplasm. In the present studies, we find Mre11 in mitochondria isolated from primary renal cells and show that the amount of Mre11 in mitochondria increases with elevation of extracellular NaCl. We confirm the presence of Mre11 in the mitochondria of cells by confocal microscopy and show that some of the Mre11 colocalizes with mtDNA. Furthermore, crosslinking of Mre11 to DNA followed by Mre11 immunoprecipitation directly demonstrates that some Mre11 binds to mtDNA. Abundant Mre11 is also present in tissue sections from normal mouse kidneys, colocalized with mitochondria of proximal tubule and thick ascending limb cells. To explore whether distribution of Mre11 changes with cell differentiation, we used an experimental model of tubule formation by culturing primary kidney cells in Matrigel matrix. In nondifferentiated cells, Mre11 is mostly in the nucleus, but it becomes mostly cytoplasmic upon cell differentiation. We conclude that Mre11 is present in mitochondria where it binds to mtDNA and that the amount in mitochondria varies depending on cellular stress and differentiation. Our results suggest a role for Mre11 in the maintenance of genome integrity in mitochondria in addition to its previously known role in maintenance of nuclear DNA. C1 [Dmitrieva, Natalia I.; Burg, Maurice B.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. [Malide, Daniela] NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. RP Dmitrieva, NI (reprint author), 9000 Rockville Pike,Bldg 10,Rm 6N260, Bethesda, MD 20892 USA. EM dmitrien@nhlbi.nih.gov RI Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 FU National Institutes of Health FX This work was supported by the National Institutes of Health Intramural Research Program. NR 50 TC 12 Z9 12 U1 0 U2 5 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 SEP PY 2011 VL 301 IS 3 BP R632 EP R640 DI 10.1152/ajpregu.00853.2010 PG 9 WC Physiology SC Physiology GA 814LJ UT WOS:000294454300006 PM 21677273 ER PT J AU Goldman, D AF Goldman, David TI Molecular Etiologies of Schizophrenia: Are We Almost There Yet? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material C1 NIAAA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, Bethesda, MD 20892 USA. EM david.goldman@nih.hhs.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z01 AA000301-09] NR 6 TC 2 Z9 2 U1 3 U2 7 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 SEP PY 2011 VL 168 IS 9 BP 879 EP 881 DI 10.1176/appi.ajp.2011.11050694 PG 3 WC Psychiatry SC Psychiatry GA 814VA UT WOS:000294484100003 PM 21890799 ER PT J AU Pine, DS Freedman, R AF Pine, Daniel S. Freedman, Robert TI Imaging a Brighter Future SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material C1 [Pine, Daniel S.; Freedman, Robert] Univ Colorado, Sch Med, Natl Inst Mental Hlth, Denver, CO 80202 USA. RP Pine, DS (reprint author), Univ Colorado, Sch Med, Natl Inst Mental Hlth, Denver, CO 80202 USA. EM pined@mail.nih.gov; Robert.Freedman@ucdenver.edu NR 3 TC 0 Z9 0 U1 0 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2011 VL 168 IS 9 BP 885 EP 887 DI 10.1176/appi.ajp.2011.11050788 PG 3 WC Psychiatry SC Psychiatry GA 814VA UT WOS:000294484100005 PM 21890801 ER PT J AU Connolly, JM Bakay, MA Alferiev, IS Gorman, RC Gorman, JH Kruth, HS Ashworth, PE Kutty, JK Schoen, FJ Bianco, RW Levy, RJ AF Connolly, Jeanne M. Bakay, Marina A. Alferiev, Ivan S. Gorman, Robert C. Gorman, Joseph H., III Kruth, Howard S. Ashworth, Paul E. Kutty, Jaishankar K. Schoen, Frederick J. Bianco, Richard W. Levy, Robert J. TI Triglycidyl Amine Crosslinking Combined With Ethanol Inhibits Bioprosthetic Heart Valve Calcification SO ANNALS OF THORACIC SURGERY LA English DT Article ID EPOXY COMPOUNDS; CARDIAC VALVES; GLUTARALDEHYDE; PREVENTION; TISSUE; MECHANISMS; CUSPS; ANTICALCIFICATION; BISPHOSPHONATE; PREINCUBATION AB Background. One of the most important factors responsible for the calcific failure of bioprosthetic heart valves is glutaraldehyde crosslinking. Ethanol (EtOH) incubation after glutaraldehyde crosslinking has previously been reported to confer anticalcification efficacy for bioprostheses. The present studies investigated the anticalcification efficacy in vivo of the novel crosslinking agent, triglycidyl amine (TGA), with or without EtOH incubation, in comparison with glutaraldehyde. Methods. The TGA crosslinking (+/- EtOH) was used to prepare porcine aortic valves for both rat subdermal implants and sheep mitral valve replacements, for comparisons with glutaraldehyde-fixed controls. Thermal denaturation temperature, an index of crosslinking, cholesterol extraction, and hydrodynamic properties were quantified. Explant endpoints included quantitative and morphologic assessment of calcification. Results. Thermal denaturation temperatures after TGA were intermediate between unfixed and glutaraldehyde-fixed. EtOH incubation resulted in almost complete extraction of cholesterol from TGA or glutaraldehyde-fixed cusps. Rat subdermal explants (90 days) demonstrated that TGA-EtOH resulted in a significantly greater level of inhibition of calcification than other conditions. Thus, TGA-ethanol stent mounted porcine aortic valve bioprostheses were fabricated for comparisons with glutaraldehyde-pretreated controls. In hydrodynamic studies, TGA-EtOH bioprostheses had lower pressure gradients than glutaraldehyde-fixed. The TGA-ethanol bioprostheses used as mitral valve replacements in juvenile sheep (150 days) demonstrated significantly lower calcium levels in both explanted porcine aortic cusp and aortic wall samples compared with glutaraldehyde-fixed controls. However, TGA-EtOH sheep explants also demonstrated isolated calcific nodules and intracuspal hematomas. Conclusions. The TGA-EtOH pretreatment of porcine aortic valves confers significant calcification resistance in both rat subdermal and sheep circulatory implants, but with associated structural instability. (Ann Thorac Surg 2011;92:858-65) (C) 2011 by The Society of Thoracic Surgeons C1 [Connolly, Jeanne M.] Childrens Hosp Philadelphia, Abramson Res Ctr 702, Div Cardiol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. NHLBI, NIH, Bethesda, MD 20892 USA. St Jude Med Inc, St Paul, MN USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Minnesota, Minneapolis, MN USA. RP Connolly, JM (reprint author), Childrens Hosp Philadelphia, Abramson Res Ctr 702, Div Cardiol, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM connolly@email.chop.edu FU National Institutes of Health [HL74731, HL101820, HL007915]; Kibel Foundation; William J. Rashkind Endowment of the Children's Hospital of Philadelphia FX This study was funded by National Institutes of Health grants HL74731, HL101820, and HL007915, The Kibel Foundation, and the William J. Rashkind Endowment of the Children's Hospital of Philadelphia. NR 23 TC 6 Z9 6 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD SEP PY 2011 VL 92 IS 3 BP 858 EP 865 DI 10.1016/j.athoracsur.2011.04.104 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 811WJ UT WOS:000294247400023 PM 21871270 ER PT J AU Johne, R Buck, CB Allander, T Atwood, WJ Garcea, RL Imperiale, MJ Major, EO Ramqvist, T Norkin, LC AF Johne, Reimar Buck, Christopher B. Allander, Tobias Atwood, Walter J. Garcea, Robert L. Imperiale, Michael J. Major, Eugene O. Ramqvist, Torbjorn Norkin, Leonard C. TI Taxonomical developments in the family Polyomaviridae SO ARCHIVES OF VIROLOGY LA English DT Article ID GOOSE HEMORRHAGIC POLYOMAVIRUS; MERKEL CELL POLYOMAVIRUS; VIRUS FAMILY; INFECTION; NEPHRITIS; ENTERITIS; GENOME; MEMBER; BIRDS AB The Polyomaviridae Study Group of the International Committee on Taxonomy of Viruses (ICTV) has recommended several taxonomical revisions, as follows: The family Polyomaviridae, which is currently constituted as a single genus (Polyomavirus), will be comprised of three genera: two containing mammalian viruses and one containing avian viruses. The two mammalian genera will be designated Orthopolyomavirus and Wukipolyomavirus, and the avian genus will be named Avipolyomavirus. These genera will be created by the redistribution of species from the current single genus (Polyomavirus) and by the inclusion of several new species. In addition, the names of several species will be changed to reflect current usage. C1 [Norkin, Leonard C.] Univ Massachusetts, Dept Microbiol, Amherst, MA 01003 USA. [Johne, Reimar] Fed Inst Risk Assessment, D-12277 Berlin, Germany. [Buck, Christopher B.] NCI, Tumor Virus Mol Biol Sect, Cellular Oncol Lab, Bethesda, MD 20892 USA. [Allander, Tobias] Karolinska Univ Hosp, Karolinska Inst, Lab Clin Microbiol, Dept Microbiol Tumor & Cell Biol, S-17176 Stockholm, Sweden. [Atwood, Walter J.] Brown Univ, Dept Mol & Cell Biol & Biochem, Providence, RI 02912 USA. [Garcea, Robert L.] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. [Imperiale, Michael J.] Univ Michigan, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, Mol Med & Virol Sect, NIH, Bethesda, MD 20892 USA. [Ramqvist, Torbjorn] Karolinska Univ, Hosp Solna, Canc Ctr Karolinska, Dept Oncol Pathol,Karolinska Inst, S-17176 Stockholm, Sweden. RP Norkin, LC (reprint author), Univ Massachusetts, Dept Microbiol, Room 203 Morrill Sci Ctr, Amherst, MA 01003 USA. EM Reimar.Johne@bfr.bund.de; lnorkin@microbio.umass.edu OI Buck, Christopher/0000-0003-3165-8094 FU NCI NIH HHS [R01 CA037667-28, R01 CA037667] NR 25 TC 98 Z9 101 U1 1 U2 19 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PD SEP PY 2011 VL 156 IS 9 BP 1627 EP 1634 DI 10.1007/s00705-011-1008-x PG 8 WC Virology SC Virology GA 814ND UT WOS:000294461800018 PM 21562881 ER PT J AU Tsang, KY Gulley, JL AF Tsang, Kwong Y. Gulley, James L. TI Highlights on FOXO3 and tumor-associated dendritic cells in prostate cancer SO ASIAN JOURNAL OF ANDROLOGY LA English DT Editorial Material ID REGULATORY T-CELLS; PERIPHERAL-BLOOD C1 [Tsang, Kwong Y.; Gulley, James L.] NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Tsang, KY (reprint author), NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. EM tsangkwo@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 10 TC 0 Z9 0 U1 0 U2 1 PU SHANGHAI INST MATERIA MEDICA PI SHANGHAI PA 555 ZU CHONG ZHI RD, ZHANG JIANG HI-TECH PARK, SHANGHAI, PUDONG 201203, PEOPLES R CHINA SN 1008-682X J9 ASIAN J ANDROL JI Asian J. Androl. PD SEP PY 2011 VL 13 IS 5 BP 657 EP 658 DI 10.1038/aja.2011.78 PG 2 WC Andrology; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 814YS UT WOS:000294493800004 PM 21685924 ER PT J AU Olnes, MJ AF Olnes, Matthew J. TI FISHing for aneuploidy in HSCT donors SO BLOOD LA English DT Editorial Material ID COLONY-STIMULATING FACTOR; CONGENITAL NEUTROPENIA; STEM-CELLS; LEUKEMIA; BLOOD; RISK C1 Natl Inst Hlth, Bethesda, MD 20892 USA. RP Olnes, MJ (reprint author), Natl Inst Hlth, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 1 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 SEP 1 PY 2011 VL 118 IS 9 BP 2384 EP 2385 DI 10.1182/blood-2011-07-366179 PG 4 WC Hematology SC Hematology GA 814SC UT WOS:000294476400007 PM 21885609 ER PT J AU Biswas, K Das, R Alter, BP Kuznetsov, SG Stauffer, S North, SL Burkett, S Brody, LC Meyer, S Byrd, RA Sharan, SK AF Biswas, Kajal Das, Ranabir Alter, Blanche P. Kuznetsov, Sergey G. Stauffer, Stacey North, Susan L. Burkett, Sandra Brody, Lawrence C. Meyer, Stefan Byrd, R. Andrew Sharan, Shyam K. TI A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay SO BLOOD LA English DT Article ID SHARED GENETIC SUSCEPTIBILITY; BREAST-CANCER; BIALLELIC MUTATIONS; GERMLINE MUTATIONS; DNA-DAMAGE; LEUKEMIA; PALB2; IDENTIFICATION; RECOMBINATION; BRCA2/FANCD1 AB Biallelic mutations in the human breast cancer susceptibility gene, BRCA2, are associated with Fanconi anemia, implying that some persons who inherit 2 deleterious variants of BRCA2 are able to survive even though it is well established that BRCA2 is indispensable for viability in mice. One such variant, IVS7 + 2T > G, results in premature protein truncation because of skipping of exon 7. Surprisingly, the persons who are either IVS7 + 2T > Ghomozygous or compound heterozygous are born alive but die of malignancy associated with Fanconi anemia. Using a mouse embryonic stem cell-based functional assay, we found that the IVS7 + 2T > G allele produces an alternatively spliced transcript lacking exons 4-7, encoding an in-frame BRCA2 protein with an internal deletion of 105 amino acids (BRCA2(Delta 105)). We demonstrate that BRCA2(Delta 105) is proficient in homologous recombination-mediated DNA repair as measured by different functional assays. Evaluation of this transcript in normal and leukemia cells suggests that BRCA2(Delta 105) may contribute to the viability of persons inheriting this mutation. In this study, we have also characterized 5 other BRCA2 variants and found 3 of these (p.L2510P, p.R2336H, and p.W2626C) to be deleterious and 2 (p.I2490T and p.K2729N) probably neutral. Such studies are important to understand the functional significance of unclassified BRCA2 variants. (Blood. 2011;118(9):2430-2442) C1 [Biswas, Kajal; Kuznetsov, Sergey G.; Stauffer, Stacey; North, Susan L.; Burkett, Sandra; Sharan, Shyam K.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Das, Ranabir; Byrd, R. Andrew] NCI, Struct Biophys Lab, Frederick, MD 21702 USA. [Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Brody, Lawrence C.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Meyer, Stefan] Stem Cell & Leukemia Prote Lab, Manchester, Lancs, England. [Meyer, Stefan] Univ Manchester, Royal Manchester Childrens Hosp, Cent Manchester & Christie Hosp Natl Hlth Serv NH, Pediat & Adolescent Oncol Unit,Manchester Acad Hl, Manchester, Lancs, England. RP Sharan, SK (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Bldg 560,Rm 32-31C,1050 Boyles St, Frederick, MD 21702 USA. EM sharans@mail.nih.gov RI Byrd, R. Andrew/F-8042-2015; OI Byrd, R. Andrew/0000-0003-3625-4232; Kuznetsov, Sergey/0000-0002-5662-9700 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; CRUK FX This work was supported by the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and a CRUK Clinical Scientist Fellowship (S.M.). NR 42 TC 14 Z9 14 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2011 VL 118 IS 9 BP 2430 EP 2442 DI 10.1182/blood-2010-12-324541 PG 13 WC Hematology SC Hematology GA 814SC UT WOS:000294476400015 PM 21719596 ER PT J AU Lugli, E Mueller, YM Lewis, MG Villinger, F Katsikis, PD Roederer, M AF Lugli, Enrico Mueller, Yvonne M. Lewis, Mark G. Villinger, Francois Katsikis, Peter D. Roederer, Mario TI IL-15 delays suppression and fails to promote immune reconstitution in virally suppressed chronically SIV-infected macaques SO BLOOD LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; T-CELL DEPLETION; GASTROINTESTINAL-TRACT; ANTIRETROVIRAL THERAPY; DISEASE PROGRESSION; NONHUMAN-PRIMATES; HIV-1 INFECTION; MEMORY CD4; INTERLEUKIN-15; DIFFERENTIATION AB Human immunodeficiency virus (HIV) infection is characterized by a progressive loss of memory CD4(+) T cells in multiple tissues, especially at mucosal surfaces where most of these cells reside. Although antiretroviral therapy (ART) suppresses viral replication and promotes the recovery of peripheral CD4(+) T cells, HIV-infected patients fail to fully reconstitute the CD4(+) T-cell pool at mucosal sites. IL-15 has been shown to preferentially expand memory-phenotype T cells and promote their migration to nonlymphoid tissues. Here we examined IL-15 treatment in combination with highly active ART in chronically SIV-infected rhesus macaques and found that IL-15 delayed viral suppression and failed to enhance ART-induced total and antigen-specific CD4(+) T-cell reconstitution at mucosal and lymphoid sites. IL-15 was able to induce the transient proliferation of SIV-specific, CMV-specific, and total memory CD8(+) T cells, but not of SIV-specific or total CD4(+) T cells. Moreover, upon treatment interruption, macaques receiving combined IL-15+ ART lost CD4(+) T cells faster than those receiving ART alone. These results suggest that the combination of IL-15 with highly active ART is not more efficient than ART alone in promoting CD4(+) T-cell recovery in HIV-infected individuals and may accelerate CD4(+) T-cell loss after treatment interruption. (Blood. 2011;118(9):2520-2529) C1 [Mueller, Yvonne M.; Katsikis, Peter D.] Drexel Univ, Dept Microbiol & Immunol, Coll Med, Philadelphia, PA 19104 USA. [Lugli, Enrico; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Lewis, Mark G.] Bioqual Inc, Rockville, MD USA. [Villinger, Francois] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. [Villinger, Francois] Yerkes Natl Primate Res Ctr, Div Pathol, Atlanta, GA USA. RP Katsikis, PD (reprint author), Drexel Univ, Dept Microbiol & Immunol, Coll Med, 2900 Queen Ln, Philadelphia, PA 19104 USA. EM peter.katsikis@drexelmed.edu OI Katsikis, Peter/0000-0001-7690-5218; Mueller, Yvonne/0000-0002-4654-7509 FU National Institutes of Health [R01 AI046719, R21 AI082680, R24RR016988]; NIAID, National Institutes of Health FX This work has been supported in part by grants National Institutes of Health R01 AI046719 and R21 AI082680 to P.D.K., R24RR016988 to F.V. and by the intramural research program of the NIAID, National Institutes of Health. NR 33 TC 21 Z9 22 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2011 VL 118 IS 9 BP 2520 EP 2529 DI 10.1182/blood-2011-05-351155 PG 10 WC Hematology SC Hematology GA 814SC UT WOS:000294476400024 PM 21757617 ER PT J AU Vazquez, N Schmeisser, H Dolan, MA Bekisz, J Zoon, KC Wahl, SM AF Vazquez, Nancy Schmeisser, Hana Dolan, Michael A. Bekisz, Joseph Zoon, Kathryn C. Wahl, Sharon M. TI Structural variants of IFN alpha preferentially promote antiviral functions SO BLOOD LA English DT Article ID TUMOR-NECROSIS-FACTOR; KAPPA-B ACTIVATION; I-INTERFERON; INDOLEAMINE 2,3-DIOXYGENASE; HIV-INFECTION; TRYPTOPHAN DEPLETION; DENDRITIC CELLS; VIRUS-INFECTION; HEPATITIS-C; PROTEIN AB IFN alpha, a cytokine with multiple functions in innate and adaptive immunity and a potent inhibitor of HIV, exerts antiviral activity, in part, by enhancing apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3 (APOBEC3) family members. Although IFN alpha therapy is associated with reduced viral burden, this cytokine also mediates immune dysfunction and toxicities. Through detailed map-ping of IFN alpha receptor binding sites, we generated IFN alpha hybrids and mutants and determined that structural changes in the C-helix alter the ability of IFN to limit retroviral activity. Selective IFN alpha constructs differentially block HIV replication and their directional magnitude of inhibition correlates with APOBEC3 levels. Importantly, certain mutants exhibited reduced toxicity as reflected by induced indoleamine 2,3-dioxygenase (IDO), suggesting discreet and shared intracellular signaling pathways. Defining IFN structure and function relative to APOBEC and other antiviral genes may enable design of novel IFN-related molecules preserving beneficial antiviral roles while minimizing negative effects. (Blood. 2011;118(9):2567-2577) C1 [Vazquez, Nancy; Wahl, Sharon M.] NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Schmeisser, Hana; Dolan, Michael A.; Bekisz, Joseph; Zoon, Kathryn C.] NIAID, NIH, Bethesda, MD 20892 USA. RP Vazquez, N (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Rm 332,30 Convent Dr,MSC 4352, Bethesda, MD 20892 USA. EM nvazquez@mail.nih.gov FU National Institutes of Health; National Institute of Dental and Craniofacial Research (NIDCR); National Institute of Allergy and Infectious Diseases (NIAID) FX This research was supported by Intramural Research Program of National Institutes of Health, National Institute of Dental and Craniofacial Research (NIDCR) and National Institute of Allergy and Infectious Diseases (NIAID). NR 50 TC 14 Z9 15 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 SEP 1 PY 2011 VL 118 IS 9 BP 2567 EP 2577 DI 10.1182/blood-2010-12-325027 PG 11 WC Hematology SC Hematology GA 814SC UT WOS:000294476400029 PM 21757613 ER PT J AU Kapetanovic, IM Muzzio, M Huang, ZH Thompson, TN McCormick, DL AF Kapetanovic, Izet M. Muzzio, Miguel Huang, Zhihua Thompson, Thomas N. McCormick, David L. TI Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Resveratrol; Pterostilbene; Pharmacokinetics; Bioavailability; Metabolites; Rat ID TRANS-RESVERATROL; MOLECULAR-MECHANISMS; COLON CARCINOGENESIS; CANCER PREVENTION; ABSORPTION; DISEASE; CHEMOPREVENTION; BLUEBERRIES; CONSTITUENT; RESISTANCE AB Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a naturally occurring polyphenol with a broad range of possible health benefits, including anti-cancer activity. However, the biological activity of resveratrol may be limited by poor absorption and first-pass metabolism: only low plasma concentrations of resveratrol are seen following oral administration, and metabolism to glucuronide and sulfate conjugates is rapid. Methylated polyphenol analogs (such as pterostilbene [3,5-dimethoxy-4'-hydroxy-trans-stilbene], the dimethylether analog of resveratrol) may overcome these limitations to pharmacologic efficacy. The present study was designed to compare the bioavailability, pharmacokinetics, and metabolism of resveratrol and pterostilbene following equimolar oral dosing in rats. The agents were administered orally via gavage for 14 consecutive days at 50 or 150 mg/kg/day for resveratrol and 56 or 168 mg/kg/day for pterostilbene. Two additional groups were dosed once intravenously with 10 and 11.2 mg/kg for resveratrol and pterostilbene, respectively. Plasma concentrations of agents and metabolites were measured using a high-pressure liquid chromatograph-tandem mass spectrometer system. Noncompartmental analysis was used to derive pharmacokinetic parameters. Resveratrol and pterostilbene were approximately 20 and 80% bioavailable, respectively. Following oral dosing, plasma levels of pterostilbene and pterostilbene sulfate were markedly greater than were plasma levels of resveratrol and resveratrol sulfate. Although plasma levels of resveratrol glucuronide exceeded those of pterostilbene glucuronide, those differences were smaller than those of the parent drugs and sulfate metabolites. When administered orally, pterostilbene demonstrates greater bioavailability and total plasma levels of both the parent compound and metabolites than does resveratrol. These differences in agent pharmacokinetics suggest that the in vivo biological activity of equimolar doses of pterostilbene may be greater than that of resveratrol. C1 [Muzzio, Miguel; Huang, Zhihua; McCormick, David L.] IIT, Res Inst, Life Sci Grp, Chicago, IL 60616 USA. [Kapetanovic, Izet M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Thompson, Thomas N.] R&D Serv Pharma Consulting, Omaha, NE 68154 USA. RP Muzzio, M (reprint author), IIT, Res Inst, Life Sci Grp, 10 W 35th St, Chicago, IL 60616 USA. EM mmuzzio@iitri.org FU National Cancer Institute, Department of Health and Human Services [N01-CN-43304] FX These studies were supported by contract number N01-CN-43304 from the National Cancer Institute, Department of Health and Human Services. The authors thank Leigh Ann Senoussi for assistance in preparing the manuscript. NR 44 TC 127 Z9 128 U1 6 U2 58 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 SEP PY 2011 VL 68 IS 3 BP 593 EP 601 DI 10.1007/s00280-010-1525-4 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 813CW UT WOS:000294345400005 PM 21116625 ER PT J AU Reid, JM Buhrow, SA Kuffel, MJ Jia, L Spanswick, VJ Hartley, JA Thurston, DE Tomaszewski, JE Ames, MM AF Reid, Joel M. Buhrow, Sarah A. Kuffel, Mary J. Jia, Lee Spanswick, Victoria J. Hartley, John A. Thurston, David E. Tomaszewski, Joseph E. Ames, Matthew M. TI Pharmacokinetics, pharmacodynamics and metabolism of the dimeric pyrrolobenzodiazepine SJG-136 in rats SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Pyrrolobenzodiazepine dimer; DNA damage; Pharmacokinetics; Metabolism; Pharmacodynamics; Comet assay ID CROSS-LINKING AGENT; ELECTROPHORESIS COMET ASSAY; SPECTRUM ANTITUMOR-ACTIVITY; ADVANCED SOLID TUMORS; IN-VITRO; CELLULAR PHARMACOLOGY; DNA DAMAGE; PHASE-I; NSC-694501; POTENT AB The dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501, SG2000) has potent in vitro antiproliferative activity and in vivo antitumor activity associated with binding in the minor groove of DNA and formation of covalent interstrand DNA cross-links. The pharmacokinetics and in vitro metabolism of SJG-136 and as well as the feasibility of using the Comet assay to measure in vivo interstrand DNA cross-links, was assessed in the rat. SJG-136 pharmacokinetics and pharmacodynamics were characterized in rats following single-dose administration of 15 and 50 mu g/kg or multiple-dose administration of 25 mu g/kg/day for 5 days. DNA damage was measured in peripheral blood mononuclear cells using the Comet assay. SJG-136 oxidative metabolism was characterized in rat liver microsomes. SJG-136 half-life, clearance and volume of distribution values were 9 min, 190 ml/min/m(2), and 1780 ml/m(2), respectively. SJG-136 did not accumulate in plasma during treatment with 25 mu g/kg/day for 5 days. Treatment with SJG-136 produced the anticipated DNA interstrand cross-links, as well as DNA strand breaks, in rat PBMCs. Oxidative metabolism of SJG-136 in rat liver microsomes was catalyzed by CYP3A isoforms and produced a previously unreported monomeric metabolite. Plasma concentrations of SJG-136 associated with pharmacological activity and in vitro antiproliferative activity were achieved with doses that were tolerated by rats. CYP3A isoforms are the predominant P450s catalyzing SJG-136 metabolism. The comet assay detects DNA damage in PBMCs from rats treated with SJG-136 and is being used in clinical trials to monitor in vivo lesions produced by SJG-136. C1 [Reid, Joel M.; Buhrow, Sarah A.; Kuffel, Mary J.; Ames, Matthew M.] Mayo Clin, Div Oncol Res, Rochester, MN 55905 USA. [Jia, Lee; Tomaszewski, Joseph E.] NCI, DTP, Bethesda, MD 20892 USA. [Spanswick, Victoria J.; Hartley, John A.] UCL, UCL Canc Inst, Canc Res UK Drug DNA Interact Res Grp, London, England. [Thurston, David E.] Univ London, Sch Pharm, London WC1N 1AX, England. RP Ames, MM (reprint author), Mayo Clin, Div Oncol Res, Gonda 19-363,200 1st St SW, Rochester, MN 55905 USA. EM ames.matthew@mayo.edu FU National Cancer Institute [N01-CM-07105]; Cancer Research UK [C2259/A9994]; UCL Experimental Cancer Medicine Centre FX Supported by National Cancer Institute contract N01-CM-07105. Supported by Cancer Research UK grant C2259/A9994 to JAH and the UCL Experimental Cancer Medicine Centre. NR 25 TC 4 Z9 4 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD SEP PY 2011 VL 68 IS 3 BP 777 EP 786 DI 10.1007/s00280-010-1517-4 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 813CW UT WOS:000294345400025 PM 21188379 ER PT J AU Kreimer, AR Chaturvedi, AK AF Kreimer, Aimee R. Chaturvedi, Anil K. TI HPV-associated Oropharyngeal Cancers-Are They Preventable? SO CANCER PREVENTION RESEARCH LA English DT Article ID HUMAN-PAPILLOMAVIRUS INFECTION; ORAL HUMAN-PAPILLOMAVIRUS; SQUAMOUS-CELL CARCINOMAS; UNITED-STATES; QUADRIVALENT VACCINE; INCIDENCE TRENDS; NATURAL-HISTORY; WOMEN; PREVALENCE; MEN AB It is not known whether a human papillomavirus (HPV)-induced oropharyngeal precancerous lesion could be identified by screening with a pap test equivalent or whether one even exists. In this issue of the journal (beginning on page 1378), Fakhry and colleagues report their results showing that cytologic evaluation of the oropharynx, although useful in detecting invasive oropharyngeal cancers, may have limited utility as a screening modality for detecting precancer. These findings argue against the potential for secondary prevention of HPV-associated oropharyngeal cancers through screening for and preventing the progression of precancer and highlight the opportunity for primary prevention through prophylactic HPV vaccination, if proven efficacious and cost-effective. Cancer Prev Res; 4(9); 1346-9. (C) 2011 AACR. C1 [Kreimer, Aimee R.; Chaturvedi, Anil K.] NCI, NIH, Bethesda, MD 20892 USA. RP Kreimer, AR (reprint author), NCI, NIH, 6120 Execut Blvd,EPS-7084, Rockville, MD 20852 USA. EM kreimera@mail.nih.gov RI Kreimer, Aimee/H-1687-2015; Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 FU Intramural NIH HHS [ZIA CP010209-01] NR 27 TC 18 Z9 18 U1 1 U2 4 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 SEP PY 2011 VL 4 IS 9 BP 1346 EP 1349 DI 10.1158/1940-6207.CAPR-11-0379 PG 4 WC Oncology SC Oncology GA 814XI UT WOS:000294490100002 PM 21893495 ER PT J AU Rajaraman, P AF Rajaraman, Preetha TI Hunting for the Causes of Meningioma-Obesity Is a Suspect SO CANCER PREVENTION RESEARCH LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; CHILDHOOD-CANCER SURVIVOR; BREAST-CANCER; PRIMARY NEOPLASMS; RISK-FACTORS; TUMORS; BRAIN; WOMEN; INFLAMMATION; GLIOMA AB In this issue of the journal, Michaud and colleagues report a 48% increased risk of meningioma in obese individuals compared with individuals with a normal body mass index (BMI). This large prospective cohort study adds weight to the suggested link between BMI and meningioma, thus contributing to the growing number of cancer sites likely associated with body fatness. Although the exact mechanisms underlying the BMI-meningioma link are unclear, possible mediators include hormonal factors, immunologic response, and levels of insulin or insulin-like growth factors, each of which has been implicated by various levels of evidence in meningioma risk. Understanding the relationships between body fatness, height, and hormonal and immunologic factors could provide important clues to the etiology of meningioma and may have implications for the early detection and prevention of these tumors. Cancer Prev Res; 4(9); 1353-5. (C) 2011 AACR. C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Rajaraman, P (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. EM rajarama@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 37 TC 4 Z9 4 U1 0 U2 3 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 SEP PY 2011 VL 4 IS 9 BP 1353 EP 1355 DI 10.1158/1940-6207.CAPR-11-0360 PG 3 WC Oncology SC Oncology GA 814XI UT WOS:000294490100004 PM 21893497 ER PT J AU Land, SR Cronin, WM Wickerham, DL Costantino, JP Christian, NJ Klein, WMP Ganz, PA AF Land, Stephanie R. Cronin, Walter M. Wickerham, D. Lawrence Costantino, Joseph P. Christian, Nicholas J. Klein, William M. P. Ganz, Patricia A. TI Cigarette Smoking, Obesity, Physical Activity, and Alcohol Use As Predictors of Chemoprevention Adherence in the National Surgical Adjuvant Breast and Bowel Project P-1 Breast Cancer Prevention Trial SO CANCER PREVENTION RESEARCH LA English DT Article ID EARLY DISCONTINUATION; DECISION-MAKING; DRUG ADHERENCE; DIETARY-INTAKE; BODY-MASS; TAMOXIFEN; WOMEN; THERAPY; RISK; RALOXIFENE AB The double-blind, prospective, National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT) showed a 50% reduction in the risk of breast cancer for tamoxifen versus placebo, yet many women at risk of breast cancer do not adhere to the 5-year course. This first report of the rich BCPT drug adherence data examines predictors of adherence. Between June, 1992 and September, 1997 13,338 women at high risk of breast cancer were randomly assigned to 20 mg/d tamoxifen versus placebo; we analyzed the 11,064 enrolled more than 3 years before trial unblinding. Primary endpoint was full drug adherence (100% of assigned pills per staff report, excluding protocol-required discontinuation) at 1 and 36 months; secondary was adequate adherence (76%-100%). Protocol-specified multi-variable logistic regression tested lifestyle factors, controlling for demographic and medical predictors. About 13% were current smokers; 60% were overweight/obese; 46% had moderate/heavy physical activity; 21%, 66%, 13% drank 0, 0-1, 1 + drinks per day, respectively; 91% were adequately adherent at 1 month; and 79% were at 3 years. Alcohol use was associated with reduced full adherence at 1 month (P = 0.016; OR = 0.79 1+ vs. 0), as was college education (P <0.001; OR = 0.78 vs. high school); age (P < 0.001; OR = 1.4 age 60+) and per capita household annual income (P < 0.001; OR = 1.2 per $30,000) with increased adherence. Current smoking (P = 0.003; OR = 0.75), age (P = 0.024, OR = 1.1), college education (P = 0.037; OR = 1.4), tamoxifen assignment (P = 0.031; OR = 0.84), and breast cancer risk (P < .001; OR = 1.5 high vs. low) predicted adequate adherence at 36 months. There were no significant associations with obesity or physical activity. Alcohol use and smoking might indicate a need for greater adherence support. Cancer Prev Res; 4(9); 1393-400. (C) 2011 AACR. C1 [Land, Stephanie R.; Cronin, Walter M.; Wickerham, D. Lawrence; Costantino, Joseph P.; Christian, Nicholas J.; Ganz, Patricia A.] Natl Surg Adjuvant Breast & Bowel Project NSABP O, Pittsburgh, PA USA. [Land, Stephanie R.; Cronin, Walter M.; Wickerham, D. Lawrence; Costantino, Joseph P.; Christian, Nicholas J.; Ganz, Patricia A.] Ctr Biostat, Pittsburgh, PA USA. [Land, Stephanie R.; Cronin, Walter M.; Costantino, Joseph P.; Christian, Nicholas J.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Wickerham, D. Lawrence] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Land, Stephanie R.; Klein, William M. P.] NCI, Div Canc Control & Populat Sci, Behav Res Program, Bethesda, MD 20892 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Ganz, Patricia A.] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Dept Hlth Serv, Los Angeles, CA 90034 USA. RP Land, SR (reprint author), NCI, Div Canc Control & Populat Sci, Behav Res Program, Bethesda, MD 20892 USA. EM stephanie.land@nih.gov FU National Cancer Institute, Department of Health and Human Services [U10-CA-37377, U10-CA-69974, R03CA134199-02] FX This work was supported by Public Health Service Grants U10-CA-37377, U10-CA-69974, and R03CA134199-02 from the National Cancer Institute, Department of Health and Human Services. NR 47 TC 31 Z9 32 U1 0 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 SEP PY 2011 VL 4 IS 9 BP 1393 EP 1400 DI 10.1158/1940-6207.CAPR-11-0172 PG 8 WC Oncology SC Oncology GA 814XI UT WOS:000294490100010 PM 21862698 ER PT J AU Skates, SJ Mai, P Horick, NK Piedmonte, M Drescher, CW Isaacs, C Armstrong, DK Buys, SS Rodriguez, GC Horowitz, IR Berchuck, A Daly, MB Domchek, S Cohn, DE Van Le, L Schorge, JO Newland, W Davidson, SA Barnes, M Brewster, W Azodi, M Nerenstone, S Kauff, ND Fabian, CJ Sluss, PM Nayfield, SG Kasten, CH Finkelstein, DM Greene, MH Lu, K AF Skates, Steven J. Mai, Phuong Horick, Nora K. Piedmonte, Marion Drescher, Charles W. Isaacs, Claudine Armstrong, Deborah K. Buys, Saundra S. Rodriguez, Gustavo C. Horowitz, Ira R. Berchuck, Andrew Daly, Mary B. Domchek, Susan Cohn, David E. Van Le, Linda Schorge, John O. Newland, William Davidson, Susan A. Barnes, Mack Brewster, Wendy Azodi, Masoud Nerenstone, Stacy Kauff, Noah D. Fabian, Carol J. Sluss, Patrick M. Nayfield, Susan G. Kasten, Carol H. Finkelstein, Dianne M. Greene, Mark H. Lu, Karen TI Large Prospective Study of Ovarian Cancer Screening in High-Risk Women: CA125 Cut-Point Defined by Menopausal Status SO CANCER PREVENTION RESEARCH LA English DT Article ID REDUCING SALPINGO-OOPHORECTOMY; SERUM CA-125 LEVELS; TRIAL; PROSTATE; LUNG AB Previous screening trials for early detection of ovarian cancer in postmenopausal women have used the standard CA125 cut-point of 35 U/mL, the 98th percentile in this population yielding a 2% false positive rate, whereas the same cut-point in trials of premenopausal women results in substantially higher false positive rates. We investigated demographic and clinical factors predicting CA125 distributions, including 98th percentiles, in a large population of high-risk women participating in two ovarian cancer screening studies with common eligibility criteria and screening protocols. Baseline CA125 values and clinical and demographic data from 3,692 women participating in screening studies conducted by the National Cancer Institute-sponsored Cancer Genetics Network and Gynecologic Oncology Group were combined for this preplanned analysis. Because of the large effect of menopausal status on CA125 levels, statistical analyses were conducted separately in pre- and postmenopausal subjects to determine the impact of other baseline factors on predicted CA125 cut-points on the basis of 98th percentile. The primary clinical factor affecting CA125 cut-points was menopausal status, with premenopausal women having a significantly higher cut-point of 50 U/mL, while in postmenopausal subjects the standard cut-point of 35 U/mL was recapitulated. In premenopausal women, current oral contraceptive (OC) users had a cut-point of 40 U/mL. To achieve a 2% false positive rate in ovarian cancer screening trials and in high-risk women choosing to be screened, the cut-point for initial CA125 testing should be personalized primarily for menopausal status (50 for premenopausal women, 40 for premenopausal on OC, and 35 for postmenopausal women). Cancer Prev Res; 4(9); 1401-8. (C) 2011 AACR. C1 [Skates, Steven J.; Horick, Nora K.; Finkelstein, Dianne M.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Sluss, Patrick M.] Massachusetts Gen Hosp, Clin Pathol Core Labs, Boston, MA 02114 USA. [Mai, Phuong] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Nayfield, Susan G.; Kasten, Carol H.] NCI, Epidemiol & Genet Res Program, Div Canc Control & Prevent Sci, Bethesda, MD 20892 USA. [Kasten, Carol H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Off Director, Bethesda, MD USA. [Piedmonte, Marion] Roswell Pk Canc Inst, GOG Stat & Data Ctr, Buffalo, NY 14263 USA. [Drescher, Charles W.] Swedish Med Ctr, Dept Gynecol, Seattle, WA USA. [Isaacs, Claudine] Georgetown Univ, Dept Med & Oncol, Lombardi Comprehens Ctr, Washington, DC USA. [Armstrong, Deborah K.] Johns Hopkins Kimmel Canc Ctr, Baltimore, MD USA. [Buys, Saundra S.] Huntsman Canc Inst, Salt Lake City, UT USA. [Rodriguez, Gustavo C.] NorthShore Univ Hlth Syst, NW Healthcare, Evanston, IL USA. [Horowitz, Ira R.] Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Daly, Mary B.] Univ Penn, Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA 19104 USA. [Domchek, Susan] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Cohn, David E.] Ohio State Univ, Coll Med, Div Gynecol Oncol, James Canc Hosp, Columbus, OH 43210 USA. [Cohn, David E.] Ohio State Univ, Coll Med, Solove Res Inst, Columbus, OH 43210 USA. [Van Le, Linda] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Newland, William] Iowa Methodist Med Ctr, Dept Obstet & Gynecol, John Stoddard Canc Ctr, Des Moines, IA USA. [Davidson, Susan A.] Univ Colorado Denver, Dept Obstet & Gynecol, Div Gynecol Oncol, Aurora, CO USA. [Barnes, Mack] Univ Alabama, Birmingham, AL USA. [Lu, Karen] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Div Surg, Houston, TX 77030 USA. [Nayfield, Susan G.] Univ Florida, Coll Med, Dept Aging & Geriatr Res, Inst Aging, Gainesville, FL USA. [Fabian, Carol J.] Univ Kansas, Ctr Canc, Westwood, KS USA. [Kauff, Noah D.] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, New York, NY 10021 USA. [Kauff, Noah D.] Mem Sloan Kettering Canc Ctr, Gynecol Serv, New York, NY 10021 USA. [Nerenstone, Stacy] Hartford Hosp, Cent Connecticut Canc Consortium, Hartford, CT 06115 USA. [Azodi, Masoud] Yale Univ, Dept Obstet & Gynecol, Div Gynecol Oncol, New Haven, CT USA. [Brewster, Wendy] Univ Calif Irvine, Dept Obstet & Gynecol, Div Gynecol Oncol, Sch Med, Orange, CA 92668 USA. RP Finkelstein, DM (reprint author), Massachusetts Gen Hosp, Ctr Biostat, 50 Staniford St,Suite 560, Boston, MA 02114 USA. EM dfinkelstein@partners.org OI Kauff, Noah/0000-0001-7242-6156 FU NCI [CA078284, CA078134, CA078164, CA078156, CA078148, CA078146, CA078174, CA078157, CA078142, HHSN2612007440000C, CA086381, CA152990]; Cancer Genetics Network; Ovarian SPORE program; Early Detection Research Network; Fujirebio Diagnostics Inc.; NCI/NIH; Cancer Prevention and Control Committee FX The ROCA study was supported mostly by research grants/contracts from NCI (CA078284, CA078134, CA078164, CA078156, CA078148, CA078146, CA078174, CA078157, CA078142, HHSN2612007440000C, CA086381, and CA152990) to sites in the Cancer Genetics Network, the Ovarian SPORE program, and the Early Detection Research Network; Fujirebio Diagnostics Inc., supported the study for one year after NCI funding ended. P. Mai and M. H. Greene were supported by the Intramural Research Program, NCI/NIH. The Gynecologic Oncology Group's participation (GOG0199) was supported by its Cancer Prevention and Control Committee. Programming assistance from Ying Zhou MS is gratefully acknowledged. In addition to the clinical site principal investigators who enrolled more than 50 patients in the CGN study and are listed as authors, the following clinical sites and PI's contributed patients to the study and are gratefully acknowledged: Holly Gallion MD (Magee Women's Hospital 46), Powel Brown MD(Baylor College of Medicine 41), Alex Miller MD (University of Texas Health Sciences Center San Antonio 38), Paula Ryan MD PhD (Massachusetts General Hospital 21), Judy Garber MD PhD (Dana Farber Cancer Institute 20), Henry Lynch MD (Creighton University 19), James Evans MD PhD (University of North Carolina 15), Henry Lynch MD (EDRN High Risk Registry 12), Lee-May Chen MD (University of California San Francisco 10), Olufunmilayo Olopade MD (University of Chicago 3), Thomas Caputo MD(Cornell University 3). The CGN study was conducted under the auspices of the Cancer Genetics Network with the support of the CGN PI's which is gratefully acknowledged: Deborah Bowen PhD (Fred Hutchinson Cancer Center), Claudine Isaacs MD (Georgetown University), Constance Griffin MD (Johns Hopkins University), Geraldine Mineau PhD (Huntsman Cancer Institute), Joellen Schildkraut PhD (Duke University), Louise Strong MD (MD Anderson Cancer Center), Susan Domchek MD (University of Pennsylvannia), Gail Tomlinson MD PhD (University of Texas Southwestern Medical Center), Dennis Ahnen MD (University of Colorado), Hoda Anton-Culver PhD (University of California Irvine), Sharon Plon MD PhD (Baylor College of Medicine), James Evans MD PhD (University of North Carolina), William Wood MD (Emory University), Alex Miller MD (University of Texas Health Sciences Ctr. at San Antonio). NR 17 TC 14 Z9 15 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2011 VL 4 IS 9 BP 1401 EP 1408 DI 10.1158/1940-6207.CAPR-10-0402 PG 8 WC Oncology SC Oncology GA 814XI UT WOS:000294490100011 PM 21893500 ER PT J AU Cross, AJ Sinha, R Wood, RJ Xue, XN Huang, WY Yeager, M Hayes, RB Gunter, MJ AF Cross, Amanda J. Sinha, Rashmi Wood, Richard J. Xue, Xiaonan Huang, Wen-Yi Yeager, Meredith Hayes, Richard B. Gunter, Marc J. TI Iron Homeostasis and Distal Colorectal Adenoma Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO CANCER PREVENTION RESEARCH LA English DT Article ID C-REACTIVE PROTEIN; DIETARY IRON; HEME IRON; CELL-PROLIFERATION; GENE-MUTATIONS; OCCULT BLOOD; COLON-CANCER; HFE GENE; MEAT; MICE AB Red meat consumption has been positively associated with colorectal cancer; however, the biological mechanism underlying this relationship is not understood. Red meat is a major source of iron, which may play a role in colorectal carcinogenesis via increased crypt cell proliferation, cytotoxicity, and endogenous N-nitrosation. In a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we prospectively evaluated multiple iron exposure parameters, including dietary intake and serum measures of iron, ferritin, transferrin, total iron binding capacity (TIBC), and unsaturated iron binding capacity (UIBC) in relation to incident colorectal adenoma in 356 cases and 396 matched polyp-free controls. We also investigated variation in eight key genes involved in iron homeostasis in relation to colorectal adenoma in an additional series totaling 1,126 cases and 1,173 matched controls. We observed a positive association between red meat intake and colorectal adenoma [OR comparing extreme quartiles (OR(q4-q1)) = 1.59, 95% CI = 1.02-2.49, P(trend) = 0.03]. Serum TIBC and UIBC were inversely associated with colorectal adenoma (OR(q4-q1) = 0.57, 95% CI = 0.37-0.88, P(trend) = 0.03; and OR(q4-q1) = 0.62, 95% CI = 0.40-0.95, P(trend) = 0.04, respectively). Colorectal adenoma was not associated with serum ferritin, iron, or transferrin saturation or with polymorphisms in genes involved in iron homeostasis. Serum TIBC and UIBC, parameters that have a reciprocal relationship with overall iron load, were inversely related to colorectal adenoma, suggesting that individuals with lower iron status have a reduced risk of developing colorectal adenoma. Cancer Prev Res; 4(9); 1465-75. (C) 2011 AACR. C1 [Cross, Amanda J.; Sinha, Rashmi; Huang, Wen-Yi] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Yeager, Meredith] NCI, Core Genotyping Facil, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Wood, Richard J.] Univ Massachusetts, Dept Nutr, Sch Publ Hlth & Hlth Sci, Amherst, MA 01003 USA. [Xue, Xiaonan; Gunter, Marc J.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Hayes, Richard B.] NYU, Dept Environm Med, Div Epidemiol, Langone Med Ctr, New York, NY 10016 USA. RP Cross, AJ (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd, Rockville, MD 20852 USA. EM crossa@mail.nih.gov RI Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Hayes, Richard/0000-0002-0918-661X FU Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, Department of Health and Human Services. NR 42 TC 21 Z9 22 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2011 VL 4 IS 9 BP 1465 EP 1475 DI 10.1158/1940-6207.CAPR-11-0103 PG 11 WC Oncology SC Oncology GA 814XI UT WOS:000294490100018 PM 21685236 ER PT J AU Kummar, S Chen, A Ji, JP Zhang, YP Reid, JM Ames, M Jia, L Weil, M Speranza, G Murgo, AJ Kinders, R Wang, LH Parchment, RE Carter, J Stotler, H Rubinstein, L Hollingshead, M Melillo, G Pommier, Y Bonner, W Tomaszewski, JE Doroshow, JH AF Kummar, Shivaani Chen, Alice Ji, Jiuping Zhang, Yiping Reid, Joel M. Ames, Matthew Jia, Lee Weil, Marcie Speranza, Giovanna Murgo, Anthony J. Kinders, Robert Wang, Lihua Parchment, Ralph E. Carter, John Stotler, Howard Rubinstein, Larry Hollingshead, Melinda Melillo, Giovanni Pommier, Yves Bonner, William Tomaszewski, Joseph E. Doroshow, James H. TI Phase I Study of PARP Inhibitor ABT-888 in Combination with Topotecan in Adults with Refractory Solid Tumors and Lymphomas SO CANCER RESEARCH LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE INHIBITOR; 0 CLINICAL-TRIAL; ADP-RIBOSE POLYMERASE; TOPOISOMERASE-I; ADVANCED MALIGNANCIES; DNA-DAMAGE; CELLS; GAMMA-H2AX; REPAIR; DRUG AB A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I-targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker gamma H2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m(2)/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in gamma H2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic. Cancer Res; 71(17);5626-34. (C) 2011 AACR. C1 [Doroshow, James H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Ji, Jiuping; Zhang, Yiping; Kinders, Robert; Wang, Lihua; Parchment, Ralph E.; Carter, John; Stotler, Howard; Melillo, Giovanni] NCI, Sci Applicat Int Corp Frederick Inc, Appl Dev Res Support Directorate, Frederick, MD 21701 USA. [Reid, Joel M.; Ames, Matthew] Mayo Clin, Rochester, MN USA. RP Doroshow, JH (reprint author), NCI, Ctr Canc Res, NIH, Bldg 31,Room 3A44,31 Ctr Dr, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov FU National Cancer Institute (NCI); NIH [HHSN261200800001E]; Division of Cancer Treatment and Diagnosis of the NCI FX This project was funded in whole or in part with federal funds from the National Cancer Institute (NCI), NIH, under Contract No. HHSN261200800001E. This research was also supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research and the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the NCI. NR 25 TC 124 Z9 126 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2011 VL 71 IS 17 BP 5626 EP 5634 DI 10.1158/0008-5472.CAN-11-1227 PG 9 WC Oncology SC Oncology GA 814LL UT WOS:000294454700006 PM 21795476 ER PT J AU Zhang, YJ Chertov, O Zhang, JL Hassan, R Pastan, I AF Zhang, Yujian Chertov, Oleg Zhang, Jingli Hassan, Raffit Pastan, Ira TI Cytotoxic Activity of Immunotoxin SS1P Is Modulated by TACE-Dependent Mesothelin Shedding SO CANCER RESEARCH LA English DT Article ID CD8(+) T-CELLS; PHASE-I; MOLECULAR-CLONING; OVARIAN-CARCINOMA; TUMOR XENOGRAFTS; LIPID RAFTS; PROTEIN; ADAM17; DIAGNOSIS; CANCERS AB Mesothelin is a cell-surface tumor-associated antigen expressed in several human cancers. The limited expression of mesothelin on normal tissues and its high expression in many cancers make it an attractive candidate for targeted therapies using monoclonal antibodies, immunoconjugates, and immunotoxins. Mesothelin is actively shed from the cell surface and is present in the serum of patients with malignant mesothelioma, which could negatively affect the response to these therapies. We have found that mesothelin sheddase activity is mediated by a TNF-alpha converting enzyme (TACE), a member of the matrix metalloproteinase/a disintegrin and metalloprotease family. We showed that EGF and TIMP-3 act through TACE as endogenous regulators of mesothelin shedding. We also found that reducing shedding significantly improved the in vitro cytotoxicity of immunotoxin SS1P, which targets mesothelin and is currently in clinical trials for the treatment of patients with mesothelioma and lung cancer. Our findings provide a mechanistic understanding of mesothelin shedding and could help improve mesothelin-based targeted therapies. Cancer Res; 71(17); 5915-22. (C) 2011 AACR. C1 [Zhang, Yujian; Zhang, Jingli; Hassan, Raffit; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chertov, Oleg] NCI, Prot Chem Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Rm 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and, in part, with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. NR 33 TC 10 Z9 10 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2011 VL 71 IS 17 BP 5915 EP 5922 DI 10.1158/0008-5472.CAN-11-0466 PG 8 WC Oncology SC Oncology GA 814LL UT WOS:000294454700032 PM 21775520 ER PT J AU Hayes, CS Defeo, K Dang, H Trempus, CS Morris, RJ Gilmour, SK AF Hayes, Candace S. DeFeo, Karen Dang, Hong Trempus, Carol S. Morris, Rebecca J. Gilmour, Susan K. TI A prolonged and exaggerated wound response with elevated ODC activity mimics early tumor development SO CARCINOGENESIS LA English DT Article ID ORNITHINE-DECARBOXYLASE GENE; MOUSE SKIN; EPIDERMAL HYPERPLASIA; NORMAL KERATINOCYTES; POLYAMINE OXIDASE; TRANSGENIC MICE; CELL-CYCLE; RAT SKIN; C-MYC; EXPRESSION AB Induction of ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, in ODC transgenic skin stimulates epidermal proliferation but not hyperplasia, activates underlying stromal cells and promotes skin tumorigenesis following a single subthreshold dose of a carcinogen. Because chronic wounds are a well-recognized risk factor for skin cancer, we investigated the response to a tissue remodeling event in normal skin that is abraded to remove only the epidermal layer in K6/ODC transgenic (follicular ODC expression) and in inducible ODCER transgenic mice (suprabasal ODC expression). When regenerative epidermal hyperplasia was resolved in normal littermates following abrasion, ODC transgenic mice exhibited progressive epidermal hyperplasia with formation of benign tumor growths and maintained an increased epidermal proliferation index and activation of translation-associated proteins at abrasion sites. The epidermal hyperplasia and tumor-like growth was accompanied by activation of underlying stromal cells and prolonged infiltration of inflammatory cells. Treatment with the anti-inflammatory agent dexamethasone did not reduce the high proliferative index in the regenerated epidermis but dramatically reduced the epidermal hyperplasia and prevented the wound-induced tumor growths in abraded ODCER skin. Treatment with alpha-difluoromethylornithine, a specific inhibitor of ODC activity, normalized the wound response in transgenic mice and decreased wound-induced inflammation if administered from the time of abrasion but not if initiated 4 days following abrasion. These results suggest a role for polyamines in prolonging wound-associated inflammation in addition to stimulating proliferation both of which are sufficient to sustain epidermal hyperplasia and benign tumor growth even in the absence of genetic damage. C1 [Hayes, Candace S.; DeFeo, Karen; Gilmour, Susan K.] Lankenau Inst Med Res, Wynnewood, PA 19096 USA. [Dang, Hong] Univ N Carolina, Cyst Fibrosis & Pulm Dis Res & Treatment Ctr, Chapel Hill, NC 27599 USA. [Trempus, Carol S.] NIEHS, Matrix Biol Grp, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Morris, Rebecca J.] Univ Minnesota, Hormel Inst, Lab Stem Cells & Canc, Austin, MN 55912 USA. [Gilmour, Susan K.] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Gilmour, Susan K.] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. RP Gilmour, SK (reprint author), Lankenau Inst Med Res, 100 Lancaster Ave, Wynnewood, PA 19096 USA. EM gilmours@mlhs.org FU National Institutes of Health [CA070739] FX National Institutes of Health (CA070739 to S.G.). NR 51 TC 12 Z9 12 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2011 VL 32 IS 9 BP 1340 EP 1348 DI 10.1093/carcin/bgr129 PG 9 WC Oncology SC Oncology GA 814ZI UT WOS:000294495500007 PM 21730362 ER PT J AU Taioli, E Flores-Obando, RE Agalliu, I Blanchet, P Bunker, CH Ferrell, RE Jackson, M Kidd, LR Kolb, S Lavender, NA McFarlane-Anderson, N Morrison, SS Multigner, L Ostrande, EA Park, JY Patrick, AL Rebbeck, TR Romana, M Stanford, JL Ukoli, F VanCleave, TT Zeigler-Johnson, CM Mutetwa, B Ragin, C AF Taioli, Emanuela Flores-Obando, Rafael E. Agalliu, Ilir Blanchet, Pascal Bunker, Clareann H. Ferrell, Robert E. Jackson, Maria Kidd, La Creis R. Kolb, Suzanne Lavender, Nicol A. McFarlane-Anderson, Norma Morrison, Seian S. Multigner, Luc Ostrande, Elaine A. Park, Jong Y. Patrick, Alan L. Rebbeck, Timothy R. Romana, Marc Stanford, Janet L. Ukoli, Flora VanCleave, Tiva T. Zeigler-Johnson, Charnita M. Mutetwa, Batsirai Ragin, Camille TI Multi-institutional prostate cancer study of genetic susceptibility in populations of African descent SO CARCINOGENESIS LA English DT Article ID S-TRANSFERASE-MU; GLUTATHIONE TRANSFERASES; ILE105VAL POLYMORPHISM; RISK; METAANALYSIS; SMOKING; GSTP1; GSTM1; GSTT1; MEN AB Prostate cancer disparities have been reported in men of African descent who show the highest incidence, mortality, compared with other ethnic groups. Few studies have explored the genetic and environmental factors for prostate cancer in men of African ancestry. The glutathione-S-transferases family conjugates carcinogens before their excretion and is expressed in prostate tissue. This study addressed the role of GSTM1 and GSTT1 deletions on prostate cancer risk in populations of African descent. This multi-institutional case-control study gathered data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database, the African-Caribbean Cancer Consortium (AC3) and Men of African Descent and Carcinoma of the Prostate Consortium (MADCaP). The analysis included 10 studies (1715 cases and 2363 controls), five in African-Americans, three in African-Caribbean and two in African men. Both the GSTM1 and the GSTT1 deletions showed significant inverse associations with prostate cancer [odds ratio (OR): 0.90, 95% confidence interval (CI) 0.83-0.97 and OR 0.88, 95% CI: 0.82-0.96, respectively]. The association was restricted to Caribbean and African populations. A significant positive association was observed between GSTM1 deletion and prostate cancer in smokers in African-American studies (OR: 1.28, 95% CI: 1.01-1.56), whereas a reduced risk was observed in never-smokers (OR: 0.66, 95% CI: 0.46-0.95). The risk of prostate cancer increased across quartiles of pack-years among subjects carrying the deletion of GSTM1 but not among subjects carrying a functional GSTM1. Gene-environment interaction between smoking and GSTM1 may be involved in the etiology of prostate cancer in populations of African descent. C1 [Taioli, Emanuela] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. [Flores-Obando, Rafael E.; Mutetwa, Batsirai] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Agalliu, Ilir] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Bunker, Clareann H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Ferrell, Robert E.] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Jackson, Maria; Morrison, Seian S.] Univ W Indies, Dept Community Hlth & Psychiat, Kingston 7, Jamaica. [Kidd, La Creis R.] Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. [Kidd, La Creis R.; Lavender, Nicol A.] Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. [Kolb, Suzanne; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [McFarlane-Anderson, Norma] Univ W Indies, Dept Basic Med Sci, Kingston 7, Jamaica. [Multigner, Luc] Inst Natl Sante & Rech Med, U625, Irset, Guadeloupe. [Ostrande, Elaine A.] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. [Park, Jong Y.; Zeigler-Johnson, Charnita M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Patrick, Alan L.] Tobago Hlth Studies Off, Scarborough, Tobago, Trinid & Tobago. [Rebbeck, Timothy R.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Romana, Marc] Inst Natl Sante & Rech Med, U763, Irset, Guadeloupe. [Ukoli, Flora] Meharry Med Coll, Dept Surg, Nashville, TN 37208 USA. [VanCleave, Tiva T.] Univ Louisville, Dept Microbiol & Immunol, Louisville, KY 40292 USA. [Ragin, Camille] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. RP Taioli, E (reprint author), Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. EM taiolema@gmail.com RI Blanchet, Pascal/K-3532-2015; Multigner, Luc/I-2926-2015; OI Zeigler-Johnson, Charnita/0000-0003-2641-7755; Romana, marc/0000-0002-8715-9836 FU National Institutes of Health [R01-CA085074, P50-CA105641, R01-CA056678, R01-CA092579]; Department of Defense [PC094423] FX National Institutes of Health (R01-CA085074 and P50-CA105641 to T.R.R., R01-CA056678 and R01-CA092579 to J.L.S.); Department of Defense (PC094423 to C.R.R. and E.T.). NR 43 TC 17 Z9 18 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2011 VL 32 IS 9 BP 1361 EP 1365 DI 10.1093/carcin/bgr119 PG 5 WC Oncology SC Oncology GA 814ZI UT WOS:000294495500010 PM 21705483 ER PT J AU Raufman, JP Shant, J Xie, G Cheng, K Gao, XM Shiu, B Shah, N Drachenberg, CB Heath, J Wess, J Khurana, S AF Raufman, Jean-Pierre Shant, Jasleen Xie, Guofeng Cheng, Kunrong Gao, Xue-Min Shiu, Brian Shah, Nirish Drachenberg, Cinthia B. Heath, Jonathon Wess, Juergen Khurana, Sandeep TI Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apc(min/+) mice SO CARCINOGENESIS LA English DT Article ID COLON-CANCER CELLS; ACETYLCHOLINE-RECEPTOR; CHOLINERGIC-RECEPTOR; MESSENGER-RNA; PROLIFERATION; AZOXYMETHANE; ACTIVATION; EXPRESSION; EPITHELIUM; KINASE AB M3 subtype muscarinic receptors (CHRM3) are over-expressed in colon cancer. In this study, we used Apc(min/+) mice to identify the role of Chrm3 expression in a genetic model of intestinal neoplasia, explored the role of Chrm3 in intestinal mucosal development and determined the translational potential of inhibiting muscarinic receptor activation. We generated Chrm3-deficient Apc(min/+) mice and compared intestinal morphology and tumor number in 12-week-old Apc(min/+)Chrm3(-/-) and Apc(min/+)Chrm3(+/+) control mice. Compared with Apc(min/+)Chrm3(+/+) mice, Apc(min/+)Chrm3(-/-) mice showed a 70 and 81% reduction in tumor number and volume, respectively (P < 0.01). In adenomas, beta-catenin nuclear staining was reduced in Apc(min/+)Chrm3(-/-) compared with Apc(min/+)Chrm3(+/+) mice (P < 0.02). Whereas Apc gene mutation increased the number of crypt and Paneth cells and decreased villus goblet cells, these changes were absent in Apc(min/+)Chrm3(-/-) mice. To determine whether pharmacological inhibition of muscarinic receptor activation attenuates intestinal neoplasia, we treated 6-week-old Apc(min/+) mice with scopolamine butylbromide, a non-subtype-selective muscarinic receptor antagonist. After 8 weeks of continuous treatment, scopolamine butylbromide-treated mice showed a 22% reduction in tumor number (P = 0.027) and a 36% reduction in tumor volume (P = 0.004) as compared with control mice. Compared with Chrm3 gene ablation, the muscarinic antagonist was less efficacious, most probably due to shorter duration of treatment and incomplete blockade of muscarinic receptors. Overall, these findings indicate that interplay of Chrm3 and beta-catenin signaling is important for intestinal mucosal differentiation and neoplasia and provide a proof-of-concept that pharmacological inhibition of muscarinic receptor activation can attenuate intestinal neoplasia in vivo. C1 [Raufman, Jean-Pierre; Shant, Jasleen; Xie, Guofeng; Cheng, Kunrong; Gao, Xue-Min; Shiu, Brian; Shah, Nirish; Khurana, Sandeep] VA Maryland Hlth Care Syst, Sch Med, Div Gastroenterol & Hepatol, Dept Med, Baltimore, MD 21201 USA. [Heath, Jonathon; Wess, Juergen] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Raufman, JP (reprint author), Univ Maryland, Sch Med, Div Gastroenterol & Hepatol, 22 S Greene St,N3W62, Baltimore, MD 21201 USA. EM jraufman@medicine.umaryland.edu FU Office of Research and Development, Medical Research Service, Department of Veterans Affairs; National Institutes of Health [CA107345, CA120407, DK067872, DK081479, DK080843]; Baltimore Research and Education Foundation FX The Office of Research and Development, Medical Research Service, Department of Veterans Affairs; the National Institutes of Health (CA107345, CA120407, DK067872 to J.P.R., DK081479 to S.K., DK080843 to G.X.); Baltimore Research and Education Foundation to S.K. NR 29 TC 20 Z9 20 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2011 VL 32 IS 9 BP 1396 EP 1402 DI 10.1093/carcin/bgr118 PG 7 WC Oncology SC Oncology GA 814ZI UT WOS:000294495500015 PM 21705482 ER PT J AU Schetter, AJ Harris, CC AF Schetter, Aaron J. Harris, Curtis C. TI MicroRNAs as molecular classifiers for cancer SO CELL CYCLE LA English DT News Item ID PROGNOSIS; PROFILES C1 [Schetter, Aaron J.; Harris, Curtis C.] NCI, NIH, Bethesda, MD 20892 USA. RP Schetter, AJ (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM harrisc@mail.nih.gov NR 10 TC 3 Z9 3 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 1 PY 2011 VL 10 IS 17 BP 2827 EP 2828 DI 10.4161/cc.10.17.16570 PG 2 WC Cell Biology SC Cell Biology GA 814TS UT WOS:000294480700007 PM 21869596 ER PT J AU Caputo, E Maiorana, L Vasta, V Pezzino, FM Sunkara, S Wynne, K Elia, G Marincola, FM McCubrey, JA Libra, M Travali, S Kane, M AF Caputo, Emilia Maiorana, Luigi Vasta, Valeria Pezzino, Franca M. Sunkara, Sudhir Wynne, Kieran Elia, Giuliano Marincola, Francesco M. McCubrey, James A. Libra, Massimo Travali, Salvatore Kane, Marian TI Characterization of human melanoma cell lines and melanocytes by proteome analysis SO CELL CYCLE LA English DT Article DE melanoma biology; biomarkers; protein analysis; LC-MS/MS; therapeutic targets ID STAGE-IV MELANOMA; CYCLOPHILIN-A; MALIGNANT-MELANOMA; TUMOR-GROWTH; CATHEPSIN-D; IN-VITRO; CANCER METASTASIS; MASS-SPECTROMETRY; DRUG-RESISTANCE; BREAST CANCERS AB We have analyzed the proteomes of two human melanoma cell lines (A375 and 526), and of the human melanocytes, (FOM 78), by two-dimensional electrophoresis (2D-PAGE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our comparative proteomic analysis revealed that six proteins were overexpressed in both melanoma cell lines as compared with melanocytes: galectin-1, inosine-5'-monophosphate dehydrogenase 2, serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform, protein DJ-1, cyclophilin A and cofilin-1. We show, for the first time, that only specific isoforms of these molecules are overexpressed in melanoma. Different protein profiles were also found between each individual melanoma cell line and the melanocytes. s-Methyl-5-thioadenosine phosphorylase, ubiquitin and ribosomal protein S27 a precursor, the basic form of protein DJ-1, annexin a1, proliferation associated protein 2g4, isoform alfa-enolase of alfa-enolase, protein disulfide-isomerase precursor and elongation factor 2 were more strongly expressed in A375 cells compared with melanocytes. In 526 cells, 60s acidic ribosomal protein p1 and calreticulin precursor were more highly expressed than in melanocytes. These molecular differences may help in better understanding melanoma development and its different responsiveness to therapies. The identified proteins could be exploited as biomarkers or therapeutic targets for melanoma. C1 [Caputo, Emilia] CNR, Inst Genet & Biophys A Buzzati Traverso, I-80125 Naples, Italy. [Caputo, Emilia; Maiorana, Luigi; Vasta, Valeria; Pezzino, Franca M.; Libra, Massimo; Travali, Salvatore] Univ Catania, Dipartimento Sci Biomed, Catania, Italy. [Caputo, Emilia; Sunkara, Sudhir; Kane, Marian] Natl Univ Ireland Galway, Natl Ctr Biomed Engn Sci, Galway, Ireland. [Wynne, Kieran; Elia, Giuliano] Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 2, Ireland. [Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, CHI, Bethesda, MD 20892 USA. [McCubrey, James A.] E Carolina Univ, Brody Sch Med, Dept Microbiol & Immunol, Greenville, NC 27858 USA. RP Caputo, E (reprint author), CNR, Inst Genet & Biophys A Buzzati Traverso, I-80125 Naples, Italy. EM caputo@igb.cnr.it RI Elia, Giuliano/H-3438-2011; OI Elia, Giuliano/0000-0001-8216-9560; CAPUTO, EMILIA/0000-0002-6485-8802; Libra, Massimo/0000-0002-7232-7737; McCubrey, James/0000-0001-6027-3156 FU European Commission [MTKD-CT-2004-013701] FX We are grateful to Guillermo Del Riego for technical assistance. Thanks are due to Dr. M. Bettinotti for her support and encouragement. The authors wish to thank Dr. E.J. Patriarca for his critical comments. EC was supported by Marie Curie Transfer of Knowledge grant no. MTKD-CT-2004-013701 from the European Commission. Access to and use of instrumentation of the UCD Conway Mass Spectrometry Resource are gratefully acknowledged. NR 85 TC 10 Z9 11 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 1 PY 2011 VL 10 IS 17 BP 2924 EP 2936 DI 10.4161/cc.10.17.17068 PG 13 WC Cell Biology SC Cell Biology GA 814TS UT WOS:000294480700027 PM 21857157 ER PT J AU Mattson, MP AF Mattson, Mark P. TI A reaction to mitochondria in action SO CELL RESEARCH LA English DT Editorial Material ID INSULIN-RESISTANCE; DYSFUNCTION; SUPEROXIDE; DISORDERS C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM MattsonM@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 16 TC 1 Z9 1 U1 0 U2 4 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYAND ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 J9 CELL RES JI Cell Res. PD SEP PY 2011 VL 21 IS 9 BP 1279 EP 1282 DI 10.1038/cr.2011.87 PG 4 WC Cell Biology SC Cell Biology GA 814YG UT WOS:000294492500002 ER PT J AU Bokesch, HR Gardella, RS Rabe, DC Bottaro, DP Linehan, WM McMahon, JB McKee, TC AF Bokesch, Heidi Rose Gardella, Roberta Scott Rabe, Daniel Christopher Bottaro, Donald Paul Linehan, William Marston McMahon, James Brislin McKee, Tawnya Carlene TI A New Hypoxia Inducible Factor-2 Inhibitory Pyrrolinone Alkaloid from Roots and Stems of Piper sarmentosum SO CHEMICAL & PHARMACEUTICAL BULLETIN LA English DT Article DE Piper sarmentosum; hypoxia inducible factor-2; pyrrolinone alkaloid; Piperaceae ID CANCER; HIF-2-ALPHA; GENES AB A new trimethoxycinnamoyl-2-pyrrolinone alkaloid, langkamide (1), along with the known compounds piplartine (2) and 3,4,5-trimethoxycinnamic acid (3) were isolated from the roots and stems of the shrub Piper sarmentosum ROXB. The structures were established by spectroscopic analyses and comparison of their spectral data with values reported in the literature. The compounds were tested for their ability to modulate hypoxia inducible factor-2 (HIF-2) transcription activity and all three showed HIF-2 inhibitory activity with EC50 values of 14.0, 4.8, and 60.6 mu m, respectively, for compounds 1, 2, and 3. C1 [Bokesch, Heidi Rose; Gardella, Roberta Scott; McMahon, James Brislin; McKee, Tawnya Carlene] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Bokesch, Heidi Rose; Gardella, Roberta Scott] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. [Rabe, Daniel Christopher; Bottaro, Donald Paul; Linehan, William Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 21702 USA. RP McKee, TC (reprint author), NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM mckeeta@mail.nih.gov RI Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E and has been supported in part by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We thank G. Cragg (NPB) for the contract collection, T. McCloud for extractions, and G. Woldemichael for generation of the cells used in the HIF-2 screen. We also thank S. Tarasov and M. Dyba, Biophysics Resource, Structural Biophysics Laboratory for assistance in mass spectral analysis. NR 13 TC 17 Z9 17 U1 1 U2 12 PU PHARMACEUTICAL SOC JAPAN PI TOKYO PA 2-12-15 SHIBUYA, SHIBUYA-KU, TOKYO, 150-0002, JAPAN SN 0009-2363 J9 CHEM PHARM BULL JI Chem. Pharm. Bull. PD SEP PY 2011 VL 59 IS 9 BP 1178 EP 1179 PG 2 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 813RY UT WOS:000294387500019 PM 21881266 ER PT J AU Burbelo, PD Bren, KE Ching, KH Coleman, A Yang, XL Kariu, T Iadarola, MJ Pal, U AF Burbelo, Peter D. Bren, Kathleen E. Ching, Kathryn H. Coleman, Adam Yang, Xiuli Kariu, Toru Iadarola, Michael J. Pal, Utpal TI Antibody Profiling of Borrelia burgdorferi Infection in Horses SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; LUCIFERASE IMMUNOPRECIPITATION SYSTEMS; BINDING-PROTEIN-A; LYME-DISEASE; SEROLOGIC DIAGNOSIS; 4-ANTIGEN MIXTURE; SERODIAGNOSIS; PEPTIDE; NEUROBORRELIOSIS; ANTIGENS AB Infection with Borrelia burgdorferi is common in horses and ponies from the New England and mid-Atlantic regions of the United States. Here, we evaluated luciferase immunoprecipitation systems (LIPS) for profiling antibody responses against three different antigenic targets for the diagnosis of equine B. burgdorferi infection. LIPS testing of horse serum samples suspected of Lyme infection revealed that approximately 75% of the horse samples (114/159) were seropositive against the synthetic VOVO antigen, comprising repeated immunodominant C6 epitopes as well as OspC immunodominant epitopes. A comparison of VOVO and immunofluorescence assays (IFA) showed that 51% of the samples were positive in both assays (VOVO(+)/IFA(+)), 13% were VOVO(-)/IFA(+), 21% were VOVO(+)/IFA(-), and 15% were negative in both. To further understand humoral responses to B. burgdorferi and reconcile the diagnostic differences between IFA and VOVO, two additional B. burgdorferi LIPS tests were performed with DbpA and DbpB. Robust seropositive antibody responses against DbpA and/or DbpB were detected in 98% (79/81) of the VOVO(+)/IFA(+) and 93% (50/54) of the discrepant samples. Additionally, some of the samples negative by both VOVO and IFA showed immunoreactivity against DbpA and/or DbpB. Overall, 94% of the suspected horse samples were seropositive by LIPS, and heat map analysis revealed that seropositive samples often were immunoreactive with at least two of the three antigens. These results suggest that LIPS tests employing multiple recombinant antigens offer a promising approach for the evaluation of antibody responses in Lyme disease. C1 [Burbelo, Peter D.; Bren, Kathleen E.; Ching, Kathryn H.; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. [Coleman, Adam; Yang, Xiuli; Kariu, Toru; Pal, Utpal] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. RP Burbelo, PD (reprint author), Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, 49 Covent Dr,Bldg 49,Rm 1C30, Bethesda, MD 20892 USA. EM burbelop@nidcr.nih.gov; upal@umd.edu RI Pal, Utpal/I-5265-2015 FU Division of Intramural Research, National Institute of Dental and Craniofacial Research; NIH/NIAID [AI080615, AR055323] FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research. This research was supported in part by NIH/NIAID awards (AI080615 and AR055323) to U.P. NR 33 TC 2 Z9 2 U1 0 U2 7 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 SEP PY 2011 VL 18 IS 9 BP 1562 EP 1567 DI 10.1128/CVI.05123-11 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 814LA UT WOS:000294452800026 PM 21775514 ER PT J AU Argiris, A Duffy, AG Kummar, S Simone, NL Arai, Y Kim, SW Rudy, SF Kannabiran, VR Yang, XP Jang, M Chen, Z Suksta, N Cooley-Zgela, T Ramanand, SG Ahsan, A Nyati, MK Wright, JJ Van Waes, C AF Argiris, Athanassios Duffy, Austin G. Kummar, Shivaani Simone, Nicole L. Arai, Yoshio Kim, Seungwon W. Rudy, Susan F. Kannabiran, Vishnu R. Yang, Xinping Jang, Minyoung Chen, Zhong Suksta, Nanette Cooley-Zgela, Theresa Ramanand, Susmita G. Ahsan, Aarif Nyati, Mukesh K. Wright, John J. Van Waes, Carter TI Early Tumor Progression Associated with Enhanced EGFR Signaling with Bortezomib, Cetuximab, and Radiotherapy for Head and Neck Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-RECEPTOR; SQUAMOUS-CELL CARCINOMA; FACTOR-KAPPA-B; PROTEASOME INHIBITOR; PROANGIOGENIC CYTOKINES; RADIATION RESPONSE; COMBINED THERAPY; SOLID TUMORS; ACTIVATION; SURVIVAL AB Purpose: A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy. Experimental Design: Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m(2)) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1. Results: Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6-6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m(2), without dose-limiting toxicities; one patient treated at 1.3 mg/m(2) was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab-and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1. Conclusions: Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination. Clin Cancer Res; 17(17); 5755-64. (C) 2011 AACR. C1 [Van Waes, Carter] Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, NIH, CRC, Bethesda, MD 20892 USA. [Ramanand, Susmita G.; Ahsan, Aarif; Nyati, Mukesh K.] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Argiris, Athanassios] Univ Pittsburgh, Hematol Oncol & Head & Neck Canc Program, Div Hematol Oncol, Pittsburgh, PA 15232 USA. [Duffy, Austin G.; Kummar, Shivaani] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Simone, Nicole L.; Cooley-Zgela, Theresa] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Wright, John J.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Van Waes, C (reprint author), Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, NIH, CRC, Bldg 10,Room 4-2732, Bethesda, MD 20892 USA. EM argirisae@upmc.edu; vanwaesc@nidcd.nih.gov FU NCI; Milliennium Pharmaceuticals; Millennium Pharmaceuticals Bristol-Myers Squibb; NIH [ZIADC-000016, U01 CA099168-01]; National Cancer Institute [P50 CA097190-06]; NCI CTEP FX C. Van Waes received research funding through a Clinical Trials Agreement between NCI and Milliennium Pharmaceuticals, and A. Argiris received a commercial research grant from Millennium Pharmaceuticals Bristol-Myers Squibb.; This work is supported by NIH Projects ZIADC-000016, U01 CA099168-01, Head and Neck Cancer SPORE grant no. P50 CA097190-06 from the National Cancer Institute, Millennium Pharmaceuticals (to A. Argiris), and a Clinical Trials Agreement between NCI CTEP and Millennium Pharmaceuticals (to C. Van Waes). NR 42 TC 33 Z9 33 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2011 VL 17 IS 17 BP 5755 EP 5764 DI 10.1158/1078-0432.CCR-11-0861 PG 10 WC Oncology SC Oncology GA 814SN UT WOS:000294477600026 PM 21750205 ER PT J AU Moye, LA Sayre, SL Westbrook, L Jorgenson, BC Handberg, E Anwaruddin, S Wagner, KA Skarlatos, SI AF Moye, Lemuel A. Sayre, Shelly L. Westbrook, Lynette Jorgenson, Beth C. Handberg, Eileen Anwaruddin, Saif Wagner, Kristi A. Skarlatos, Sonia I. CA CCTRN TI Oversight and management of a cell therapy clinical trial network: Experience and lessons learned SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Cell therapy; Clinical trial network; Institutional Review Boards; Data Safety and Monitoring Boards ID ACUTE MYOCARDIAL-INFARCTION; MARROW MONONUCLEAR-CELLS; ISCHEMIC-HEART-DISEASE; STEM-CELLS; METAANALYSIS; QUALITY AB The Cardiovascular Cell Therapy Research Network (CCTRN), sponsored by the National Heart, Lung, and Blood Institute (NHLBI), was established to develop, coordinate, and conduct multiple collaborative protocols testing the effects of cell therapy on cardiovascular diseases. The Network was born into a difficult political and ethical climate created by the recent removal of a dozen drugs from the US formulary and the temporary halting of 27 gene therapy trials due to safety concerns. This article describes the Network's challenges as it initiated three protocols in a polarized cultural atmosphere at a time when oversight bodies were positioning themselves for the tightest vigilance of promising new therapies. Effective strategies involving ongoing education, open communication, and relationship building with the oversight community are discussed. (C) 2011 Elsevier Inc. All rights reserved. C1 [Moye, Lemuel A.; Sayre, Shelly L.] Univ Texas Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Westbrook, Lynette] Texas Heart Inst, Houston, TX 77025 USA. [Jorgenson, Beth C.] Abbott NW Hosp, Minneapolis Heart Inst, Minneapolis, MN 55407 USA. [Handberg, Eileen; Wagner, Kristi A.] Univ Florida, Coll Med, Gainesville, FL USA. [Anwaruddin, Saif] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Skarlatos, Sonia I.] Natl Heart Lung & Blood Inst, Maryland, TX USA. RP Moye, LA (reprint author), Univ Texas Houston, Sch Publ Hlth, 1200 Herman Pressler,E801, Houston, TX 77030 USA. EM Lemmoye@msn.com FU NHLBI NIH HHS [UM1 HL087318, U01 HL087318, R01 HL091005, U01 HL087318-01] NR 21 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD SEP PY 2011 VL 32 IS 5 BP 614 EP 619 DI 10.1016/j.cct.2011.05.003 PG 6 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 815KS UT WOS:000294525100003 PM 21616173 ER PT J AU Shuch, B Linehan, WM Bratslavsky, G AF Shuch, Brian Linehan, W. Marston Bratslavsky, Gennady TI Repeat partial nephrectomy: surgical, functional and oncological outcomes SO CURRENT OPINION IN UROLOGY LA English DT Review DE nephron-sparing surgery; postablation partial nephrectomy; RCC; reoperative surgery; salvage renal surgery ID RENAL-CELL CARCINOMA; NEPHRON-SPARING SURGERY; LAPAROSCOPIC PARTIAL NEPHRECTOMY; CHRONIC KIDNEY-DISEASE; TUMOR-SUPPRESSOR GENE; QUALITY-OF-LIFE; RADICAL NEPHRECTOMY; SIMPLE ENUCLEATION; 7 CM; SURVIVAL AB Purpose of review The greater utilization of partial nephrectomy and ablative procedures has increased the incidence of patients presenting with local renal recurrence. The choice to either perform a partial or radical nephrectomy in these situations can be a challenging decision. Recent findings Repeat and salvage partial nephrectomy, while challenging and potentially associated with increased complications, offers patients the ability to maintain excellent renal functional outcomes and promising oncologic outcomes at intermediate follow-up. Summary Surgeons should be familiar with the surgical complications and the functional and oncologic outcomes of reoperative nephron-sparing surgery (NSS). Recent data and outcome analysis support utilization of these procedures in patients presenting with either local recurrence or de-novo lesions in the ipsilateral kidney. C1 [Bratslavsky, Gennady] NCI, Urol Oncol Branch, NIH, CRC, Bethesda, MD 20892 USA. RP Bratslavsky, G (reprint author), NCI, Urol Oncol Branch, NIH, CRC, 10 Ctr Dr,MSC 1107,Bldg 10,Room 2W-5942, Bethesda, MD 20892 USA. EM bratslag@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research, USA FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, USA. NR 76 TC 6 Z9 8 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0963-0643 J9 CURR OPIN UROL JI Curr. Opin. Urol. PD SEP PY 2011 VL 21 IS 5 BP 368 EP 375 DI 10.1097/MOU.0b013e32834964ea PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 813PG UT WOS:000294378800004 PM 21788903 ER PT J AU Elis, S Wu, YJ Courtland, HW Cannata, D Sun, H Beth-On, M Liu, CY Jasper, H Domene, H Karabatas, L Guida, C Basta-Pljakic, J Cardoso, L Rosen, CJ Frystyk, J Yakar, S AF Elis, Sebastien Wu, Yingjie Courtland, Hayden-William Cannata, Dara Sun, Hui Beth-On, Mordechay Liu, Chengyu Jasper, Hector Domene, Horacio Karabatas, Liliana Guida, Clara Basta-Pljakic, Jelena Cardoso, Luis Rosen, Clifford J. Frystyk, Jan Yakar, Shoshana TI Unbound (bioavailable) IGF1 enhances somatic growth SO DISEASE MODELS & MECHANISMS LA English DT Article ID ACID-LABILE SUBUNIT; FACTOR (IGF)-BINDING PROTEINS; FACTOR-I; PLASMA-CLEARANCE; TRANSGENIC MICE; BIOLOGICAL-ACTIVITIES; TISSUE DISTRIBUTION; POSTNATAL-GROWTH; BINDING-PROTEINS; BODY-COMPOSITION AB Understanding insulin-like growth factor-1 (IGF1) biology is of particular importance because, apart from its role in mediating growth, it plays key roles in cellular transformation, organ regeneration, immune function, development of the musculoskeletal system and aging. IGF1 bioactivity is modulated by its binding to IGF-binding proteins (IGFBPs) and the acid labile subunit (ALS), which are present in serum and tissues. To determine whether IGF1 binding to IGFBPs is necessary to facilitate normal growth and development, we used a gene-targeting approach and generated two novel knock-in mouse models of mutated IGF1, in which the native Igf1 gene was replaced by Des-Igf1 (KID mice) or R3-Igf1 (KIR mice). The KID and KIR mutant proteins have reduced affinity for the IGFBPs, and therefore present as unbound IGF1, or 'free IGF1'. We found that both KID and KIR mice have reduced serum IGF1 levels and a concomitant increase in serum growth hormone levels. Ternary complex formation of IGF1 with the IGFBPs and the ALS was markedly reduced in sera from KID and KIR mice compared with wild type. Both mutant mice showed increased body weight, body and bone lengths, and relative lean mass. We found selective organomegaly of the spleen, kidneys and uterus, enhanced mammary gland complexity, and increased skeletal acquisition. The KID and KIR models show unequivocally that IGF1-complex formation with the IGFBPs is fundamental for establishing normal body and organ size, and that uncontrolled IGF bioactivity could lead to pathological conditions. C1 [Elis, Sebastien; Wu, Yingjie; Courtland, Hayden-William; Cannata, Dara; Sun, Hui; Beth-On, Mordechay; Yakar, Shoshana] Mt Sinai Sch Med, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Liu, Chengyu] NHLBI, Transgen Core Facil, NIH, Bethesda, MD 20892 USA. [Jasper, Hector; Domene, Horacio; Karabatas, Liliana; Guida, Clara] R Gutierrez Childrens Hosp, Endocrinol Res Ctr, Div Endocrinol, RA-1425 Buenos Aires, DF, Argentina. [Basta-Pljakic, Jelena; Cardoso, Luis] CUNY City Coll, Dept Biomed Engn, New York, NY 10031 USA. [Rosen, Clifford J.] Maine Med Ctr Res Inst, Scarborough, ME 04074 USA. [Frystyk, Jan] Aarhus Univ Hosp, Med Res Labs, Inst Clin Med, DK-8000 Aarhus, Denmark. [Frystyk, Jan] Aarhus Univ Hosp, Med Dept Diabet & Endocrinol M, DK-8000 Aarhus, Denmark. RP Yakar, S (reprint author), Mt Sinai Sch Med, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. EM shoshana.yakar@mssm.edu RI Cardoso, Luis/F-1234-2013 OI Cardoso, Luis/0000-0002-2252-7802 FU NIH, United States [AR054919, AR055141]; NIH/NIA, United States [AG034198]; NIH/HLI, United States [HL101157]; NSF/MRI, United States [CBET-0723027]; NIH/NIAMS, United States [AR53853, AR45433]; Argentina CONICET [PIP 11420090100045] FX Financial support was received from funding agencies in the United States: NIH Grants AR054919 (S.Y.), AR055141 (S.Y.); NIH/NIA AG034198 (L. C.), NIH/HLI HL101157 (L. C.) and NSF/MRI CBET-0723027 (L. C.); NIH/NIAMS AR53853 (C.J.R.), AR45433 (C.J.R.); and Argentina CONICET PIP 11420090100045 (H.J.). We thank Lone Kvist (Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark) for helping with the KIRA assay. NR 52 TC 11 Z9 11 U1 1 U2 7 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD SEP PY 2011 VL 4 IS 5 BP 649 EP 658 DI 10.1242/dmm.006775 PG 10 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 813ZZ UT WOS:000294411800011 PM 21628395 ER PT J AU Freeman, LEB Rusiecki, JA Hoppin, JA Lubin, JH Koutros, S Andreotti, G Zahm, SH Hines, CJ Coble, JB Barone-Adesi, F Sloan, J Sandler, DP Blair, A Alavanja, MCR AF Freeman, Laura E. Beane Rusiecki, Jennifer A. Hoppin, Jane A. Lubin, Jay H. Koutros, Stella Andreotti, Gabriella Zahm, Shelia Hoar Hines, Cynthia J. Coble, Joseph B. Barone-Adesi, Francesco Sloan, Jennifer Sandler, Dale P. Blair, Aaron Alavanja, Michael C. R. TI Atrazine and Cancer Incidence Among Pesticide Applicators in the Agricultural Health Study (1994-2007) SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE agriculture; atrazine; cancer; cohort study; epidemiology; pesticide ID NON-HODGKINS-LYMPHOMA; HERBICIDE MANUFACTURING WORKERS; RISK-FACTORS; TRIAZINE HERBICIDES; PUBERTAL DEVELOPMENT; THYROID-FUNCTION; WISTAR RATS; EXPOSURE; BREAST; MEN AB BACKGROUND: Atrazine is a triazine herbicide used widely in the United States. Although it is an animal carcinogen, the mechanism in rodents does not appear to operate in humans. Few epidemiologic studies have provided evidence for an association. METHODS: The Agricultural Health Study (AHS) is a prospective cohort that includes 57,310 licensed pesticide applicators. In this report, we extend a previous AHS analysis of cancer risk associated with self-reported atrazine use with six additional years of follow-up and more than twice as many cancer cases. Using Poisson regression, we calculated relative risk estimates and 95% confidence intervals for lifetime use of atrazine and intensity-weighted lifetime days, which accounts for factors that impact exposure. RESULTS: Overall, 36,357 (68%) of applicators reported using atrazine, among whom there were 3,146 cancer cases. There was no increase among atrazine users in overall cancer risk or at most cancer sites in the higher exposure categories compared with the lowest. Based on 29 exposed cases of thyroid cancer, there was a statistically significant risk in the second and fourth quartiles of intensity-weighted lifetime days. There was a similar pattern for lifetime days, but neither the risk estimates nor the trend were statistically significant and for neither metric was the trend monotonic. CONCLUSIONS: Overall, there was no consistent evidence of an association between atrazine use and any cancer site. There was a suggestion of increased risk of thyroid cancer, but these results are based on relatively small numbers and minimal supporting evidence. C1 [Freeman, Laura E. Beane] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rusiecki, Jennifer A.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Hoppin, Jane A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Hines, Cynthia J.] NIOSH, Cincinnati, OH 45226 USA. RP Freeman, LEB (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Room 8112,MSC 7240, Bethesda, MD 20892 USA. EM freemala@mail.nih.gov RI Zahm, Shelia/B-5025-2015; OI Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health (National Cancer Institute, National Institute of Environmental Health Sciences) [Z01 CP010119, Z01ES049030] FX This study was supported by funds from the Intramural Research Program of the National Institutes of Health (National Cancer Institute Z01 CP010119 and National Institute of Environmental Health Sciences Z01ES049030). NR 52 TC 33 Z9 33 U1 9 U2 54 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2011 VL 119 IS 9 BP 1253 EP 1259 DI 10.1289/ehp.1103561 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 814SV UT WOS:000294478400025 PM 21622085 ER PT J AU Nuckols, JR Freeman, LEB Lubin, JH Airola, MS Baris, D Ayotte, JD Taylor, A Paulu, C Karagas, MR Colt, J Ward, MH Huang, AT Bress, W Cherala, S Silverman, DT Cantor, KP AF Nuckols, John R. Freeman, Laura E. Beane Lubin, Jay H. Airola, Matthew S. Baris, Dalsu Ayotte, Joseph D. Taylor, Anne Paulu, Chris Karagas, Margaret R. Colt, Joanne Ward, Mary H. Huang, An-Tsun Bress, William Cherala, Sai Silverman, Debra T. Cantor, Kenneth P. TI Estimating Water Supply Arsenic Levels in the New England Bladder Cancer Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE arsenic; environmental epidemiology; exposure assessment; geographic information systems; water quality modeling; water supply ID DISINFECTION BY-PRODUCTS; DRINKING-WATER; EXPOSURE ASSESSMENT; RISK; GROUNDWATER; TIME AB BACKGROUND: Ingestion of inorganic arsenic in drinking water is recognized as a cause of bladder cancer when levels are relatively high (>= 150 mu g/L). The epidemiologic evidence is less clear at the low-to-moderate concentrations typically observed in the United States. Accurate retrospective exposure assessment over a long time period is a major challenge in conducting epidemiologic studies of environmental factors and diseases with long latency, such as cancer. OBJECTIVE: We estimated arsenic concentrations in the water supplies of 2,611 participants in a population-based case-control study in northern New England. METHODS: Estimates covered the lifetimes of most study participants and were based on a combination of arsenic measurements at the homes of the participants and statistical modeling of arsenic concentrations in the water supply of both past and current homes. We assigned a residential water supply arsenic concentration for 165,138 (95%) of the total 173,361 lifetime exposure years (EYs) and a workplace water supply arsenic level for 85,195 EYs (86% of reported occupational years). RESULTS: Three methods accounted for 93% of the residential estimates of arsenic concentration: direct measurement of water samples (27%; median, 0.3 mu g/L; range, 0.1-11.5), statistical models of water utility measurement data (49%; median, 0.4 mu g/L; range, 0.3-3.3), and statistical models of arsenic concentrations in wells using aquifers in New England (17%; median, 1.6 mu g/L; range, 0.6-22.4). CONCLUSIONS: We used a different validation procedure for each of the three methods, and found our estimated levels to be comparable with available measured concentrations. This methodology allowed us to calculate potential drinking water exposure over long periods. C1 [Nuckols, John R.; Freeman, Laura E. Beane; Lubin, Jay H.; Baris, Dalsu; Colt, Joanne; Ward, Mary H.; Huang, An-Tsun; Silverman, Debra T.; Cantor, Kenneth P.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Nuckols, John R.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. [Airola, Matthew S.] Westat Corp, Rockville, MD USA. [Ayotte, Joseph D.] US Geol Survey NH VT Water Sci Ctr, Pembroke, NH USA. [Taylor, Anne] Informat Management Serv Inc, Silver Spring, MD USA. [Paulu, Chris] Maine Ctr Dis Control & Prevent, Augusta, ME USA. [Karagas, Margaret R.] Dartmouth Med Sch, Hanover, NH USA. [Bress, William] Vermont Dept Hlth, Div Hlth Protect, Burlington, VT 05402 USA. [Cherala, Sai] New Hampshire Canc Registry, Concord, NH USA. [Cantor, Kenneth P.] KP Cantor Environm LLC, Silver Spring, MD USA. RP Nuckols, JR (reprint author), Colorado State Univ, 10916 Wickshire Way, Rockville, MD 20852 USA. EM jnuckols@colostate.edu OI Cherala, Sai/0000-0002-3485-574X FU National Cancer Institute (NCI)-Occupational and Environmental Epidemiology Branch; Colorado State University; NIH, NCI, Division of Cancer Epidemiology and Genetics FX This study was made possible, in part, through an intergovernmental personnel agreement between the National Cancer Institute (NCI)-Occupational and Environmental Epidemiology Branch and Colorado State University. This work was supported by the Intramural Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics. NR 34 TC 13 Z9 13 U1 1 U2 17 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2011 VL 119 IS 9 BP 1279 EP 1285 DI 10.1289/ehp.1002345 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 814SV UT WOS:000294478400029 PM 21421449 ER PT J AU McElwee, MK Freedman, JH AF McElwee, Matthew K. Freedman, Jonathan H. TI COMPARATIVE TOXICOLOGY OF MERCURIALS IN CAENORHABDITIS ELEGANS SO ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY LA English DT Article DE Caenorhabditis elegans; Mercury; Methylmercury; Stress response; Metal toxicity ID OXIDATIVE STRESS; RESPONSIVE GENES; TOXICITY; METHYLMERCURY; CELLS; NEMATODE; MODEL; GLUTATHIONE; RESISTANCE; ASTROCYTES AB Mercury (Hg) is a toxic metal that can exist in multiple chemical species. Humans are commonly exposed to methylmercury and Hg vapor, which are converted to mercuric species in the body. Despite years of research, little information exists on the similarities and differences in the mechanisms of Hg toxicity. The relative toxicity of mercuric chloride (HgCl(2)) and methylmercury chloride (MeHgCl) in Caenorhabditis elegans was determined in assays that measured growth, feeding, reproduction, and locomotion. The effect of HgCl(2) and MeHgCl on the expression of several archetypal stress-response genes was also determined. There was no significant difference between the EC50s of the two mercurials in terms of C. elegans growth. However, MeHgCl was more toxic to C. elegans than HgCl(2) when assessing feeding, movement, and reproduction, all of which require proper neuromuscular activity. Methylmercury chloride exposure resulted in increased steady-state levels of the stress response genes at lower concentrations than HgCl(2). In general, MeHgCl was more toxic to C. elegans than HgCl(2), particularly when assaying behaviors that require neuromuscular function. Environ. Toxicol. Chem. 2011;30:2135-2141. (C) 2011 SETAC C1 [McElwee, Matthew K.; Freedman, Jonathan H.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Freedman, JH (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM freedma1@niehs.nih.gov FU NIH; NIEHS [Z01 ES102045] FX We thank Windy Boyd, Julie Rice, Marjolein Smith, and Daniel Snyder for their assistance in experiments using the COPAS Biosort. This work was supported in part by the Intramural Research Program of the NIH and NIEHS (Z01 ES102045). NR 52 TC 9 Z9 12 U1 1 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0730-7268 J9 ENVIRON TOXICOL CHEM JI Environ. Toxicol. Chem. PD SEP PY 2011 VL 30 IS 9 BP 2135 EP 2141 DI 10.1002/etc.603 PG 7 WC Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA 813AH UT WOS:000294337300023 PM 21692103 ER PT J AU Popat, RA Van Den Eeden, SK Tanner, M Kamel, F Umbach, DM Marder, K Ritz, B Ross, GW Petrovitch, H Topol, B McGuire, V Nelson, LM AF Popat, R. A. Van Den Eeden, S. K. Tanner, M. Kamel, F. Umbach, D. M. Marder, K. Ritz, B. Ross, G. Webster Petrovitch, H. Topol, B. McGuire, V. Nelson, L. M. TI Response to Hill-Burns et al. letter: An attempt to replicate interaction between coffee and CYP1A2 gene in connection to Parkinson's disease SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Letter DE movement disorders; neurological disorders; Parkinson's disease ID CAFFEINE; RISK C1 [Popat, R. A.; Topol, B.; McGuire, V.; Nelson, L. M.] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Div Epidemiol, Stanford, CA 94305 USA. [Van Den Eeden, S. K.] Kaiser Fdn Res Inst, Div Res, Oakland, CA USA. [Tanner, M.] Parkinsons Inst, Sunnyvale, CA USA. [Kamel, F.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. [Umbach, D. M.] Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Res Triangle Pk, NC USA. [Marder, K.] Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY USA. [Marder, K.] Columbia Univ, Gertrude H Sergievsky Ctr, Coll Phys & Surg, New York, NY 10027 USA. [Marder, K.] Columbia Univ, Coll Phys & Surg, Taub Inst, New York, NY USA. [Ritz, B.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Ross, G. Webster; Petrovitch, H.] Vet Affairs Pacif Isl Hlth Care Syst, Honolulu, HI USA. [Ross, G. Webster; Petrovitch, H.] Pacific Hlth Res Inst, Honolulu, HI USA. RP Popat, RA (reprint author), Stanford Univ, Dept Hlth Res & Policy, Sch Med, Div Epidemiol, HRP Redwood Bldg,Room T209, Stanford, CA 94305 USA. EM rpopat@stanford.edu RI Ritz, Beate/E-3043-2015 NR 7 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD SEP PY 2011 VL 18 IS 9 BP E109 EP E109 DI 10.1111/j.1468-1331.2011.03461.x PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 813DO UT WOS:000294347200002 ER PT J AU Penesova, A Venti, CA Bunt, JC Bonfiglio, SM Votruba, SB Krakoff, J AF Penesova, Adela Venti, Colleen A. Bunt, Joy C. Bonfiglio, Susan M. Votruba, Susanne B. Krakoff, Jonathan TI Short-term isocaloric manipulation of carbohydrate intake: effect on subsequent ad libitum energy intake SO EUROPEAN JOURNAL OF NUTRITION LA English DT Article DE Carbohydrates; Adiposity; Energy intake; High-fat diet; Clinical nutrition ID HIGH-FAT DIET; FOOD-INTAKE; PASSIVE OVERCONSUMPTION; LEPTIN CONCENTRATIONS; RESPIRATORY CHAMBER; SUBSTRATE OXIDATION; WEIGHT-GAIN; EXPENDITURE; BALANCE; HUMANS AB Isocaloric manipulation of carbohydrate or fat intake could alter subsequent ad libitum food intake. In a controlled inpatient study, we investigated whether isocaloric manipulation of carbohydrate or fat would alter subsequent ad libitum energy intake. Eighteen non-diabetic subjects (age range 19-53 years.; 15 M/3F; % body fat 38.5 +/- A 9.1 (mean +/- A SD)) were fed for 3 days an isocaloric high-carbohydrate diet (HC; 60% carbohydrate, 20% fat, 20% protein) and a high-fat diet (HF; 50% fat, 30% carbohydrate, 20% protein) in random order each followed by 3 days of ad libitum food intake. There were no differences in mean daily energy intake (EI) following each diet (HC vs. HF: 4,811 +/- A 1,190 vs. 4,823 +/- A 1,238 kcal/d; P = 0.7) or in the percent of weight maintenance energy needs (%EN-WM; 173 +/- A 41 vs. 173 +/- A 46%, P = 0.5). However, the individual difference in EI between the HF versus HC diet (Delta EI) both on day one and over the 3 days of each ad libitum period was negatively associated with % body fat (%BF) and waist circumference (day 1: Delta EI vs. %BF, r = -0.49, P = 0.04; mean day 1-3 kcal Delta EI vs. %BF, r = -0.66, P = 0.003, and Delta EI vs. waist, r = -0.65, P = 0.004). A short-term isocaloric HC diet did not result in overall lower EI compared with a HF diet in the same individuals. However, we did find that increasing body fat was associated with less decline in EI following the HC versus HF diet indicating that increasing adiposity is associated with altered regulation of EI in response to macronutrient changes. C1 [Penesova, Adela; Venti, Colleen A.; Bunt, Joy C.; Bonfiglio, Susan M.; Votruba, Susanne B.; Krakoff, Jonathan] NIDDK, Dept Hlth & Human Serv, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch,NIH, Phoenix, AZ 85016 USA. RP Penesova, A (reprint author), NIDDK, Dept Hlth & Human Serv, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch,NIH, 4212N 16th St, Phoenix, AZ 85016 USA. EM adela.penesova@savba.sk FU Intramural NIH HHS NR 33 TC 2 Z9 3 U1 0 U2 8 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1436-6207 J9 EUR J NUTR JI Eur. J. Nutr. PD SEP PY 2011 VL 50 IS 6 BP 455 EP 463 DI 10.1007/s00394-010-0152-5 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 811AI UT WOS:000294173300008 PM 21165629 ER PT J AU Csokmay, JM Hill, MJ Chason, RJ Hennessy, S James, AN Cohen, J DeCherney, AH Segars, JH Payson, MD AF Csokmay, John M. Hill, Micah J. Chason, Rebecca J. Hennessy, Sasha James, Aidita N. Cohen, Jacques DeCherney, Alan H. Segars, James H. Payson, Mark D. TI Experience with a patient-friendly, mandatory, single-blastocyst transfer policy: the power of one SO FERTILITY AND STERILITY LA English DT Article DE ART; blastocyst; clinical pregnancy; implantation; infertility; IVF; mandatory; multiple gestation; single ID IN-VITRO FERTILIZATION; PREGNANCY RATES; EMBRYO-TRANSFER; MULTIPLE-BIRTH; LIVE-BIRTH; METAANALYSIS; IVF AB Objective: To determine whether a mandatory single-blastocyst transfer (mSBT) algorithm reduced multiple gestation rates without sacrificing clinical pregnancy rates. Design: Retrospective review. Setting: U.S. university-based assisted reproductive technology (ART) program. Patient(s): All women younger than 38 years undergoing their first ART cycle from 2009 to 2010 with >= 4 high-grade embryos on day 3 after oocyte retrieval (patients from 2009 were the "before'' group, and patients completing ART under the mSBT policy in 2010 were the "after'' group). Intervention(s): mSBT algorithm. Main Outcome Measure(s): Multiple gestation and clinical pregnancy rates. Result(s): Of the qualified patients, 136 women met inclusion criteria (62 from 2009, 74 from 2010). The baseline demographics were similar between the groups. Statistically significantly fewer blastocysts were transferred per patient in 2010 compared with 2009 (1.5 vs. 1.9). The clinical pregnancy rates before (67.7%) or after (63.5%) the mSBT policy were not statistically significantly different. Multiple gestation rates were statistically significantly reduced, from 43.8% (2009) to 14.6% (2010) after the mSBT policy was instituted. More patients from 2010 had >= 1 blastocyst cryopreserved compared with 2009 (52.9% vs. 30.6%). Conclusion(s): A novel single-blastocyst transfer algorithm reduced multiple gestation rates and improved cryopreservation rates without compromising clinical pregnancy rates in good-prognosis patients. (Fertil Steril (R) 2011;96:580-4. (C) 2011 by American Society for Reproductive Medicine.) C1 [Csokmay, John M.; Hill, Micah J.; Chason, Rebecca J.; Segars, James H.; Payson, Mark D.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Csokmay, John M.; Hill, Micah J.; Chason, Rebecca J.; DeCherney, Alan H.; Segars, James H.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Hennessy, Sasha; James, Aidita N.] Washington Inc, ART Inst, Washington, DC USA. [Cohen, Jacques] Reprogenetics, Livingston, NJ USA. RP Csokmay, JM (reprint author), Walter Reed Army Med Ctr, 6900 Georgia Ave NW, Washington, DC 20307 USA. EM csokmayj@mail.nih.gov FU NICHD, National Institutes of Health FX Supported in part by the Intramural Research Program in Reproductive and Adult Endocrinology, NICHD, National Institutes of Health. The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government. NR 11 TC 10 Z9 11 U1 0 U2 1 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 SEP PY 2011 VL 96 IS 3 BP 580 EP 584 DI 10.1016/j.fertnstert.2011.06.043 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814BC UT WOS:000294417000023 PM 21774925 ER PT J AU Taveira-DaSilva, AM Rabel, A Gochuico, BR Avila, NA Moss, J AF Taveira-DaSilva, Angelo M. Rabel, Antoinette Gochuico, Bernadette R. Avila, Nilo A. Moss, Joel TI Prevalence of uterine leiomyomas in lymphangioleiomyomatosis SO FERTILITY AND STERILITY LA English DT Article DE Uterine leiomyomas; hysterectomy; lymphangioleiomyomatosis ID TUBEROUS SCLEROSIS COMPLEX; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; ULTRASONOGRAPHIC FINDINGS; WOMEN; EPIDEMIOLOGY; FIBROIDS; FEATURES; MYOMAS; GENE; LAM AB Objective: To determine the frequency of uterine leiomyomas and hysterectomy in patients with lymphangioleiomyomatosis (LAM), a disease characterized by proliferation of abnormal-appearing smooth muscle-like cells. Design: Retrospective study. Setting: Natural history study at the National Institutes of Health. Patient(s): 456 patients with sporadic LAM and LAM associated with tuberous sclerosis complex (LAM/TSC). Intervention(s): Review of records and pelvic computed axial tomography scans. Main Outcome Measure(s): Prevalence of uterine leiomyomas and hysterectomy. Result(s): A total of 174 women had uterine leiomyomas (38%). One hundred eighteen were diagnosed by computed tomographic scan and 56 were diagnosed by hysterectomy. Among 323 patients who did not have hysterectomy, 105 of 270 patients (39%) with sporadic LAM and 13 of 53 (25%) with LAM/TSC had uterine leiomyomas. Hysterectomy was performed in 108 of 378 subjects with sporadic LAM and 25 of 78 with LAM/TSC. Fifty-six patients were found to have uterine fibroids on hysterectomy. The most common indications for hysterectomy were uterine leiomyoma, LAM, and endometriosis. Conclusion(s): Uterine leiomyomas are not more common in LAM than in the general population. However, in LAM, the frequency of hysterectomy is higher because of it having been recommended for treatment of LAM. (Fertil Steril (R) 2011;96:711-4. (C)2011 by American Society for Reproductive Medicine.) C1 [Taveira-DaSilva, Angelo M.; Rabel, Antoinette; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Gochuico, Bernadette R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Avila, Nilo A.] NIH, Dept Diagnost Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Taveira-DaSilva, AM (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Room 6D05,Bldg 10,MSC 1590, Bethesda, MD 20892 USA. EM dasilvaa@nhlbi.nih.gov FU Division of Intramural Research, National Institutes of Health, National Heart, Lung, and Blood Institute; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland FX Supported in part by Division of Intramural Research, National Institutes of Health, National Heart, Lung, and Blood Institute and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. NR 24 TC 4 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 BP 711 EP U238 DI 10.1016/j.fertnstert.2011.06.038 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814BC UT WOS:000294417000050 PM 21880281 ER PT J AU Alford, CE Pang, ALY Clark, JB Segars, JH DeCherney, AH Rennert, OM AF Alford, C. E. Pang, A. L. Y. Clark, J. B. Segars, J. H. DeCherney, A. H. Rennert, O. M. TI IDENTIFICATION OF THE BINDING PROTEINS OF THE 3 ' UNTRANSLATED REGION OF MOUSE Ard1b THAT MAY BE RESPONSIBLE FOR ITS TRANSLATIONAL DELAY DURING SPERMATOGENESIS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod Adult Endocrinol, Bethesda, MD USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Clin & Dev Genom, 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S228 EP S229 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452701016 ER PT J AU Armstrong, AY Wawrousek, E Feng, YL AF Armstrong, A. Y. Wawrousek, E. Feng, Y. -L. TI COMPLETE REMOVAL OF THE ZONA PELLUCIDA AND PREGNANCY OUTCOME IN A MOUSE MODEL SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NEI, 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S85 EP S85 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700287 ER PT J AU Beall, SA Levy, G Maguire, M Stegmann, B Payson, M Segars, J AF Beall, S. A. Levy, G. Maguire, M. Stegmann, B. Payson, M. Segars, J. TI BODY MASS INDEX (BMI) DOES NOT IMPACT NUMBER OF OOCYTES RETRIEVED OR OOCYTE MATURATION IN WOMEN UNDERGOING ART SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 NICHHD, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Dept Reprod Endocrinol & Infertil, Washington, DC 20307 USA. Univ Iowa Hosp & Clin, Dept Reprod Endocrinol & Infertil, Iowa City, IA 52242 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S81 EP S82 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700276 ER PT J AU Catherino, WH Locastro, M Gilden, M Britten, J Malik, M AF Catherino, W. H. Locastro, M. Gilden, M. Britten, J. Malik, M. TI LEIOMYOMA GROWTH MEDIATED BY DISRUPTIONS IN INJURY RESPONSE AND ANGIOGENESIS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NICHHD, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S51 EP S51 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700170 ER PT J AU Chason, RJ Sundaram, R Louis, GMB Segars, JH Pyper, C AF Chason, R. J. Sundaram, R. Louis, G. M. Buck Segars, J. H. Pyper, C. TI DOES PRECONCEPTION STRESS ALTER THE SECONDARY SEX RATIO? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. Univ Oxford, Natl Perinatal Epidemiol Unit, Oxford, England. 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S154 EP S154 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700528 ER PT J AU Gemmill, JAL Sinaii, N Khachikyan, I Stegmann, B Chrousos, G Stratton, P Segars, J AF Gemmill, J. A. L. Sinaii, N. Khachikyan, I. Stegmann, B. Chrousos, G. Stratton, P. Segars, J. TI HYPOTHALAMIC-PITUITARY-ADRENAL RESPONSES ARE ALTERED IN WOMEN WITH DISTURBED SLEEP DUE TO CHRONIC PELVIC PAIN ASSOCIATED WITH ENDOMETRIOSIS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. CC NIH, Biostat & Clin Epidemiol Serv, Bethesda, MD USA. Univ Iowa, Dept Obstet & Gynecol, Iowa City, IA 52242 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S45 EP S46 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700152 ER PT J AU Hill, MJ Csokmay, JM Chason, R Hennessy, S Segars, JH Payson, MD AF Hill, M. J. Csokmay, J. M. Chason, R. Hennessy, S. Segars, J. H. Payson, M. D. TI EXPERIENCE WITH A PATIENT FRIENDLY, MANDATORY SINGLE HIGH GRADE BLASTOCYST TRANSFER POLICY: THE POWER OF ONE SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Walter Reed Army Med Ctr, IVF, Washington, DC 20307 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S271 EP S271 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452701156 ER PT J AU Hill, MJ Retzloff, MG Palumbo, M Van Horne, AK Bates, GW Propst, AM AF Hill, M. J. Retzloff, M. G. Palumbo, M. Van Horne, A. K. Bates, G. W. Propst, A. M. TI LOW-DOSE URINARY hCG IMPROVES IVF CYCLE OUTCOMES IN PATIENTS WITH LOW LH LEVELS IN GnRH ANTAGONIST CYCLES SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. Wilford Hall USAF Med Ctr, Dept Obstet & Gynecol, Lackland AFB, TX 78236 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S253 EP S254 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452701100 ER PT J AU Hill, MJ Csokmay, JM Levy, G DeCherney, AH Levens, ED AF Hill, M. J. Csokmay, J. M. Levy, G. DeCherney, A. H. Levens, E. D. TI THE EFFECT OF EXOGENOUS LUTEINIZING HORMONE ADMINISTRATION DURING IVF STIMULATION IN PATIENTS OF ADVANCE REPRODUCTIVE AGE SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. Walter Reed Army Med Ctr, OBGYN, Washington, DC 20307 USA. Shady Grove Fertil, Annandale, VA 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S253 EP S253 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452701099 ER PT J AU Levy, G Beall, S Alford, C Propst, AM AF Levy, G. Beall, S. Alford, C. Propst, A. M. TI DOES A FALL IN SERUM ESTRADIOL LEVELS AFTER HCG ADMINISTRATION CORRELATE WITH LOWER PREGNANCY RATES IN PATIENTS UNDERGOING FRESH ART CYCLES? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Adult & Reprod Endocrinol, NIH, Bethesda, MD USA. Walter Reed Army Med Ctr, Washington, DC 20307 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S193 EP S194 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700661 ER PT J AU Lynch, CD Sundaram, R Louis, GMB Lum, KJ Pyper, C AF Lynch, C. D. Sundaram, R. Louis, G. M. Buck Lum, K. J. Pyper, C. TI ARE INCREASED LEVELS OF SELF-REPORTED PSYCHOSOCIAL STRESS, ANXIETY AND DEPRESSION ASSOCIATED WITH FERTILITY PROBLEMS? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. NICHD, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. Univ Oxford, Natl Perinatal Epidemiol Unit, Oxford, England. Johns Hopkins Bloomberg Publ Hlth, Dept Biostat, Baltimore, MD 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S11 EP S11 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700035 ER PT J AU Maguire, M Driggers, P AF Maguire, M. Driggers, P. TI AKAP-BRX INFLUENCES FOLLICLE STIMULATING HORMONE SIGNALING SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S121 EP S122 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700412 ER PT J AU Moon, KS Richter, KS Emarievbe, AU Segars, JH Widra, EA AF Moon, K. S. Richter, K. S. Emarievbe, A. U. Segars, J. H. Widra, E. A. TI DIMINISHED OVARIAN RESERVE IS NOT INDEPENDENTLY ASSOCIATED WITH CLINICAL REPRODUCTIVE LOSS IN PREGNANCIES ACHIEVED BY ASSISTED REPRODUCTIVE TECHNOLOGIES (ART) SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. Georgetown Univ Hosp, Dept Obstet & Gynecol, Washington, DC 20007 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S178 EP S178 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700608 ER PT J AU Moon, KS Richter, KS Segars, JH Wolff, EF Widra, EA AF Moon, K. S. Richter, K. S. Segars, J. H. Wolff, E. F. Widra, E. A. TI RACIAL/ETHNIC DISPARITIES IN ASSISTED REPRODUCTIVE TECHNOLOGY (ART) OUTCOMES: AN ANALYSIS OF 10,413 PATIENTS FROM A SINGLE FERTILITY PRACTICE SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. Shady Grove Fertil Reprod Sci Ctr, 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S64 EP S64 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700214 ER PT J AU Mumford, SL Schisterman, EF Dasharathy, S Pollack, AZ Zhang, C Wactawski-Wende, J AF Mumford, S. L. Schisterman, E. F. Dasharathy, S. Pollack, A. Z. Zhang, C. Wactawski-Wende, J. TI OMEGA-3 FATTY ACIDS AND OVULATORY FUNCTION SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Rockville, MD USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S15 EP S15 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700050 ER PT J AU Shanis, DL Jessmon, P Sinaii, N Armant, DR Stratton, P AF Shanis, D. L. Jessmon, P. Sinaii, N. Armant, D. R. Stratton, P. TI IVF AND INCREASED RISK FOR PREECLAMPSIA REVISITED: A META-ANALYSIS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 Eunice Kennedy Shriver NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. Sinai Hosp Baltimore, Baltimore, MD USA. Wayne State Univ, Detroit, MI USA. NIH Clin Ctr, Biostat & Clin Epidemiol Serv, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S181 EP S181 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700620 ER PT J AU Thoma, M Sundaram, R Chen, Z Peterson, CM Croughan, M Louis, G AF Thoma, M. Sundaram, R. Chen, Z. Peterson, C. M. Croughan, M. Louis, G. TI COMPARING "APPLES AND PEARS": HOW WELL DO WOMEN PERCEIVE THEIR BODY SIZE AND SHAPE? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 NICHD, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. Univ Utah, Salt Lake City, UT USA. Univ Calif Oakland, Oakland, CA 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S14 EP S14 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700047 ER PT J AU Wolff, EF Hediger, M Chen, Z Peterson, CM Sundaram, R Louis, GB AF Wolff, E. F. Hediger, M. Chen, Z. Peterson, C. M. Sundaram, R. Louis, G. Buck TI IN UTERO EXPOSURES AND INCIDENT ENDOMETRIOSIS, THE ENDO STUDY SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NICHD, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. Univ Utah, Salt Lake City, UT 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S138 EP S139 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700471 ER PT J AU Yu, B Parker, C Merino, M Hill, M Armstrong, A AF Yu, B. Parker, C. Merino, M. Hill, M. Armstrong, A. TI NORMAL PUBERTY IS NOT EQUAL TO NORMAL GONADAL FUNCTION IN MALE AND FEMALE CHILDHOOD CANCER SURVIVORS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 NICHD, Program Adult & Reprod Endocrinol, NIH, Bethesda, MD USA. Walter Reed Army Med Ctr, Dept Pediat, Washington, DC 20307 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S78 EP S78 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700266 ER PT J AU Yu, B Mumford, S Segars, JH Armstrong, A AF Yu, B. Mumford, S. Segars, J. H. Armstrong, A. TI COST-EFFECTIVENESS ANALYSIS COMPARING CONTINUATION OF ART WITH CONVERSION TO IUI IN PATIENTS WITH LOW FOLLICLE NUMBERS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 15-19, 2011 CL Orlando, FL SP Amer Soc Reprod Med C1 NICHD, Program Adult & Reprod Endocrinol, NIH, Bethesda, MD USA. NICHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2011 VL 96 IS 3 SU 1 BP S2 EP S2 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KZ UT WOS:000294452700007 ER PT J AU Hoefs, JC Shiffman, ML Goodman, ZD Kleiner, DE Dienstag, JL Stoddard, AM AF Hoefs, John C. Shiffman, Mitchell L. Goodman, Zachary D. Kleiner, David E. Dienstag, Jules L. Stoddard, Anne M. CA HALT-C Trial Grp TI Rate of Progression of Hepatic Fibrosis in Patients With Chronic Hepatitis C: Results From the HALT-C Trial SO GASTROENTEROLOGY LA English DT Article DE Rate of Fibrosis Progression; Hepatitis C; Liver Biopsy Fibrosis; Ishak Score ID CHRONIC VIRAL-HEPATITIS; LIVER-BIOPSY; SAMPLING VARIABILITY; NATURAL-HISTORY; VIRUS-INFECTION; CLASSIFICATION; PEGINTERFERON; CIRRHOSIS; THERAPY; DISEASE AB BACKGROUND & AIMS: The gradual accumulation of hepatic fibrosis in chronic liver disease results in clinical complications. The rate of hepatic fibrosis score progression (RFSP) in predicting clinical outcomes was assessed by extending the 4-year Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial to include preenrollment liver biopsies. METHODS: The RFSP was calculated from the linear regression slope of Ishak fibrosis score vs time in 457 patients with liver biopsies (>= 10-mm length) prior to the HALT-C Trial (575 biopsies) plus 1101 on-study biopsies (total 1676 biopsies). Individual slopes were calculated if duration from first to last biopsy was > 4 years. RESULTS: The RFSP as average fibrosis score vs average time in intervals (0 - 3 and > 3 years prestudy, screening, month 24 and 48 on-study) in 455 patients in cohorts of baseline Ishak score ranged from 0.005 with Ishak score 2 to 0.124 with Ishak 6. The RFSP in individual patients (-0.35 to +0.97 Ishak units/year) had a mean of 0.12 +/- 0.23 in 344 patients with prestudy and on-study biopsies (group A) and only 0.17 +/- 0.22 in 169 with prestudy and screening biopsies (group B). Group A patients with RFSP slope >= 0.2 (95 patients, 27.6%) had higher 7-year cumulative rates of non-hepatocellular carcinoma outcomes (46% vs 8%, respectively) and with a hepatocellular carcinoma (10% vs 3%, respectively) than RFSP slope < 02 (249 patients, 72.4%) (P < .0001). RFSP and screening Ishak score correlated independently (P < .0001) with clinical outcomes in multivariate analysis. CONCLUSIONS: Rapid RFSP (> 0.2), which occurred in 26.7% of HALT-C Trial patients, correlated strongly with clinical outcomes. C1 [Hoefs, John C.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Shiffman, Mitchell L.] Bon Secours Hlth Syst, Liver Inst Virginia, Richmond, VA USA. [Goodman, Zachary D.] Inova Fairfax Hosp, Ctr Liver Dis, Falls Church, VA USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Dienstag, Jules L.] Massachusetts Gen Hosp, Med Serv, Gastrointestinal Unit, Boston, MA 02114 USA. [Dienstag, Jules L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Stoddard, Anne M.] New England Res Inst, Watertown, MA 02172 USA. RP Hoefs, JC (reprint author), Univ Calif Irvine, Med Ctr, 333 Manchester Dr, Orange, CA 92828 USA. EM jchoefs@uci.edu OI Kleiner, David/0000-0003-3442-4453 FU NIH, National Cancer Institute FX Supported in part by the Intramural Research Program of the NIH, National Cancer Institute. NR 32 TC 14 Z9 15 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD SEP PY 2011 VL 141 IS 3 BP 900 EP U629 DI 10.1053/j.gastro.2011.06.007 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 812HG UT WOS:000294281200030 PM 21699796 ER PT J AU O'Brien, TR Kohaar, I Pfeiffer, RM Maeder, D Yeager, M Schadt, EE Prokunina-Olsson, L AF O'Brien, T. R. Kohaar, I. Pfeiffer, R. M. Maeder, D. Yeager, M. Schadt, E. E. Prokunina-Olsson, L. TI Risk alleles for chronic hepatitis B are associated with decreased mRNA expression of HLA-DPA1 and HLA-DPB1 in normal human liver SO GENES AND IMMUNITY LA English DT Article DE chronic hepatitis B; HLA; gene expression; genetics; genomics ID GENOME-WIDE ASSOCIATION; GLOBAL GENE-EXPRESSION; VARIANTS; HLA; COMPLEX; LOCUS; DETERMINANTS; SEQUENCE; TISSUES; DISEASE AB A genome-wide association study identified single nucleotide polymorphisms (SNPs) rs3077 and rs9277535 located in the 30 untranslated regions of human leukocyte antigen (HLA) class II genes HLA-DPA1 and HLA-DPB1, respectively, as the independent variants most strongly associated with chronic hepatitis B. We examined whether these SNPs are associated with mRNA expression of HLA-DPA1 and HLA-DPB1. We identified gene expression-associated SNPs (eSNPs) in normal liver samples obtained from 651 individuals of European ancestry by integrating genotype (similar to 650 000 SNPs) and gene expression (>39 000 transcripts) data from each sample. We used the Kruskal-Wallis test to determine associations between gene expression and genotype. To confirm findings, we measured allelic expression imbalance (AEI) of complementary DNA compared with DNA in liver specimens from subjects who were heterozygous for rs3077 and rs9277535. On a genome-wide basis, rs3077 was the SNP most strongly associated with HLA-DPA1 expression (p = 10(-48)), and rs9277535 was strongly associated with HLA-DPB1 expression (p = 10(-15)). Consistent with these gene expression associations, we observed AEI for both rs3077 (p = 3.0 x 10(-7); 17 samples) and rs9277535 (p = 0.001; 17 samples). We conclude that the variants previously associated with chronic hepatitis B are also strongly associated with mRNA expression of HLA-DPA1 and HLA-DPB1, suggesting that expression of these genes is important in control of HBV. Genes and Immunity (2011) 12, 428-433; doi:10.1038/gene.2011.11; published online 24 February 2011 C1 [O'Brien, T. R.] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kohaar, I.; Prokunina-Olsson, L.] NCI, Lab Translat Genom, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Pfeiffer, R. M.] NCI, Biostat Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Maeder, D.; Yeager, M.] NCI, Human Genet Program, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Yeager, M.] SAIC Frederick Inc, NCI Frederick, NCI Core Genotyping Facil, Gaithersburg, MD USA. [Schadt, E. E.] Sage Bionetworks, Seattle, WA USA. [Schadt, E. E.] Pacific Biosci, Menlo Pk, CA USA. RP O'Brien, TR (reprint author), NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 5052,MSC 7246, Bethesda, MD 20892 USA. EM obrient@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU NIH [N01-DK-7-0004/HHSN267200700004C]; National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We acknowledge the assistance of Sabrina Chen (Information Management Services, Silver Spring, Maryland) and Myhanh Dotrang (CSC, Rockville, Maryland) with databases, David Check with graphics and Natalia Orduz with the AEI studies. Liver tissue samples for AEI testing were kindly provided by the Liver Tissue Cell Distribution System under NIH Contract # N01-DK-7-0004/HHSN267200700004C. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. It was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract 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. NR 23 TC 48 Z9 52 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD SEP PY 2011 VL 12 IS 6 BP 428 EP 433 DI 10.1038/gene.2011.11 PG 6 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 814WR UT WOS:000294488400003 PM 21346778 ER PT J AU Canudas, S Houghtaling, BR Bhanot, M Sasa, G Savage, SA Bertuch, AA Smith, S AF Canudas, Silvia Houghtaling, Benjamin R. Bhanot, Monica Sasa, Ghadir Savage, Sharon A. Bertuch, Alison A. Smith, Susan TI A role for heterochromatin protein 1 gamma at human telomeres SO GENES & DEVELOPMENT LA English DT Article DE telomeres; TIN2; HP1; dyskeratosis congenita ID LINKED DYSKERATOSIS-CONGENITA; CELL-CYCLE; COHESIN COMPLEXES; LENGTH REGULATOR; MAMMALIAN-CELLS; CHROMOSOME ENDS; DNA-REPLICATION; HP1 PROTEINS; HISTONE H3; LYSINE 9 AB Human telomere function is mediated by shelterin, a six-subunit complex that is required for telomere replication, protection, and cohesion. TIN2, the central component of shelterin, has binding sites to three subunits: TRF1, TRF2, and TPP1. Here we identify a fourth partner, heterochromatin protein 1 gamma (HP1 gamma), that binds to a conserved canonical HP1-binding motif, PXVXL, in the C-terminal domain of TIN2. We show that HP1 gamma localizes to telomeres in S phase, where it is required to establish/maintain cohesion. We further demonstrate that the HP1-binding site in TIN2 is required for sister telomere cohesion and can impact telomere length maintenance by telomerase. Remarkably, the PTVML HP1-binding site is embedded in the recently identified cluster of mutations in TIN2 that gives rise to dyskeratosis congenita (DC), an inherited bone marrow failure syndrome caused by defects in telomere maintenance. We show that DC-associated mutations in TIN2 abrogate binding to HP1 gamma and that DC patient cells are defective in sister telomere cohesion. Our data indicate a novel requirement for HP1 gamma in the establishment/maintenance of cohesion at human telomeres and, furthermore, may provide insight into the mechanism of pathogenesis in TIN2-mediated DC. C1 [Canudas, Silvia; Houghtaling, Benjamin R.; Bhanot, Monica; Smith, Susan] NYU, Sch Med, Mol Pathogenesis Program, Dept Pathol,Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10016 USA. [Sasa, Ghadir; Bertuch, Alison A.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Bertuch, Alison A.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Smith, S (reprint author), NYU, Sch Med, Mol Pathogenesis Program, Dept Pathol,Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10016 USA. EM susan.smith@med.nyu.edu RI Savage, Sharon/B-9747-2015; OI Savage, Sharon/0000-0001-6006-0740; Smith, Susan/0000-0002-8213-5915 FU Lisa Leath-wood, RN, Westat, Inc. (NIH) [N02-CP-11019, N02-CP65504, N02-CP-65501]; NIH [R01 CA116352]; NSF [0543553]; Division of Cancer Epidemiology, National Cancer Institute FX We thank Tom Meier and members of the Smith laboratory for comments on the manuscript and helpful discussion. We are grateful to the patients for their participation in these studies. We thank Drs. Blanche Alter and Neelam Giri, National Cancer Institute, for collecting patient materials and data. Lisa Leath-wood, RN, Westat, Inc. (NIH contracts N02-CP-11019, N02-CP65504, and N02-CP-65501), provided outstanding study support. This work was supported by NIH grant R01 CA116352 to S. S. and by a NSF grant (0543553) to S. S. S. C. was the 2010 Helen and Martin Kimmel Senior Fellow in Stem Cell Biology. S. A. S. was supported by the intramural research program of the Division of Cancer Epidemiology, National Cancer Institute. NR 67 TC 45 Z9 48 U1 1 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD SEP 1 PY 2011 VL 25 IS 17 BP 1807 EP 1819 DI 10.1101/gad.17325211 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 815UO UT WOS:000294555500006 PM 21865325 ER PT J AU Yewdell, J Young, H AF Yewdell, Jonathan Young, Howard TI Revamping Research Funding SO GENETIC ENGINEERING & BIOTECHNOLOGY NEWS LA English DT Article C1 [Yewdell, Jonathan; Young, Howard] NIH, Bethesda, MD 20892 USA. RP Yewdell, J (reprint author), NIH, Bethesda, MD 20892 USA. EM YoungHow@mailmih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1935-472X J9 GENET ENG BIOTECHN N JI Genet. Eng. Biotechnol. News PD SEP 1 PY 2011 VL 31 IS 15 BP 6 EP 7 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 815GR UT WOS:000294514600003 ER PT J AU Ajay, SS Parker, SCJ Abaan, HO Fajardo, KVF Margulies, EH AF Ajay, Subramanian S. Parker, Stephen C. J. Abaan, Hatice Ozel Fajardo, Karin V. Fuentes Margulies, Elliott H. TI Accurate and comprehensive sequencing of personal genomes SO GENOME RESEARCH LA English DT Article ID SHORT-READ; DISCOVERY; PATIENT AB As whole-genome sequencing becomes commoditized and we begin to sequence and analyze personal genomes for clinical and diagnostic purposes, it is necessary to understand what constitutes a complete sequencing experiment for determining genotypes and detecting single-nucleotide variants. Here, we show that the current recommendation of similar to 30x coverage is not adequate to produce genotype calls across a large fraction of the genome with acceptably low error rates. Our results are based on analyses of a clinical sample sequenced on two related Illumina platforms, GAII(x) and HiSeq 2000, to a very high depth (126x). We used these data to establish genotype-calling filters that dramatically increase accuracy. We also empirically determined how the callable portion of the genome varies as a function of the amount of sequence data used. These results help provide a "sequencing guide'' for future whole-genome sequencing decisions and metrics by which coverage statistics should be reported. C1 [Ajay, Subramanian S.; Parker, Stephen C. J.; Abaan, Hatice Ozel; Margulies, Elliott H.] NHGRI, Genome Informat Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Fajardo, Karin V. Fuentes] NHGRI, Undiagnosed Dis Program, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Margulies, EH (reprint author), Illumina Cambridge Ltd, Chesterford Res Pk, Saffron Walden CB10 1XL, Essex, England. EM emargulies@illumina.com RI Sincan, Murat /A-3794-2010 FU National Human Genome Research Institute at the National Institutes of Health FX We thank J.C. Mullikin, N.F. Hansen, J.K. Teer, and P. Cruz for valuable advice; A.C. Young, R.W. Blakesley, and the NIH Intramural Sequencing Center for sequencing support; T.G. Belgard for critical review of the manuscript; the NHGRI genomics core for help with SNP-chip validation; J. Becker, M. Lesko, and B. Stanfield for IT support; and D.R. Bentley and K. Hall for early access to data generated on the HiSeq2000 platform. The data analyzed here were primarily generated for a continuing fruitful interdisciplinary collaboration with Drs. D. Adams, G. Golas, A. Gropman, C. Groden, R. Fisher, and W.A. Gahl, and other members of the NIH Undiagnosed Diseases Program. This work was funded by the Intramural Research Program of the National Human Genome Research Institute at the National Institutes of Health. NR 29 TC 82 Z9 87 U1 0 U2 20 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD SEP PY 2011 VL 21 IS 9 BP 1498 EP 1505 DI 10.1101/gr.123638.111 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 814SH UT WOS:000294477000010 PM 21771779 ER PT J AU Jiang, LC Schlesinger, F Davis, CA Zhang, Y Li, RH Salit, M Gingeras, TR Oliver, B AF Jiang, Lichun Schlesinger, Felix Davis, Carrie A. Zhang, Yu Li, Renhua Salit, Marc Gingeras, Thomas R. Oliver, Brian TI Synthetic spike-in standards for RNA-seq experiments SO GENOME RESEARCH LA English DT Article ID TRANSCRIPTOME; EXPRESSION; ARRAYS; GENOME; YEAST; CELLS AB High-throughput sequencing of cDNA (RNA-seq) is a widely deployed transcriptome profiling and annotation technique, but questions about the performance of different protocols and platforms remain. We used a newly developed pool of 96 synthetic RNAs with various lengths, and GC content covering a 2(20) concentration range as spike-in controls to measure sensitivity, accuracy, and biases in RNA-seq experiments as well as to derive standard curves for quantifying the abundance of transcripts. We observed linearity between read density and RNA input over the entire detection range and excellent agreement between replicates, but we observed significantly larger imprecision than expected under pure Poisson sampling errors. We use the control RNAs to directly measure reproducible protocol-dependent biases due to GC content and transcript length as well as stereotypic heterogeneity in coverage across transcripts correlated with position relative to RNA termini and priming sequence bias. These effects lead to biased quantification for short transcripts and individual exons, which is a serious problem for measurements of isoform abundances, but that can partially be corrected using appropriate models of bias. By using the control RNAs, we derive limits for the discovery and detection of rare transcripts in RNA-seq experiments. By using data collected as part of the model organism and human Encyclopedia of DNA Elements projects (ENCODE and modENCODE), we demonstrate that external RNA controls are a useful resource for evaluating sensitivity and accuracy of RNA-seq experiments for transcriptome discovery and quantification. These quality metrics facilitate comparable analysis across different samples, protocols, and platforms. C1 [Schlesinger, Felix; Davis, Carrie A.; Gingeras, Thomas R.] Cold Spring Harbor Lab, Genome Ctr, Woodbury, NY 11797 USA. [Jiang, Lichun; Zhang, Yu; Li, Renhua; Oliver, Brian] NIDDK, Sect Dev Genom, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Schlesinger, Felix] Cold Spring Harbor Lab, Watson Sch Biol Sci, Cold Spring Harbor, NY 11724 USA. [Salit, Marc] NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. RP Schlesinger, F (reprint author), Cold Spring Harbor Lab, Genome Ctr, Woodbury, NY 11797 USA. EM schlesin@cshl.edu RI Schlesinger, Felix/E-2143-2011; jiang, lichun/F-3776-2012; OI jiang, lichun/0000-0003-2462-7636; Gingeras, Thomas/0000-0001-9106-3573 FU National Institute of Diabetes and Digestive and Kidney Disease; National Human Genome Research Institute [5U54HG004557-05] FX We thank the members of our laboratories as well as the mod-ENCODE, ENCODE, and ERCC consortia for valuable discussions. We thank Carlo Artieri and David Sturgill for pilot work on data analysis and comments on the manuscript. This work was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Disease, and by the National Human Genome Research Institute Grant 5U54HG004557-05. Disclaimer: Certain commercial equipment, instruments, or materials are identified in this document. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the products identified are necessarily the best available for the purpose. NR 42 TC 156 Z9 158 U1 5 U2 32 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD SEP PY 2011 VL 21 IS 9 BP 1543 EP 1551 DI 10.1101/gr.121095.111 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 814SH UT WOS:000294477000014 PM 21816910 ER PT J AU Clark, TR Lackey, AM Kleba, B Driskell, LO Lutter, EI Martens, C Wood, DO Hackstadt, T AF Clark, Tina R. Lackey, Amanda M. Kleba, Betsy Driskell, Lonnie O. Lutter, Erika I. Martens, Craig Wood, David O. Hackstadt, Ted TI Transformation Frequency of a mariner-Based Transposon in Rickettsia rickettsii SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ACTIN POLYMERIZATION; CHICKEN-EMBRYO; SPOTTED-FEVER; PLAQUE ASSAY; PROWAZEKII; CELLS; MUTAGENESIS; INFECTION; VIRULENT; CONORII AB Transformation frequencies of a mariner-based transposon system in Rickettsia rickettsii were determined using a plaque assay system for enumeration and isolation of mutants. Sequence analysis of insertion sites in both R. rickettsii and R. prowazekii indicated that insertions were random. Transposon mutagenesis provides a useful tool for rickettsial research. C1 [Clark, Tina R.; Kleba, Betsy; Lutter, Erika I.; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. [Lackey, Amanda M.; Driskell, Lonnie O.; Wood, David O.] Univ S Alabama, Dept Microbiol & Immunol, Coll Med, Mobile, AL 36688 USA. [Martens, Craig] NIAID, Genom Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM Ted_Hackstadt@nih.gov FU NIAID at the NIH; Public Health Service [AI20384] FX This work was supported by the Intramural Research Program of the NIAID at the NIH and by Public Health Service grant AI20384 to D.O.W. NR 23 TC 10 Z9 10 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 2011 VL 193 IS 18 BP 4993 EP 4995 DI 10.1128/JB.05279-11 PG 3 WC Microbiology SC Microbiology GA 812BC UT WOS:000294261700045 PM 21764933 ER PT J AU Pickhardt, PJ Lee, LJ del Rio, AM Lauder, T Bruce, RJ Summers, RM Pooler, BD Binkley, N AF Pickhardt, Perry J. Lee, Lawrence J. del Rio, Alejandro Munoz Lauder, Travis Bruce, Richard J. Summers, Ron M. Pooler, B. Dustin Binkley, Neil TI Simultaneous Screening for Osteoporosis at CT Colonography: Bone Mineral Density Assessment Using MDCT Attenuation Techniques Compared With the DXA Reference Standard SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE OSTEOPOROSIS; SCREENING; BONE MINERAL DENSITY; COMPUTED TOMOGRAPHY; CT COLONOGRAPHY ID QUANTITATIVE COMPUTED-TOMOGRAPHY; X-RAY ABSORPTIOMETRY; POSTMENOPAUSAL WOMEN; ASYMPTOMATIC ADULTS; EXTRACOLONIC FINDINGS; OFFICIAL POSITIONS; DIAGNOSIS; DENSITOMETRY; COLONOSCOPY; OSTEOPENIA AB The purpose of this study was to evaluate the utility of lumbar spine attenuation measurement for bone mineral density (BMD) assessment at screening computed tomographic colonography (CTC) using central dual-energy X-ray absorptiometry (DXA) as the reference standard. Two-hundred and fifty-two adults (240 women and 12 men; mean age 58.9 years) underwent CTC screening and central DXA BMD measurement within 2 months (mean interval 25.0 days). The lowest DXA T-score between the spine and hip served as the reference standard, with low BMD defined per World Health Organization as osteoporosis (DXA T-score <= -2.5) or osteopenia (DXA T-score between -1.0 and -2.4). Both phantomless quantitative computed tomography (QCT) and simple nonangled region-of-interest (ROI) multi-detector CT (MDCT) attenuation measurements were applied to the T-12-L-5 levels. The ability to predict osteoporosis and low BMD (osteoporosis or osteopenia) by DXA was assessed. A BMD cut-off of 90 mg/mL at phantomless QCT yielded 100% sensitivity for osteoporosis (29 of 29) and a specificity of 63.8% (143 of 224); 87.2% (96 of 110) below this threshold had low BMD and 49.6% (69 of 139) above this threshold had normal BMD at DXA. At L-1, a trabecular ROI attenuation cut-off of 160 HU was 100% sensitive for osteoporosis (29 of 29), with a specificity of 46.4% (104 of 224); 83.9% (125 of 149) below this threshold had low BMD and 57.5% (59/103) above had normal BMD at DXA. ROI performance was similar at all individual T-12-L-5 levels. At ROC analysis, AUC for osteoporosis was 0.888 for phantomless QCT [95% confidence interval (CI) 0.780-0.946] and ranged from 0.825 to 0.853 using trabecular ROIs at single lumbar levels (0.864; 95% CI 0.752-0.930 at multivariate analysis). Supine-prone reproducibility was better with the simple ROI method compared with QCT. It is concluded that both phantomless QCT and simple ROI attenuation measurements of the lumbar spine are effective for BMD screening at CTC with high sensitivity for osteoporosis, as defined by the DXA T-score. (C) 2011 American Society for Bone and Mineral Research. C1 [Pickhardt, Perry J.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Radiol, Clin Sci Ctr E3 311, Madison, WI 53792 USA. [Summers, Ron M.] NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. RP Pickhardt, PJ (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Radiol, Clin Sci Ctr E3 311, 600 Highland Ave, Madison, WI 53792 USA. EM ppickhardt2@uwhealth.org FU National Institutes of Health [1R01CA144835-01]; iCAD FX PJP serves as a consultant for Medicsight, Viatronix, Bracco, and Check Cap and is cofounder of VirtuoCTC. RMS receives royalties and research support from iCAD and owns stock in Johnson & Johnson. Binkley is a consultant for Merck, Amgen, Lilly, and Tarsa. All the other authors state that they have no conflicts of interest.; This research was supported in part by the National Institutes of Health (Grant 1R01CA144835-01). NR 33 TC 63 Z9 65 U1 3 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2011 VL 26 IS 9 BP 2194 EP 2203 DI 10.1002/jbmr.428 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 814JG UT WOS:000294444300019 PM 21590738 ER PT J AU Padberg, RM AF Padberg, Rose Mary TI Cancer Clinical Trial Accrual: We Have a Problem SO JOURNAL OF CANCER EDUCATION LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Padberg, RM (reprint author), NCI, Bethesda, MD 20892 USA. EM padbergr@mail.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD SEP PY 2011 VL 26 IS 3 BP 403 EP 404 DI 10.1007/s13187-011-0224-0 PG 2 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 812CX UT WOS:000294266400002 PM 21445681 ER PT J AU Rutten, LJF Blake, K Hesse, BW Ackerson, LK AF Rutten, Lila J. Finney Blake, Kelly Hesse, Bradford W. Ackerson, Leland K. TI Isolated and Skeptical: Social Engagement and Trust in Information Sources Among Smokers SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Smoking; Social engagement; Health ID RANDOMIZED CONTROLLED-TRIAL; SELF-RATED HEALTH; SMOKING; COMMUNITY; NETWORKS; MORTALITY AB Our study compared indicators of social engagement and trust among current, former, and never smokers. Multinomial regression analyses of data from the 2005 U.S. Health Information National Trends Survey (n = 5586) were conducted to identify independent associations between social engagement, trust in health information sources, and smoking status. Never smokers (odds ratio (OR) = 2.08) and former smokers (OR = 2.48) were significantly more likely to belong to community organizations than current smokers. Never (OR = 4.59) and former smokers (OR = 1.96) were more likely than current smokers to attend religious services. Never smokers (OR = 1.38) were significantly more likely than current smokers to use the Internet. Former smokers (OR = 1.41) were more likely than current smokers to be married. Compared to current smokers, never smokers were significantly more likely to trust health care professionals (OR = 1.52) and less likely to trust the Internet (OR=0.59) for health information. Current smokers are less socially engaged and less trusting of information resources than non-smokers. C1 [Rutten, Lila J. Finney] NCI, Clin Monitoring Res Program, SAIC Frederick Inc, Frederick, MD 21704 USA. [Blake, Kelly; Hesse, Bradford W.] NCI, Hlth Commun & Informat Res Branch, Bethesda, MD 20892 USA. [Ackerson, Leland K.] Univ Massachusetts, Dept Community Hlth & Sustainabil, Lowell, MA USA. RP Rutten, LJF (reprint author), 6130 Execut Blvd,MSC 7365, Bethesda, MD 20892 USA. EM finneyl@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 32 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD SEP PY 2011 VL 26 IS 3 BP 465 EP 473 DI 10.1007/s13187-011-0201-7 PG 9 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 812CX UT WOS:000294266400011 PM 21340632 ER PT J AU Villa, A Kreimer, AR Pasi, M Polimeni, A Cicciu, D Strohmenger, L Gherlone, E Abati, S AF Villa, Alessandro Kreimer, Aimee R. Pasi, Massimo Polimeni, Antonella Cicciu, Domenico Strohmenger, Laura Gherlone, Enrico Abati, Silvio TI Oral Cancer Knowledge: A Survey Administered to Patients in Dental Departments at Large Italian Hospitals SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Oral cancer; Oral cancer knowledge; Risk factors ID YOUNG-PEOPLE; PRIMARY-CARE; RISK-FACTORS; DENTISTS; CARCINOMA; ATTITUDES; AWARENESS; ENGLAND; SMOKING; HEALTH AB We assessed the oral cancer (OC) knowledge, including risk factors and clinical symptoms, among patients attending dental departments within Italian university hospitals. Two thousand and two hundred questionnaires were sent to four hospitals in order to assess patients' knowledge regarding clinical and epidemiological aspects of OC; OC knowledge was evaluated overall and stratified by oral cancer family history. Participants frequently identified cigarette smoking (87.8%) and heavy alcohol consumption (58.6%) as a risk factor for oral cancer, knew the clinical signs of OC (65-79% depending on the specific symptom) and reported that early detection was related to better prognosis of oral cancer (94%). Individuals with a positive family history for oral cancer were significantly more likely to identify risk factors for oral cancer correctly yet family history of OC did not affect smoking status. Less than 15% of patients reported having received OC counseling by a dentist or physician. C1 [Villa, Alessandro; Strohmenger, Laura; Abati, Silvio] Univ Milan, Dent Clin, Dept Med Surg & Dent, I-20142 Milan, Italy. [Villa, Alessandro; Kreimer, Aimee R.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Pasi, Massimo; Gherlone, Enrico] Univ Vita Salute San Raffaele, Hosp San Raffaele, Dept Dent, I-20132 Milan, Italy. [Polimeni, Antonella] Univ Roma La Sapienza, Dept Oral & Maxillofacial Sci, Dent Clin, I-00161 Rome, Italy. [Cicciu, Domenico] Univ Messina, Dept Dent, Messina, Italy. [Cicciu, Domenico] Policlin Univ, I-98125 Messina, Italy. RP Villa, A (reprint author), Univ Milan, Dent Clin, Dept Med Surg & Dent, Via Beldiletto 1-3, I-20142 Milan, Italy. EM alessandro.villa@unimi.it RI Abati, Silvio/I-9286-2012; Kreimer, Aimee/H-1687-2015; Gherlone, Enrico/M-7376-2016; OI Villa, Alessandro/0000-0002-1966-6000 FU Intramural NIH HHS [ZIA CP010209-01] NR 23 TC 4 Z9 4 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD SEP PY 2011 VL 26 IS 3 BP 505 EP 509 DI 10.1007/s13187-010-0189-4 PG 5 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 812CX UT WOS:000294266400017 PM 21207219 ER PT J AU Richie, CT Bembenek, JN Chestnut, B Furuta, T Schumacher, JM Wallenfang, M Golden, A AF Richie, Christopher T. Bembenek, Joshua N. Chestnut, Barry Furuta, Tokiko Schumacher, Jill M. Wallenfang, Matthew Golden, Andy TI Protein phosphatase 5 is a negative regulator of separase function during cortical granule exocytosis in C. elegans SO JOURNAL OF CELL SCIENCE LA English DT Article DE Separase; Cortical granule exocytosis; Protein phosphatase 5 ID SISTER-CHROMATID SEPARATION; ANTERIOR-POSTERIOR AXIS; CAENORHABDITIS-ELEGANS; CELL-CYCLE; MEIOSIS-I; CHONDROITIN PROTEOGLYCANS; PHOSPHORYLATION; INHIBITION; COHESION; LOCALIZATION AB Mutations in the Caenorhabditis elegans separase gene, sep-1, are embryonic lethal. Newly fertilized mutant embryos have defects in polar body extrusion, fail to undergo cortical granule exocytosis, and subsequently fail to complete cytokinesis. Chromosome nondisjunction during the meiotic divisions is readily apparent after depletion of sep-1 by RNAi treatment, but much less so in hypomorphic mutant embryos. To identify factors that influence the activity of separase in cortical granule exocytosis and cytokinesis, we carried out a genetic suppressor screen. A mutation in the protein phosphatase 5 (pph-5) gene was identified as an extragenic suppressor of sep-1. This mutation suppressed the phenotypes of hypomorphic separase mutants but not RNAi depleted animals. Depletion of pph-5 caused no phenotypes on its own, but was effective in restoring localization of mutant separase to vesicles and suppressing cortical granule exocytosis and cytokinesis phenotypes. The identification of PPH-5 as a suppressor of separase suggests that a new phospho-regulatory pathway plays an important role in regulating anaphase functions of separase. C1 [Richie, Christopher T.; Chestnut, Barry; Golden, Andy] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Bembenek, Joshua N.] Univ Wisconsin, Mol Biol Lab, Madison, WI 53706 USA. [Furuta, Tokiko; Schumacher, Jill M.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Wallenfang, Matthew] Columbia Univ Barnard Coll, Dept Biol Sci, New York, NY 10027 USA. RP Golden, A (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM andyg@mail.nih.gov RI Schumacher, Jill/B-2932-2012; OI Bembenek, Joshua/0000-0002-0966-2268 FU NIH National Center for Research Resources; NIH [5R01GM062181]; NIH, National Institute of Diabetes and Digestive and Kidney Disease FX We acknowledge Mike Boxem (Harvard Medical School) for pDEST-MB16, Shohei Mitani (Tokyo Women's Medical University School of Medicine) for generating the pph-5(tm2979) allele and the C. elegans Gene Knockout Consortium (Oklahoma Medical Research Foundation) for generating the sep-1(ok1749) allele. Some strains were provided by the Caenorhabditis Genetics Center, funded by the NIH National Center for Research Resources. We are grateful for the suggestions and comments from Kevin O'Connell, Kathryn Stein, and members of the Baltimore Worm Club. This research was supported by NIH grant 5R01GM062181 (J.M.S.) and the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (A.G.). Deposited in PMC for release after 12 months. NR 46 TC 2 Z9 5 U1 0 U2 5 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 SEP 1 PY 2011 VL 124 IS 17 BP 2903 EP 2913 DI 10.1242/jcs.073379 PG 11 WC Cell Biology SC Cell Biology GA 814BK UT WOS:000294419200004 PM 21878498 ER PT J AU Deng, P Pang, ZP Lei, ZG Shikano, S Xiong, QJ Harvey, BK London, B Wang, Y Li, M Xu, ZC AF Deng, Ping Pang, Zhi-Ping Lei, Zhigang Shikano, Sojin Xiong, Qiaojie Harvey, Brandon K. London, Barry Wang, Yun Li, Min Xu, Zao C. TI Up-regulation of A-type potassium currents protects neurons against cerebral ischemia SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE excitotoxicity; neuroprotection; potassium channels; striatum; stroke ID TRANSIENT FOREBRAIN ISCHEMIA; LARGE ASPINY NEURONS; STRIATAL CHOLINERGIC INTERNEURONS; IN-VITRO; PYRAMIDAL NEURONS; KINASE-C; RAT; CHANNELS; DEATH; LOCALIZATION AB Excitotoxicity is the major cause of many neurologic disorders including stroke. Potassium currents modulate neuronal excitability and therefore influence the pathological process. A-type potassium current (I-A) is one of the major voltage-dependent potassium currents, yet its roles in excitotoxic cell death are not well understood. We report that, following ischemic insults, the I-A increases significantly in large aspiny (LA) neurons but not medium spiny (MS) neurons in the striatum, which correlates with the higher resistance of LA neurons to ischemia. Activation of protein kinase increases I-A in LA neurons after ischemia. Cultured neurons from transgenic mice lacking both Kv1.4 and Kv4.2 subunits exhibit an increased vulnerability to ischemic insults. Increase of I-A by recombinant expression of Kv1.4 or Kv4.2 is sufficient in improving the survival of MS neurons against ischemic insults both in vitro and in vivo. These results, taken together, provide compelling evidence for a protective role of I-A against ischemia. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1823-1835; doi:10.1038/jcbfm.2011.88; published online 15 June 2011 C1 [Deng, Ping; Pang, Zhi-Ping; Lei, Zhigang; Xu, Zao C.] Indiana Univ Sch Med, Dept Anat & Cell Biol, Indianapolis, IN 46202 USA. [Shikano, Sojin; Xiong, Qiaojie; Li, Min] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Shikano, Sojin; Xiong, Qiaojie; Li, Min] Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Baltimore, MD 21205 USA. [Harvey, Brandon K.; Wang, Yun] NIDA, NIH, Baltimore, MD USA. [London, Barry] Univ Pittsburgh, Sch Med, Div Cardiol, Pittsburgh, PA USA. RP Xu, ZC (reprint author), Indiana Univ Sch Med, Dept Anat & Cell Biol, 635 Barnhill Dr,MS 507, Indianapolis, IN 46202 USA. EM zcxu@iupui.edu OI Pang, Zhiping/0000-0002-6183-1233 FU EIA of AHA [NS071238, AHA0655747Z, MH084691, GM070959]; AHA [0425689Z, 0526007Z, 0630172N] FX This work was supported by Grants NS071238, AHA0655747Z to ZCX, MH084691 and GM070959, EIA of AHA to ML. PD and ZGL are recipients of AHA postdoctoral fellowships (0425689Z, 0526007Z, 0630172N). NR 39 TC 14 Z9 14 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD SEP PY 2011 VL 31 IS 9 BP 1823 EP 1835 DI 10.1038/jcbfm.2011.88 PG 13 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 815KK UT WOS:000294524300002 PM 21673715 ER PT J AU Lu, YN Ma, HY Malone, KE Norman, SA Sullivan-Halley, J Strom, BL Marchbanks, PA Spirtas, R Burkman, RT Deapen, D Folger, SG Simon, MS Press, MF McDonald, JA Bernstein, L AF Lu, Yani Ma, Huiyan Malone, Kathleen E. Norman, Sandra A. Sullivan-Halley, Jane Strom, Brian L. Marchbanks, Polly A. Spirtas, Robert Burkman, Ronald T. Deapen, Dennis Folger, Suzanne G. Simon, Michael S. Press, Michael F. McDonald, Jill A. Bernstein, Leslie TI Obesity and Survival Among Black Women and White Women 35 to 64 Years of Age at Diagnosis With Invasive Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BODY-MASS INDEX; RECEIVING ADJUVANT CHEMOTHERAPY; AMERICAN WOMEN; RISK-FACTORS; AFRICAN-AMERICAN; WEIGHT-LOSS; LIFE-STYLE; MORTALITY; STAGE; OVERWEIGHT AB Purpose To evaluate the effect of obesity on survival among black women and white women with invasive breast cancer and to determine whether obesity explains the poorer survival of black women relative to white women. Patients and Methods We observed 4,538 (1,604 black, 2,934 white) women who were 35 to 64 years of age when diagnosed with incident invasive breast cancer between 1994 and 1998. Multivariate Cox regression models were used to examine the effect of body mass index (BMI, in kilograms per square meter) 5 years before diagnosis on risk of death from any cause and from breast cancer. Results During a median of 8.6 years of follow-up, 1,053 women died (519 black, 534 white), 828 as a result of breast cancer (412 black, 416 white). Black women were more likely to die than white women (multivariate-adjusted relative risk [RR], 1.33; 95% CI, 1.16 to 1.53). Compared with women with BMI of 20 to 24.9 kg/m(2), those who were obese (BMI >= 30 kg/m(2)) had a greater risk of all-cause mortality (RR, 1.23; 95% CI, 1.04 to 1.47) and breast cancer-specific mortality (RR, 1.20; 95% CI, 0.99 to 1.46). These associations were observed among white women (all-cause RR, 1.54; 95% CI, 1.21 to 1.96; breast cancer RR, 1.46; 95% CI, 1.11 to 1.92), but not among black women (all-cause RR, 1.03; 95% CI, 0.81 to 1.29; breast cancer RR, 1.02; 95% CI, 0.79 to 1.33). Conclusion Obesity may play an important role in mortality among white but not black patients with breast cancer. It is unlikely that differences in obesity distributions between black women and white women account for the poorer survival of black women. J Clin Oncol 29:3358-3365. (C) 2011 by American Society of Clinical Oncology C1 [Lu, Yani] City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Beckman Res Inst, Duarte, CA 91010 USA. [Deapen, Dennis; Press, Michael F.] Univ So Calif, Los Angeles, CA USA. [Malone, Kathleen E.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Norman, Sandra A.; Strom, Brian L.] Univ Penn, Philadelphia, PA 19104 USA. [Marchbanks, Polly A.; Folger, Suzanne G.; McDonald, Jill A.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Spirtas, Robert] Natl Inst Child Hlth & Dev, NIH, Bethesda, MD USA. [Burkman, Ronald T.] Tufts Univ, Sch Med, Springfield, MA 01199 USA. [Burkman, Ronald T.] Baystate Med Ctr, Springfield, MA USA. [Simon, Michael S.] Wayne State Univ, Detroit, MI USA. RP Lu, YN (reprint author), City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Beckman Res Inst, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM yalu@coh.org FU Genentech; Ventana Medical; California Breast Cancer Research Program [15FB-0004]; National Institute of Child Health and Human Development; National Cancer Institute; Emory University [N01-HD-2-3168]; Fred Hutchinson Cancer Research Center [N01-HD-2-3166]; Karmanos Cancer Institute at Wayne State University [N01-HD-3-3174]; University of Pennsylvania [N01-HD-3-3176]; University of Southern California [N01-HD-3-3175]; US Centers for Disease Control and Prevention [Y01-HD-7022]; [N01-PC-67006]; [N01-CN-65064]; [N01-PC-67010]; [N01-CN-05230] FX Research Funding: Michael F. Press, Genentech, Ventana Medical; Supported by the California Breast Cancer Research Program (Grant No. 15FB-0004). The Women's Contraceptive and Reproductive Experiences Study was funded by the National Institute of Child Health and Human Development, with additional support from the National Cancer Institute, through contracts with Emory University (Grant No. N01-HD-2-3168), Fred Hutchinson Cancer Research Center (Grant No. N01-HD-2-3166), Karmanos Cancer Institute at Wayne State University (Grant No. N01-HD-3-3174), the University of Pennsylvania (Grant No. N01-HD-3-3176), and the University of Southern California (Grant No. N01-HD-3-3175), and through an intra-agency agreement with the US Centers for Disease Control and Prevention (Grant No. Y01-HD-7022). Support for use of Surveillance, Epidemiology, and End Results cancer registries for case identification was through Grants No. N01-PC-67006 (Atlanta), N01-CN-65064 (Detroit), N01-PC-67010 (Los Angeles), and N01-CN-05230 (Seattle). NR 46 TC 35 Z9 35 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 1 PY 2011 VL 29 IS 25 BP 3358 EP 3365 DI 10.1200/JCO.2010.34.2048 PG 8 WC Oncology SC Oncology GA 814EO UT WOS:000294429900012 PM 21788570 ER PT J AU Crea, F Fornaro, L Masi, G Falcone, A Danesi, R Farrar, W AF Crea, Francesco Fornaro, Lorenzo Masi, Gianluca Falcone, Alfredo Danesi, Romano Farrar, William TI Faithful Markers of Circulating Cancer Stem Cells: Is CD133 Sufficient for Validation in Clinics? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID TUMOR-CELLS; COLORECTAL-CANCER; COLON-CANCER; POLYCOMB; STAGE; DIFFERENTIATION; EXPRESSION; PROGNOSIS; EZH2 C1 [Crea, Francesco; Danesi, Romano] Univ Pisa, Pisa, Italy. [Fornaro, Lorenzo; Masi, Gianluca; Falcone, Alfredo] Azienda Osped Univ Pisana, Pisa, Italy. [Farrar, William] NCI, Frederick, MD 21701 USA. RP Crea, F (reprint author), Univ Pisa, Pisa, Italy. RI Crea, Francesco /I-8383-2015; OI Fornaro, Lorenzo/0000-0002-0187-5904; Crea, Francesco/0000-0002-4903-2973 NR 13 TC 9 Z9 9 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 1 PY 2011 VL 29 IS 25 BP 3487 EP 3488 DI 10.1200/JCO.2011.37.0122 PG 2 WC Oncology SC Oncology GA 814EO UT WOS:000294429900029 PM 21788560 ER PT J AU Driscoll, C Yamaguchi, N O'Brien, SJ Macdonald, DW AF Driscoll, Carlos Yamaguchi, Nobuyuki O'Brien, Stephen J. Macdonald, David W. TI A Suite of Genetic Markers Useful in Assessing Wildcat (Felis silvestris ssp.)- Domestic Cat (Felis silvestris catus) Admixture SO JOURNAL OF HEREDITY LA English DT Article DE captive breeding; conservation genetics; hybridization; introgression; reintroduction microsatellite ID CRANIOLOGICAL DIFFERENTIATION; SCOTTISH WILDCAT; CONSERVATION; POPULATIONS; HYBRIDS; HYBRIDIZATION; BRITAIN; HUNGARY AB The wildcat (Felis silvestris ssp.) is a conservation concern largely due to introgressive hybridization with its congener F. s. rates, the common domestic cat. Because of a recent divergence and entirely overlapping ranges, hybridization is common and pervasive between these taxa threatening the genetic integrity of remaining wildcat populations. Identifying pure wildcats for inclusion in conservation programs using current morphological discriminants is difficult because of gross similarity between them and the domestic, critically hampering conservation efforts. Here, we present a vetted panel of microsatellite loci and mitochondrial polymorphisms informative for each of the 5 naturally evolved wildcat subspecies and the derived domestic cat. We also present reference genotypes for each assignment class. Together, these marker sets and corresponding reference genotypes allow for the development of a genetic rational for defining "units of conservation" within a phylogenetically based taxonomy of the entire F. silvestris species complex. We anticipate this marker panel will allow conservators to assess genetic integrity and quantify admixture in managed wildcat populations and to be a starting point for more in-depth analysis of hybridization. C1 [Driscoll, Carlos; Yamaguchi, Nobuyuki; Macdonald, David W.] Univ Oxford, Dept Zool, Wildlife Conservat Res Unit, Recanati Kaplan Ctr, Abingdon OX13 5QL, Oxon, England. [Driscoll, Carlos; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Yamaguchi, Nobuyuki] Univ Qatar, Dept Biol & Environm Sci, Doha, Qatar. RP Driscoll, C (reprint author), Univ Oxford, Dept Zool, Wildlife Conservat Res Unit, Recanati Kaplan Ctr, Tubney House, Abingdon OX13 5QL, Oxon, England. EM driscoll.carlos@gmail.com FU National Institutes of Health FX National Institutes of Health. NR 37 TC 8 Z9 8 U1 2 U2 49 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD SEP-OCT PY 2011 VL 102 SU 1 BP S87 EP S90 DI 10.1093/jhered/esr047 PG 4 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 813ME UT WOS:000294370500013 PM 21846752 ER PT J AU Huson, HJ Byers, AM Runstadler, J Ostrander, EA AF Huson, Heather J. Byers, Alexandra M. Runstadler, Jonathan Ostrander, Elaine A. TI An SNP within the Angiotensin-Converting Enzyme Distinguishes between Sprint and Distance Performing Alaskan Sled Dogs in a Candidate Gene Analysis SO JOURNAL OF HEREDITY LA English DT Article DE Alaskan sled dogs; angiotensin-converting enzyme; myostatin; performance genetics ID MYOSTATIN GENE; ATHLETIC PERFORMANCE; PHYSICAL PERFORMANCE; DELETION; POLYMORPHISM; MUTATION; ASSOCIATION; CATTLE; MUSCLE AB The Alaskan sled dog offers a unique mechanism for studying the genetics of elite athletic performance. They are a group of mixed breed dogs, comprised of multiple common breeds, and a unique breed entity seen only as a part of the sled dog mix. Alaskan sled dogs are divided into 2 primary groups as determined by their racing skills. Distance dogs are capable of running over 1000 miles in 10 days, whereas sprint dogs run much shorter distances, approximately 30 miles, but in faster times, that is, 18-25 mph. Finding the genes that distinguish these 2 types of performers is likely to illuminate genetic contributors to human athletic performance. In this study, we tested for association between polymorphisms in 2 candidate genes; angiotensin-converting enzyme (ACE) and myostatin (MSTN) and enhanced speed and endurance performance in 174 Alaskan sled dogs. We observed 81 novel genetic variants within the ACE gene and 4 within the MSTN gene, including a polymorphism within the ACE gene that significantly (P value 2.38 x 10(-5)) distinguished the sprint versus distance populations. C1 [Huson, Heather J.; Byers, Alexandra M.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Huson, Heather J.; Runstadler, Jonathan] Univ Alaska Fairbanks, Inst Arctic Biol, Fairbanks, AK USA. RP Ostrander, EA (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov FU IDeA Networks of Biomedical Research Excellence (INBRE); NCRR [5P20RR016466]; National Human Genome Research Institute FX IDeA Networks of Biomedical Research Excellence (INBRE). INBRE grant 5P20RR016466 from NCRR (J.R.) and the Intramural program of the National Human Genome Research Institute for their support (H.H., H.P. E.A.O). NR 26 TC 3 Z9 3 U1 1 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD SEP-OCT PY 2011 VL 102 SU 1 BP S19 EP S27 DI 10.1093/jhered/esr022 PG 9 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 813ME UT WOS:000294370500004 PM 21846742 ER PT J AU Walters-Conte, KB Johnson, DLE Allard, MW Pecon-Slattery, J AF Walters-Conte, Kathryn B. Johnson, Diana L. E. Allard, Marc W. Pecon-Slattery, Jill TI Carnivore-Specific SINEs (Can-SINEs): Distribution, Evolution, and Genomic Impact SO JOURNAL OF HEREDITY LA English DT Article DE carnivore; genome; SINE ID LINKED MYOTUBULAR MYOPATHY; NON-LTR RETROTRANSPOSONS; TRANSFER-RNA; ALU REPEATS; PHYLOGENETIC-RELATIONSHIPS; TRANSPOSABLE ELEMENTS; RETROPOSON ANALYSIS; R2 RETROTRANSPOSON; ORDER CARNIVORA; DOMESTIC DOG AB Short interspersed nuclear elements (SINEs) are a type of class 1 transposable element (retrotransposon) with features that allow investigators to resolve evolutionary relationships between populations and species while providing insight into genome composition and function. Characterization of a Carnivora-specific SINE family, Can-SINEs, has, has aided comparative genomic studies by providing rare genomic changes, and neutral sequence variants often needed to resolve difficult evolutionary questions. In addition, Can-SINEs constitute a significant source of functional diversity with Carnivora. Publication of the whole-genome sequence of domestic dog, domestic cat, and giant panda serves as a valuable resource in comparative genomic inferences gleaned from Can-SINEs. In anticipation of forthcoming studies bolstered by new genomic data, this review describes the discovery and characterization of Can-SINE motifs as well as describes composition, distribution, and effect on genome function. As the contribution of noncoding sequences to genomic diversity becomes more apparent, SIN Es and other transposable elements will play an increasingly large role in mammalian comparative genomics. C1 [Walters-Conte, Kathryn B.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Johnson, Diana L. E.] George Washington Univ, Dept Biol Sci, Washington, DC 20052 USA. [Allard, Marc W.] US FDA, Div Microbiol, College Pk, MD USA. [Pecon-Slattery, Jill] NCI, Lab Genom Div, Frederick, MD 21701 USA. RP Walters-Conte, KB (reprint author), Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. EM kwalt@sas.upenn.edu FU National Cancer institute, National Institutes of Health [N01-CO-12400]; George Washington University FX This project has been supported in part with federal funds from the National Cancer institute, National Institutes of Health, under contract N01-CO-12400. The Robert Weintraub Program in Systematics and Evolution administered by The George Washington University also provided financial support. NR 70 TC 4 Z9 4 U1 3 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD SEP-OCT PY 2011 VL 102 SU 1 BP S2 EP S10 DI 10.1093/jhered/esr051 PG 9 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 813ME UT WOS:000294370500002 PM 21846743 ER PT J AU Duplessis, CA Tilley, D Bavaro, M Hale, B Holland, SM AF Duplessis, Christopher A. Tilley, Drake Bavaro, Mary Hale, Braden Holland, Steven M. TI Two cases illustrating successful adjunctive interferon-gamma immunotherapy in refractory disseminated coccidioidomycosis SO JOURNAL OF INFECTION LA English DT Article DE Interferon; Coccidioidomycosis; Immunotherapy; IFN-gamma; IL-12 ID MYCOBACTERIAL INFECTION; RECEPTOR AB Protective immunity and host resistance to coccidioidomycosis require a robust cell-mediated immunity with adequate production of Th1 cytokines including interleukin-12, and IFN-gamma and appropriate regulation and coordinated functionality of Th1/Th2 responses and IL-12/IFN-gamma cytokine axes. IFN-gamma augments the anti-fungal activity of effector immune cells against a variety of fungi. Numerous animal models have demonstrated the potential efficacy of adjunctive IFN-gamma in treatment of invasive mycoses. Yet, despite these promising data, a paucity of literature documents efficacious adjunctive IFN-gamma administration in refractory coccidioidomycosis. We present two cases of refractory disease occurring at our institution who responded to adjunctive IFN-gamma. Published by Elsevier Ltd on behalf of The British Infection Association. C1 [Duplessis, Christopher A.; Tilley, Drake; Bavaro, Mary; Hale, Braden] Infect Dis Naval Hosp, Naval Med Ctr San Diego, San Diego, CA 92134 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Duplessis, CA (reprint author), Infect Dis Naval Hosp, Naval Med Ctr San Diego, 34800 Bob Wilson Dr,Ste 5, San Diego, CA 92134 USA. EM christopher.duplessis@med.navy.mil FU Intramural NIH HHS [Z01 AI000647-16] NR 11 TC 8 Z9 8 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 J9 J INFECTION JI J. Infect. PD SEP PY 2011 VL 63 IS 3 BP 223 EP 228 DI 10.1016/j.jinf.2011.07.006 PG 6 WC Infectious Diseases SC Infectious Diseases GA 814JX UT WOS:000294448000006 PM 21791226 ER PT J AU Eberle, FC Salaverria, I Steidl, C Summers, TA Pittaluga, S Ben Neriah, S Rodriguez-Canales, J Xi, LQ Ylaya, K Liewehr, D Dunleavy, K Wilson, WH Hewitt, SM Raffeld, M Gascoyne, RD Siebert, R Jaffe, ES AF Eberle, Franziska C. Salaverria, Itziar Steidl, Christian Summers, Thomas A., Jr. Pittaluga, Stefania Ben Neriah, Susana Rodriguez-Canales, Jaime Xi, Liqiang Ylaya, Kris Liewehr, David Dunleavy, Kieron Wilson, Wyndham H. Hewitt, Stephen M. Raffeld, Mark Gascoyne, Randy D. Siebert, Reiner Jaffe, Elaine S. TI Chromosomal aberrations in gray zone lymphomas SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 41st Annual Meeting of the European-Society-for-Dermatological-Research CY SEP 07-10, 2011 CL Barcelona, SPAIN SP European Soc Dermatol Res C1 [Eberle, Franziska C.; Summers, Thomas A., Jr.; Pittaluga, Stefania; Rodriguez-Canales, Jaime; Xi, Liqiang; Ylaya, Kris; Hewitt, Stephen M.; Raffeld, Mark; Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Eberle, Franziska C.] Eberhard Karls Univ Tubingen, Dept Dermatol, Tubingen, Germany. [Salaverria, Itziar; Siebert, Reiner] Univ Kiel, Kiel & Univ Hosp Schleswig Holstein, Inst Human Genet, D-24098 Kiel, Germany. [Steidl, Christian; Ben Neriah, Susana; Gascoyne, Randy D.] Ctr Lymphoid Canc, Dept Pathol & Lab Med, Vancouver, BC, Canada. [Steidl, Christian; Ben Neriah, Susana; Gascoyne, Randy D.] Ctr Translat & Appl Genom CTAG, Vancouver, BC, Canada. [Liewehr, David; Dunleavy, Kieron] NIH, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2011 VL 131 SU 2 BP S25 EP S25 PG 1 WC Dermatology SC Dermatology GA 813IY UT WOS:000294361300145 ER PT J AU Mascia, F Lam, G Yuspa, S AF Mascia, Francesca Lam, Gary Yuspa, Stuart TI Genetic and pharmacologic ablation of EGFR reveals its role as endogenous anti-inflammatory agent in mouse and human skin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 41st Annual Meeting of the European-Society-for-Dermatological-Research CY SEP 07-10, 2011 CL Barcelona, SPAIN SP European Soc Dermatol Res C1 [Mascia, Francesca; Lam, Gary; Yuspa, Stuart] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2011 VL 131 SU 2 BP S33 EP S33 PG 1 WC Dermatology SC Dermatology GA 813IY UT WOS:000294361300194 ER PT J AU Schmuth, M Elentner, A Gonzalez, FJ Dubrac, S AF Schmuth, Matthias Elentner, Andreas Gonzalez, Frank J. Dubrac, Sandrine TI Pregnane X Receptor (PXR) links xenobiotic metabolism to the cutaneous immune response SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 41st Annual Meeting of the European-Society-for-Dermatological-Research CY SEP 07-10, 2011 CL Barcelona, SPAIN SP European Soc Dermatol Res C1 [Schmuth, Matthias; Elentner, Andreas; Dubrac, Sandrine] Innsbruck Med Sch, Innsbruck, Austria. [Gonzalez, Frank J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2011 VL 131 SU 2 BP S90 EP S90 PG 1 WC Dermatology SC Dermatology GA 813IY UT WOS:000294361300534 ER PT J AU Segre, J Kong, H Oh, J Grice, E Conlan, S Deming, C Murray, P Turner, M AF Segre, Julia Kong, Heidi Oh, Julia Grice, Elizabeth Conlan, Sean Deming, Clay Murray, Patrick Turner, Maria TI Skin Microbiome Analyses of Healthy Individuals and Atopic Dermatitis Patients SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 41st Annual Meeting of the European-Society-for-Dermatological-Research CY SEP 07-10, 2011 CL Barcelona, SPAIN SP European Soc Dermatol Res C1 [Segre, Julia; Oh, Julia; Grice, Elizabeth; Conlan, Sean; Deming, Clay; Murray, Patrick] NHGRI, NIH, Bethesda, MD 20892 USA. [Kong, Heidi; Turner, Maria] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2011 VL 131 SU 2 BP S64 EP S64 PG 1 WC Dermatology SC Dermatology GA 813IY UT WOS:000294361300380 ER PT J AU Textor, S Becker, MR Senger, T Waterboer, T Kaufmann, A Susal, C Enk, AH Gissmann, L Lonsdorf, AS AF Textor, Sonja Becker, Maria R. Senger, Tilo Waterboer, Tim Kaufmann, Andreas Suesal, Caner Enk, Alexander H. Gissmann, Lutz Lonsdorf, Anke S. TI Evaluation of systemic immune responses against cutaneous wart-associated alpha-Papillomaviruses in solid organ transplant recipients SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 41st Annual Meeting of the European-Society-for-Dermatological-Research CY SEP 07-10, 2011 CL Barcelona, SPAIN SP European Soc Dermatol Res C1 [Becker, Maria R.; Enk, Alexander H.; Lonsdorf, Anke S.] Univ Heidelberg, Dept Dermatol, D-6900 Heidelberg, Germany. [Senger, Tilo; Waterboer, Tim; Gissmann, Lutz] German Canc Res Ctr, Infect & Canc Program, Heidelberg, Germany. [Becker, Maria R.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Kaufmann, Andreas] Charite, Clin Gynecol, D-13353 Berlin, Germany. [Suesal, Caner] Univ Heidelberg, Dept Transplantat Immunol, D-6900 Heidelberg, Germany. RI Gissmann, Lutz/H-4688-2011; Pawlita, Labor/C-9720-2011; Waterboer, Tim/G-1252-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2011 VL 131 SU 2 BP S96 EP S96 PG 1 WC Dermatology SC Dermatology GA 813IY UT WOS:000294361300573 ER PT J AU Knerr, S Wayman, D Bonham, VL AF Knerr, Sarah Wayman, Dawn Bonham, Vence L. TI Inclusion of Racial and Ethnic Minorities in Genetic Research: Advance the Spirit by Changing the Rules? SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID RESEARCH ETHICS; RACE; HEALTH; DISPARITIES; POPULATION; CATEGORIES; WOMEN; NIH C1 [Wayman, Dawn] NHGRI, Div Intramural Res, Social & Behav Res Branch, NIH,Bonham Res Group, Bethesda, MD 20892 USA. RP Knerr, S (reprint author), Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. FU Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health FX This research was supported (in part) by the Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health. The content is solely the responsibility of the authors and does not represent the official position of the National Human Genome Research Institute, National Institutes of Health, or the Department of Health and Human Services. The authors thank Larry Brody and S. Malia Fullerton for helpful comments and suggestions on earlier drafts of this paper. NR 29 TC 6 Z9 6 U1 3 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD FAL PY 2011 VL 39 IS 3 BP 502 EP 512 DI 10.1111/j.1748-720X.2011.00617.x PG 11 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 810MI UT WOS:000294129000017 PM 21871045 ER PT J AU Aerbajinai, W Liu, LH Chin, K Zhu, JQ Parent, CA Rodgers, GP AF Aerbajinai, Wulin Liu, Lunhua Chin, Kyung Zhu, Jianqiong Parent, Carole A. Rodgers, Griffin P. TI Glia maturation factor-gamma mediates neutrophil chemotaxis SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE migration; fMLF; CXCL8; p38 ID CELL-MIGRATION; RHO-GTPASES; CHAIN PHOSPHORYLATION; ACTIN-FILAMENTS; ARP2/3 COMPLEX; ACTIVATION; PROTEIN; KINASE; WASP; PAK1 AB Chemotaxis is fundamental to the directional migration of neutrophils toward endogenous and exogenous chemoattractants. Recent studies have demonstrated that ADF/cofilin superfamily members play important roles in reorganizing the actin cytoskeleton by disassembling actin filaments. GMFG, a novel ADF/cofilin superfamily protein that is expressed in inflammatory cells, has been implicated in regulating actin reorganization in microendothelial cells, but its function in neutrophils remains unclear. Here, we show that GMFG is an important regulator for cell migration and polarity in neutrophils. Knockdown of endogenous GMFG impaired fMLF- and IL-8 (CXCL8)-induced chemotaxis in dHL-60 cells. GMFG knockdown attenuated the formation of lamellipodia at the leading edge of cells exposed to fMLF or CXCL8, as well as the phosphorylation of p38 and PAK1/2 in response to fMLF or CXCL8. Live cell imaging revealed that GMFG was recruited to the leading edge of cells in response to fMLF, as well as CXCL8. Overexpression of GMFG enhanced phosphorylation of p38 but not of PAK1/2 in dHL-60 cells. In addition, we found that GMFG is associated with WAVE2. Taken together, our findings suggest that GMFG is a novel factor in regulating neutrophil chemotaxis by modulating actin cytoskeleton reorganization. J. Leukoc. Biol. 90: 529-538; 2011. C1 [Aerbajinai, Wulin; Chin, Kyung; Zhu, Jianqiong; Rodgers, Griffin P.] NHLBI, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. [Liu, Lunhua; Parent, Carole A.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NIH, Mol & Clin Hematol Branch, Bldg 10,Room 9N-113A, Bethesda, MD 20892 USA. EM gr5n@nih.gov NR 43 TC 12 Z9 13 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD SEP PY 2011 VL 90 IS 3 BP 529 EP 538 DI 10.1189/jlb.0710424 PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 814IK UT WOS:000294441700013 PM 21653232 ER PT J AU Prates, DB Araujo-Santos, T Luz, NF Andrade, BB Franca-Costa, J Afonso, L Clarencio, J Miranda, JC Bozza, PT DosReis, GA Brodskyn, C Barral-Netto, M Borges, VD Barral, A AF Prates, Deboraci Brito Araujo-Santos, Theo Luz, Nivea Farias Andrade, Bruno B. Franca-Costa, Jaqueline Afonso, Lilian Clarencio, Jorge Miranda, Jose Carlos Bozza, Patricia T. DosReis, George A. Brodskyn, Claudia Barral-Netto, Manoel Borges, Valeria de Matos Barral, Aldina TI Lutzomyia longipalpis saliva drives apoptosis and enhances parasite burden in neutrophils SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE Leishmania chagasi; sand fly; cell death; FasL; chemotaxis ID LEISHMANIA-MAJOR INFECTION; PROSTAGLANDIN E-2 PRODUCTION; CUTANEOUS LEISHMANIASIS; BALB/C MICE; IMMUNE-RESPONSES; NATURAL MODEL; TGF-BETA; MACROPHAGES; PROTEINS; VECTOR AB Neutrophils are considered the host's first line of defense against infections and have been implicated in the immunopathogenesis of Leishmaniasis. Leishmania parasites are inoculated alongside vectors' saliva, which is a rich source of pharmacologically active substances that interfere with host immune response. In the present study, we tested the hypothesis that salivary components from Lutzomyia longipalpis, an important vector of visceral Leishmaniasis, enhance neutrophil apoptosis. Murine inflammatory peritoneal neutrophils cultured in the presence of SGS presented increased surface expression of FasL and underwent caspase-dependent and FasL-mediated apoptosis. This proapoptosis effect of SGS on neutrophils was abrogated by pretreatment with protease as well as pre-incubation with antisaliva antibodies. Furthermore, in the presence of Leishmania chagasi, SGS also increased apoptosis on neutrophils and increased PGE(2) release and decreased ROS production by neutrophils, while enhancing parasite viability inside these cells. The increased parasite burden was abrogated by treatment with z-VAD, a pan caspase inhibitor, and NS-398, a COX-2 inhibitor. In the presence of SGS, Leishmania-infected neutrophils produced higher levels of MCP-1 and attracted a high number of macrophages by chemotaxis in vitro assays. Both of these events were abrogated by pretreatment of neutrophils with bindarit, an inhibitor of CCL2/MCP-1 expression. Taken together, our data support the hypothesis that vector salivary proteins trigger caspase-dependent and FasL-mediated apoptosis, thereby favoring Leishmania survival inside neutrophils, which may represent an important mechanism for the establishment of Leishmania infection. J. Leukoc. Biol. 90: 575-582; 2011. C1 [Prates, Deboraci Brito; Araujo-Santos, Theo; Luz, Nivea Farias; Franca-Costa, Jaqueline; Afonso, Lilian; Clarencio, Jorge; Miranda, Jose Carlos; Brodskyn, Claudia; Barral-Netto, Manoel; Borges, Valeria de Matos; Barral, Aldina] Fundacao Oswaldo Cruz FIOCRUZ, Ctr Pesquisa Goncalo Moniz CPqGM, Salvador, BA, Brazil. [Prates, Deboraci Brito; Araujo-Santos, Theo; Luz, Nivea Farias; Franca-Costa, Jaqueline; Afonso, Lilian; Barral-Netto, Manoel; Barral, Aldina] Univ Fed Bahia, Salvador, BA, Brazil. [Andrade, Bruno B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [DosReis, George A.] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, BR-21941 Rio De Janeiro, Brazil. [Bozza, Patricia T.] Inst Oswaldo Cruz, Lab Imunofarmacol, BR-20001 Rio De Janeiro, Brazil. [Brodskyn, Claudia; Barral-Netto, Manoel; Borges, Valeria de Matos; Barral, Aldina] Inst Nacl Ciencia & Tecnol Invest Imunol Iii INCT, Salvador, BA, Brazil. RP Borges, VD (reprint author), Fundacao Oswaldo Cruz FIOCRUZ, Ctr Pesquisa Goncalo Moniz CPqGM, Av Waldemar Falcao, Salvador, BA, Brazil. EM vborges@bahia.fiocruz.br; abarral@bahia.fiocruz.br RI Barral Netto, Manoel/B-3904-2009; Clarencio, Jorge/H-3940-2012; Andrade, Bruno/J-9111-2012; Imunologia, Inct/I-2124-2013; Araujo-Santos, Theo/F-9807-2014; OI Barral Netto, Manoel/0000-0002-5823-7903; Farias Luz, Nivea/0000-0003-1958-7043; Borges, Valeria/0000-0002-2775-5409; Andrade, Bruno/0000-0001-6833-3811; Araujo-Santos, Theo/0000-0001-9861-6660; Bozza, Patricia/0000-0001-8349-9529 FU CNPq; Instituto Nacional de Ciencia e Tecnologia de Investigacao em Imunologia (iii-INCT); Fundacao de Amparo a Pesquisa do Estado da Bahia (FAPESB); CAPES FX This work was supported by CNPq, Instituto Nacional de Ciencia e Tecnologia de Investigacao em Imunologia (iii-INCT), and Fundacao de Amparo a Pesquisa do Estado da Bahia (FAPESB). D. B. P., T. A-S., N.F.L., and L. A. are recipients of a CNPq fellowship. J.F-C. is the recipient of a CAPES fellowship. P. T. B., G. A. D., C. B., M.B-N., V. M. B., and A. B. are senior investigators from CNPq. We thank Edvaldo Passos for technical assistance with the insect colony. NR 46 TC 20 Z9 20 U1 1 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD SEP PY 2011 VL 90 IS 3 BP 575 EP 582 DI 10.1189/jlb.0211105 PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 814IK UT WOS:000294441700017 PM 21685247 ER PT J AU Heim, S Friedman, JT Keil, A Benasich, AA AF Heim, Sabine Friedman, Jennifer Thomas Keil, Andreas Benasich, April A. TI Reduced sensory oscillatory activity during rapid auditory processing as a correlate of language-learning impairment SO JOURNAL OF NEUROLINGUISTICS LA English DT Article DE Specific language impairment; Dyslexia; Auditory rate processing; Electroencephalography; Gamma-band activity ID EVENT-RELATED POTENTIALS; GAMMA-BAND ACTIVITY; ALTERED HEMISPHERIC-ASYMMETRY; DEVELOPMENTAL DYSLEXIA; NEURAL SYNCHRONY; FUNCTIONAL MRI; VISUAL-CORTEX; POOR READERS; SPEECH; PERCEPTION AB Successful language acquisition has been hypothesized to involve the ability to integrate rapidly presented, brief acoustic cues in sensory cortex. A body of work has suggested that this ability is compromised in language-learning impairment (LLI). The present research aimed to examine sensory integration during rapid auditory processing by means of electrophysiological measures of oscillatory brain activity using data from a larger longitudinal study. Twenty-nine children with LLI and control participants with typical language development (n = 18) listened to tone doublets presented at a temporal interval that is essential for accurate speech processing (70-ms interstimulus interval). The children performed a deviant (pitch change of second tone) detection task, or listened passively. The electroencephalogram was recorded from 64 electrodes. Data were source-projected to the auditory cortices and submitted to wavelet analysis, resulting in time-frequency representations of electrocortical activity. Results show significantly reduced amplitude and phase-locking of early (45-75 ms) oscillations in the gamma-band range (29-52 Hz), specifically in the LLI group, for the second stimulus of the tone doublet. This suggests altered temporal organization of sensory oscillatory activity in LLI when processing rapid sequences. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Heim, Sabine] German Inst Int Educ Res DIPF, Ctr Res Individual Dev & Adapt Educ, D-60486 Frankfurt, Germany. [Friedman, Jennifer Thomas; Benasich, April A.] Rutgers State Univ, Ctr Mol & Behav Neurosci, Infancy Studies Lab, Newark, NJ 07102 USA. [Keil, Andreas] Univ Florida, Natl Inst Mental Hlth Ctr Study Emot & Attent, Gainesville, FL USA. RP Heim, S (reprint author), German Inst Int Educ Res DIPF, Ctr Res Individual Dev & Adapt Educ, Solmsstr 73-75, D-60486 Frankfurt, Germany. EM heim@dipf.de RI Keil, Andreas/F-9427-2011; OI Keil, Andreas/0000-0002-4064-1924; Benasich, April A/0000-0002-5137-776X FU National Institute of Child Health and Human Development [RO1-HD29419]; National Science Foundation [SBE-0542013] FX This work was supported by grants from the National Institute of Child Health and Human Development (RO1-HD29419) and the National Science Foundation (#SBE-0542013 to the "Temporal Dynamics of Learning Center") with additional support from the Elizabeth H. Solomon Center for Neurodevelopmental Research to A. A. Benasich, and from the National Institute of Mental Health to A. Keil. We would like to thank the children, who volunteered their time to participate in this research, as well as to the parents for their commitment. Special thanks to Cecylia Chojnowska and Stephani Babcock for help in acquisition and reduction of electrophysiological data. NR 95 TC 8 Z9 9 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0911-6044 J9 J NEUROLINGUIST JI J. Neurolinguist. PD SEP PY 2011 VL 24 IS 5 SI SI BP 538 EP 555 DI 10.1016/j.jneuroling.2010.09.006 PG 18 WC Linguistics; Neurosciences; Psychology, Experimental SC Linguistics; Neurosciences & Neurology; Psychology GA 815HQ UT WOS:000294517100003 ER PT J AU Kurdziel, KA Kalen, JD Hirsch, JI Wilson, JD Bear, HD Logan, J McCumisky, J Moorman-Sykes, K Adler, S Choyke, PL AF Kurdziel, Karen A. Kalen, Joseph D. Hirsch, Jerry I. Wilson, John D. Bear, Harry D. Logan, Jean McCumisky, James Moorman-Sykes, Kathy Adler, Stephen Choyke, Peter L. TI Human Dosimetry and Preliminary Tumor Distribution of F-18-Fluoropaclitaxel in Healthy Volunteers and Newly Diagnosed Breast Cancer Patients Using PET/CT SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE F-18-fluoropaclitaxel (FPAC); multidrug resistance (MDR); PET/CT imaging; paclitaxel; dosimetry; breast cancer ID P-GLYCOPROTEIN; IN-VIVO; PACLITAXEL; BIODISTRIBUTION; TISSUES AB F-18-fluoropaclitaxel is a radiolabeled form of paclitaxel, a widely used chemotherapy agent. Preclinical data suggest that F-18-fluoropaclitaxel may be a reasonable surrogate for measuring the uptake of paclitaxel. As a substrate of P-glycoprotein, a drug efflux pump associated with multidrug resistance, F-18-fluoropaclitaxel may also be useful in identifying multidrug resistance and predicting tumor response for drugs other than paclitaxel. Methods: After informed consent was obtained, 3 healthy volunteers and 3 patients with untreated breast cancer (neoadjuvant chemotherapy candidates, tumor size. 2 cm) received an intravenous infusion of F-18-fluoropaclitaxel and then underwent PET/CT. Healthy volunteers underwent serial whole-body imaging over an approximately 3-h interval, and organ F-18 residence times were determined from the time-activity curves uncorrected for decay to determine dosimetry. Radiation dose estimates were calculated using OLINDA/EXM software. For breast cancer patients, dynamic imaging of the primary tumor was performed for 60 min, followed by static whole-body scans at 1 and 2 h after injection. Results: Dosimetry calculations showed that the gallbladder received the highest dose (229.50 mGy/MBq [0.849 rad/mCi]), followed by the small and large intestines (161.26 mGy/MBq [0.597 rad/mCi] and 184.59 mGy/MBq [0.683 rad/mCi]). The resultant effective dose was 28.79 mGy/MBq (0.107 rem/mCi). At approximately 1 h after injection, an average of 42% of the decay-corrected activity was in the gastrointestinal system, with a mean of 0.01% in the tumor. All 3 breast cancer patients showed retention of 18F-fluoropaclitaxel and ultimately demonstrated a complete pathologic response (no invasive cancer in the breast or axillary nodes) to chemotherapy that included a taxane (either paclitaxel or docetaxel) at surgical resection. The tumor-to-background ratio increased with time to a maximum of 7.7 at 20 min. Conclusion: This study demonstrates the feasibility of using F-18-fluoropaclitaxel PET/CT tumor imaging and provides radiation dosimetry measurements in humans. Although further study is needed, it is hoped that the measured intratumoral F-18-fluoropaclitaxel distribution can serve as a surrogate for paclitaxel, and potentially other chemotherapeutic agent retention, in solid tumors. C1 [Kurdziel, Karen A.; Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kalen, Joseph D.] SAIC Frederick Inc, Lab Anim Sci Program, Small Anim Imaging Program, Frederick, MD USA. [Hirsch, Jerry I.; Wilson, John D.; McCumisky, James; Moorman-Sykes, Kathy] Virginia Commonwealth Univ, Dept Radiol, Richmond, VA USA. [Bear, Harry D.] Virginia Commonwealth Univ, Dept Surg, Richmond, VA USA. [Bear, Harry D.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Logan, Jean] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Adler, Stephen] NCI, SAIC Fredrick Inc, Contractor Mol Imaging Program, Frederick, MD 20892 USA. RP Kurdziel, KA (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, 10 Ctr Dr,Room B3B403, Bethesda, MD 20892 USA. EM kurdziek@mail.nih.gov OI Kalen, Joseph/0000-0002-7163-4604 FU American Cancer Society [IRG-100036]; NCI [1R21 CA098334-01A1] FX We thank William C. Eckelman for preliminary review of this manuscript. This work was funded in part by the American Cancer Society, IRG-100036, and NCI, 1R21 CA098334-01A1. No other potential conflict of interest relevant to this article was reported. NR 15 TC 6 Z9 6 U1 0 U2 3 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD SEP 1 PY 2011 VL 52 IS 9 BP 1339 EP 1345 DI 10.2967/jnumed.111.091587 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 814TU UT WOS:000294480900026 PM 21849404 ER PT J AU Thoma, ME Klebanoff, MA Rovner, AJ Nanse, TR Neggers, Y Andrews, WW Schwebke, JR AF Thoma, Marie E. Klebanoff, Mark A. Rovner, Alisha J. Nanse, Tonja R. Neggers, Yasmin Andrews, William W. Schwebke, Jane R. TI Bacterial Vaginosis Is Associated with Variation in Dietary Indices SO JOURNAL OF NUTRITION LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; GLYCEMIC INDEX; NATIONAL-HEALTH; CANCER RISK; US WOMEN; LOAD; NUTRITION; INFECTION; PREGNANCY; DISEASE AB Bacterial vaginosis (BV) is a common condition of unknown etiology and has been linked to adverse reproductive and obstetric health outcomes. Prior dietary research on BV has focused on specific macro- and micronutrients, but not dietary indices. We assessed the relationship between BV and selected dietary indicators among a cohort of 1735 nonpregnant women ages 15-44 y from Birmingham, Alabama. Annual intake was assessed with the Block98 FFQ, and the glycemic index, glycemic load (GL), and Healthy Eating Index were calculated by the Block Dietary Data System. The Naturally Nutrient Rich (NNR) score was also calculated. Vaginal flora was evaluated using Nugent Gram-stain criteria. Crude OR and adjusted OR were determined by multinomial and logistic regression in cross-sectional and prospective analyses, respectively. Participants were predominantly African American (85.5%) aged 25.3 +/- 6.8 y (mean +/- SD). Per 10-unit increase, GL was positively (adjusted OR = 1.01, 95% CI = 1.00-1.03) and NNR was negatively (adjusted OR = 0.93, 95% CI = 0.88-0.99) associated with BV compared to normal vaginal flora. In prospective analyses, only GL was associated with BV progression (adjusted OR = 1.03, 95% CI = 1.00-1.05) and persistence (adjusted OR = 1.02, 95% CI = 1.01-1.041 after adjustment. Both GL and NNR were associated with greater BV prevalence and GL was associated with an increase in BV persistence and acquisition. These results suggest that diet composition may contribute to vaginal flora imbalances and be important for elucidating the etiology of BV. J. Nutr. 141: 1698-1704, 2011. C1 [Thoma, Marie E.; Klebanoff, Mark A.; Rovner, Alisha J.; Nanse, Tonja R.] Kennedy Shriver Natl Inst Child Hlth & Human Dev, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Neggers, Yasmin] Univ Alabama, Dept Human Nutr, Tuscaloosa, AL USA. [Andrews, William W.] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Schwebke, Jane R.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. RP Thoma, ME (reprint author), Kennedy Shriver Natl Inst Child Hlth & Human Dev, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. EM thomame@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595 FU NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-8-3293] FX Supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development and contract N01-HD-8-3293. NR 49 TC 6 Z9 6 U1 1 U2 7 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD SEP PY 2011 VL 141 IS 9 BP 1698 EP 1704 DI 10.3945/jn.111.140541 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 815KC UT WOS:000294523500017 PM 21734062 ER PT J AU Semba, RD Arab, L Sun, K Nicklett, EJ Ferrucci, L AF Semba, Richard D. Arab, Lenore Sun, Kai Nicklett, Emily J. Ferrucci, Luigi TI Fat Mass Is Inversely Associated with Serum Carboxymethyl-Lysine, An Advanced Glycation End Product, in Adults SO JOURNAL OF NUTRITION LA English DT Article ID CARDIOVASCULAR-DISEASE MORTALITY; DENSITY-LIPOPROTEIN CHOLESTEROL; LIQUID-CHROMATOGRAPHY; HUMAN HEALTH; ENDPRODUCTS; PLASMA; AGES; ADIPOCYTES; ALBUMIN; RISK AB High levels of circulating advanced glycation end products (AGE) are associated with cardiovascular disease, diabetes, chronic kidney disease, and increased mortality, but factors that influence levels of circulating AGE are not well known. Our objective was to characterize the relationship between serum carboxymethyl-lysine (CML), a major circulating AGE, and body composition in adults. In a cross-sectional study, total body DXA was performed and serum CM L was measured in 592 adults, aged 26-93 y, from the Baltimore Longitudinal Study of Aging. Median (25th, 75th percentile) CML concentrations were 2.26 (1.86, 2.67) mu mol/L. Total fat mass [beta = -0.17(95% CI -0.10, -0.24); P < 0.0001], truncal fat mass [beta = -0.17(95% CI -0.10, -0.25); P< 0.0001], and appendicular fat mass [beta = -0.13 (95% CI -0.05, -0.20); P = 0.001] per 1 SD increase were inversely associated with serum CML in separate multivariate linear regression models, adjusting for age, sex, BMI, systolic blood pressure, TG, HDL cholesterol, and renal function. Lean body mass was not independently associated with serum CML. These findings suggest that serum CML concentration is strongly affected by body fat, possibly because CML is preferentially deposited in fat tissue or because adipocytes affect the metabolism of AGE. J. Nutr. 141: 1726-1730, 2011. C1 [Semba, Richard D.; Sun, Kai; Nicklett, Emily J.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Arab, Lenore] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Branch, Div Clin Res, NIH, Baltimore, MD 21224 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu RI Nicklett, Emily/A-4281-2012 FU NIH [R01 AG027012, R01 AG029148, R01 HL094507, R37 AG019905]; National Institute on Aging, NIH FX Supported by NIH grants R01 AG027012, R01 AG029148, R01 HL094507, and R37 AG019905, and the Intramural Research Program, National Institute on Aging, NIH. NR 39 TC 27 Z9 28 U1 1 U2 6 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD SEP PY 2011 VL 141 IS 9 BP 1726 EP 1730 DI 10.3945/jn.111.143172 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 815KC UT WOS:000294523500021 PM 21775524 ER PT J AU Sutin, AR Ferrucci, L Zonderman, AB Terracciano, A AF Sutin, Angelina R. Ferrucci, Luigi Zonderman, Alan B. Terracciano, Antonio TI Personality and Obesity Across the Adult Life Span SO JOURNAL OF PERSONALITY AND SOCIAL PSYCHOLOGY LA English DT Article DE obesity; body mass index; five-factor model; personality; weight gain ID BODY-MASS INDEX; CORONARY-HEART-DISEASE; WEIGHT-LOSS TREATMENT; 5-FACTOR MODEL; EATING-DISORDER; ENERGY-EXPENDITURE; LONGITUDINAL DATA; COLLEGE-STUDENTS; UNITED-STATES; OVERWEIGHT AB Personality traits contribute to health outcomes, in part through their association with major controllable risk factors, such as obesity. Body weight, in turn, reflects our behaviors and lifestyle and contributes to the way we perceive ourselves and others. In this study, the authors use data from a large (N = 1,988) longitudinal study that spanned more than 50 years to examine how personality traits are associated with multiple measures of adiposity and with fluctuations in body mass index (BMI). Using 14,531 anthropometric assessments, the authors modeled the trajectory of BMI across adulthood and tested whether personality predicted its rate of change. Measured concurrently, participants higher on Neuroticisin or Extraversion or lower on Conscientiousness had higher BMI; these associations replicated across body fat, waist, and hip circumference. The strongest association was found for the impulsivity facet: Participants who scored in the top 10% of impulsivity weighed, on average, 11Kg more than those in the bottom 10%. Longitudinally, high Neuroticism and low Conscientiousness, and the facets of these traits related to difficulty with impulse control, were associated with weight fluctuations, measured as the variability in weight over time. Finally, low Agreeableness and impulsivity-related traits predicted a greater increase in BMI across the adult life span. BMI was mostly unrelated to change in personality traits. Personality traits are defined by cognitive, emotional, and behavioral patterns that likely contribute to unhealthy weight and difficulties with weight management. Such associations may elucidate the role of personality traits in disease progression and may help to design more effective interventions. C1 [Sutin, Angelina R.; Ferrucci, Luigi; Zonderman, Alan B.; Terracciano, Antonio] NIA, NIH, DHHS, Baltimore, MD 21224 USA. RP Sutin, AR (reprint author), NIA, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sutina@mail.nih.gov RI terracciano, antonio/B-1884-2008; OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS [ZIA AG000197-03, ZIA AG000183-22, ZIA AG000183-23, ZIA AG000197-04] NR 92 TC 104 Z9 105 U1 8 U2 48 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-3514 J9 J PERS SOC PSYCHOL JI J. Pers. Soc. Psychol. PD SEP PY 2011 VL 101 IS 3 BP 579 EP 592 DI 10.1037/a0024286 PG 14 WC Psychology, Social SC Psychology GA 812SZ UT WOS:000294314500012 PM 21744974 ER PT J AU Manna, SK Patterson, AD Yang, Q Krausz, KW Idle, JR Fornace, AJ Gonzalez, FJ AF Manna, Soumen K. Patterson, Andrew D. Yang, Qian Krausz, Kristopher W. Idle, Jeffrey R. Fornace, Albert J., Jr. Gonzalez, Frank J. TI UPLC-MS-based Urine Metabolomics Reveals Indole-3-lactic Acid and Phenyllactic Acid as Conserved Biomarkers for Alcohol-induced Liver Disease in the Ppara-null Mouse Model SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE metabolomics; alcohol; Ppara-null mouse; genetic background; liver disease; UPLC-ESI-QTOF mass spectrometry; biomarker ID ACTIVATED-RECEPTOR-ALPHA; OXIDATIVE STRESS; ASPARTATE-AMINOTRANSFERASE; HEPATOCELLULAR-CARCINOMA; FATTY LIVER; METABOLISM; GENE; DEHYDROGENASE; POLYMORPHISMS; PURIFICATION AB Since the development and prognosis of alcohol-induced liver disease (ALD) vary significantly with genetic background, identification of a genetic background-independent noninvasive ALD biomarker would significantly improve screening and diagnosis. This study explored the effect of genetic background on the ALD-associated urinary metabolome using the Ppara-null mouse model on two different backgrounds, C57BL/6 (B6) and 129/SvJ (129S), along with their wild-type counterparts. Reversed-phase gradient UPLC-ESI-QTOF-MS analysis revealed that urinary excretion of a number of metabolites, such as ethylsulfate, 4-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid sulfate, adipic acid, pimelic acid, xanthurenic acid, and taurine, were background-dependent. Elevation of ethyl-beta-D-glucuronide and N-acetylglycine was found to be a common signature of the metabolomic response to alcohol exposure in wild-type as well as in Ppara-null mice of both strains. However, increased excretion of indole-3-lactic acid and phenyllactic acid was found to be a conserved feature exclusively associated with the alcohol-treated Ppara-null mouse on both backgrounds that develop liver pathologies similar to the early stages of human ALD. These markers reflected the biochemical events associated with early stages of ALD pathogenesis. The results suggest that indole-3-lactic acid and phenyllactic acid are potential candidates for conserved and pathology-specific high-throughput noninvasive biamarkers for early stages of ALD. C1 [Manna, Soumen K.; Patterson, Andrew D.; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Yang, Qian; Fornace, Albert J., Jr.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Idle, Jeffrey R.] Univ Bern, CH-3010 Bern, Switzerland. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. EM gonzalef@mail.r.ih.gov RI Patterson, Andrew/G-3852-2012; OI Patterson, Andrew/0000-0003-2073-0070; Fornace, Albert/0000-0001-9695-085X; Idle, Jeff/0000-0002-6143-1520 FU National Cancer Institute; National Institute of Environmental Health Sciences [U01ES016013] FX This work was supported by the National Cancer Institute Intramural Research Program and the National Institute of Environmental Health Sciences grant (U01ES016013) to A.J.F. and F.J.G. NR 48 TC 34 Z9 36 U1 1 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD SEP PY 2011 VL 10 IS 9 BP 4120 EP 4133 DI 10.1021/pr200310s PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 814JN UT WOS:000294446600023 PM 21749142 ER PT J AU Burstein, M He, JP Kattan, G Albano, AM Avenevoli, S Merikangas, KR AF Burstein, Marcy He, Jian-Ping Kattan, Gabriela Albano, Anne Marie Avenevoli, Shelli Merikangas, Kathleen R. TI Social Phobia and Subtypes in the National Comorbidity Survey-Adolescent Supplement: Prevalence, Correlates, and Comorbidity SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE epidemiology; adolescents; social phobia; subtypes; National Comorbidity Survey-Adolescent Supplement ID CHILDHOOD ANXIETY DISORDERS; SURVEY REPLICATION; NCS-A; YOUNG-ADULTS; GENERAL-POPULATION; MENTAL-DISORDERS; COMMUNITY SAMPLE; SERVICE USE; DSM-V; FEARS AB Social phobia typically develops during the adolescent years, yet no nationally representative studies in the United States have examined the rates and features of this condition among youth in this age range. The objectives of this investigation were to: (1) present the lifetime prevalence, sociodemographic and clinical correlates, and comorbidity of social phobia in a large, nationally representative sample of U.S. adolescents; and (2) examine differences in the rates and features of social phobia across the proposed DSM-5 social phobia subtypes. Method: The National Comorbidity Survey Replication Adolescent Supplement is a nationally representative face-to-face survey of 10,123 adolescents 13 to 18 years of age in the continental United States. Results: Approximately 9% of adolescents met criteria for any social phobia in their lifetime. Of these adolescents, 55.8% were affected with the generalized subtype and 44.2% exhibited nongeneralized social phobia. Only 0.7% met criteria for the proposed DSM-5 performance-only subtype. Generalized social phobia was more common among female adolescents and risk for this subtype increased with age. Adolescents with generalized social phobia also had a younger age of onset, higher levels of disability and clinical severity, and a greater degree of comorbidity relative to adolescents with nongeneralized forms of the disorder. Conclusions: This study indicates that social phobia is a highly prevalent, persistent, and impairing psychiatric disorder among adolescent youth. Results of this study also provide evidence for the clinical utility of the generalized subtype and highlight the importance of considering the heterogeneity of social phobia in this age group. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(9):870-880. C1 [Burstein, Marcy; He, Jian-Ping; Kattan, Gabriela; Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Albano, Anne Marie] Columbia Univ, Med Ctr, New York, NY 10027 USA. [Avenevoli, Shelli] NIMH, Div Dev Translat Res, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bldg 35,Room 1A201,35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM kathleen.merikangas@nih.gov FU National Institute of Mental Health [U01-MH60220]; National Institute of Drug Abuse [R01 DA016558] FX The National Comorbidity Survey-Adolescent Supplement (NCS-A) is supported by the National Institute of Mental Health (U01-MH60220) and the National Institute of Drug Abuse (R01 DA016558) with supplemental support from the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; 044708), and the John W. Alden Trust. The NCS-A was carried out in conjunction with the World Health Organization World Mental Health (WMH) Survey Initiative. NR 47 TC 33 Z9 33 U1 5 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD SEP PY 2011 VL 50 IS 9 BP 870 EP 880 DI 10.1016/j.jaac.2011.06.005 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 815FP UT WOS:000294511800005 PM 21871369 ER PT J AU Riggs, PD Winhusen, T Davies, RD Leimberger, JD Mikulich-Gilbertson, S Klein, C Macdonald, M Lohman, M Bailey, GL Haynes, L Jaffee, WB Haminton, N Hodgkins, C Whitmore, E Trello-Rishel, K Tamm, L Acosta, MC Royer-Malvestuto, C Subramaniam, G Fishman, M Holmes, BW Kaye, ME Vargo, MA Woody, GE Nunes, EV Liu, D AF Riggs, Paula D. Winhusen, Theresa Davies, Robert D. Leimberger, Jeffrey D. Mikulich-Gilbertson, Susan Klein, Constance Macdonald, Marilyn Lohman, Michelle Bailey, Genie L. Haynes, Louise Jaffee, William B. Haminton, Nancy Hodgkins, Candace Whitmore, Elizabeth Trello-Rishel, Kathlene Tamm, Leanne Acosta, Michelle C. Royer-Malvestuto, Charlotte Subramaniam, Geetha Fishman, Marc Holmes, Beverly W. Kaye, Mary Elyse Vargo, Mark A. Woody, George E. Nunes, Edward V. Liu, David TI Randomized Controlled Trial of Osmotic-Release Methylphenidate With Cognitive-Behavioral Therapy in Adolescents With Attention-Deficit/Hyperactivity Disorder and Substance Use Disorders SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE osmotic-release methylphenidate; randomized controlled trial; ADHD; substance use disorders ID ADULT ADHD; YOUNG-ADULTS; ABUSE; PLACEBO; RELIABILITY; ATOMOXETINE; PREVALENCE; VALIDITY; DESIGNS; SAMPLE AB To evaluate the efficacy and safety of osmotic-release methylphenidate (OROSMPH) compared with placebo for attention-deficit/hyperactivity disorder (ADHD), and the impact on substance treatment outcomes in adolescents concurrently receiving cognitive-behavioral therapy (CBT) for substance use disorders (SUD). Method: This was a 16-week, randomized, controlled, multi-site trial of OROS-MPH + CBT versus placebo + CBT in 303 adolescents (aged 13 through 18 years) meeting DSM-IV diagnostic criteria for ADHD and SUD. Primary outcome measures included the following: for ADHD, clinician-administered ADHD Rating Scale (ADHD-RS), adolescent informant; for substance use, adolescent-reported days of use in the past 28 days. Secondary outcome measures included parent ADHD-RS and weekly urine drug screens (UDS). Results: There were no group differences on reduction in ADHD-RS scores (OROS-MPH: -19.2, 95% confidence interval [CI], -17.1 to -21.2; placebo, -21.2, 95% CI, -19.1 to -23.2) or reduction in days of substance use (OROS-MPH: -5.7 days, 95% Cl, 4.0-7.4; placebo: -5.2 days, 95% CI, 3.5-7.0). Some secondary outcomes favored OROS-MPH, including lower parent ADHD-RS scores at 8 (mean difference = 4.4, 95% CI, 0.8-7.9) and 16 weeks (mean difference =6.9; 95% CI, 2.9-10.9) and more negative UDS in OROS-MPH (mean = 3.8) compared with placebo (mean = 2.8; p =.04). Conclusions: OROS-MPH did not show greater efficacy than placebo for ADHD or on reduction in substance use in adolescents concurrently receiving individual CBT for co-occurring SUD. However, OROS-MPH was relatively well tolerated and was associated with modestly greater clinical improvement on some secondary ADHD and substance outcome measures. Clinical Trial Registration Information Attention Deficit Hyperactivity Disorder (ADHD) in Adolescents with Substance Use Disorders (SUD); http://www.clinicaltrials.gov; NCT00264797. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(9):903-914. C1 [Riggs, Paula D.; Davies, Robert D.; Mikulich-Gilbertson, Susan; Klein, Constance; Macdonald, Marilyn; Lohman, Michelle; Whitmore, Elizabeth] Univ Colorado Denver, Aurora, CO 80045 USA. [Winhusen, Theresa] Univ Cincinnati, Cincinnati, OH 45221 USA. [Bailey, Genie L.] Brown Univ, Providence, RI 02912 USA. [Haynes, Louise] Med Univ S Carolina, Charleston, SC USA. [Jaffee, William B.] Harvard Univ, Cambridge, MA 02138 USA. [Royer-Malvestuto, Charlotte; Woody, George E.] Univ Penn, Philadelphia, PA 19104 USA. [Subramaniam, Geetha; Fishman, Marc] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Subramaniam, Geetha] NIDA, Div Clin Neurosci & Behav Res, NIH, Bethesda, MD USA. [Kaye, Mary Elyse] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Nunes, Edward V.] Columbia Univ, New York, NY 10027 USA. [Nunes, Edward V.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Liu, David] NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD USA. RP Riggs, PD (reprint author), Univ Colorado Denver, Mail Stop F478,12469 E 17th Pl,Room 235, Aurora, CO 80045 USA. EM paula.riggs@ucdenver.edu OI Winhusen, Theresa/0000-0002-3364-0739; Acosta, Michelle/0000-0003-4827-7271 FU Notional Institute on Drug Abuse (NIDA) [U10 DA13716, U10 DA13732, U10 DA15831, U10 DA13727, U10 DA13720, U10 DA20024, U10 DA13035, K24 DA022412, U10 DA13043, U10 DA13034, K12 DA000357, U10 DA20036]; Titan Pharmaceuticals, Inc.; Alkermes, Inc FX The project described was supported by the following grants from the Notional Institute on Drug Abuse (NIDA): U10 DA13716 (P.D.R., R.D.D., S.M.G., C.K., MM., ML., E.W.); U10 DA13732 (P.D.R., T.W., R.D.D., S.M.G., C.K., MM., M.L., E.W.); U10 DA15831 (G.L.B., W.B.J.); U10 DA13727 (LH., B.W.H.); U10 DA13720 (N.H., C.H., M.A.V.); U10 DA20024 (K.T.R., L.T.); U10 DA13035 (E.V.N., M.C.A.); K24 DA022412 (E.V.N.); U10 DA13043 (C.R.M., G.E.W.); U10 DA13034 (OS., M.F.); K12 DA000357 (OS.); and U10 DA20036 (M.E.K.). Drug and matching placebo were provided by Ortho McNeil Janssen Scientific Affairs, LLC.; Disclosure: Dr. Bailey has received research support from the National Institute of Drug Abuse (NIDA), Titan Pharmaceuticals, Inc., and Alkermes, Inc. Dr. Trello-Rishel has served on the speakers' bureau for Shire. Dr. Woody is a member of the RADARS System post-marketing study external advisory group, which is administered by Denver Health, and supported by pharmaceutical companies. He has served as a consultant for Alkermes. Drs. Riggs, Winhusen, Davies, Leimberger, Mikulich-Gilbertson, Jaffee, Hodgkins, Whitmore, Tamm, Acosta, Royer-Molvestuto, Subramaniam, Fishman, Vargo, Nunes, and Liu, and Ms. Klein, Ms. Macdonald, Ms. Lohnmon, Ms. Haynes, Ms. Hamilton, Ms. Holmes, and Ms. Kaye report no biomedical financial interests or potential conflicts of interest. NR 39 TC 27 Z9 27 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD SEP PY 2011 VL 50 IS 9 BP 903 EP 914 DI 10.1016/j.jaac.2011.06.010 PG 12 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 815FP UT WOS:000294511800008 PM 21871372 ER PT J AU Huang, ML Neveol, A Lu, ZY AF Huang, Minlie Neveol, Aurelie Lu, Zhiyong TI Recommending MeSH terms for annotating biomedical articles SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID ASSIGNMENT; SIMILARITY; MEDLINE AB Background Due to the high cost of manual curation of key aspects from the scientific literature, automated methods for assisting this process are greatly desired. Here, we report a novel approach to facilitate MeSH indexing, a challenging task of assigning MeSH terms to MEDLINE citations for their archiving and retrieval. Methods Unlike previous methods for automatic MeSH term assignment, we reformulate the indexing task as a ranking problem such that relevant MeSH headings are ranked higher than those irrelevant ones. Specifically, for each document we retrieve 20 neighbor documents, obtain a list of MeSH main headings from neighbors, and rank the MeSH main headings using List Net a learning-to-rank algorithm. We trained our algorithm on 200 documents and tested on a previously used benchmark set of 200 documents and a larger dataset of 1000 documents. Results Tested on the benchmark dataset, our method achieved a precision of 0.390, recall of 0.712, and mean average precision (MAP) of 0.626. In comparison to the state of the art, we observe statistically significant improvements as large as 39% in MAP (p-value <0.001). Similar significant improvements were also obtained on the larger document set. Conclusion Experimental results show that our approach makes the most accurate MeSH predictions to date, which suggests its great potential in making a practical impact on MeSH indexing. Furthermore, as discussed the proposed learning framework is robust and can be adapted to many other similar tasks beyond MeSH indexing in the biomedical domain. All data sets are available at: http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/indexing. C1 [Huang, Minlie; Neveol, Aurelie; Lu, Zhiyong] NIH, NCBI, US Natl Lib Med, Bethesda, MD 20894 USA. [Huang, Minlie] Tsinghua Univ, Dept Comp Sci & Technol, State Key Lab Intelligent Technol & Syst, Tsinghua Natl Lab Informat Sci & Technol, Beijing 100084, Peoples R China. RP Lu, ZY (reprint author), NIH, NCBI, Natl Lib Med, Bldg 38A,Room 1003A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM zhiyong.lu@nih.gov FU National Institutes of Health, National Library of Medicine; Chinese Natural Science Foundation [60803075] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. The first author was also supported by the Chinese Natural Science Foundation under grant no. 60803075. NR 31 TC 37 Z9 37 U1 2 U2 13 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2011 VL 18 IS 5 BP 660 EP 667 DI 10.1136/amiajnl-2010-000055 PG 8 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 816AV UT WOS:000294572000021 PM 21613640 ER PT J AU Fischer, MJ Kimmel, PL Greene, T Gassman, JJ Wang, XL Brooks, DH Charleston, J Dowie, D Thornley-Brown, D Cooper, LA Bruce, MA Kusek, JW Norris, KC Lash, JP AF Fischer, Michael J. Kimmel, Paul L. Greene, Tom Gassman, Jennifer J. Wang, Xuelei Brooks, Deborah H. Charleston, Jeanne Dowie, Donna Thornley-Brown, Denyse Cooper, Lisa A. Bruce, Marino A. Kusek, John W. Norris, Keith C. Lash, James P. CA AASK Study Grp TI Elevated depressive affect is associated with adverse cardiovascular outcomes among African Americans with chronic kidney disease SO KIDNEY INTERNATIONAL LA English DT Article DE AASK (African American Study of Kidney Disease and Hypertension); cardiovascular events; chronic kidney disease; depression ID QUALITY-OF-LIFE; STAGE RENAL-DISEASE; HEMODIALYSIS-PATIENTS; UNITED-STATES; DIALYSIS PATIENTS; RACIAL DISPARITIES; HYPERTENSION AASK; MAJOR DEPRESSION; RISK-FACTOR; MORTALITY AB This study was designed to examine the impact of elevated depressive affect on health outcomes among participants with hypertensive chronic kidney disease in the African-American Study of Kidney Disease and Hypertension (AASK) Cohort Study. Elevated depressive affect was defined by Beck Depression Inventory II (BDI-II) thresholds of 11 or more, above 14, and by 5-Unit increments in the score. Cox regression analyses were used to relate cardiovascular death/hospitalization, doubling of serum creatinine/end-stage renal disease, overall hospitalization, and all-cause death to depressive affect evaluated at baseline, the most recent annual visit (time-varying), or average from baseline to the most recent visit (cumulative). Among 628 participants at baseline, 42% had BDI-II scores of 11 or more and 26% had a score above 14. During a 5-year follow-up, the cumulative incidence of cardiovascular death/hospitalization was significantly greater for participants with baseline BDI-II scores of 11 or more compared with those with scores o11. The baseline, time-varying, and cumulative elevated depressive affect were each associated with a significant higher risk of cardiovascular death/hospitalization, especially with a time-varying BDI-II score over 14 (adjusted HR 1.63) but not with the other outcomes. Thus, elevated depressive affect is associated with unfavorable cardiovascular outcomes in African Americans with hypertensive chronic kidney disease. Kidney International (2011) 80, 670-678; doi: 10.1038/ki.2011.153;published online 1 June 2011 C1 [Fischer, Michael J.; Lash, James P.] Jesse Brown VA Med Ctr, Dept Med & Biostat & Epidemiol, Chicago, IL USA. [Fischer, Michael J.; Lash, James P.] Univ Illinois, Med Ctr, Chicago, IL USA. [Fischer, Michael J.] VA Hosp, Ctr Management Complex Chron Care, Hines, IL USA. [Kimmel, Paul L.; Kusek, John W.] NIDDK, NIH, Bethesda, MD 20892 USA. [Kimmel, Paul L.] George Washington Univ, Dept Med & Biostat & Epidemiol, Washington, DC USA. [Greene, Tom] Univ Utah, Dept Med & Biostat & Epidemiol, Salt Lake City, UT USA. [Gassman, Jennifer J.; Wang, Xuelei] Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. [Brooks, Deborah H.] Med Univ S Carolina, Dept Med & Biostat & Epidemiol, Charleston, SC 29425 USA. [Charleston, Jeanne; Cooper, Lisa A.] Johns Hopkins Univ, Dept Med & Biostat & Epidemiol, Baltimore, MD USA. [Dowie, Donna] Columbia Univ, Dept Med & Biostat & Epidemiol, Harlem Hosp, Med Ctr, New York, NY USA. [Thornley-Brown, Denyse] Univ Alabama, Dept Med & Biostat & Epidemiol, Birmingham, AL USA. [Bruce, Marino A.] Univ Mississippi, Dept Med & Biostatist & Epidemiol, Med Ctr, Jackson, MS 39216 USA. [Norris, Keith C.] Charles R Drew Univ, Dept Med & Biostatist & Epidemiol, Los Angeles, CA USA. RP Fischer, MJ (reprint author), Hines VA Hosp, Ctr Management Complex Chron Care, 5000 S 5th Ave 151H, Hines, IL 60141 USA. EM fischerm@uic.edu FU National Institutes of Diabetes and Digestive and Kidney Diseases [5U01DK045388]; National Center for Minority Health and Health Disparities at the National Institutes of Health [5M01RR00071]; King Pharmaceuticals; Pfizer; Astra Zeneca Pharmaceuticals; National Institutes of Health [RR-00080, RR-00071, RR-00827, RR-00032, RR-11145, RR-11104, RR-00052, RR-00095, DK-2818]; Department of Veterans Affairs; Veterans Health Administration; Health Services Research and Development Service FX Part of these results was presented in abstract and poster format at the American Society of Nephrology Annual Meeting in November 2009 (San Diego, CA). A special acknowledgement is extended to the AASK participants for their time and extraordinary commitment to the AASK Trial and now the AASK Cohort Study. We also acknowledge all members of the AASK Collaborative Research Group, which includes investigators and staff from 21 clinical centers. This study was supported by cooperative agreements from the National Institutes of Diabetes and Digestive and Kidney Diseases (5U01DK045388) and the National Center for Minority Health and Health Disparities at the National Institutes of Health (5M01RR00071). Support was also provided by King Pharmaceuticals, Pfizer, and Astra Zeneca Pharmaceuticals. The following National Institutes of Health institutional grants provided additional support: RR-00080, RR-00071, RR-00827, RR-00032, RR-11145, RR-11104, RR-00052, RR-00095, and DK-2818. Support was also provided by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (VA HSR&D Career Development Award-MJF). NR 47 TC 16 Z9 16 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2011 VL 80 IS 6 BP 670 EP 678 DI 10.1038/ki.2011.153 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 814ML UT WOS:000294458900015 PM 21633409 ER PT J AU Kreimer, AR Gonzalez, P Katki, HA Porras, C Schiffman, M Rodriguez, AC Solomon, D Jimenez, S Schiller, JT Lowy, DR van Doorn, LJ Struijk, L Quint, W Chen, S Wacholder, S Hildesheim, A Herrero, R AF Kreimer, Aimee R. Gonzalez, Paula Katki, Hormuzd A. Porras, Carolina Schiffman, Mark Cecilia Rodriguez, Ana Solomon, Diane Jimenez, Silvia Schiller, John T. Lowy, Douglas R. van Doorn, Leen-Jan Struijk, Linda Quint, Wim Chen, Sabrina Wacholder, Sholom Hildesheim, Allan Herrero, Rolando CA CVT Vaccine Grp TI Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial SO LANCET ONCOLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS; QUADRIVALENT VACCINE; PARTICLE VACCINE; BROAD-SPECTRUM; CANCER; ASSAY; PCR; EPIDEMIOLOGY; PREVENTION; CARCINOMA AB Background Anal cancer remains rare (incidence of about 1.5 per 100 000 women yearly), but rates are increasing in many countries. Human papillomavirus (HPV) 16 and 18 infections cause most cases of anal cancer. We assessed efficacy of an AS04-adjuvanted HPV 16 and HPV 18 vaccine against anal infection with HPV 16, HPV 18, or both (HPV 16/18). Methods Women from Costa Rica were registered between June 28, 2004, and Dec 21, 2005, in a randomised double-blind controlled trial that was designed to assess vaccine efficacy against persistent cervical HPV 16/18 infections and associated precancerous lesions. Eligible women were residents of Guanacaste and selected areas of Puntarenas, Costa Rica, age 18-25 years, in good general health, willing to provide informed consent, and were not pregnant or breastfeeding. Participants were randomly assigned (1: 1) to receive an HPV vaccine (Cervarix, GlaxoSmithKline, Rixensart, Belgium) or a control hepatitis A vaccine (modified preparation of Havrix, GlaxoSmithKline, Rixensart, Belgium). Vaccines were administered in three 0.5 mL doses at enrolment, 1 month, and 6 months. Women, selected at the final blinded study visit 4 years after vaccination, provided anal specimens for assessment of vaccine efficacy against anal HPV 16/18 infection. Prevalence of anal HPV 16/18 infections, reported as vaccine efficacy, was the primary endpoint of the study described here. Vaccine efficacy against cervical HPV 16/18 infection in the same women at the 4-year visit was used as a comparator. Analyses were done in a restricted cohort of women who were negative for both cervical HPV 16 and HPV 18 DNA and who were HPV 16 and HPV 18 seronegative before enrolment (HPV naive), and also in the full cohort of women who provided an anal specimen. Investigators were masked to group assignment. This study is registered at ClinicalTrials.gov, number NCT00128661. Findings All women who attended the final blinded study visit and consented to anal specimen collection were included in the analysis (4210 of 6352 eligible women). In the full cohort, vaccine efficacy against prevalent HPV 16/18 infection measured one-time, 4 years post vaccination was lower at the anus (62.0%, 95% CI 47.1-73.1) compared with the cervix (76.4%, 67.0-83.5; p for interaction by anatomical site 0.031). In the restricted cohort, vaccine efficacy against anal HPV 16/18 infection was 83.6% (66.7-92.8), which was similar to vaccine efficacy against cervical HPV 16/18 infection (87.9%, 77.4-94.0). Safety issues were not addressed in the current analysis. Additional safety data will be published later in a separate article. Interpretation The AS04-adjuvanted vaccine affords strong protection against anal HPV infection, particularly among women more likely to be HPV naive at enrolment. C1 [Kreimer, Aimee R.; Katki, Hormuzd A.; Schiffman, Mark; Wacholder, Sholom; Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Solomon, Diane] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Schiller, John T.; Lowy, Douglas R.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gonzalez, Paula; Porras, Carolina; Cecilia Rodriguez, Ana; Jimenez, Silvia; Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [van Doorn, Leen-Jan; Struijk, Linda; Quint, Wim] DDL Diagnost Lab, Voorburg, Netherlands. [Chen, Sabrina] Informat Management Syst, Rockville, MD USA. [Herrero, Rolando] Int Agcy Res Canc, Early Detect & Prevent Sect, F-69372 Lyon, France. RP Kreimer, AR (reprint author), 6120 Execut Blvd,EPS 7084, Rockville, MD 20852 USA. EM kreimera@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; Hildesheim, Allan/B-9760-2015; Kreimer, Aimee/H-1687-2015 OI Hildesheim, Allan/0000-0003-0257-2363; FU NCI [N01-CP-11005]; National Institutes of Health Office of Research on Women's Health; Ministry of Health of Costa Rica; GlaxoSmithKline; GlaxoSmithKline Biologicals; US Food and Drug Administration [BB-IND 7920] FX The Costa Rica HPV Vaccine Trial is a long-standing collaboration between investigators in Costa Rica and the National Cancer Institute (NCI). The trial is sponsored and funded by the NCI (contract N01-CP-11005), with funding support from the National Institutes of Health Office of Research on Women's Health, and done with support from the Ministry of Health of Costa Rica. Vaccine was provided for our trial by GlaxoSmithKline Biologicals, under a Clinical Trials Agreement with the NCI. GlaxoSmithKline also provided support for aspects of the trial associated with regulatory submission needs of the company under US Food and Drug Administration BB-IND 7920. Cervarix is a registered trade mark of the GlaxoSmithKline Biologicals group of companies. For a full list of acknowledgments see webappendix (p 3).; National Cancer Institute with contributions from the National Institutes of Health Office of Research on Women's Health. Vaccine was provided by GlaxoSmithKline Biologicals. NR 28 TC 89 Z9 91 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD SEP PY 2011 VL 12 IS 9 BP 862 EP 870 DI 10.1016/S1470-2045(11)70213-3 PG 9 WC Oncology SC Oncology GA 812KX UT WOS:000294293500017 PM 21865087 ER PT J AU Hinnebusch, AG AF Hinnebusch, Alan G. TI Molecular Mechanism of Scanning and Start Codon Selection in Eukaryotes SO MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS LA English DT Review ID TRANSLATION INITIATION-FACTOR; 40S RIBOSOMAL-SUBUNIT; RNA RECOGNITION MOTIF; YEAST SACCHAROMYCES-CEREVISIAE; REOVIRUS MESSENGER-RNA; GTP EXCHANGE FACTORS; BOX PROTEIN EIF4A; C-TERMINAL DOMAIN; SMALL SIZE CLASS; FACTOR 4G EIF4G AB The correct translation of mRNA depends critically on the ability to initiate at the right AUG codon. For most mRNAs in eukaryotic cells, this is accomplished by the scanning mechanism, wherein the small (40S) ribosomal subunit attaches to the 5' end of the mRNA and then inspects the leader base by base for an AUG in a suitable context, using complementarity with the anticodon of methionyl initiator tRNA (Met-tRNA(i)(Met)) as the key means of identifying AUG. Over the past decade, a combination of yeast genetics, biochemical analysis in reconstituted systems, and structural biology has enabled great progress in deciphering the mechanism of ribosomal scanning. A robust molecular model now exists, describing the roles of initiation factors, notably eukaryotic initiation factor 1 (eIF1) and eIF1A, in stabilizing an "open" conformation of the 40S subunit with Met-tRNA(i)(Met) bound in a low-affinity state conducive to scanning and in triggering rearrangement into a "closed" conformation incompatible with scanning, which features Met-tRNA(i)(Met) more tightly bound to the "P" site and base paired with AUG. It has also emerged that multiple DEAD-box RNA helicases participate in producing a single-stranded "landing pad" for the 40S subunit and in removing the secondary structure to enable the mRNA to traverse the 40S mRNA-binding channel in the single-stranded form for base-by-base inspection in the P site. C1 Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM alanh@mail.nih.gov NR 233 TC 125 Z9 127 U1 1 U2 27 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1092-2172 J9 MICROBIOL MOL BIOL R JI Microbiol. Mol. Biol. Rev. PD SEP PY 2011 VL 75 IS 3 BP 434 EP 467 DI 10.1128/MMBR.00008-11 PG 34 WC Microbiology SC Microbiology GA 814SY UT WOS:000294478700002 PM 21885680 ER PT J AU Bhatt, S Holmes, EC Pybus, OG AF Bhatt, Samir Holmes, Edward C. Pybus, Oliver G. TI The Genomic Rate of Molecular Adaptation of the Human Influenza A Virus SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE influenza; McDonald-Kreitman test; neutrality tests; rate of adaptation ID ADAPTIVE PROTEIN EVOLUTION; CYTOTOXIC T-LYMPHOCYTES; MCDONALD-KREITMAN TEST; ADAMANTANE RESISTANCE; DISEASE PROGRESSION; NATURAL-SELECTION; STRANDED-RNA; NS1 PROTEIN; HEMAGGLUTININ; GENE AB Quantifying adaptive evolution at the genomic scale is an essential yet challenging aspect of evolutionary biology. Here, we develop a method that extends and generalizes previous approaches to estimate the rate of genomic adaptation in rapidly evolving populations and apply it to a large data set of complete human influenza A virus genome sequences. In accord with previous studies, we observe particularly high rates of adaptive evolution in domain 1 of the viral hemagglutinin (HA1). However, our novel approach also reveals previously unseen adaptation in other viral genes. Notably, we find that the rate of adaptation (per codon per year) is higher in surface residues of the viral neuraminidase than in HA1, indicating strong antibody-mediated selection on the former. We also observed high rates of adaptive evolution in several nonstructural proteins, which may relate to viral evasion of T-cell and innate immune responses. Furthermore, our analysis provides strong quantitative support for the hypothesis that human H1N1 influenza experiences weaker antigenic selection than H3N2. As well as shedding new light on the dynamics and determinants of positive Darwinian selection in influenza viruses, the approach introduced here is applicable to other pathogens for which densely sampled genome sequences are available, and hence is ideally suited to the interpretation of next-generation genome sequencing data. C1 [Bhatt, Samir; Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Bhatt, Samir] Wellcome Trust Sanger Inst, Cambridge, England. [Holmes, Edward C.] Penn State Univ, Mueller Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Pybus, OG (reprint author), Univ Oxford, Dept Zool, S Parks Rd, Oxford OX1 3PS, England. EM oliver.pybus@zoo.ox.ac.uk RI pybus, oliver/B-2640-2012; OI Pybus, Oliver/0000-0002-8797-2667; Holmes, Edward/0000-0001-9596-3552 FU Natural Environment Research Council; COSI UK; National Institute of Health [R01 GM080533]; Royal Society FX S.B. was funded by the Natural Environment Research Council and in part by COSI UK, E. C. H. in part by grant R01 GM080533 from the National Institute of Health, and O.G.P. by The Royal Society. O.G.P. acknowledges the generous advice of Scott Williamson in 2005, to whom this work is dedicated. Many thanks to Thomas Bowden for assistance with gene structures. S. B. thanks Alexandros Vardoulakis, Udara Pieris, and Denise Xifara. NR 52 TC 47 Z9 49 U1 1 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD SEP PY 2011 VL 28 IS 9 BP 2443 EP 2451 DI 10.1093/molbev/msr044 PG 9 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 815TO UT WOS:000294552700006 PM 21415025 ER PT J AU Vishnoi, A Sethupathy, P Simola, D Plotkin, JB Hannenhalli, S AF Vishnoi, Anchal Sethupathy, Praveen Simola, Daniel Plotkin, Joshua B. Hannenhalli, Sridhar TI Genome-Wide Survey of Natural Selection on Functional, Structural, and Network Properties of Polymorphic Sites in Saccharomyces paradoxus SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE evolution; natural selection; yeast; derived allele frequency ID INTRINSICALLY UNSTRUCTURED PROTEINS; SYNONYMOUS CODON USAGE; POSITIVE SELECTION; NONCODING SEQUENCES; FREQUENCY-SPECTRUM; EVOLUTIONARY RATES; DUPLICATE GENES; BINDING-SITES; AMINO-ACIDS; YEAST AB Background. To characterize the genetic basis of phenotypic evolution, numerous studies have identified individual genes that have likely evolved under natural selection. However, phenotypic changes may represent the cumulative effect of similar evolutionary forces acting on functionally related groups of genes. Phylogenetic analyses of divergent yeast species have identified functional groups of genes that have evolved at significantly different rates, suggestive of differential selection on the functional properties. However, due to environmental heterogeneity over long evolutionary timescales, selection operating within a single lineage may be dramatically different, and it is not detectable via interspecific comparisons alone. Moreover, interspecific studies typically quantify selection on protein-coding regions using the D(n)/D(s) ratio, which cannot be extended easily to study selection on noncoding regions or synonymous sites. The population genetic-based analysis of selection operating within a single lineage ameliorates these limitations. Findings. We investigated selection on several properties associated with genes, promoters, or polymorphic sites, by analyzing the derived allele frequency spectrum of single nucleotide polymorphisms (SNPs) in 28 strains of Saccharomyces paradoxus. We found evidence for significant differential selection between many functionally relevant categories of SNPs, underscoring the utility of function-centric approaches for discovering signatures of natural selection. When comparable, our findings are largely consistent with previous studies based on interspecific comparisons, with one notable exception: our study finds that mutations from an ancient amino acid to a relatively new amino acid are selectively disfavored, whereas interspecific comparisons have found selection against ancient amino acids. Several of our findings have not been addressed through prior interspecific studies: we find that synonymous mutations from preferred to unpreferred codons are selected against and that synonymous SNPs in the linker regions of proteins are relatively less constrained than those within protein domains. Conclusions. We present the first global survey of selection acting on various functional properties in S. paradoxus. We found that selection pressures previously detected over long evolutionary timescales have also shaped the evolution of S. paradoxus. Importantly, we also make novel discoveries untenable via conventional interspecific analyses. C1 [Vishnoi, Anchal; Simola, Daniel; Plotkin, Joshua B.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Sethupathy, Praveen] NHGRI, NIH, Bethesda, MD USA. [Hannenhalli, Sridhar] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. RP Plotkin, JB (reprint author), Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. EM jplotkin@sas.upenn.edu; sridhar@umiacs.umd.edu RI Phelps, Steve/H-2263-2011; Plotkin, Joshua/E-6947-2013 FU Burroughs Wellcome Fund; David and Lucile Packard Foundation; James S. McDonnell Foundation; Alfred P. Sloan Foundation; Defense Advanced Research Projects Agency [HR0011-09-1-0055]; National Institute of Health [GM085226] FX J.B.P. acknowledges funding from the Burroughs Wellcome Fund, the David and Lucile Packard Foundation, the James S. McDonnell Foundation, the Alfred P. Sloan Foundation, the Defense Advanced Research Projects Agency (HR0011-09-1-0055). J.B.P. and S. H. acknowledge support from National Institute of Health grant GM085226. NR 99 TC 11 Z9 11 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD SEP PY 2011 VL 28 IS 9 BP 2615 EP 2627 DI 10.1093/molbev/msr085 PG 13 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 815TO UT WOS:000294552700021 PM 21478372 ER PT J AU Xiao, L Cui, YH Rao, JN Zou, TT Liu, L Smith, A Turner, DJ Gorospe, M Wang, JY AF Xiao, Lan Cui, Yu-Hong Rao, Jaladanki N. Zou, Tongtong Liu, Lan Smith, Alexis Turner, Douglas J. Gorospe, Myriam Wang, Jian-Ying TI Regulation of cyclin-dependent kinase 4 translation through CUG-binding protein 1 and microRNA-222 by polyamines SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; REPRESSES CDK4 TRANSCRIPTION; MESSENGER-RNA DECAY; GU-RICH ELEMENTS; POSTTRANSCRIPTIONAL REGULATION; ORNITHINE-DECARBOXYLASE; MYOTONIC-DYSTROPHY; C-MYC; DEPLETION; HUR AB The amino acid-derived polyamines are organic cations that are essential for growth in all mammalian cells, but their exact roles at the molecular level remain largely unknown. Here we provide evidence that polyamines promote the translation of cyclin-dependent kinase 4 (CDK4) by the action of CUG-binding protein 1 (CUGBP1) and microRNA-222 (miR-222) in intestinal epithelial cells. Both CUGBP1 and miR-222 were found to bind the CDK4 mRNA coding region and 3'-untranslated region and repressed CDK4 translation synergistically. Depletion of cellular polyamines increased cytoplasmic CUGBP1 abundance and miR-222 levels, induced their associations with the CDK4 mRNA, and inhibited CDK4 translation, whereas increasing the levels of cellular polyamines decreased CDK4 mRNA interaction with CUGBP1 and miR-222, in turn inducing CDK4 expression. Polyamine-deficient cells exhibited an increased colocalization of tagged CDK4 mRNA with processing bodies; this colocalization was abolished by silencing CUGBP1 and miR-222. Together, our findings indicate that polyamine-regulated CUGBP1 and miR-222 modulate CDK4 translation at least in part by altering the recruitment of CDK4 mRNA to processing bodies. C1 [Xiao, Lan; Cui, Yu-Hong; Rao, Jaladanki N.; Zou, Tongtong; Liu, Lan; Smith, Alexis; Turner, Douglas J.; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. [Xiao, Lan; Cui, Yu-Hong; Rao, Jaladanki N.; Zou, Tongtong; Liu, Lan; Smith, Alexis; Turner, Douglas J.; Wang, Jian-Ying] Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. RP Wang, JY (reprint author), Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. EM jwang@smail.umaryland.edu FU U.S. Department of Veterans Affairs; National Institutes of Health [DK57819, DK61972, DK68491]; National Institute on Aging, National Institutes of Health FX This work was supported by Merit Review Grants (to J.N.R and J.Y.W.) from the U.S. Department of Veterans Affairs and by National Institutes of Health Grants DK57819, DK61972, and DK68491 (to J.Y.W.). M. Gorospe is supported by the National Institute on Aging-Intramural Research Program, National Institutes of Health. J.Y.W. is a Senior Research Career Scientist, Medical Research Service, U.S. Department of Veterans Affairs. NR 57 TC 36 Z9 39 U1 1 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP 1 PY 2011 VL 22 IS 17 BP 3055 EP 3069 DI 10.1091/mbc.E11-01-0069 PG 15 WC Cell Biology SC Cell Biology GA 814BL UT WOS:000294419300007 PM 21737690 ER PT J AU Sims, JK Wade, PA AF Sims, Jennifer K. Wade, Paul A. TI Mi-2/NuRD complex function is required for normal S phase progression and assembly of pericentric heterochromatin SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CHROMATIN-REMODELING COMPLEX; REPLICATION FORK PROGRESSION; DNA-DAMAGE CHECKPOINT; HISTONE H3; SCREEN REVEALS; HP1 PROTEINS; FACTOR CHD4; LYSINE 9; METHYLATION; CELLS AB During chromosome duplication, it is essential to replicate not only the DNA sequence, but also the complex nucleoprotein structures of chromatin. Pericentric heterochromatin is critical for silencing repetitive elements and plays an essential structural role during mitosis. However, relatively little is understood about its assembly and maintenance during replication. The Mi2/NuRD chromatin remodeling complex tightly associates with actively replicating pericentric heterochromatin, suggesting a role in its assembly. Here we demonstrate that depletion of the catalytic ATPase subunit CHD4/Mi-2 beta in cells with a dampened DNA damage response results in a slow-growth phenotype characterized by delayed progression through S phase. Furthermore, we observe defects in pericentric heterochromatin maintenance and assembly. Our data suggest that chromatin assembly defects are sensed by an ATM-dependent intra-S phase chromatin quality checkpoint, resulting in a temporal block to the transition from early to late S phase. These findings implicate Mi-2 beta in the maintenance of chromatin structure and proper cell cycle progression. C1 [Sims, Jennifer K.; Wade, Paul A.] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Wade, PA (reprint author), Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM wadep2@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health [Z01ES101965] FX We gratefully acknowledge C. J. Tucker, Agnus Janoshazi, and the Fluorescence Microscopy and Imaging Center, National Institute of Environmental Health Sciences, for assistance with microscopy and quantitation of images. We thank Carl Bortner, Maria Sifre, and the Flow Cytometry Center, National Institute of Environmental Health Sciences, for assistance with flow cytometry. This work was substantially improved by critical comments on the manuscript and discussion with Karen Adelman, Aleksandra Adomas, Archana Dhasarathy, Guang Hu, and Anne Lai. This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (Project Z01ES101965 to P.A.W.). NR 41 TC 37 Z9 37 U1 0 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP 1 PY 2011 VL 22 IS 17 BP 3094 EP 3102 DI 10.1091/mbc.E11-03-0258 PG 9 WC Cell Biology SC Cell Biology GA 814BL UT WOS:000294419300010 PM 21737684 ER PT J AU Eyster, CA Cole, NB Petersen, S Viswanathan, K Fruh, K Donaldson, JG AF Eyster, Craig A. Cole, Nelson B. Petersen, Shariska Viswanathan, Kasinath Frueh, Klaus Donaldson, Julie G. TI MARCH ubiquitin ligases alter the itinerary of clathrin-independent cargo from recycling to degradation SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MHC CLASS-II; GROWTH-FACTOR RECEPTOR; COMPLEX CLASS-I; DOWN-REGULATION; ENDOCYTIC PATHWAY; PLASMA-MEMBRANE; ENDOSOMAL TRAFFICKING; DENDRITIC CELLS; IMMUNE EVASION; PROTEINS AB Following endocytosis, internalized plasma membrane proteins can be recycled back to the cell surface or trafficked to late endosomes/lysosomes for degradation. Here we report on the trafficking of multiple proteins that enter cells by clathrin-independent endocytosis (CIE) and determine that a set of proteins (CD44, CD98, and CD147) found primarily in recycling tubules largely failed to reach late endosomes in HeLa cells, whereas other CIE cargo proteins, including major histocompatibility complex class I protein (MHCI), trafficked to both early endosome antigen 1 (EEA1) and late endosomal compartments in addition to recycling tubules. Expression of the membrane-associated RING-CH 8 (MARCH8) E3 ubiquitin ligase completely shifted the trafficking of CD44 and CD98 proteins away from recycling tubules to EEA1 compartments and late endosomes, resulting in reduced surface levels. Cargo affected by MARCH expression, including CD44, CD98, and MHCI, still entered cells by CIE, suggesting that the routing of ubiquitinated cargo occurs after endocytosis. MARCH8 expression led to direct ubiquitination of CD98 and routing of CD98 to late endosomes/lysosomes. C1 [Eyster, Craig A.; Cole, Nelson B.; Petersen, Shariska; Donaldson, Julie G.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Viswanathan, Kasinath; Frueh, Klaus] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR 97006 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov FU National Heart, Lung, and Blood Institute at the National Institutes of Health FX We thank Lois Greene, Edward Korn, Lymarie Maldonado-Baez, Natalie Porat-Shliom, and Paul Roche for comments on the manuscript and critical discussions. We also acknowledge the assistance of Philip McCoy and Pradeep Dagur at the National Heart, Lung, and Blood Institute Flow Cytometry Core. This work was supported by the Intramural Research Program in the National Heart, Lung, and Blood Institute at the National Institutes of Health. NR 50 TC 42 Z9 43 U1 0 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP 1 PY 2011 VL 22 IS 17 BP 3218 EP 3230 DI 10.1091/mbc.E10-11-0874 PG 13 WC Cell Biology SC Cell Biology GA 814BL UT WOS:000294419300020 PM 21757542 ER PT J AU Apps, R Sharkey, A Gardner, L Male, V Kennedy, P Masters, L Farrell, L Jones, D Thomas, R Moffett, A AF Apps, Richard Sharkey, Andrew Gardner, Lucy Male, Victoria Kennedy, Pippa Masters, Leanne Farrell, Lydia Jones, Des Thomas, Rasmi Moffett, Ashley TI Ex vivo functional responses to HLA-G differ between blood and decidual NK cells SO MOLECULAR HUMAN REPRODUCTION LA English DT Article DE HLA-G; immunology; implantation; leucocytes; trophoblast ID NATURAL-KILLER-CELLS; CLASS-I MOLECULES; IFN-GAMMA PRODUCTION; DENDRITIC CELLS; INHIBITORY RECEPTOR; MONOCLONAL-ANTIBODY; TROPHOBLAST CELLS; GESTATIONAL-AGE; TARGET-CELLS; G GENE AB Restricted expression of human leucocyte antigen-G (HLA-G) to fetal extravillous trophoblast cells, which invade the decidua during implantation, suggests a role for HLA-G in placentation. In this study, we have investigated several aspects of HLA-G expression and function. Surface levels of HLA-G expression were measured in 70 normal pregnancies. We show the dimeric conformation that is unique to HLA-G forms after passage through the Golgi apparatus. Differences were found in the receptor repertoire of decidual natural killer (dNK) cells that express the leucocyte immunoglobulin-like receptor B1 (LILRB1), which binds dimeric HLA-G strongly. We then measured functional responses of dNK cells with LILRB1, when stimulated by HLA-G in both monomeric and dimeric conformations. Degranulation, interferon-gamma and interleukin-8 production by dNK cells freshly isolated from the first trimester implantation site were either undetected or not affected by HLA-G. These findings should be considered when inferring the activity of tissue NK cells from results obtained with cell lines, peripheral NK or cultured dNK cells. C1 [Apps, Richard; Sharkey, Andrew; Gardner, Lucy; Male, Victoria; Kennedy, Pippa; Masters, Leanne; Farrell, Lydia; Jones, Des; Moffett, Ashley] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Apps, Richard; Sharkey, Andrew; Gardner, Lucy; Male, Victoria; Kennedy, Pippa; Masters, Leanne; Farrell, Lydia; Jones, Des; Moffett, Ashley] Univ Cambridge, Ctr Trophoblast Res, Cambridge CB2 1QP, England. [Apps, Richard; Thomas, Rasmi] SAIC Frederick Inc, Canc & Inflammat Program, Expt Immunol Lab, NCI Frederick, Frederick, MD USA. RP Moffett, A (reprint author), Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge CB2 1QP, England. EM am485@cam.ac.uk RI Moffett, Ashley/J-9754-2013; Kennedy, Philippa/F-7262-2015; OI Kennedy, Philippa/0000-0003-0239-5440; Farrell, Lydia/0000-0002-7643-6009; Sharkey, Andrew/0000-0002-5072-7748 FU Wellcome Trust; British Heart Foundation; Wellbeing of Women; Centre for Trophoblast Research; Centre for Trophoblast Research, Cambridge FX A.M. is supported by the Wellcome Trust, British Heart Foundation, Wellbeing of Women and the Centre for Trophoblast Research. R.A. is supported by a Next Generation fellowship from the Centre for Trophoblast Research, Cambridge. NR 48 TC 22 Z9 25 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1360-9947 J9 MOL HUM REPROD JI Mol. Hum. Reprod. PD SEP PY 2011 VL 17 IS 9 BP 577 EP 586 DI 10.1093/molehr/gar022 PG 10 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 815TZ UT WOS:000294553900005 PM 21471023 ER PT J AU Germain, RN Paul, WE AF Germain, Ronald N. Paul, William E. TI Baruj Benacerraf (1920-2011) OBITUARY SO NATURE LA English DT Biographical-Item C1 [Germain, Ronald N.; Paul, William E.] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Germain, Ronald N.; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. EM rgermain@nih.gov; wpaul@niaid.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 1 PY 2011 VL 477 IS 7362 BP 34 EP 34 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 813XT UT WOS:000294404300021 PM 21886149 ER PT J AU Mariappan, M Mateja, A Dobosz, M Bove, E Hegde, RS Keenan, RJ AF Mariappan, Malaiyalam Mateja, Agnieszka Dobosz, Malgorzata Bove, Elia Hegde, Ramanujan S. Keenan, Robert J. TI The mechanism of membrane-associated steps in tail-anchored protein insertion SO NATURE LA English DT Article ID YEAST ENDOPLASMIC-RETICULUM; SACCHAROMYCES-CEREVISIAE; ALPHA-FACTOR; ER MEMBRANE; TRANSLOCATION; GET3; COMPLEX; BINDING; SYSTEM; MODEL AB Tail-anchored (TA) membrane proteins destined for the endoplasmic reticulum are chaperoned by cytosolic targeting factors that deliver them to a membrane receptor for insertion. Although a basic framework for TA protein recognition is now emerging, the decisive targeting and membrane insertion steps are not understood. Here we reconstitute the TA protein insertion cycle with purified components, present crystal structures of key complexes between these components and perform mutational analyses based on the structures. We show that a committed targeting complex, formed by a TA protein bound to the chaperone ATPase Get3, is initially recruited to the membrane through an interaction with Get2. Once the targeting complex has been recruited, Get1 interacts with Get3 to drive TA protein release in an ATPase-dependent reaction. After releasing its TA protein cargo, the now-vacant Get3 recycles back to the cytosol concomitant with ATP binding. This work provides a detailed structural and mechanistic framework for the minimal TA protein insertion cycle. C1 [Mateja, Agnieszka; Dobosz, Malgorzata; Bove, Elia; Keenan, Robert J.] Univ Chicago, Dept Biochem & Mol Biol, Gordon Ctr Integrat Sci, Chicago, IL 60637 USA. [Mariappan, Malaiyalam; Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Keenan, RJ (reprint author), Univ Chicago, Dept Biochem & Mol Biol, Gordon Ctr Integrat Sci, Room W238,929 E 57th St, Chicago, IL 60637 USA. EM hegde.science@gmail.com; bkeenan@uchicago.edu RI mariappan, malaiyalam/K-9024-2012; OI Hegde, Ramanujan/0000-0001-8338-852X FU US DOE [DE-AC02-06CH11357]; NIH [R01 GM086487]; Camille and Henry Dreyfus Postdoctoral Program in Environmental Chemistry; Edward Mallinckrodt, Jr. Foundation FX Data were collected at beamline 21-IDG at the Advanced Photon Source (APS), Argonne National Laboratory, and we thank the beamline staff for support. We thank T. Dever for yeast strains, T. Rapoport for the Sec61 alpha antibody, M. Downing for technical assistance, members of the Hegde, Keenan and E. Perozo labs and D. Freymann for advice, and A. Shiau and S. Shao for discussions and comments on the manuscript. Use of the APS, an Office of Science User Facility operated for the US Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the US DOE under contract no. DE-AC02-06CH11357. This work was supported by the Intramural Research Program of the NIH (to R.S.H.), the Camille and Henry Dreyfus Postdoctoral Program in Environmental Chemistry (to R.J.K. and E.B.), an Edward Mallinckrodt, Jr. Foundation Grant (to R.J.K.) and NIH Grant R01 GM086487 (to R.J.K.). NR 39 TC 61 Z9 62 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 1 PY 2011 VL 477 IS 7362 BP 61 EP U69 DI 10.1038/nature10362 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 813XT UT WOS:000294404300030 PM 21866104 ER PT J AU Yamano, K Youle, RJ AF Yamano, Koji Youle, Richard J. TI Coupling mitochondrial and cell division SO NATURE CELL BIOLOGY LA English DT Editorial Material ID FISSION; DRP1; PHOSPHORYLATION; DEGRADATION; PROTECTS; MITOSIS; FUSION AB The mitochondrial network fragments during mitosis to allow proper segregation of the organelles between daughter cells. Two mitotic kinases, the cyclin B-CDK1 complex and Aurora A, are now shown to cooperate with the small G protein RALA and its effector RALBP1 to promote DRP1 phosphorylation and mitochondrial fission. C1 [Yamano, Koji; Youle, Richard J.] Natl Inst Neurol Disorders & Stroke, Biochem Sect, NIH, Bethesda, MD 20892 USA. RP Yamano, K (reprint author), Natl Inst Neurol Disorders & Stroke, Biochem Sect, NIH, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 15 TC 18 Z9 19 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD SEP PY 2011 VL 13 IS 9 BP 1026 EP 1027 DI 10.1038/ncb2334 PG 3 WC Cell Biology SC Cell Biology GA 814WD UT WOS:000294487000006 PM 21892144 ER PT J AU Scaffidi, P Misteli, T AF Scaffidi, Paola Misteli, Tom TI In vitro generation of human cells with cancer stem cell properties SO NATURE CELL BIOLOGY LA English DT Article ID BREAST-CANCER; INITIATING CELLS; TRANSFORMATION; IDENTIFICATION; LEUKEMIA; DIFFERENTIATION; MEDULLOBLASTOMA; FIBROBLASTS; BLASTOCYSTS; EXPRESSION AB Cancer stem cells (CSCs) have been implicated in the maintenance and progression of several types of cancer. The origin and cellular properties of human CSCs are poorly characterized. Here we show that CSC-like cells can be generated in vitro by oncogenic reprogramming of human somatic cells during neoplastic transformation. We find that in vitro transformation confers stem-cell properties to primary differentiated fibroblasts, including the ability to self-renew and to differentiate along multiple lineages. Tumours induced by transformed fibroblasts are hierarchically organized, and the cells that act as CSCs to initiate and maintain tumour growth are marked by the stage-specific embryonic antigen SSEA-1. Heterogeneous lineages of cancer cells in the bulk of the tumour arise through differentiation of SSEA-1 fibroblasts, and differentiation is associated with loss of tumorigenic potential. These findings establish an experimental system to characterize cellular and molecular properties of human CSCs and demonstrate that somatic cells have the potential to de-differentiate and acquire properties of CSCs. C1 [Scaffidi, Paola; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Scaffidi, P (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM scaffidp@mail.nih.gov FU National Institutes of Health (NIH), NCI, Center for Cancer Research FX We thank J. Lee for instruction in mice injections, K. McKinnon (NCI CCR Vaccine Branch FAGS Core Facility) for support with flow cytometry, P. Adams, R. A. Weinberg and L. Li for providing reagents and X. Wu for help with microarray analysis. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research. NR 42 TC 57 Z9 58 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD SEP PY 2011 VL 13 IS 9 BP 1051 EP U72 DI 10.1038/ncb2308 PG 13 WC Cell Biology SC Cell Biology GA 814WD UT WOS:000294487000009 PM 21857669 ER PT J AU Liu, F Park, JE Qian, WJ Lim, D Graber, M Berg, T Yaffe, MB Lee, KS Burke, TR AF Liu, Fa Park, Jung-Eun Qian, Wen-Jian Lim, Dan Graeber, Martin Berg, Thorsten Yaffe, Michael B. Lee, Kyung S. Burke, Terrence R., Jr. TI Serendipitous alkylation of a Plk1 ligand uncovers a new binding channel SO NATURE CHEMICAL BIOLOGY LA English DT Article ID POLO-LIKE KINASES; SMALL-MOLECULE INHIBITOR; BOX DOMAIN; CANCER-THERAPY; POLO-LIKE-KINASE-1; CELLS; PEPTIDE; LOCALIZATION; KINETOCHORES; RECOGNITION AB We obtained unanticipated synthetic byproducts from alkylation of the delta(1) nitrogen (N3) of the histidine imidazole ring of the polo-like kinase-1 (Plk1) polo-box domain (PBD)-binding peptide PLHSpT. For the highest-affinity byproduct, bearing a C(6)H(5)(CH(2))(8)- group, a Plk1 PBD cocrystal structure revealed a new binding channel that had previously been occluded. An N-terminal PEGylated version of this peptide containing a hydrolytically stable phosphothreonyl residue (pT) bound the Plk1 PBD with affinity equal to that of the non-PEGylated parent but showed markedly less interaction with the PBDs of the two closely related proteins Plk2 and Plk3. Treatment of cultured cells with this PEGylated peptide resulted in delocalization of Plk1 from centrosomes and kinetochores and in chromosome misalignment that effectively induced mitotic block and apoptotic cell death. This work provides insights that might advance efforts to develop Plk1 PBD-binding inhibitors as potential Plk1-specific anticancer agents. C1 [Liu, Fa; Qian, Wen-Jian; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res, Frederick, MD 21701 USA. [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lim, Dan; Yaffe, Michael B.] MIT, Ctr Canc Res, Dept Biol & Biol Engn, Cambridge, MA 02139 USA. [Graeber, Martin; Berg, Thorsten] Univ Leipzig, Inst Organ Chem, Leipzig, Germany. RP Liu, F (reprint author), NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res, Frederick, MD 21701 USA. EM kyunglee@mail.nih.gov; tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 FU US National Institutes of Health [ZIA BC 006198, ZIA BC 010681, GM60594, GM68762, CA112967]; Center for Cancer Research; National Cancer Institute-Frederick; US National Cancer Institute; Deutsche Forschungsgemeinschaft [BE 4572/1-1] FX This work was supported in part by grants ZIA BC 006198 (T.R.B.) and ZIA BC 010681 (K.S.L..) of the Intramural Research Program of the US National Institutes of Health, Center for Cancer Research, National Cancer Institute-Frederick and the US National Cancer Institute, US National Institutes of Health (F.L., J.-E.P., W.-J.Q., K.S.L. and T.R.B.), US National Institutes of Health grants GM60594, GM68762 and CA112967 (M. BY.) and the Deutsche Forschungsgemeinschaft (grant BE 4572/1-1) (TB.). We thank M. Dyba of the Biophysics Resource of the Structural Biophysics Laboratory, National Cancer Institute Frederick for assistance in performing tandem MS studies and W. Dai, New York University School of Medicine for the Flag-Plk3 construct. 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 product or organizations imply endorsement by the US government. NR 49 TC 49 Z9 51 U1 3 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD SEP PY 2011 VL 7 IS 9 BP 595 EP 601 DI 10.1038/NHEMBIO.614 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 813QG UT WOS:000294381400009 PM 21765407 ER PT J AU Gui, YT Guo, GW Huang, Y Hu, XD Tang, AF Gao, SJ Wu, RH Chen, C Li, XX Zhou, L He, MH Li, ZS Sun, XJ Jia, WL Chen, JN Yang, SM Zhou, FJ Zhao, XK Wan, SQ Ye, R Liang, CZ Liu, ZS Huang, PD Liu, CX Jiang, H Wang, Y Zheng, HC Sun, L Liu, XW Jiang, ZM Feng, DF Chen, J Wu, S Zou, J Zhang, ZF Yang, RL Zhao, J Xu, CJ Yin, WH Guan, ZC Ye, JX Zhang, H Li, JX Kristiansen, K Nickerson, ML Theodorescu, D Li, YR Zhang, XQ Li, SG Wang, J Yang, HM Wang, J Cai, ZM AF Gui, Yaoting Guo, Guangwu Huang, Yi Hu, Xueda Tang, Aifa Gao, Shengjie Wu, Renhua Chen, Chao Li, Xianxin Zhou, Liang He, Minghui Li, Zesong Sun, Xiaojuan Jia, Wenlong Chen, Jinnong Yang, Shangming Zhou, Fangjian Zhao, Xiaokun Wan, Shengqing Ye, Rui Liang, Chaozhao Liu, Zhisheng Huang, Peide Liu, Chunxiao Jiang, Hui Wang, Yong Zheng, Hancheng Sun, Liang Liu, Xingwang Jiang, Zhimao Feng, Dafei Chen, Jing Wu, Song Zou, Jing Zhang, Zhongfu Yang, Ruilin Zhao, Jun Xu, Congjie Yin, Weihua Guan, Zhichen Ye, Jiongxian Zhang, Hong Li, Jingxiang Kristiansen, Karsten Nickerson, Michael L. Theodorescu, Dan Li, Yingrui Zhang, Xiuqing Li, Songgang Wang, Jian Yang, Huanming Wang, Jun Cai, Zhiming TI Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder SO NATURE GENETICS LA English DT Article ID SOMATIC MUTATIONS; RENAL-CARCINOMA; HUMAN CANCER; PATHWAYS; FGFR3; TUMORIGENESIS; PATTERNS; LEUKEMIA AB Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer. C1 [Gui, Yaoting; Huang, Yi; Tang, Aifa; Li, Xianxin; Zhou, Liang; Li, Zesong; Wang, Yong; Sun, Liang; Jiang, Zhimao; Chen, Jing; Wu, Song; Zhang, Zhongfu; Yang, Ruilin; Zhao, Jun; Xu, Congjie; Yin, Weihua; Guan, Zhichen; Ye, Jiongxian; Zhang, Hong; Cai, Zhiming] Peking Univ, Shenzhen Hosp, Guangdong & Shenzhen Key Lab Male Reprod Med & Ge, Inst Urol,Shenzhen PKU HKUST Med Ctr, Shenzhen, Peoples R China. [Guo, Guangwu; Hu, Xueda; Gao, Shengjie; Wu, Renhua; Chen, Chao; He, Minghui; Jia, Wenlong; Chen, Jinnong; Yang, Shangming; Wan, Shengqing; Ye, Rui; Liu, Zhisheng; Huang, Peide; Jiang, Hui; Zheng, Hancheng; Liu, Xingwang; Feng, Dafei; Zou, Jing; Li, Jingxiang; Kristiansen, Karsten; Li, Yingrui; Zhang, Xiuqing; Li, Songgang; Wang, Jian; Yang, Huanming; Wang, Jun] BGI Shenzhen, Shenzhen, Peoples R China. [Tang, Aifa; Li, Zesong; Sun, Xiaojuan] Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Shenzhen, Peoples R China. [Zhou, Fangjian] Sun Yat Sen Univ, Ctr Canc, Dept Urol, Guangzhou 510275, Guangdong, Peoples R China. [Zhao, Xiaokun] Cent So Univ, Dept Urol, Xiangya Hosp 2, Changsha, Hunan, Peoples R China. [Liang, Chaozhao] Anhui Med Univ, Affiliated Hosp 1, Dept Urol, Hefei, Peoples R China. [Liu, Chunxiao] So Med Univ, Zhujiang Hosp, Dept Urol, Guangzhou, Guangdong, Peoples R China. [Kristiansen, Karsten; Wang, Jun] Univ Copenhagen, Dept Biol, Copenhagen, Denmark. [Nickerson, Michael L.] NCI, Canc & Inflammat Program, US Natl Inst Hlth NIH, Frederick, MD 21701 USA. [Theodorescu, Dan] Univ Colorado, Dept Surg, Ctr Comprehens Canc, Aurora, CO USA. [Theodorescu, Dan] Univ Colorado, Dept Pharmacol, Ctr Comprehens Canc, Aurora, CO USA. RP Cai, ZM (reprint author), Peking Univ, Shenzhen Hosp, Guangdong & Shenzhen Key Lab Male Reprod Med & Ge, Inst Urol,Shenzhen PKU HKUST Med Ctr, Shenzhen, Peoples R China. EM yanghm@genomics.org.cn; wangj@genomics.org.cn; caizhiming2000@yahoo.com.cn RI Li, Yingrui/K-1064-2015; Kristiansen, Karsten/J-5148-2014; Wang, Jun/C-8434-2016; Wang, Jun/B-9503-2016 OI Kristiansen, Karsten/0000-0002-6024-0917; Wang, Jun/0000-0002-8540-8931; Peide, Huang/0000-0001-6108-5069; Wang, Jun/0000-0002-2113-5874 FU National High Technology Research and Development Program of China (863 Program) [2006AA02A302, 2009AA022707]; Promotion Program for Shenzhen Key Laboratory, Shenzhen, China [CXB200903090055A, CXB201005250016A]; Research Fund for the Doctoral Program of Higher Education of China [20100001110100] FX This work was supported by grants from the National High Technology Research and Development Program of China (863 Program, 2006AA02A302 to H.Y. 2009AA022707 to X.Z.), the Promotion Program for Shenzhen Key Laboratory, Shenzhen, China (CXB200903090055A and CXB201005250016A to Z.C.), and Research Fund for the Doctoral Program of Higher Education of China (20100001110100). NR 30 TC 335 Z9 353 U1 9 U2 69 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD SEP PY 2011 VL 43 IS 9 BP 875 EP 878 DI 10.1038/ng.907 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 812XE UT WOS:000294325800014 PM 21822268 ER PT J AU Sloan, JL Johnston, JJ Manoli, I Chandler, RJ Krause, C Carrillo-Carrasco, N Chandrasekaran, SD Sysol, JR O'Brien, K Hauser, NS Sapp, JC Dorward, HM Huizing, M Barshop, BA Berry, SA James, PM Champaigne, NL de Lonlay, P Valayannopoulos, V Geschwind, MD Gavrilov, DK Nyhan, WL Biesecker, LG Venditti, CP AF Sloan, Jennifer L. Johnston, Jennifer J. Manoli, Irini Chandler, Randy J. Krause, Caitlin Carrillo-Carrasco, Nuria Chandrasekaran, Suma D. Sysol, Justin R. O'Brien, Kevin Hauser, Natalie S. Sapp, Julie C. Dorward, Heidi M. Huizing, Marjan Barshop, Bruce A. Berry, Susan A. James, Philip M. Champaigne, Neena L. de Lonlay, Pascale Valayannopoulos, Vassilli Geschwind, Michael D. Gavrilov, Dimitar K. Nyhan, William L. Biesecker, Leslie G. Venditti, Charles P. CA NIH Intramural Sequencing Ctr Grp TI Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria SO NATURE GENETICS LA English DT Article ID MUTATIONAL ANALYSIS; ACYL-COENZYME; SYNTHETASE; RESIDUES; ENZYMES; GENOME; COA AB We used exome sequencing to identify the genetic basis of combined malonic and methylmalonic aciduria (CMAMMA). We sequenced the exome of an individual with CMAMMA and followed up with sequencing of eight additional affected individuals (cases). This included one individual who was identified and diagnosed by searching an exome database. We identify mutations in ACSF3, encoding a putative methylmalonyl-CoA and malonyl-CoA synthetase as a cause of CMAMMA. We also examined a canine model of CMAMMA, which showed pathogenic mutations in a predicted ACSF3 ortholog. ACSF3 mutant alleles occur with a minor allele frequency of 0.0058 in similar to 1,000 control individuals, predicting a CMAMMA population incidence of similar to 1:30,000. ACSF3 deficiency is the first human disorder identified as caused by mutations in a gene encoding a member of the acyl-CoA synthetase family, a diverse group of evolutionarily conserved proteins, and may emerge as one of the more common human metabolic disorders. C1 [Johnston, Jennifer J.; Krause, Caitlin; Sapp, Julie C.; Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Sloan, Jennifer L.; Manoli, Irini; Chandler, Randy J.; Carrillo-Carrasco, Nuria; Chandrasekaran, Suma D.; Sysol, Justin R.; Hauser, Natalie S.; Venditti, Charles P.] NHGRI, Genet & Mol Biol Branch, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. [Chandler, Randy J.] George Washington Univ, Dept Pharmacol, Inst Biomed Sci, Washington, DC 20052 USA. [O'Brien, Kevin; Dorward, Heidi M.; Huizing, Marjan] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [NIH Intramural Sequencing Ctr Grp] NIH Intramural Sequencing Ctr, NIH, Rockville, MD USA. [Barshop, Bruce A.; Nyhan, William L.] Univ Calif San Diego, Dept Pediat, Biochem Genet Lab, San Diego, CA 92103 USA. [Berry, Susan A.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [James, Philip M.] Harvard Univ, Sch Med, Dept Pediat, Childrens Hosp Boston, Boston, MA 02115 USA. [Champaigne, Neena L.] Greenwood Genet Ctr, Greenwood, SC 29646 USA. [de Lonlay, Pascale; Valayannopoulos, Vassilli] Necker Enfants Malades Hosp, Reference Ctr Inherited Metab Disorders, Paris, France. [Geschwind, Michael D.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Gavrilov, Dimitar K.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov RI Carrillo-Carrasco, Nuria/B-9034-2009; OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808; Manoli, Irini/0000-0003-1543-2941; Berry, Susan/0000-0001-7970-688X FU NHGRI, NIH; NIA [K23 AG021989, R01-AG031189] FX We thank the subjects and families for participating, E. Ostrander for the gift of unrelated Labrador DNA samples, K. M. Gibson and R. Wander for performing the malonyl-CoA decarboxylase assay on fibroblasts from subjects 2 and 9, J. Teer for bioinformatics assistance, S. Suchy for subject referral, M. Podell and W. Gahl for helpful discussions, R. Fisher, I. Bernardini, A. Gropman, L. Hecht, F. Facio, C. Gitiaux, C. Ottolenghi, D. Rabier and G. Touati for laboratory assistance and clinical care, and M. Oglesbee and A. Genders for searching for dogs related to the affected Labrador retriever. J. L. S., J. J. J., I. M., R. J. C., N.C.-C., S. D. C., J. R. S., H. M. D., M. H., K.O., N.S.H., J. C. S., C. K., L. G. B. and C. P. V. were supported by the Intramural Research Program of the NHGRI, NIH. M. D. G. was supported by NIA K23 AG021989 and R01-AG031189. NR 13 TC 30 Z9 31 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2011 VL 43 IS 9 BP 883 EP U96 DI 10.1038/ng.908 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 812XE UT WOS:000294325800016 PM 21841779 ER PT J AU Torgerson, DG Ampleford, EJ Chiu, GY Gauderman, WJ Gignoux, CR Graves, PE Himes, BE Levin, AM Mathias, RA Hancock, DB Baurley, JW Eng, C Stern, DA Celedon, JC Rafaels, N Capurso, D Conti, DV Roth, LA Soto-Quiros, M Togias, A Li, XN Myers, RA Romieu, I Van Den Berg, DJ Hu, DL Hansel, NN Hernandez, RD Israel, E Salam, MT Galanter, J Avila, PC Avila, L Rodriquez-Santana, JR Chapela, R Rodriguez-Cintron, W Diette, GB Adkinson, NF Abel, RA Ross, KD Shi, M Faruque, MU Dunston, GM Watson, HR Mantese, VJ Ezurum, SC Liang, LM Ruczinski, I Ford, JG Huntsman, S Chung, KF Vora, H Li, X Calhoun, WJ Castro, M Sienra-Monge, JJ del Rio-Navarro, B Deichmann, KA Heinzmann, A Wenzel, SE Busse, WW Gern, JE Lemanske, RF Beaty, TH Bleecker, ER Raby, BA Meyers, DA London, SJ Gilliland, FD Burchard, EG Martinez, FD Weiss, ST Williams, LK Barnes, KC Ober, C Nicolae, DL AF Torgerson, Dara G. Ampleford, Elizabeth J. Chiu, Grace Y. Gauderman, W. James Gignoux, Christopher R. Graves, Penelope E. Himes, Blanca E. Levin, Albert M. Mathias, Rasika A. Hancock, Dana B. Baurley, James W. Eng, Celeste Stern, Debra A. Celedon, Juan C. Rafaels, Nicholas Capurso, Daniel Conti, David V. Roth, Lindsey A. Soto-Quiros, Manuel Togias, Alkis Li, Xingnan Myers, Rachel A. Romieu, Isabelle Van Den Berg, David J. Hu, Donglei Hansel, Nadia N. Hernandez, Ryan D. Israel, Elliott Salam, Muhammad T. Galanter, Joshua Avila, Pedro C. Avila, Lydiana Rodriquez-Santana, Jose R. Chapela, Rocio Rodriguez-Cintron, William Diette, Gregory B. Adkinson, N. Franklin Abel, Rebekah A. Ross, Kevin D. Shi, Min Faruque, Mezbah U. Dunston, Georgia M. Watson, Harold R. Mantese, Vito J. Ezurum, Serpil C. Liang, Liming Ruczinski, Ingo Ford, Jean G. Huntsman, Scott Chung, Kian Fan Vora, Hita Li, Xia Calhoun, William J. Castro, Mario Sienra-Monge, Juan J. del Rio-Navarro, Blanca Deichmann, Klaus A. Heinzmann, Andrea Wenzel, Sally E. Busse, William W. Gern, James E. Lemanske, Robert F., Jr. Beaty, Terri H. Bleecker, Eugene R. Raby, Benjamin A. Meyers, Deborah A. London, Stephanie J. Gilliland, Frank D. Burchard, Esteban G. Martinez, Fernando D. Weiss, Scott T. Williams, L. Keoki Barnes, Kathleen C. Ober, Carole Nicolae, Dan L. CA Mexico City Childhood Asthma Childrens Hlth Study HARBORS Study Study Genes Environm Admixture Study African Amer Asthma CARE Network CAMP SAPPHIRE GRAAD Study TI Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations SO NATURE GENETICS LA English DT Article ID ORMDL3 EXPRESSION; CHILDHOOD ASTHMA; VARIANTS; 17Q21; SUSCEPTIBILITY; SEQUENCE; CHILDREN; ONSET; GENE AB Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 x 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma. C1 [Torgerson, Dara G.; Capurso, Daniel; Myers, Rachel A.; Abel, Rebekah A.; Ross, Kevin D.; Ober, Carole; Nicolae, Dan L.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Ampleford, Elizabeth J.; Li, Xingnan; Bleecker, Eugene R.; Meyers, Deborah A.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Genom, Winston Salem, NC USA. [Chiu, Grace Y.] Westat Corp, Res Triangle Pk, NC USA. [Gauderman, W. James; Baurley, James W.; Conti, David V.; Van Den Berg, David J.; Salam, Muhammad T.; Vora, Hita; Li, Xia; Gilliland, Frank D.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Gignoux, Christopher R.; Eng, Celeste; Roth, Lindsey A.; Hu, Donglei; Galanter, Joshua; Huntsman, Scott; Burchard, Esteban G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Graves, Penelope E.; Stern, Debra A.; Martinez, Fernando D.] Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA. [Graves, Penelope E.; Stern, Debra A.; Martinez, Fernando D.] Univ Arizona, Inst BIO5, Tucson, AZ USA. [Himes, Blanca E.; Israel, Elliott; Raby, Benjamin A.; Weiss, Scott T.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Himes, Blanca E.; Israel, Elliott; Raby, Benjamin A.; Weiss, Scott T.] Harvard Univ, Sch Med, Boston, MA USA. [Levin, Albert M.] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI USA. [Mathias, Rasika A.; Rafaels, Nicholas; Togias, Alkis; Hansel, Nadia N.; Diette, Gregory B.; Adkinson, N. Franklin; Mantese, Vito J.; Barnes, Kathleen C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Hancock, Dana B.; Shi, Min; London, Stephanie J.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Celedon, Juan C.] Univ Pittsburgh, Div Pediat Pulmonol, Pittsburgh, PA USA. [Soto-Quiros, Manuel; Avila, Lydiana] Hosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa Rica. [Romieu, Isabelle] Inst Nacl Salud Publ, Mexico City, DF, Mexico. [Hansel, Nadia N.; Diette, Gregory B.; Ford, Jean G.; Beaty, Terri H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Hernandez, Ryan D.; Burchard, Esteban G.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Avila, Pedro C.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Rodriquez-Santana, Jose R.] Ctr Neumol Pediat, San Juan, PR USA. [Chapela, Rocio] Inst Nacl Enfermedades Resp, Mexico City, DF, Mexico. [Rodriguez-Cintron, William] Vet Affairs Med Ctr, San Juan, PR USA. [Faruque, Mezbah U.] Howard Univ, Coll Med, Dept Community & Family Med, Washington, DC USA. [Dunston, Georgia M.] Howard Univ, Dept Microbiol, Washington, DC 20059 USA. [Watson, Harold R.] Univ W Indies, Fac Med Sci, St Michael, Barbados. [Watson, Harold R.] Queen Elizabeth Hosp, St Michael, Barbados. [Ezurum, Serpil C.] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA. [Ezurum, Serpil C.] Cleveland Clin, Resp Inst, Cleveland, OH 44106 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Ruczinski, Ingo] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Chung, Kian Fan] Imperial Coll Sch Med, London, England. [Calhoun, William J.] Univ Texas Med Branch, Dept Internal Med, Galveston, TX USA. [Castro, Mario] Washington Univ, Dept Med, St Louis, MO USA. [Sienra-Monge, Juan J.; del Rio-Navarro, Blanca] Hosp Infantil Mexico Dr Federico Gomez, Mexico City, DF, Mexico. [Deichmann, Klaus A.; Heinzmann, Andrea] Univ Freiburg, Dept Pediat, D-7800 Freiburg, Germany. [Wenzel, Sally E.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Busse, William W.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Lemanske, Robert F., Jr.] Univ Wisconsin, Dept Pediat, Sch Med & Publ Hlth, Madison, WI USA. [Williams, L. Keoki] Henry Ford Hlth Syst, Ctr Hlth Serv Res, Dept Internal Med, Detroit, MI USA. [Nicolae, Dan L.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Nicolae, Dan L.] Univ Chicago, Dept Stat, Chicago, IL 60637 USA. RP Nicolae, DL (reprint author), Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. EM nicolae@galton.uchicago.edu RI Hancock, Dana/D-8577-2012; OI Hancock, Dana/0000-0003-2240-3604; Chung, Kian Fan/0000-0001-7101-1426; London, Stephanie/0000-0003-4911-5290 FU Office of the Director, NIH; National Heart, Lung, and Blood Institute [HL087665, HL070831, HL072414, HL049596, HL064307, HL064313, HL075419, HL65899, HL083069, HL066289, HL101543, HL101651, HL079055, HL087699, HL49612, HL075417, HL04266, HL072433, HL061768, HL076647, HL087680, HL078885, HL088133, HL87665, HL69116, HL69130, HL69149]; National Institutes of Allergy and Infectious Disease [AI070503, AI079139, AI061774, AI50024, AI44840, AI41040, AI077439]; National Institute of Diabetes and Digestive and Kidney Diseases [DK064695]; National Institutes of Environmental Health Sciences [ES09606, ES018176, ES015903, ES007048, ES009581, R826708, RD831861, ES011627, ES015794]; Division of Intramural Research [Z01 ES049019]; National Center for Research Resources [RR03048]; Environmental Protection Agency [83213901, R-826724]; American Asthma Foundation; Fund for Henry Ford Hospital; Mary Beryl Patch Turnbull Scholar Program; National Council of Science and Technology (Mexico) [26206-M]; Centers for Disease Control, US; Eudowood Foundation; Flight Attendant Medical Research Institute (FAMRI); Robert Wood Johnson Foundation (RWJF); Sandler Foundation FX This work was supported by grants from the Office of the Director, NIH to C.O. and D.L.N. and the National Heart, Lung, and Blood Institute (HL101651 to C.O. and D.L.N.; HL087665 to D.L.N.; HL070831, HL072414 and HL049596 to C.O.; HL064307 and HL064313 to F. D. M.; HL075419, HL65899, HL083069, HL066289, HL087680, HL101543 and HL101651 to S. T. W.; HL079055 to L. K. W.; HL087699, HL49612, HL075417, HL04266 and HL072433 to K. C. B.; HL061768 and HL076647 to F. D. G.; HL087680 to W. J. G.; HL078885 and HL088133 to E. G. B.; HL87665 to D. A. M.; and HL69116, HL69130, HL69149, HL69155, HL69167, HL69170, HL69174 and HL69349 to D. A. M., E. R. B., W. W. B., W. J. C., M. C., K. F. C., S. C. E., E. I. and S. E. W.), the National Institutes of Allergy and Infectious Disease (AI070503 to C.O.; AI079139 and AI061774 to L. K. W.; AI50024, AI44840 and AI41040 to K. C. B.; and AI077439 to E. G. B.), the National Institute of Diabetes and Digestive and Kidney Diseases to L. K. W. (DK064695); the National Institutes of Environmental Health Sciences (ES09606, ES018176 and ES015903 to K. C. B.; ES007048, ES009581, R826708, RD831861 and ES011627 to F. D. G.; ES015794 to E. G. B.; and the Division of Intramural Research, Z01 ES049019, to S. J. L.); the National Center for Research Resources (RR03048 to K. C. B.), the Environmental Protection Agency (83213901 and R-826724 to K. C. B.), the American Asthma Foundation and the Fund for Henry Ford Hospital (to L. K. W.), Mary Beryl Patch Turnbull Scholar Program (to K. C. B.), the National Council of Science and Technology (Mexico) (26206-M to I. Ruczinski), the Centers for Disease Control, US (to I. Ruczinski), the Eudowood Foundation (to N. N. H.); and the Flight Attendant Medical Research Institute (FAMRI), Robert Wood Johnson Foundation (RWJF) Amos Medical Faculty Development Award, the American Asthma Foundation, and the Sandler Foundation (to E. G. B.). NR 26 TC 290 Z9 297 U1 5 U2 42 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2011 VL 43 IS 9 BP 887 EP U103 DI 10.1038/ng.888 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 812XE UT WOS:000294325800017 PM 21804549 ER PT J AU Chen, WJ AF Chen, WanJun TI IDO: more than an enzyme SO NATURE IMMUNOLOGY LA English DT Editorial Material ID PLASMACYTOID DENDRITIC CELLS; TRYPTOPHAN CATABOLISM AB In addition to its recognized function as an enzyme that catalyzes tryptophan, indoleamine 2,3-dioxygenase (IDO) acts as an intracellular signal transducer, in response to transforming growth factor-beta (TGF-beta), to induce a stably regulatory phenotype in plasmacytoid dendritic cells. C1 Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, NIH, Bethesda, MD USA. RP Chen, WJ (reprint author), Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, NIH, Bethesda, MD USA. EM wchen@dir.nidcr.nih.gov NR 11 TC 41 Z9 45 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD SEP PY 2011 VL 12 IS 9 BP 809 EP U DI 10.1038/ni.2088 PG 3 WC Immunology SC Immunology GA 814NA UT WOS:000294461200001 PM 21852775 ER PT J AU Sullivan, NJ Hensley, L Asiedu, C Geisbert, TW Stanley, D Johnson, J Honko, A Olinger, G Bailey, M Geisbert, JB Reimann, KA Bao, S Rao, S Roederer, M Jahrling, PB Koup, RA Nabel, GJ AF Sullivan, Nancy J. Hensley, Lisa Asiedu, Clement Geisbert, Thomas W. Stanley, Daphne Johnson, Joshua Honko, Anna Olinger, Gene Bailey, Michael Geisbert, Joan B. Reimann, Keith A. Bao, Saran Rao, Srinivas Roederer, Mario Jahrling, Peter B. Koup, Richard A. Nabel, Gary J. TI CD8(+) cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates SO NATURE MEDICINE LA English DT Article ID HEMORRHAGIC-FEVER; MARBURG VIRUS; INDUCTION; ANTIBODY AB Vaccine-induced immunity to Ebola virus infection in nonhuman primates (NHPs) is marked by potent antigen-specific cellular and humoral immune responses(1,2); however, the immune mechanism of protection remains unknown. Here we define the immune basis of protection conferred by a highly protective recombinant adenovirus virus serotype 5 (rAd5) encoding Ebola virus glycoprotein (GP)(1,3) in NHPs. Passive transfer of high-titer polyclonal antibodies from vaccinated Ebola virus-immune cynomolgus macaques to naive macaques failed to confer protection against disease, suggesting a limited role of humoral immunity. In contrast, depletion of CD3(+) T cells in vivo after vaccination and immediately before challenge eliminated immunity in two vaccinated macaques, indicating a crucial requirement for T cells in this setting. The protective effect was mediated largely by CD8(+) cells, as depletion of CD8(+) cells in vivo using the cM-T807 monoclonal antibody (mAb), which does not affect CD4(+) T cell or humoral immune responses, abrogated protection in four out of five subjects. These findings indicate that CD8(+) cells have a major role in rAd5-GP-induced immune protection against Ebola virus infection in NHPs. Understanding the immunologic mechanism of Ebola virus protection will facilitate the development of vaccines for Ebola and related hemorrhagic fever viruses in humans. C1 [Sullivan, Nancy J.; Asiedu, Clement; Stanley, Daphne; Bailey, Michael; Bao, Saran; Rao, Srinivas; Roederer, Mario; Koup, Richard A.; Nabel, Gary J.] US Natl Inst Allergy & Infect Dis, Vaccine Res Ctr, US Natl Inst Hlth, Bethesda, MD USA. [Hensley, Lisa; Geisbert, Thomas W.; Johnson, Joshua; Honko, Anna; Olinger, Gene; Geisbert, Joan B.] USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Reimann, Keith A.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Jahrling, Peter B.] US Natl Inst Allergy & Infect Dis, Integrated Res Facil, US Natl Inst Hlth, Bethesda, MD USA. RP Sullivan, NJ (reprint author), US Natl Inst Allergy & Infect Dis, Vaccine Res Ctr, US Natl Inst Hlth, Bethesda, MD USA. EM nsullivan@nih.gov OI Olinger, Gene/0000-0001-7338-0292; Johnson, Joshua/0000-0002-5677-3841; Honko, Anna/0000-0001-9165-148X FU National Center for Research Resource, US National Institutes of Health [R24RR016001]; US National Institutes of Health FX We thank D. Jeffers, T. Suhana, A. Tislerics and B. Hartman for help with manuscript preparation; M. Cichanowski for graphics; D. Braun, K. Daddario and C. Rice for technical and animal care assistance; S. Norris and M. Nason for assistance with statistical considerations; and K. Kenyon for editorial support. We thank D. Neville (US National Institute of Mental Health) for the generous gift of FN18-CRM9 immunotoxin. Reagent support was provided by the Nonhuman Primate Reagent Resource (grant number R24RR016001 from the National Center for Research Resource, US National Institutes of Health). Support for this work was provided by the Intramural Research Program of the US National Institutes of Health. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the US Army or the Department of Defense. NR 20 TC 86 Z9 87 U1 1 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2011 VL 17 IS 9 BP 1128 EP U135 DI 10.1038/nm.2447 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 816MM UT WOS:000294605100034 PM 21857654 ER PT J AU Savidge, TC Urvil, P Oezguen, N Ali, K Choudhury, A Acharya, V Pinchuk, I Torres, AG English, RD Wiktorowicz, JE Loeffelholz, M Kumar, R Shi, LF Nie, WJ Braun, W Herman, B Hausladen, A Feng, HP Stamler, JS Pothoulakis, C AF Savidge, Tor C. Urvil, Petri Oezguen, Numan Ali, Kausar Choudhury, Aproteem Acharya, Vinay Pinchuk, Irina Torres, Alfredo G. English, Robert D. Wiktorowicz, John E. Loeffelholz, Michael Kumar, Raj Shi, Lianfa Nie, Weijia Braun, Werner Herman, Bo Hausladen, Alfred Feng, Hanping Stamler, Jonathan S. Pothoulakis, Charalabos TI Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins SO NATURE MEDICINE LA English DT Article ID CYSTEINE PROTEASE DOMAIN; DIFFICILE TOXIN; NITRIC-OXIDE; RTX TOXIN; CLEAVAGE; DENITROSYLATION; INFLAMMATION; ENTEROTOXIN; VIRULENCE; RELEASE AB The global prevalence of severe Clostridium difficile infection highlights the profound clinical significance of clostridial glucosylating toxins(1-4). Virulence is dependent on the autoactivation of a toxin cysteine protease(5-9), which is promoted by the allosteric cofactor inositol hexakisphosphate (InsP(6))(10-17). Host mechanisms that protect against such exotoxins are poorly understood. It is increasingly appreciated that the pleiotropic functions attributed to nitric oxide (NO), including host immunity, are in large part mediated by S-nitrosylation of proteins(18,19). Here we show that C. difficile toxins are S-nitrosylated by the infected host and that S-nitrosylation attenuates virulence by inhibiting toxin self-cleavage and cell entry. Notably, InsP(6)- and inositol pyrophosphate (InsP(7))-induced conformational changes in the toxin enabled host S-nitrosothiols to transnitrosylate the toxin catalytic cysteine, which forms part of a structurally conserved nitrosylation motif. Moreover, treatment with exogenous InsP(6) enhanced the therapeutic actions of oral S-nitrosothiols in mouse models of C. difficile infection. Allostery in bacterial proteins has thus been successfully exploited in the evolutionary development of nitrosothiol-based innate immunity and may provide an avenue to new therapeutic approaches. C1 [Savidge, Tor C.; Urvil, Petri; Ali, Kausar; Choudhury, Aproteem; Acharya, Vinay; Pinchuk, Irina] Univ Texas Med Branch, Dept Gastroenterol & Hepatol, Galveston, TX 77555 USA. [Oezguen, Numan; Wiktorowicz, John E.; Braun, Werner] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX USA. [Torres, Alfredo G.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX USA. [English, Robert D.; Wiktorowicz, John E.] Univ Texas Med Branch, Natl Heart Lung & Blood Inst Prote Ctr, Galveston, TX USA. [Loeffelholz, Michael] Univ Texas Med Branch, Dept Pathol, Galveston, TX USA. [Kumar, Raj] Commonwealth Med Coll, Dept Basic Sci, Scranton, PA USA. [Shi, Lianfa; Nie, Weijia; Feng, Hanping] Tufts Univ Cummings Sch Vet Med, Div Infect Dis, Dept Biomed Sci, North Grafton, MA USA. [Herman, Bo; Hausladen, Alfred; Stamler, Jonathan S.] Case Western Reserve Univ, Inste Transformat Mol Med, Cleveland, OH 44106 USA. [Herman, Bo; Hausladen, Alfred; Stamler, Jonathan S.] Univ Hosp, Cleveland, OH USA. [Herman, Bo; Hausladen, Alfred; Stamler, Jonathan S.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Herman, Bo; Hausladen, Alfred; Stamler, Jonathan S.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Pothoulakis, Charalabos] Univ Calif Los Angeles, Div Digest Dis, Los Angeles, CA USA. RP Savidge, TC (reprint author), Univ Texas Med Branch, Dept Gastroenterol & Hepatol, Galveston, TX 77555 USA. EM tcsavidg@utmb.edu RI Oezguen, Numan/C-9267-2009; Braun, Werner/A-6642-2012; Pinchuk, Irina/A-7227-2008 OI Oezguen, Numan/0000-0002-3175-2382; Pinchuk, Irina/0000-0003-1505-5779 FU Eli & Edith Broad Foundation; John S. Dunn Gulf Coast Consortium for Chemical Genomics; Howard Hughes Medical Institute; US National Institutes of Health National Institute of Allergy and Infectious Diseases [R01AI088748, N01AI30050]; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK084509, K01DK076549, R21-DK078032-01]; National Heart, Lung, and Blood Institute [R01-HL059130, R01-HL091876, R01-HL095463, P01-HL075443-06A, NO1-HV-00245]; [1UL1RR029876-01] FX This work was supported by the Eli & Edith Broad Foundation, the John S. Dunn Gulf Coast Consortium for Chemical Genomics Robert A. Welch Collaborative Grant Program, the Howard Hughes Medical Institute and grants from the US National Institutes of Health National Institute of Allergy and Infectious Diseases (R01AI088748, N01AI30050), National Institute of Diabetes and Digestive and Kidney Diseases (R01DK084509, K01DK076549; R21-DK078032-01), National Heart, Lung, and Blood Institute (R01-HL059130, R01-HL091876, R01-HL095463, P01-HL075443-06A, NO1-HV-00245) and 1UL1RR029876-01. We thank D. Powell, S. Weinman, C.S. Schein and G. Prestwich for their critiques. NR 40 TC 37 Z9 37 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2011 VL 17 IS 9 BP 1136 EP U147 DI 10.1038/nm.2405 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 816MM UT WOS:000294605100036 PM 21857653 ER PT J AU Subach, OM Patterson, GH Ting, LM Wang, YR Condeelis, JS Verkhusha, VV AF Subach, Oksana M. Patterson, George H. Ting, Li-Min Wang, Yarong Condeelis, John S. Verkhusha, Vladislav V. TI A photoswitchable orange-to-far-red fluorescent protein, PSmOrange SO NATURE METHODS LA English DT Article ID MONOMERIC RED; NANOSCOPY; PHOTOCONVERSION; LOCALIZATION; MICROSCOPY; TRACKING; BRIGHT; WINDOW; COLOR AB We report a photoswitchable monomeric Orange (PSmOrange) protein that is initially orange (excitation, 548 nm; emission, 565 nm) but becomes far-red (excitation, 636 nm; emission, 662 nm) after irradiation with blue-green light. Compared to its parental orange proteins, PSmOrange has greater brightness, faster maturation, higher photoconversion contrast and better photostability. The red-shifted spectra of both forms of PSmOrange enable its simultaneous use with cyan-to-green photoswitchable proteins to study four intracellular populations. Photoconverted PSmOrange has, to our knowledge, the most far-red excitation peak of all GFP-like fluorescent proteins, provides diffraction-limited and super-resolution imaging in the far-red light range, is optimally excited with common red lasers, and can be photoconverted subcutaneously in a mouse. PSmOrange photoswitching occurs via a two-step photo-oxidation process, which causes cleavage of the polypeptide backbone. The far-red fluorescence of photoconverted PSmOrange results from a new chromophore containing N-acylimine with a co-planar carbon-oxygen double bond. C1 [Subach, Oksana M.; Wang, Yarong; Condeelis, John S.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10467 USA. [Subach, Oksana M.; Wang, Yarong; Condeelis, John S.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Gruss Lipper Biophoton Ctr, Bronx, NY 10467 USA. [Patterson, George H.] Natl Inst Biomed Imaging & Bioengn, Biophoton Sect, NIH, Bethesda, MD USA. [Ting, Li-Min] Albert Einstein Coll Med, Dept Immunol & Microbiol, Bronx, NY 10467 USA. [Ting, Li-Min] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. RP Verkhusha, VV (reprint author), Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10467 USA. EM vladislav.verkhusha@einstein.yu.edu RI Subach, Oksana (Gritsenko)/K-7086-2014 FU US National Institutes of Health [GM073913, CA100324]; National Institutes of Health including the National Institute of Biomedical Imaging and Bioengineering FX We thank J. Zhang and L. Tesfa for assistance with flow cytometry, H. Xiao for help with mass-spectrometry analysis, K. Kim and G. Filonov for assistance with mouse experiments and useful discussions, M. Davidson (Florida State University) for vimentin, keratin, myosin and paxillin plasmids, and B. Glick (University of Chicago), D. Chudakov and K. Lukyanov (both from Institute of Bioorganic Chemistry) for plasmids encoding far-red fluorescent proteins. This work was supported by US National Institutes of Health (GM073913 to V.V.V. and CA100324 to J.C.) and by the National Institutes of Health Intramural Research Program including the National Institute of Biomedical Imaging and Bioengineering (to G.H.P.). NR 37 TC 72 Z9 75 U1 4 U2 42 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD SEP PY 2011 VL 8 IS 9 BP 771 EP U125 DI 10.1038/nmeth.1664 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 814HL UT WOS:000294439100016 PM 21804536 ER PT J AU Diamond, JS AF Diamond, Jeffrey S. TI Grilled RIBEYE stakes a claim for synaptic ribbons SO NATURE NEUROSCIENCE LA English DT Editorial Material ID INACTIVATION; TRANSIENT; DEPLETION; VESICLES; BASSOON; ROLES; CELL AB Photo-inactivation of RIBEYE, an important presynaptic protein at ribbon synapses in the retina, reveals a new role for ribbons in the vesicle priming process. C1 Natl Inst Neurol Disorders & Stroke, Synapt Physiol Sect, US Natl Inst Hlth, Bethesda, MD 20824 USA. RP Diamond, JS (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Physiol Sect, US Natl Inst Hlth, Bethesda, MD 20824 USA. EM diamondj@ninds.nih.gov RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 NR 15 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2011 VL 14 IS 9 BP 1097 EP 1098 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 812ID UT WOS:000294284900002 PM 21878922 ER PT J AU Xi, ZX Peng, XQ Li, X Song, R Zhang, HY Liu, QR Yang, HJ Bi, GH Li, J Gardner, EL AF Xi, Zheng-Xiong Peng, Xiao-Qing Li, Xia Song, Rui Zhang, Hai-Ying Liu, Qing-Rong Yang, Hong-Ju Bi, Guo-Hua Li, Jie Gardner, Eliot L. TI Brain cannabinoid CB2 receptors modulate cocaine's actions in mice SO NATURE NEUROSCIENCE LA English DT Article ID DORSAL-HORN NEURONS; PHARMACOLOGICAL CHARACTERIZATION; MOLECULAR CHARACTERIZATION; NUCLEUS-ACCUMBENS; NEUROPATHIC RATS; SENSORY NEURONS; CHRONIC PAIN; AGONISTS; EXPRESSION; DOPAMINE AB The presence and function of cannabinoid CB2 receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB2 receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB1 receptor knockout (CB1-/-, also known as Cnr1(-/-)) mice, but not in CB2-/-(Cnr2(-/-)) mice. This inhibition was mimicked by GW405833, another CB2 receptor agonist with a different chemical structure, and was blocked by AM630, a selective CB2 receptor antagonist. Intra-accumbens administration of JWH133 alone dose-dependently decreased, whereas intra-accumbens administration of AM630 elevated, extracellular dopamine and locomotion in wild-type and CB1-/- mice, but not in CB2-/- mice. Intra-accumbens administration of AM630 also blocked the reduction in cocaine self-administration and extracellular dopamine produced by systemic administration of JWH133. These findings suggest that brain CB2 receptors modulate cocaine's rewarding and locomotor-stimulating effects, likely by a dopamine-dependent mechanism. C1 [Xi, Zheng-Xiong; Peng, Xiao-Qing; Li, Xia; Song, Rui; Zhang, Hai-Ying; Liu, Qing-Rong; Yang, Hong-Ju; Bi, Guo-Hua; Li, Jie; Gardner, Eliot L.] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. [Song, Rui] Beijing Inst Pharmacol & Toxicol, Beijing, Peoples R China. RP Xi, ZX (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. EM zxi@intra.nida.nih.gov RI Liu, Qing-Rong/A-3059-2012; OI Liu, Qing-Rong/0000-0001-8477-6452; Zhang, Haiying/0000-0003-0593-5940; PENG, XIAOQING/0000-0002-7272-5428 FU National Institute on Drug Abuse FX We thank Y. Shaham and E.A. Stein of the Intramural Research Program of the National Institute on Drug Abuse, and K. Mackie of Indiana University for their helpful comments on this manuscript. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse. NR 50 TC 129 Z9 131 U1 2 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2011 VL 14 IS 9 BP 1160 EP U216 DI 10.1038/nn.2874 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 812ID UT WOS:000294284900016 PM 21785434 ER PT J AU Bromberg-Martin, ES Hikosaka, O AF Bromberg-Martin, Ethan S. Hikosaka, Okihide TI Lateral habenula neurons signal errors in the prediction of reward information SO NATURE NEUROSCIENCE LA English DT Article ID MIDBRAIN DOPAMINE NEURONS; VENTRAL TEGMENTAL AREA; OBSERVING RESPONSES; REINFORCEMENT; STIMULATION; UNCERTAINTY; ACQUISITION; ENCODE; RAT; NEUROMODULATION AB Humans and animals have the ability to predict future events, which they cultivate by continuously searching their environment for sources of predictive information. However, little is known about the neural systems that motivate this behavior. We hypothesized that information-seeking is assigned value by the same circuits that support reward-seeking, such that neural signals encoding reward prediction errors (RPEs) include analogous information prediction errors (IPEs). To test this, we recorded from neurons in the lateral habenula, a nucleus that encodes RPEs, while monkeys chose between cues that provided different chances to view information about upcoming rewards. We found that a subpopulation of lateral habenula neurons transmitted signals resembling IPEs, responding when reward information was unexpectedly cued, delivered or denied. These signals evaluated information sources reliably, even when the monkey's decisions did not. These neurons could provide a common instructive signal for reward-seeking and information-seeking behavior. C1 [Bromberg-Martin, Ethan S.; Hikosaka, Okihide] NEI, Sensorimotor Res Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Bromberg-Martin, ES (reprint author), NEI, Sensorimotor Res Lab, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. EM bromberge@mail.nih.gov FU National Eye Institute FX We thank M. Matsumoto, S. Hong, I. Monosov, M. Yasuda, S. Yamamoto, Y. Tachibana, H. Kim and D. Lee for valuable discussions. This work was supported by the intramural research program at the National Eye Institute. NR 50 TC 69 Z9 69 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2011 VL 14 IS 9 BP 1209 EP U149 DI 10.1038/nn.2902 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 812ID UT WOS:000294284900023 PM 21857659 ER PT J AU Orchard, S Al-Lazikani, B Bryant, S Clark, D Calder, E Dix, I Engkvist, O Forster, M Gaulton, A Gilson, M Glen, R Grigorov, M Hammond-Kosack, K Harland, L Hopkins, A Larminie, C Lynch, N Mann, RK Murray-Rust, P Lo Piparo, E Southan, C Steinbeck, C Wishart, D Hermjakob, H Overington, J Thornton, J AF Orchard, Sandra Al-Lazikani, Bissan Bryant, Steve Clark, Dominic Calder, Elizabeth Dix, Ian Engkvist, Ola Forster, Mark Gaulton, Anna Gilson, Michael Glen, Robert Grigorov, Martin Hammond-Kosack, Kim Harland, Lee Hopkins, Andrew Larminie, Christopher Lynch, Nick Mann, Romeena K. Murray-Rust, Peter Lo Piparo, Elena Southan, Christopher Steinbeck, Christoph Wishart, David Hermjakob, Henning Overington, John Thornton, Janet TI Minimum information about a bioactive entity (MIABE) SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID BINDING-SITES; DRUGGABILITY; ONTOLOGY; DATABASE; GENOME AB Bioactive molecules such as drugs, pesticides and food additives are produced in large numbers by many commercial and academic groups around the world. Enormous quantities of data are generated on the biological properties and quality of these molecules. Access to such data - both on licensed and commercially available compounds, and also on those that fail during development - is crucial for understanding how improved molecules could be developed. For example, computational analysis of aggregated data on molecules that are investigated in drug discovery programmes has led to a greater understanding of the properties of successful drugs. However, the information required to perform these analyses is rarely published, and when it is made available it is often missing crucial data or is in a format that is inappropriate for efficient data-mining. Here, we propose a solution: the definition of reporting guidelines for bioactive entities - the Minimum Information About a Bioactive Entity (MIABE) - which has been developed by representatives of pharmaceutical companies, data resource providers and academic groups. C1 [Orchard, Sandra; Clark, Dominic; Gaulton, Anna; Steinbeck, Christoph; Hermjakob, Henning; Overington, John; Thornton, Janet] EMBL European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England. [Al-Lazikani, Bissan] Inst Canc Res, Canc Res UK Canc Therapeut Unit, Belmont SM2 5NG, Surrey, England. [Bryant, Steve] US NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Calder, Elizabeth; Dix, Ian; Lynch, Nick] AstraZeneca R&D, R&D Informat, Macclesfield SK10 4TG, Cheshire, England. [Engkvist, Ola] AstraZeneca R&D, DECS Computat Sci, SE-43183 Molndal, Sweden. [Forster, Mark] Int Res Ctr, Bracknell RG42 6EY, Berks, England. [Gilson, Michael] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Glen, Robert; Murray-Rust, Peter] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Grigorov, Martin; Lo Piparo, Elena] Nestle Res Ctr, CH-1000 Lausanne 26, Switzerland. [Hammond-Kosack, Kim] Rothamsted Res, Harpenden AL5 2JQ, Herts, England. [Harland, Lee] Pfizer Ltd, Sandwich CT13 9NJ, Kent, England. [Harland, Lee] Connected Discovery Ltd, London WC1N 3AX, England. [Hopkins, Andrew] Univ Dundee, Coll Life Sci, Dundee DD1 5EH, Scotland. [Larminie, Christopher; Mann, Romeena K.] GlaxoSmithKline, Stevenage SG1 2NY, Herts, England. [Southan, Christopher] ChrisDS Consulting, S-42166 Gothenburg, Sweden. [Wishart, David] Univ Alberta, Dept Comp Sci, Edmonton, AB T6G 2E9, Canada. [Wishart, David] Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada. RP Orchard, S (reprint author), EMBL European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England. EM orchard@ebi.ac.uk RI Steinbeck, Christoph/B-4131-2008; Engkvist, Ola/J-1951-2012; Overington, John/G-8607-2015; OI Steinbeck, Christoph/0000-0001-6966-0814; Gaulton, Anna/0000-0003-2634-7400; Southan, Christopher/0000-0001-9580-0446; Overington, John/0000-0002-5859-1064; Clark, Dominic/0000-0002-2227-8834; Murray-Rust, Peter/0000-0003-3386-3972; Thornton, Janet/0000-0003-0824-4096; Al-Lazikani, Bissan/0000-0003-3367-2519; Orchard, Sandra/0000-0002-8878-3972; Wishart, David S/0000-0002-3207-2434; Harland, Lee/0000-0003-0461-0028; Hermjakob, Henning/0000-0001-8479-0262; Engkvist, Ola/0000-0003-4970-6461 FU European Commission under the Proteomics Standards Initiative and International Molecular Exchange (PSIMEx) [FP7-HEALTH-2007-223411] FX This work has, in part, been funded by the European Commission under the Proteomics Standards Initiative and International Molecular Exchange (PSIMEx), contract number FP7-HEALTH-2007-223411. NR 27 TC 48 Z9 48 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD SEP PY 2011 VL 10 IS 9 BP 661 EP 669 DI 10.1038/nrd3503 PG 9 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 814TC UT WOS:000294479100019 PM 21878981 ER PT J AU Lyon, AM Tesmer, VM Dhamsania, VD Thal, DM Gutierrez, J Chowdhury, S Suddala, KC Northup, JK Tesmer, JJG AF Lyon, Angeline M. Tesmer, Valerie M. Dhamsania, Vishan D. Thal, David M. Gutierrez, Joanne Chowdhury, Shoaib Suddala, Krishna C. Northup, John K. Tesmer, John J. G. TI An autoinhibitory helix in the C-terminal region of phospholipase C-beta mediates G alpha(q) activation SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID G-ALPHA-Q; G-PROTEIN; GAMMA-SUBUNITS; MEMBRANE-BINDING; ISOZYMES; GQ; PURIFICATION; C-BETA-1; DOMAIN; G(Q) AB The enzyme phospholipase C-beta (PLC beta) is a crucial regulator of intracellular calcium levels whose activity is controlled by heptahelical receptors that couple to members of the G(q) family of heterotrimeric G proteins. We have determined atomic structures of two invertebrate homologs of PLC beta (PLC21) from cephalopod retina and identified a helix from the C-terminal regulatory region that interacts with a conserved surface of the catalytic core of the enzyme. Mutations designed to disrupt the analogous interaction in human PLC beta 3 considerably increase basal activity and diminish stimulation by G alpha(q). G alpha(q) binding requires displacement of the autoinhibitory helix from the catalytic core, thus providing an allosteric mechanism for activation of PLC beta. C1 [Lyon, Angeline M.; Tesmer, Valerie M.; Dhamsania, Vishan D.; Thal, David M.; Tesmer, John J. G.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Gutierrez, Joanne; Chowdhury, Shoaib; Northup, John K.] Natl Inst Deafness & Other Commun Disorders, Cell Biol Lab, US Natl Inst Hlth, Rockville, MD USA. [Suddala, Krishna C.] Univ Michigan, Dept Biophys, Ann Arbor, MI 48109 USA. [Tesmer, John J. G.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. RP Tesmer, JJG (reprint author), Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. EM northupj@nidcd.nih.gov; tesmerjj@umich.edu FU US National Institutes of Health [HL071818, HL086865]; National Institute on Deafness and Other Communication Disorders, US National Institutes of Health; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Michigan Economic Development Corporation; Michigan's Technology Tri-Corridor [085P1000817]; [DK20572] FX We thank E. Ross (University of Texas Southwestern Medical Center at Dallas) for the vector encoding human PLC beta 3, and G. Tall (University of Rochester) for the baculovirus vector expressing glutathione S-transferase (GST)-tagged Ric8A and for insight into how to increase yields of G alphaq, before publication of his work. We also thank P. Backlund (Section on Mass Spectrometry and Metabolism, National Institute of Child Health & Human Development) for mass spectrometry of PLC21 samples. This work was supported by US National Institutes of Health grants HL071818 and HL086865 (J.J.G.T.) and by the Intramural Research program of the National Institute on Deafness and Other Communication Disorders, US National Institutes of Health (J.K.N.). Our research used the Cell and Molecular Biology Core of the Michigan Diabetes Research and Training Center, supported by DK20572. Use of the Advanced Photon Source at Argonne National Laboratory was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and Michigan's Technology Tri-Corridor (grant 085P1000817). NR 54 TC 32 Z9 34 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD SEP PY 2011 VL 18 IS 9 BP 999 EP U54 DI 10.1038/nsmb.2095 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 815TB UT WOS:000294551200007 PM 21822282 ER PT J AU Stiell, IG Nichol, G Leroux, BG Rea, TD Ornato, JP Powell, J Christenson, J Callaway, CW Kudenchuk, PJ Aufderheide, TP Idris, AH Daya, MR Wang, HE Morrison, LJ Davis, D Andrusiek, D Stephens, S Cheskes, S Schmicker, RH Fowler, R Vaillancourt, C Hostler, D Zive, D Pirrallo, RG Vilke, GM Sopko, G Weisfeldt, M AF Stiell, Ian G. Nichol, Graham Leroux, Brian G. Rea, Thomas D. Ornato, Joseph P. Powell, Judy Christenson, James Callaway, Clifton W. Kudenchuk, Peter J. Aufderheide, Tom P. Idris, Ahamed H. Daya, Mohamud R. Wang, Henry E. Morrison, Laurie J. Davis, Daniel Andrusiek, Douglas Stephens, Shannon Cheskes, Sheldon Schmicker, Robert H. Fowler, Ray Vaillancourt, Christian Hostler, David Zive, Dana Pirrallo, Ronald G. Vilke, Gary M. Sopko, George Weisfeldt, Myron CA ROC Investigators TI Early versus Later Rhythm Analysis in Patients with Out-of-Hospital Cardiac Arrest SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID AMERICAN-HEART-ASSOCIATION; VENTRICULAR-FIBRILLATION; CARDIOPULMONARY-RESUSCITATION; CLINICAL-TRIALS; LIFE-SUPPORT; SWINE MODEL; DEFIBRILLATION; OUTCOMES; SURVIVAL; CARE AB Background In a departure from the previous strategy of immediate defibrillation, the 2005 resuscitation guidelines from the American Heart Association-International Liaison Committee on Resuscitation suggested that emergency medical service (EMS) personnel could provide 2 minutes of cardiopulmonary resuscitation (CPR) before the first analysis of cardiac rhythm. We compared the strategy of a brief period of CPR with early analysis of rhythm with the strategy of a longer period of CPR with delayed analysis of rhythm. Methods We conducted a cluster-randomized trial involving adults with out-of-hospital cardiac arrest at 10 Resuscitation Outcomes Consortium sites in the United States and Canada. Patients in the early-analysis group were assigned to receive 30 to 60 seconds of EMS-administered CPR and those in the later-analysis group were assigned to receive 180 seconds of CPR, before the initial electrocardiographic analysis. The primary outcome was survival to hospital discharge with satisfactory functional status (a modified Rankin scale score of <= 3, on a scale of 0 to 6, with higher scores indicating greater disability). Results We included 9933 patients, of whom 5290 were assigned to early analysis of cardiac rhythm and 4643 to later analysis. A total of 273 patients (5.9%) in the later-analysis group and 310 patients (5.9%) in the early-analysis group met the criteria for the primary outcome, with a cluster-adjusted difference of -0.2 percentage points (95% confidence interval, -1.1 to 0.7; P = 0.59). Analyses of the data with adjustment for confounding factors, as well as subgroup analyses, also showed no survival benefit for either study group. Conclusions Among patients who had an out-of-hospital cardiac arrest, we found no difference in the outcomes with a brief period, as compared with a longer period, of EMS-administered CPR before the first analysis of cardiac rhythm. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706.) C1 [Stiell, Ian G.; Vaillancourt, Christian] Univ Ottawa, Dept Emergency Med, Ottawa, ON, Canada. [Stiell, Ian G.; Vaillancourt, Christian] Univ Ottawa, Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Nichol, Graham; Leroux, Brian G.; Powell, Judy; Schmicker, Robert H.] Univ Washington, Clin Trials Ctr, Dept Biostat, Seattle, WA 98195 USA. [Nichol, Graham; Rea, Thomas D.; Kudenchuk, Peter J.] Univ Washington, Dept Med, Seattle, WA USA. [Nichol, Graham] Univ Washington, Harborview Ctr Prehosp Emergency Care, Seattle, WA 98195 USA. [Ornato, Joseph P.] Virginia Commonwealth Univ, Dept Emergency Med, Richmond, VA USA. [Christenson, James] Univ British Columbia, Dept Emergency Med, Vancouver, BC V5Z 1M9, Canada. [Andrusiek, Douglas] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Christenson, James; Andrusiek, Douglas] British Columbia Emergency & Hlth Serv Commiss, Vancouver, BC, Canada. [Callaway, Clifton W.; Hostler, David] Univ Pittsburgh, Dept Emergency Med, Pittsburgh, PA USA. [Aufderheide, Tom P.; Pirrallo, Ronald G.] Med Coll Wisconsin, Dept Emergency Med, Milwaukee, WI 53226 USA. [Idris, Ahamed H.; Fowler, Ray] Univ Texas SW Med Ctr Dallas, Dept Surg Emergency Med, Dallas, TX 75390 USA. [Daya, Mohamud R.; Zive, Dana] Oregon Hlth & Sci Univ, Dept Emergency Med, Ctr Policy & Res Emergency Med, Portland, OR 97201 USA. [Wang, Henry E.; Stephens, Shannon] Univ Alabama, Dept Emergency Med, Birmingham, W Midlands, England. [Morrison, Laurie J.] Univ Toronto, Dept Med, Div Emergency Med, Toronto, ON, Canada. [Cheskes, Sheldon] Univ Toronto, Dept Family & Community Med, Toronto, ON M5S 1A1, Canada. [Morrison, Laurie J.; Cheskes, Sheldon] St Michaels Hosp, Li Ka Shing Knowledge Inst, Rescu Keenan Res Ctr, Toronto, ON M5B 1W8, Canada. [Davis, Daniel; Vilke, Gary M.] Univ Calif San Diego, Dept Emergency Med, San Diego, CA 92103 USA. [Sopko, George] NHLBI, NIH, Bethesda, MD 20892 USA. [Weisfeldt, Myron] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. RP Stiell, IG (reprint author), Univ Ottawa, Dept Emergency Med, Ottawa, ON, Canada. EM istiell@ohri.ca RI morrison, laurie/A-6325-2012; Leroux, Brian/H-2254-2015; OI morrison, laurie/0000-0001-8369-9774; Stephens, Shannon/0000-0001-5898-5170; Stiell, Ian/0000-0002-2583-6408 FU National Heart, Lung, and Blood Institute [5U01 HL077863, HL077881, HL077871 HL077872, HL077866, HL077908, HL077867, HL077887, HL077873, HL077865]; National Institute of Neurological Disorders and Stroke; Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health; Heart and Stroke Foundation of Canada; U.S. Army Medical Research and Material Command; Institute of Circulatory and Respiratory Health of the Canadian Institutes of Health Research, Defence Research and Development Canada; American Heart Association; Laerdal Foundation for Acute Medicine; Medtronic Foundation; Sotera Wireless; Medtronic; Jolife; Philips Healthcare; ZOLL Medical; Imricor Medical Systems FX Supported by grants from the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, the Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health, and the Heart and Stroke Foundation of Canada. The Resuscitation Outcome Consortium is supported by a series of cooperative agreements with 10 regional clinical centers and one data coordinating center (5U01 HL077863, HL077881, HL077871 HL077872, HL077866, HL077908, HL077867, HL077887, HL077873, HL077865) from the National Heart, Lung, and Blood Institute in partnership with the National Institute of Neurological Disorders and Stroke, U.S. Army Medical Research and Material Command, the Institute of Circulatory and Respiratory Health of the Canadian Institutes of Health Research, Defence Research and Development Canada, the Heart and Stroke Foundation of Canada, and the American Heart Association.; Dr. Nichol reports receiving grant support from the Laerdal Foundation for Acute Medicine and Medtronic Foundation and travel fees from Sotera Wireless, being a board member of Medic One Foundation, and participating in research collaborations with Gambro Renal, Lifebridge Medizintechnik, and Sotera Wireless; Dr. Ornato, serving on an advisory board for ZOLL Circulation; Dr. Callaway, that he and his institution receive royalties for patents from Medtronic related to the timing of defibrillation; Dr. Aufderheide, consulting fees from Jolife and Medtronic; Dr. Daya, consulting and lecture fees from Philips Healthcare and owning stock in Amgen, Johnson & Johnson, and Roche; Dr. Morrison, grant support from the Laerdal Foundation for Acute Medicine; Dr. Pirrallo, consulting fees from ZOLL Medical; and Dr. Weisfeldt, that he and his institution receive royalties for patents from Imricor Medical Systems related to an MRI Insensitive Pacemaker. No other potential conflict of interest relevant to this article was reported. NR 34 TC 107 Z9 110 U1 0 U2 12 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 SEP 1 PY 2011 VL 365 IS 9 BP 787 EP 797 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 813YC UT WOS:000294405200005 PM 21879896 ER PT J AU Aufderheide, TP Nichol, G Rea, TD Brown, SP Leroux, BG Pepe, PE Kudenchuk, PJ Christenson, J Daya, MR Dorian, P Callaway, CW Idris, AH Andrusiek, D Stephens, SW Hostler, D Davis, DP Dunford, JV Pirrallo, RG Stiell, IG Clement, CM Craig, A Van Ottingham, L Schmidt, TA Wang, HE Weisfeldt, ML Ornato, JP Sopko, G AF Aufderheide, Tom P. Nichol, Graham Rea, Thomas D. Brown, Siobhan P. Leroux, Brian G. Pepe, Paul E. Kudenchuk, Peter J. Christenson, Jim Daya, Mohamud R. Dorian, Paul Callaway, Clifton W. Idris, Ahamed H. Andrusiek, Douglas Stephens, Shannon W. Hostler, David Davis, Daniel P. Dunford, James V. Pirrallo, Ronald G. Stiell, Ian G. Clement, Catherine M. Craig, Alan Van Ottingham, Lois Schmidt, Terri A. Wang, Henry E. Weisfeldt, Myron L. Ornato, Joseph P. Sopko, George CA ROC Investigators TI A Trial of an Impedance Threshold Device in Out-of-Hospital Cardiac Arrest SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CARDIOPULMONARY-RESUSCITATION; VENTRICULAR-FIBRILLATION; CLINICAL-TRIALS; PORCINE MODEL; HEMODYNAMICS; SURVIVAL; SWINE AB Background The impedance threshold device (ITD) is designed to enhance venous return and cardiac output during cardiopulmonary resuscitation (CPR) by increasing the degree of negative intrathoracic pressure. Previous studies have suggested that the use of an ITD during CPR may improve survival rates after cardiac arrest. Methods We compared the use of an active ITD with that of a sham ITD in patients with out-of-hospital cardiac arrest who underwent standard CPR at 10 sites in the United States and Canada. Patients, investigators, study coordinators, and all care providers were unaware of the treatment assignments. The primary outcome was survival to hospital discharge with satisfactory function (i.e., a score of <= 3 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating greater disability). Results Of 8718 patients included in the analysis, 4345 were randomly assigned to treatment with a sham ITD and 4373 to treatment with an active device. A total of 260 patients (6.0%) in the sham-ITD group and 254 patients (5.8%) in the active-ITD group met the primary outcome (risk difference adjusted for sequential monitoring, -0.1 percentage points; 95% confidence interval, -1.1 to 0.8; P = 0.71). There were also no significant differences in the secondary outcomes, including rates of return of spontaneous circulation on arrival at the emergency department, survival to hospital admission, and survival to hospital discharge. Conclusions Use of the ITD did not significantly improve survival with satisfactory function among patients with out-of-hospital cardiac arrest receiving standard CPR. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706.) C1 [Aufderheide, Tom P.; Pirrallo, Ronald G.] Med Coll Wisconsin, Dept Emergency Med, Milwaukee, WI 53226 USA. [Nichol, Graham] Univ Washington, Harborview Ctr Prehosp Emergency Care, Seattle, WA 98195 USA. [Rea, Thomas D.] Univ Washington, Div Gen Med, Seattle, WA 98195 USA. [Kudenchuk, Peter J.] Univ Washington, Div Cardiol, Dept Med, Seattle, WA 98195 USA. [Nichol, Graham; Brown, Siobhan P.; Leroux, Brian G.; Van Ottingham, Lois] Univ Washington, Dept Biostat, Clin Trials Ctr, Seattle, WA 98195 USA. [Pepe, Paul E.; Idris, Ahamed H.] Univ Texas SW Med Ctr Dallas, Dept Surg Emergency Med, Dallas, TX 75390 USA. [Christenson, Jim] Univ British Columbia, Dept Emergency Med, Vancouver, BC V5Z 1M9, Canada. [Andrusiek, Douglas] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Christenson, Jim; Andrusiek, Douglas] British Columbia Emergency & Hlth Serv Commiss, Vancouver, BC, Canada. [Daya, Mohamud R.; Schmidt, Terri A.] Oregon Hlth & Sci Univ, Dept Emergency Med, Ctr Policy & Res Emergency Med, Portland, OR 97201 USA. [Dorian, Paul] Univ Toronto, Dept Med, Toronto, ON, Canada. [Craig, Alan] Toronto Emergency Med Serv, Toronto, ON, Canada. [Callaway, Clifton W.; Hostler, David] Univ Pittsburgh, Dept Emergency Med, Pittsburgh, PA USA. [Davis, Daniel P.; Dunford, James V.] Univ Calif San Diego, Dept Emergency Med, San Diego, CA 92103 USA. [Stiell, Ian G.; Clement, Catherine M.] Univ Ottawa, Dept Emergency Med, Ottawa, ON, Canada. [Stiell, Ian G.; Clement, Catherine M.] Univ Ottawa, Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Weisfeldt, Myron L.] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Sopko, George] NHLBI, NIH, Bethesda, MD 20892 USA. [Ornato, Joseph P.] Virginia Commonwealth Univ, Dept Emergency Med, Richmond, VA USA. RP Aufderheide, TP (reprint author), Med Coll Wisconsin, Dept Emergency Med, 9200 W Wisconsin Ave,Pavil 1P, Milwaukee, WI 53226 USA. EM taufderh@mcw.edu RI Leroux, Brian/H-2254-2015; OI Brown, Siobhan/0000-0002-4774-3122; Stephens, Shannon/0000-0001-5898-5170; Stiell, Ian/0000-0002-2583-6408 FU National Heart, Lung, and Blood Institute [5U01 HL077863, HL077881, HL077871, HL077872, HL077866, HL077908, HL077867, HL077887, HL077873, HL077865]; National Institute of Neurological Disorders and Stroke; U.S. Army Medical Research and Materiel Command; Institute of Circulatory and Respiratory Health of the Canadian Institutes of Health Research, Defence Research and Development Canada; Heart and Stroke Foundation of Canada; American Heart Association FX Supported by a series of cooperative agreements with 10 regional clinical centers and one data coordinating center (5U01 HL077863, HL077881, HL077871, HL077872, HL077866, HL077908, HL077867, HL077887, HL077873, HL077865) from the National Heart, Lung, and Blood Institute in partnership with the National Institute of Neurological Disorders and Stroke, U.S. Army Medical Research and Materiel Command, the Institute of Circulatory and Respiratory Health of the Canadian Institutes of Health Research, Defence Research and Development Canada, the Heart and Stroke Foundation of Canada, and the American Heart Association. NR 24 TC 101 Z9 104 U1 2 U2 13 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 SEP 1 PY 2011 VL 365 IS 9 BP 798 EP 806 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 813YC UT WOS:000294405200006 PM 21879897 ER PT J AU Xydakis, MS Butman, JA Pierpaoli, C AF Xydakis, Michael S. Butman, John A. Pierpaoli, Carlo TI Blast-Related Traumatic Brain Injury in U.S. Military Personnel SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID IRAQ C1 [Xydakis, Michael S.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Butman, John A.; Pierpaoli, Carlo] NIH, Bethesda, MD 20892 USA. RP Xydakis, MS (reprint author), Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. EM michael.xydakis@usuhs.mil RI Pierpaoli, Carlo/E-1672-2011; Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 NR 5 TC 1 Z9 2 U1 0 U2 1 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 SEP 1 PY 2011 VL 365 IS 9 BP 859 EP 859 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 813YC UT WOS:000294405200017 PM 21879909 ER PT J AU Bendtsen, KM Erdossy, J Csiszovszki, Z Lo Svenningsen, S Sneppen, K Krishna, S Semsey, S AF Bendtsen, Kristian Moss Erdossy, Janos Csiszovszki, Zsolt Lo Svenningsen, Sine Sneppen, Kim Krishna, Sandeep Semsey, Szabolcs TI Direct and indirect effects in the regulation of overlapping promoters SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ESCHERICHIA-COLI; RNA-POLYMERASE; TRANSCRIPTIONAL INTERFERENCE; GENE-EXPRESSION; IN-VITRO; INITIATION; PROTEIN; REPRESSION; ACTIVATION; BINDING AB Optimal response to environmental stimuli often requires activation of certain genes and repression of others. Dual function regulatory proteins play a key role in the differential regulation of gene expression. While repression can be achieved by any DNA binding protein through steric occlusion of RNA polymerase in the promoter region, activation often requires a surface on the regulatory protein to contact RNAP and thus facilitate transcription initiation. RNAP itself is also a DNA binding protein, therefore it can function as a transcriptional repressor. Searching the Escherichia coli promoter database we found that similar to 14% of the identified 'forward' promoters overlap with a promoter oriented in the opposite direction. In this article we combine a mathematical model with experimental analysis of synthetic regulatory regions to investigate interference of overlapping promoters. We find that promoter interference depends on the characteristics of overlapping promoters. The model predicts that promoter strength and interference can be regulated separately, which provides unique opportunities for regulation. Our experimental data suggest that in principle any DNA binding protein can be used for both activation and repression of promoter transcription, depending on the context. These findings can be exploited in the construction of synthetic networks. C1 [Bendtsen, Kristian Moss; Sneppen, Kim; Krishna, Sandeep; Semsey, Szabolcs] Niels Bohr Inst, CMOL, DK-2100 Copenhagen, Denmark. [Erdossy, Janos; Semsey, Szabolcs] Eotvos Lorand Univ, Dept Genet, H-1117 Budapest, Hungary. [Csiszovszki, Zsolt] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lo Svenningsen, Sine] Univ Copenhagen, Biomol Sci Sect, Inst Biol, DK-2100 Copenhagen, Denmark. [Krishna, Sandeep] NCBS, Bangalore 560065, Karnataka, India. RP Semsey, S (reprint author), Niels Bohr Inst, CMOL, DK-2100 Copenhagen, Denmark. EM semsey@nbi.dk RI Semsey, Szabolcs/L-6329-2013; Svenningsen, Sine/M-7925-2014; OI Svenningsen, Sine/0000-0001-7322-2681; Semsey, Szabolcs/0000-0002-4522-5495; Sneppen, Kim/0000-0001-9820-3567 FU Danish Council for Independent Research/Natural Sciences; Hungarian Scientific Research Fund [PD75496]; NIH, National Cancer Institute, Center for Cancer Research; Danish National Research Foundation FX The Danish Council for Independent Research/Natural Sciences, the Hungarian Scientific Research Fund Grant PD75496 (to S.S.), the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and the Danish National Research Foundation. Funding for open access charge: Danish National Research Foundation. NR 19 TC 15 Z9 15 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2011 VL 39 IS 16 BP 6879 EP 6885 DI 10.1093/nar/gkr390 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 815UZ UT WOS:000294556800010 PM 21609952 ER PT J AU Onyshchenko, MI Gaynutdinov, TI Englund, EA Appella, DH Neumann, RD Panyutin, IG AF Onyshchenko, Mykola I. Gaynutdinov, Timur I. Englund, Ethan A. Appella, Daniel H. Neumann, Ronald D. Panyutin, Igor G. TI Quadruplex formation is necessary for stable PNA invasion into duplex DNA of BCL2 promoter region SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PEPTIDE NUCLEIC-ACID; I-MOTIF STRUCTURES; DOUBLE-STRANDED DNA; C-MYC; LOCALIZATION SIGNAL; REGULATORY ELEMENT; PROXIMAL PROMOTER; GROWTH-FACTOR; GENE; TRANSCRIPTION AB Guanine-rich sequences are highly abundant in the human genome, especially in regulatory regions. Because guanine-rich sequences have the unique ability to form G-quadruplexes, these structures may play a role in the regulation of gene transcription. In previous studies, we demonstrated that formation of G-quadruplexes could be induced with peptide nucleic acids (PNAs). PNAs designed to bind the C-rich strand upstream of the human BCL2 gene promoted quadruplex formation in the complementary G-rich strand. However, the question whether G-quadruplex formation was essential for PNA invasion remained unanswered. In this study, we compared PNA invasion in the native and mutant, i.e. not forming G-quadruplex, BCL2 sequences and showed that G-quadruplex is required for effective PNA invasion into duplex DNA. This finding provides strong evidence for not only sequence-specific, but also quadruplex specific, gene targeting with PNA probes. In addition, we examined DNA-duplex invasion potential of PNAs of various charges. Using the gel shift assay, chemical probing and dimethyl sulfate (DMS) protection studies, we determined that uncharged zwitterionic PNA has the highest binding specificity while preserving efficient duplex invasion. C1 [Gaynutdinov, Timur I.; Neumann, Ronald D.; Panyutin, Igor G.] NIDDK, Dept Radiol & Imaging Sci, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Onyshchenko, Mykola I.] NIDDK, Imaging Sci Training Program, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Onyshchenko, Mykola I.] NIDDK, Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Englund, Ethan A.; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Panyutin, IG (reprint author), NIDDK, Dept Radiol & Imaging Sci, Ctr Clin, NIH, Bethesda, MD 20892 USA. EM igorp@helix.nih.gov OI Onyshchenko, Mykola/0000-0003-4663-0991 FU Imaging Sciences Training Program; Radiology and Imaging Sciences Department, Clinical Center and Intramural Research Program at the National Institute of Biomedical Imaging and Bioengineering, National Institute of Health; Intramural Research Program of the National Institutes of Health, USA FX The study was partially sponsored by the Imaging Sciences Training Program supported in part by the Radiology and Imaging Sciences Department, Clinical Center and Intramural Research Program at the National Institute of Biomedical Imaging and Bioengineering, National Institute of Health. Funding for open access charge: Intramural Research Program of the National Institutes of Health, USA. NR 54 TC 11 Z9 11 U1 0 U2 19 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2011 VL 39 IS 16 BP 7114 EP 7123 DI 10.1093/nar/gkr259 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 815UZ UT WOS:000294556800029 PM 21593130 ER PT J AU Kornyshev, AA Lee, DJ Wynveen, A Leikin, S AF Kornyshev, A. A. Lee, D. J. Wynveen, A. Leikin, S. TI Signatures of DNA flexibility, interactions and sequence-related structural variations in classical X-ray diffraction patterns SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DOUBLE HELICES; HOMOLOGOUS RECOMBINATION; ESCHERICHIA-COLI; HYDRATION FORCES; VARIABLE TWIST; RECOGNITION; MOLECULES; AGGREGATION; DEPENDENCE; SCATTERING AB The theory of X-ray diffraction from ideal, rigid helices allowed Watson and Crick to unravel the DNA structure, thereby elucidating functions encoded in it. Yet, as we know now, the DNA double helix is neither ideal nor rigid. Its structure varies with the base pair sequence. Its flexibility leads to thermal fluctuations and allows molecules to adapt their structure to optimize their intermolecular interactions. In addition to the double helix symmetry revealed by Watson and Crick, classical X-ray diffraction patterns of DNA contain information about the flexibility, interactions and sequence-related variations encoded within the helical structure. To extract this information, we have developed a new diffraction theory that accounts for these effects. We show how double helix non-ideality and fluctuations broaden the diffraction peaks. Meridional intensity profiles of the peaks at the first three helical layer lines reveal information about structural adaptation and intermolecular interactions. The meridional width of the fifth layer line peaks is inversely proportional to the helical coherence length that characterizes sequence-related and thermal variations in the double helix structure. Analysis of measured fiber diffraction patterns based on this theory yields important parameters that control DNA structure, packing and function. C1 [Kornyshev, A. A.; Lee, D. J.] Univ London Imperial Coll Sci Technol & Med, Fac Nat Sci, Dept Chem, London SW7 2AZ, England. [Lee, D. J.] Max Planck Inst Phys Komplexer Syst, D-01187 Dresden, Germany. [Wynveen, A.] Univ Minnesota, Sch Phys & Astron, Minneapolis, MN 55455 USA. [Wynveen, A.] Univ Dusseldorf, Inst Theoret Phys Soft Matter 2, D-40225 Dusseldorf, Germany. [Leikin, S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Kornyshev, AA (reprint author), Univ London Imperial Coll Sci Technol & Med, Fac Nat Sci, Dept Chem, London SW7 2AZ, England. EM a.kornyshev@imperial.ac.uk; leikins@mail.nih.gov RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU Leverhulme Trust [F/07568]; EPSRC [EP/H010106/1, EP/H004319/1]; HFSP [RGP0049/2010-C102]; Max-Planck Society; NICHD; Alexander von Humboldt Foundation; NICHD, National Institutes of Health FX Leverhulme Trust grant F/07568, EPSRC grants EP/H010106/1 and EP/H004319/1, HFSP grant RGP0049/2010-C102 (to A. A. K.); Max-Planck Society (to D.J.L.); Intramural Research Program of NICHD (to S. L.); Alexander von Humboldt Foundation (to A. W.). Funding for open access charge: Intramural Research Program of NICHD, National Institutes of Health. NR 58 TC 6 Z9 6 U1 0 U2 19 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2011 VL 39 IS 16 BP 7289 EP 7299 DI 10.1093/nar/gkr260 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 815UZ UT WOS:000294556800042 PM 21593127 ER PT J AU Voruganti, VS Diego, VP Haack, K Cole, SA Blangero, J Goring, HHH Laston, S Wenger, CR Ebbesson, SOE Fabsitz, RR Devereux, RB Howard, BV Umans, JG MacCluer, JW Comuzzie, AG AF Voruganti, V. Saroja Diego, Vincent P. Haack, Karin Cole, Shelley A. Blangero, John Goering, Harald H. H. Laston, Sandra Wenger, Charlotte R. Ebbesson, Sven O. E. Fabsitz, Richard R. Devereux, Richard B. Howard, Barbara V. Umans, Jason G. MacCluer, Jean W. Comuzzie, Anthony G. TI A QTL for Genotype by Sex Interaction for Anthropometric Measurements in Alaskan Eskimos (GOCADAN Study) on Chromosome 19q12-13 SO OBESITY LA English DT Article ID HORMONE-SENSITIVE LIPASE; CORONARY-HEART-DISEASE; WIDE LINKAGE ANALYSIS; BODY-FAT DISTRIBUTION; METABOLIC SYNDROME; SUSCEPTIBILITY LOCUS; PEDIGREE ANALYSIS; LIPID-METABOLISM; HERITAGE FAMILY; HUMAN OBESITY AB Variation in anthropometric measurements due to sexual dimorphism can be the result of genotype by sex interactions (GxS). The purpose of this study was to examine the sex-specific genetic architecture in anthropometric measurements in Alaskan Eskimos from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. Maximum likelihood-based variance components decomposition methods, implemented in SOLAR, were used for GxS analyses. Anthropometric measurements included BMI, waist circumference (WC), waist/height ratio, percent body fat (%BF), and subscapular and triceps skinfolds. Except for WC, mean values of all phenotypes were significantly different in men and women (P < 0.05). All anthropometric measures were significantly heritable (P < 0.001). In a preliminary analysis not allowing for GxS interaction, evidence of linkage was detected between markers D19S414 and D19S220 on chromosome 19 for WC (logarithm of odds (lod) = 3.5), %BF (lod = 1.7), BMI (lod = 2.4), waist/height ratio (lod = 2.5), subscapular (lod = 2.1), and triceps skinfolds (lod = 1.9). In subsequent analyses which allowed for GxS interaction, linkage was again found between these traits and the same two markers on chromosome 19 with significantly improved lod scores for: WC (lod = 4.5), %BF (lod = 3.8), BMI (lod = 3.5), waist/height ratio (lod = 3.2), subscapular (lod = 3.0), and triceps skinfolds (lod = 2.9). These results support the evidence of a GxS interaction in the expression of genetic effects resulting in sexual dimorphism in anthropometric phenotypes and identify the chromosome 19q12-13 region as important for adiposity-related traits in Alaskan Eskimos. C1 [Voruganti, V. Saroja; Diego, Vincent P.; Haack, Karin; Cole, Shelley A.; Blangero, John; Goering, Harald H. H.; Laston, Sandra; Wenger, Charlotte R.; MacCluer, Jean W.; Comuzzie, Anthony G.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Ebbesson, Sven O. E.] Norton Sound Hlth Corp, Nome, AK USA. [Fabsitz, Richard R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Devereux, Richard B.] Weill Cornell Med Coll, New York, NY USA. [Howard, Barbara V.; Umans, Jason G.] Medstar Res Inst, Washington, DC USA. RP Voruganti, VS (reprint author), Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. EM saroja@sfbrgenetics.org OI Diego, Vincent/0000-0002-0007-2085 FU National Center for Research Resources, National Institutes of Health (NIH) [C06 RR014578, C06 RR013556, C06 RR015456, C06 RR017515]; NIH [U01 HL64244, MH59490] FX We thank the participants of the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study for their generous participation. This investigation was conducted in facilities constructed with support from Research Facilities Improvement Program Grants (Numbers C06 RR014578, C06 RR013556, C06 RR015456, C06 RR017515) from the National Center for Research Resources, National Institutes of Health (NIH), and with support from NIH grants U01 HL64244 and MH59490. NR 44 TC 5 Z9 5 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD SEP PY 2011 VL 19 IS 9 BP 1840 EP 1846 DI 10.1038/oby.2011.78 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 813ZP UT WOS:000294410100019 PM 21527897 ER PT J AU Gill, RK Yang, SH Meerzaman, D Mechanic, LE Bowman, ED Jeon, HS Chowdhuri, SR Shakoori, A Dracheva, T Hong, KM Fukuoka, J Zhang, JH Harris, CC Jen, J AF Gill, R. K. Yang, S-H Meerzaman, D. Mechanic, L. E. Bowman, E. D. Jeon, H-S Chowdhuri, S. Roy Shakoori, A. Dracheva, T. Hong, K-M Fukuoka, J. Zhang, J-H Harris, C. C. Jen, J. TI Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer SO ONCOGENE LA English DT Article DE LKB1 gene; LOH; homozygous deletion; mutation; CISH; primary lung cancer ID PEUTZ-JEGHERS-SYNDROME; TUMOR-SUPPRESSOR GENE; SOMATIC MUTATIONS; GLUCOSE-HOMEOSTASIS; LKB1; KINASE; PATHWAYS; KNOCKOUT; PTEN; ADENOCARCINOMA AB LKB1/STK11 is a tumor suppressor and a negative regulator of mammalian target of rapamycin signaling. It is inactivated in 30% of lung cancer cell lines but only 5-15% of primary lung adenocarcinomas. There is evidence that homozygous deletion (HD) of chromosome 19p at the LKB locus contributes to the inactivation of the gene in primary human lung cancers. Here, we used several complementary genetic approaches to assess the LKB1 locus in primary non-small cell lung cancers (NSCLCs). We first analyzed 124 NSCLC cases for allelic imbalance using eight microsatellite markers on chromosome 19p, which revealed an overall rate of 65% (80 of 124) loss of heterozygosity (LOH). We next used chromogenic in situ hybridization (CISH) to directly examine the chromosomal status of the LKB1 locus. In all, 65 of 124 LOH tested samples were available for CISH and 58 of those (89%) showed either loss of one copy of chromosome 19p (LOH, 40 of 65 cases, 62%) or both copies (HD 18 of 65 cases, 28%). The occurrence of HD was significantly more frequent in Caucasian (35%) than in African-American patients (6%) (P = 0.04). A total of 62 of 124 samples with LOH at one or both markers immediately flanking the LKB1 gene were further analyzed by directly sequencing the complete coding region, which identified 7 of 62 (11%) tumors with somatic mutations in the gene. Jointly, our data identified total inactivation of the LKB1 gene by either HD or LOH with somatic mutation in 39% of tested samples, whereas loss of chromosome 19p region by HD or LOH at the LKB1 region occured in 90% of NSCLC. Oncogene (2011) 30, 3784-3791; doi:10.1038/onc.2011.98; published online 2 May 2011 C1 [Jen, J.] Mayo Clin Fdn, Div Pulm & Crit Care Med & Microarray Shared Reso, Rochester, MN USA. [Gill, R. K.; Yang, S-H; Mechanic, L. E.; Bowman, E. D.; Jeon, H-S; Shakoori, A.; Dracheva, T.; Fukuoka, J.; Harris, C. C.] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Meerzaman, D.; Chowdhuri, S. Roy; Hong, K-M; Zhang, J-H] NCI, Lab Populat Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Hong, K-M] Natl Canc Ctr, Res Inst, Goyang, South Korea. RP Jen, J (reprint author), Mayo Clin, Div Pulm & Crit Care Med & Microarray Shared Reso, Adv Genom Technol Ctr, Stabile 13-74,200 1st St SW, Rochester, MN 55905 USA. EM Jen.Jin@mayo.edu FU Center for Cancer Research at CCR; Mayo Cancer Center; Center for Individualized Medicine, Rochester, MN FX We thank John Cottrell, Ray Jones, Audrey Salabes and Mike Lipsky at University of Maryland Medical Center for tissue collection and clinical information. We thank the members of Dr. Thomas Reid's lab for technical support during the course of this study. We thank Ms Stacy Johnson for editorial and graphical/technical assistance. The current addresses are RKG, Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD 20892-4258; SHY, Wonkwang University Hospital, Department of Pulmonary and Critical Care Medicine, Iksan, South Korea; HSJ, Laboratory of Biochemistry and Cell Biology, Kyungpook National University, School of Medicine, Deagu, South Korea; SRC, Laboratory of Pathology, National Cancer Institute, Bethesda, MD; AS, Department of Medical Genetics, Tehran University of Medical Sciences, Cancer Institute Hospital, Tehran, Iran; TVD, J. Craig Venter Institute, Rockville, MD; KMH, National Cancer Center, Cancer Cell and Molecular Biology Branch, Goyang, Korea; JF, Toyama University Hospital, Department of Surgical Pathology, Toyama, Japan; and JHZ, St. Jude Children's Research Hospital, Biotechnology, Memphis, TN. This work was supported by intramural research funds from the Center for Cancer Research at CCR and funds for JJ from the Mayo Cancer Center and Center for Individualized Medicine, Rochester, MN. NR 44 TC 35 Z9 39 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP PY 2011 VL 30 IS 35 BP 3784 EP 3791 DI 10.1038/onc.2011.98 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 814TZ UT WOS:000294481400005 PM 21532627 ER PT J AU Faden, DL Elackatuu, A Platt, M AF Faden, Daniel Lawrence Elackatuu, Alphi Platt, Michael TI The "Closed-Airway Sneeze": An Unusual Cause of Laryngeal Fracture SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE laryngeal fracture; thyroid cartilage; airway; sneeze; hoarseness C1 [Faden, Daniel Lawrence; Elackatuu, Alphi; Platt, Michael] Boston Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Boston, MA 02118 USA. [Faden, Daniel Lawrence] NIH, Bethesda, MD 20892 USA. [Faden, Daniel Lawrence] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Platt, M (reprint author), Boston Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 830 Harrison Ave,4th Floor FGH, Boston, MA 02118 USA. EM miplatt@bu.edu NR 5 TC 4 Z9 4 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD SEP PY 2011 VL 145 IS 3 BP 515 EP 516 DI 10.1177/0194599811402947 PG 2 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 814OY UT WOS:000294467700029 PM 21493278 ER PT J AU Fitzkee, NC Torchia, DA Bax, A AF Fitzkee, Nicholas C. Torchia, Dennis A. Bax, Ad TI Measuring rapid hydrogen exchange in the homodimeric 36 kDa HIV-1 integrase catalytic core domain (vol 20, pg 500, 2011) SO PROTEIN SCIENCE LA English DT Correction C1 [Fitzkee, Nicholas C.; Torchia, Dennis A.; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Fitzkee, NC (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD SEP PY 2011 VL 20 IS 9 BP 1643 EP 1643 DI 10.1002/pro.701 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 813QY UT WOS:000294383900018 ER PT J AU Swanson, JM Wigal, TL Volkow, ND AF Swanson, James M. Wigal, Timothy L. Volkow, Nora D. TI Contrast of Medical and Nonmedical Use of Stimulant Drugs, Basis for the Distinction, and Risk of Addiction: Comment on Smith and Farah (2011) SO PSYCHOLOGICAL BULLETIN LA English DT Editorial Material DE ADHD; stimulant drugs; medical use of stimulants; diversion of stimulants; addiction to stimulants ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT-HYPERACTIVITY DISORDER; PRESCRIPTION STIMULANTS; UNITED-STATES; EXECUTIVE FUNCTIONS; ADHD; CHILDREN; METHYLPHENIDATE; PREVALENCE; BRAIN AB Smith and Farah (2011) presented a scholarly review of critical areas related to their intriguing title "Are Prescription Stimulants 'Smart Pills'?" We contend that they accomplished the main goal of the article, to get the facts straight about possible cognitive enhancement via the nonmedical use of stimulant drugs by individuals without a diagnosis of attention-deficit/ hyperactivity disorder (ADHD). At the same time, they justified their main conclusions that (a) individuals are seeking and engaging in nonmedical use of stimulant drugs with the expectations of cognitive enhancement despite uncertainty whether such expectations are valid and (b) on some tasks, there are small average benefits of nonmedical use, but the overall pattern is not clear (e. g., small beneficial effects across most individuals or large beneficial effects only in a few individuals, both of which result in small average effects). We offer comments in 3 areas to amplify key topics mentioned but not emphasized by Smith and Farah: (a) characterization of the cognitive effects of medical use of stimulants to contrast with the cognitive effects of nonmedical use; (b) justification of medical use of stimulants by placement on a normally distributed dimension of behavior rather than categorical diagnosis of ADHD, which varies widely across countries; and (c) evaluation of the potential risks of nonmedical use to individuals and to society (e. g., the likelihood of addiction to stimulant drugs in a small minority of the population) rather than just the potential benefits of cognitive enhancement. C1 [Swanson, James M.] Univ Calif Irvine, Child Dev Ctr, Sch Med, Irvine, CA 92612 USA. [Swanson, James M.] Florida Int Univ, Dept Psychiat, Miami, FL 33199 USA. [Volkow, Nora D.] NIDA, NIDA Directors Off, NIH, Bethesda, MD USA. RP Swanson, JM (reprint author), Univ Calif Irvine, Child Dev Ctr, Sch Med, 19722 MacArthur Blvd,Mail Code 4480, Irvine, CA 92612 USA. EM jmswanso@uci.edu FU Intramural NIH HHS [ZIA AA000550-08] NR 47 TC 15 Z9 15 U1 1 U2 16 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0033-2909 EI 1939-1455 J9 PSYCHOL BULL JI Psychol. Bull. PD SEP PY 2011 VL 137 IS 5 BP 742 EP 748 DI 10.1037/a0024898 PG 7 WC Psychology; Psychology, Multidisciplinary SC Psychology GA 813BR UT WOS:000294342000002 PM 21859175 ER PT J AU Stovsky, M Ponsky, L Vourganti, S Stuhldreher, P Siroky, MB Kipnis, V Fedotoff, O Mikheeva, L Zaslavsky, B Chait, A Jones, JS AF Stovsky, Mark Ponsky, Lee Vourganti, Srinivas Stuhldreher, Peter Siroky, Mike B. Kipnis, Victor Fedotoff, Olga Mikheeva, Larissa Zaslavsky, Boris Chait, Arnon Jones, J. Stephen TI Prostate-specific Antigen/Solvent Interaction Analysis: A Preliminary Evaluation of a New Assay Concept for Detecting Prostate Cancer Using Urinary Samples SO UROLOGY LA English DT Article ID ANTIGEN; SERUM; LECTIN; PSA; GLYCOSYLATION; PATTERNS; BINDING; LEVEL; MEN AB OBJECTIVE To provide preliminary clinical performance evaluation of a novel prostate cancer (CaP) assay, prostate-specific antigen/solvent interaction analysis (PSA/SIA) that focused on changes to the structure of PSA. METHODS Two-hundred twenty-two men undergoing prostate biopsy for accepted clinical criteria at 3 sites (University Hospitals Case Medical Center in Cleveland, Cleveland Clinic, and Veterans Administration Boston Healthcare System) were enrolled in institutional review board-approved study. Before transrectal ultrasound-guided biopsy, patients received digital rectal examination with systematic prostate massage followed by collection of urine. The PSA/SIA assay determined the relative partitioning of heterogeneous PSA isoform populations in urine between 2 aqueous phases. A structural index, K, whose numerical value is defined as the ratio of the concentration of all PSA isoforms, was determined by total PSA enzyme-linked immunosorbent assay and used to set a diagnostic threshold for CaP. Performance was assessed using receiver operating characteristic (ROC) analysis with biopsy as the gold standard. RESULTS Biopsies were pathologically classified as case (malignant, n = 100) or control (benign, n = 122). ROC performance demonstrated area under the curve = 0.90 for PSA/SIA and 0.58 for serum total PSA. At a cutoff value of k = 1.73, PSA/SIA displayed sensitivity = 100%, specificity = 80.3%, positive predictive value = 80.6%, and negative predictive value = 100%. No attempt was made in this preliminary study to further control patient population or selection criteria for biopsy, nor did we analytically investigate the type of structural differences in PSA that led to changes in k value. CONCLUSION PSA/SIA provides ratiometric information independently of PSA concentration. In this preliminary study, analysis of the overall structurally heterogeneous PSA isoform population using the SIA assay showed promising results to be further evaluated in future studies. UROLOGY 78: 601-606, 2011. (C) 2011 Elsevier Inc. All rights reserved. C1 [Stovsky, Mark] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Dept Urol, Cleveland, OH 44106 USA. Boston Healthcare Syst, Vet Adm, Boston, MA USA. NCI, Bethesda, MD 20892 USA. AnalizaDx, Cleveland, OH USA. Cleveland Clin, Cleveland, OH 44106 USA. RP Stovsky, M (reprint author), Case Western Reserve Univ, Univ Hosp Case Med Ctr, Dept Urol, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM gowildgo@aol.com OI Zaslavsky, Boris/0000-0003-0771-6696 FU Intramural NIH HHS [Z99 CA999999] NR 23 TC 11 Z9 11 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD SEP PY 2011 VL 78 IS 3 BP 601 EP 605 DI 10.1016/j.urology.2011.03.071 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 814US UT WOS:000294483300041 PM 21783231 ER PT J AU Senkevich, TG Koonin, EV Moss, B AF Senkevich, Tatiana G. Koonin, Eugene V. Moss, Bernard TI Vaccinia virus F16 protein, a predicted catalytically inactive member of the prokaryotic serine recombinase superfamily, is targeted to nucleoli SO VIROLOGY LA English DT Article DE Poxvirus orthologs; Poxvirus prokaryotic homologs; Vaccinia virus replication; Poxvirus recombinase ID SITE-SPECIFIC RECOMBINATION; GENE-EXPRESSION; TN3 RESOLVASE; TRANSCRIPTION; HOST; LOCALIZATION; REPLICATION; GENERATION; PROMOTERS; FACTORIES AB The F16L gene of vaccinia virus (VACV) is conserved in all chordopoxviruses except avipoxviruses. The crocodile poxvirus F16 protein ortholog has highly significant similarity to prokaryotic serine recombinases and contains all amino acids that comprise the catalytic site. In contrast, F16 orthologs encoded by other poxviruses show only marginally significant similarity to serine recombinases, lack essential amino acids of the active site and are most likely inactive derivatives of serine recombinases. Nevertheless, the conservation of F16L in non-avian poxviruses suggested an important function. However, a VACV mutant with the F16L gene knocked out replicated normally in dividing and quiescent cells. The F16 protein was synthesized early after infection and detected in virus cores. When expressed in infected or uninfected cells, F16 accumulated in nucleoli depending on the level of expression and confluency of cells. Evidence was obtained that F16 forms multimers, which might regulate concentration-dependent intracellular localization. Published by Elsevier Inc. C1 [Senkevich, Tatiana G.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Catherine Cotter and George Katsafanas of our laboratory for cell culture and helpful discussions on confocal imaging, respectively. Dr. Sundar Ganesan of the biological imaging facility of the Research Technologies Branch, NIAID provided help with confocal microscopy. The study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 38 TC 5 Z9 6 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 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2011 VL 417 IS 2 BP 334 EP 342 DI 10.1016/j.virol.2011.06.017 PG 9 WC Virology SC Virology GA 816DJ UT WOS:000294578600012 PM 21752417 ER PT J AU Weinrich, M AF Weinrich, Michael TI Commentary: Beyond Educational Initiatives: How Can We Change Health Care to Improve the Health of Persons With Disabilities? SO ACADEMIC MEDICINE LA English DT Editorial Material ID UNITED-STATES; HOSPITAL VOLUME; OUTCOMES; ADULTS AB Minihan and colleagues discuss necessary elements of an educational program to instruct generalist physicians in the care of individuals with disabilities. To support these physicians adequately in practice will require significant adaptations of health care financing, recognition of the unique medical needs of persons with disabilities, and efficient utilization of experienced clinical resources. The author outlines what remains to be addressed in the pursuit of better health for patients with disabilities as the U. S. health care system evolves. C1 [Weinrich, Michael] NIH, Natl Ctr Med Rehabil Res, Bethesda, MD 20892 USA. RP Weinrich, M (reprint author), 6100 Execut Blvd,Room 2A-02, Bethesda, MD 20852 USA. EM mw287k@nih.gov RI liu, jing/D-9482-2012 NR 9 TC 2 Z9 2 U1 0 U2 4 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 SEP PY 2011 VL 86 IS 9 BP 1069 EP 1070 DI 10.1097/ACM.0b013e3182263429 PG 2 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 811YH UT WOS:000294254300012 PM 21865902 ER PT J AU Murray, MM AF Murray, M. M. TI THE ROLE OF THE NIH IN RESPONSE TO THE GLOBAL BURDEN OF ALCOHOL AND HEALTH: OPPORTUNITIES FOR USA-EUROPEAN COLLABORATION SO ALCOHOL AND ALCOHOLISM LA English DT Meeting Abstract C1 [Murray, M. M.] NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 1 Z9 1 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD SEP PY 2011 VL 46 SU 1 BP 25 EP 25 PG 1 WC Substance Abuse SC Substance Abuse GA 809OM UT WOS:000294066600101 ER PT J AU Meinhardt, M Hansson, AC Perreau-Lenz, S Drescher, KU Heilig, M Spanagel, R Sommer, WH AF Meinhardt, M. Hansson, A. C. Perreau-Lenz, S. Drescher, K. U. Heilig, M. Spanagel, R. Sommer, W. H. TI DYSFUNCTION OF GLUTAMATERGIC PROJECTION NEURONS IN THE MEDIAL PREFRONTAL CORTEX OF RATS WITH A HISTORY OF ALCOHOL DEPENDENCE SO ALCOHOL AND ALCOHOLISM LA English DT Meeting Abstract C1 [Meinhardt, M.; Hansson, A. C.; Perreau-Lenz, S.; Spanagel, R.; Sommer, W. H.] Cent Inst Mental Hlth, D-6800 Mannheim, Germany. [Drescher, K. U.] Abbott GmbH & Co KG, Ludwigshafen, Germany. [Spanagel, R.] NIAAA, NIH, Bethesda, MD USA. RI Perreau-Lenz, Stephanie/D-2309-2014 OI Perreau-Lenz, Stephanie/0000-0001-9529-6403 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD SEP PY 2011 VL 46 SU 1 BP 49 EP 49 PG 1 WC Substance Abuse SC Substance Abuse GA 809OM UT WOS:000294066600193 ER PT J AU van Deventer, HE Remaley, AT AF van Deventer, Hendrick E. Remaley, Alan T. TI Classification Error Plots: A New Method for Determining the Effect of Bias and Imprecision on the Probability of Correct Classification for Cardiovascular Disease Risk SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Meeting Abstract CT 46th Annual Meeting of the Academy-of-Clinical-Laboratory-Physicians-and-Scientists (ACLPS) CY JUN 09-11, 2011 CL St Louis, MO SP Acad Clin Lab Phys Sci C1 [van Deventer, Hendrick E.; Remaley, Alan T.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP PY 2011 VL 136 IS 3 MA 53 BP 470 EP 470 PG 1 WC Pathology SC Pathology GA 809SA UT WOS:000294075800048 ER PT J AU Tross, S Campbell, ANC Calsyn, DA Metsch, LR Sorensen, JL Shoptaw, S Haynes, L Woody, GE Malow, RM Brown, LS Feaster, DJ Booth, RE Mandler, RN Masson, C Holmes, BW Colfax, G Brooks, AJ Hien, DA Schackman, BR Korthuis, PT Miele, GM AF Tross, Susan Campbell, Aimee N. C. Calsyn, Donald A. Metsch, Lisa R. Sorensen, James L. Shoptaw, Steven Haynes, Louise Woody, George E. Malow, Robert M. Brown, Lawrence S., Jr. Feaster, Daniel J. Booth, Robert E. Mandler, Raul N. Masson, Carmen Holmes, Beverly W. Colfax, Grant Brooks, Audrey J. Hien, Denise A. Schackman, Bruce R. Korthuis, P. Todd Miele, Gloria M. CA Clinical Trials Network HIV Specia TI NIDA's Clinical Trials Network: An Opportunity for HIV Research in Community Substance Abuse Treatment Programs SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE Clinical Trials Network; effectiveness research; HIV/AIDS; substance abuse ID INJECTION-DRUG USERS; ACTIVE ANTIRETROVIRAL THERAPY; SEXUALLY-TRANSMITTED INFECTIONS; RISK REDUCTION GROUPS; HEPATITIS-C VIRUS; RANDOMIZED-TRIAL; HEALTH-SERVICES; USE DISORDERS; PREVENTION; INTERVENTIONS AB Background/Objectives: HIV continues to be a significant problem among substance users and their sexual partners in the United States. The National Drug Abuse Treatment Clinical Trials Network (CTN) offers a national platform for effectiveness trials of HIV interventions in community substance abuse treatment programs. This article presents the HIV activities of the CTN during its first 10 years. Results: While emphasizing CTN HIV protocols, this article reviews the (1) HIV context for this work; (2) the collaborative process among providers, researchers, and National Institute on Drug Abuse CTN staff, on which CTN HIV work was based; (3) results of CTN HIV protocols and HIV secondary analyses in CTN non-HIV protocols; and (4) implications for future HIV intervention effectiveness research in community substance abuse treatment programs. Conclusion/Significance: While the feasibility of engaging frontline providers in this research is highlighted, the limitations of small to medium effect sizes and weak adoption and sustainability in everyday practice are also discussed. C1 [Tross, Susan] New York State Psychiat Inst & Hosp, HIV Ctr Clin & Behav Studies, New York, NY 10032 USA. [Campbell, Aimee N. C.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York State Psychiat Inst, New York, NY USA. [Calsyn, Donald A.] Univ Washington, Inst Alcohol & Drug Abuse, Seattle, WA 98195 USA. [Metsch, Lisa R.; Feaster, Daniel J.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Sorensen, James L.; Masson, Carmen] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Shoptaw, Steven] Univ Calif Los Angeles, Dept Family Med, Los Angeles, CA USA. [Shoptaw, Steven] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Haynes, Louise; Holmes, Beverly W.] Med Univ S Carolina, Div Clin Neurosci, Charleston, SC 29425 USA. [Woody, George E.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Malow, Robert M.] Florida Int Univ, Robert Stempel Sch Publ Hlth, Miami, FL 33199 USA. [Brown, Lawrence S., Jr.] Addict Res & Treatment Corp, Brooklyn, NY USA. [Booth, Robert E.] Univ Colorado, Sch Med, Dept Psychiat, Div Subst Dependence, Denver, CO 80262 USA. [Mandler, Raul N.] Natl Inst Drug Abuse, Ctr Clin Trials Network, Bethesda, MD USA. [Colfax, Grant] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Brooks, Audrey J.] Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. [Hien, Denise A.] CUNY, Dept Psychol, New York, NY 10021 USA. [Schackman, Bruce R.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Div Gen Internal Med, Portland, OR 97201 USA. [Miele, Gloria M.] New York State Psychiat Inst & Hosp, Subst Abuse Div, New York, NY 10032 USA. RP Tross, S (reprint author), New York State Psychiat Inst & Hosp, HIV Ctr Clin & Behav Studies, 1051 Riverside Dr,Unit 15, New York, NY 10032 USA. EM st130@columbia.edu RI Feaster, Daniel/I-6079-2013; OI Feaster, Daniel/0000-0002-6172-7460 FU NIDA NIH HHS [U10 DA13714, U10 DA013035, U10 DA013035-05, U10 DA013035-06, U10 DA013036, U10 DA013043, U10 DA013045, U10 DA013046, U10 DA013714, U10 DA013714-05, U10 DA013720, U10 DA013727, U10 DA015815, U10 DA13035, U10 DA13043, U10 DA13045, U10 DA13727]; NIMH NIH HHS [P30 MH058107] NR 84 TC 3 Z9 3 U1 5 U2 14 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD SEP PY 2011 VL 37 IS 5 BP 283 EP 293 DI 10.3109/00952990.2011.596977 PG 11 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 810HN UT WOS:000294116500004 PM 21854270 ER PT J AU Greenfield, SF Rosa, C Putnins, SI Green, CA Brooks, AJ Calsyn, DA Cohen, LR Erickson, S Gordon, SM Haynes, L Killeen, T Miele, G Tross, S Winhusen, T AF Greenfield, Shelly F. Rosa, Carmen Putnins, Susan I. Green, Carla A. Brooks, Audrey J. Calsyn, Donald A. Cohen, Lisa R. Erickson, Sarah Gordon, Susan M. Haynes, Louise Killeen, Therese Miele, Gloria Tross, Susan Winhusen, Theresa TI Gender Research in the National Institute on Drug Abuse National Treatment Clinical Trials Network: A Summary of Findings SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE substance use disorders; gender differences; substance abuse treatment; women; HIV risk behaviors; eating disorders; PTSD; co-occurring disorders; HIV prevention; pregnant women ID POSTTRAUMATIC-STRESS-DISORDER; COOCCURRING EATING-DISORDERS; ADDICTION TREATMENT PROGRAMS; MENSTRUAL-CYCLE PHASE; RISK REDUCTION GROUPS; SUBSTANCE-ABUSE; TREATMENT PROVIDERS; WOMEN; SEX; INTERVENTION AB Background: The National Institute of Drug Abuse's National Drug Abuse Treatment Clinical Trials Network (CTN) was established to foster translation of research into practice in substance abuse treatment settings. The CTN provides a unique opportunity to examine in multi-site, translational clinical trials, the outcomes of treatment interventions targeting vulnerable subgroups of women; the comparative effectiveness of gender-specific protocols to reduce risk behaviors; and gender differences in clinical outcomes. Objectives: To review gender-related findings from published CTN clinical trials and related studies from January 2000 to March 2010. Methods: CTN studies were selected for review if they focused on treatment outcomes or services for special populations of women with substance use disorders (SUDs) including those with trauma histories, pregnancy, co-occurring eating and other psychiatric disorders, and HIV risk behaviors; or implemented gender-specific protocols. The CTN has randomized 11,500 participants (41% women) across 200 clinics in 24 randomized controlled trials in community settings, of which 4 have been gender-specific. Results: This article summarizes gender-related findings from CTN clinical trials and related studies, focusing on trauma histories, pregnancy, co-occurring eating and other psychiatric disorders, and HIV risk behaviors. Conclusions: These published studies have expanded the evidence base regarding interventions for vulnerable groups of women with SUDs as well as gender-specific interventions to reduce HIV risk behaviors in substance-using men and women. The results also underscore the complexity of accounting for gender in the design of clinical trials and analysis of results. Scientific Significance: To fully understand the relevance of gender-specific moderators and mediators of outcome, it is essential that future translational studies adopt more sophisticated approaches to understanding and measuring gender-relevant factors and plan sample sizes that are adequate to support more nuanced analytic methods. C1 [Greenfield, Shelly F.; Putnins, Susan I.] McLean Hosp, Belmont, MA 02478 USA. [Greenfield, Shelly F.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Rosa, Carmen] Natl Inst Drug Abuse, Ctr Clin Trials Network, Bethesda, MD USA. [Green, Carla A.] Kaiser Permanente NW, Ctr Hlth Res, Portland, OR USA. [Brooks, Audrey J.] Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. [Calsyn, Donald A.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Cohen, Lisa R.; Miele, Gloria] New York State Psychiat Inst & Hosp, Subst Abuse Div, New York, NY 10032 USA. [Erickson, Sarah] Univ New Mexico, Dept Psychol & Pediat, Albuquerque, NM 87131 USA. [Gordon, Susan M.] Belmont Ctr Comprehens Treatment, Philadelphia, PA USA. [Haynes, Louise] Morris Village Alcohol & Drug Treatment Ctr, Columbia, SC USA. [Killeen, Therese] Med Univ S Carolina, Inst Psychiat, Charleston, SC 29425 USA. [Tross, Susan] New York State Psychiat Inst & Hosp, HIV Ctr, New York, NY 10032 USA. [Winhusen, Theresa] Univ Cincinnati, Dept Psychiat & Behav Neurosci, Cincinnati, OH USA. RP Greenfield, SF (reprint author), McLean Hosp, 115 Mill St, Belmont, MA 02478 USA. EM sgreenfield@mclean.harvard.edu RI Green, Carla/D-2534-2017; OI Green, Carla/0000-0002-0000-4381; Winhusen, Theresa/0000-0002-3364-0739 FU NIDA NIH HHS [U10 DA13732, DA13727, K24 DA019855, K24 DA019855-08, K24DA019855, U10 DA013035, U10 DA013036, U10 DA013036-07, U10 DA013043, U10 DA013714, U10 DA013714-05, U10 DA013727, U10 DA013732, U10 DA015815, U10 DA015831, U10 DA015833, U10 DA13035, U10 DA13036, U10 DA13043, U10 DA13714, U10 DA15815, U10 DA15831, U10 DA15833, UG1 DA013727] NR 45 TC 13 Z9 14 U1 1 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD SEP PY 2011 VL 37 IS 5 BP 301 EP 312 DI 10.3109/00952990.2011.596875 PG 12 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 810HN UT WOS:000294116500006 PM 21854272 ER PT J AU Burlew, AK Weekes, JC Montgomery, L Feaster, DJ Robbins, MS Rosa, CL Ruglass, LM Venner, KL Wu, LT AF Burlew, A. Kathleen Weekes, Jerren C. Montgomery, La'Trice Feaster, Daniel J. Robbins, Michael S. Rosa, Carmen L. Ruglass, Lesia M. Venner, Kamilla L. Wu, Li-Tzy TI Conducting Research with Racial/Ethnic Minorities: Methodological Lessons from the NIDA Clinical Trials Network SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE racial/ethnic minorities; clinical trials; health disparities; recruitment; retention; data analytic plans; measurement equivalence ID DRUG-ABUSE TREATMENT; HEALTH DISPARITIES; HISPANIC ADOLESCENTS; TREATMENT RETENTION; COCAINE DEPENDENCE; ETHNIC-DIFFERENCES; AFRICAN-AMERICANS; SUBSTANCE USERS; RECRUITMENT; OUTCOMES AB Background: Multiple studies in the National Institute on Drug Abuse Clinical Trials Network (CTN) demonstrate strategies for conducting effective substance abuse treatment research with racial/ethnic minorities (REMs). Objectives: The objectives of this article are to describe lessons learned within the CTN to (1) enhance recruitment, retention, and other outcomes; (2) assess measurement equivalence; and (3) use data analytic plans that yield more information. Method: This article includes background information and examples from multiple CTN studies on inclusion, measurement, and data analysis. Results and Conclusions: Seven recommendations are included for conducting more effective research on REMs. C1 [Burlew, A. Kathleen; Weekes, Jerren C.; Montgomery, La'Trice] Univ Cincinnati, Dept Psychol, Cincinnati, OH 45221 USA. [Feaster, Daniel J.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Robbins, Michael S.] Oregon Res Inst, Eugene, OR 97403 USA. [Rosa, Carmen L.] NIDA, Bethesda, MD 20892 USA. [Ruglass, Lesia M.] CUNY City Coll, Dept Psychol, New York, NY 10031 USA. [Venner, Kamilla L.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Venner, Kamilla L.] Univ New Mexico, CASAA, Albuquerque, NM 87131 USA. [Wu, Li-Tzy] Duke Univ, Med Ctr, Sch Med, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. RP Burlew, AK (reprint author), Univ Cincinnati, Dept Psychol, 4130D Edwards Bldg 1,POB 210376, Cincinnati, OH 45221 USA. EM Kathy.burlew@uc.edu RI Feaster, Daniel/I-6079-2013; OI Feaster, Daniel/0000-0002-6172-7460 FU NIDA NIH HHS [U10 DA13035, U10 DA013035, U10 DA013035-06, U10 DA13720, U10 DA013732, U10 DA015833, U10 DA013727]; PHS HHS [HHSN271200522071C] NR 62 TC 13 Z9 13 U1 2 U2 16 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD SEP PY 2011 VL 37 IS 5 BP 324 EP 332 DI 10.3109/00952990.2011.596973 PG 9 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 810HN UT WOS:000294116500008 PM 21854274 ER PT J AU Thomas, LR Rosa, C Forcehimes, A Donovan, DM AF Thomas, Lisa Rey Rosa, Carmen Forcehimes, Alyssa Donovan, Dennis M. TI Research Partnerships between Academic Institutions and American Indian and Alaska Native Tribes and Organizations: Effective Strategies and Lessons Learned in a Multisite CTN Study SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE American Indian and Alaska Native; CBPR/TPR; substance abuse ID PARTICIPATORY RESEARCH; COMMUNITIES; HEALTH AB Background: Community Based and Tribally Based Participatory Research (CBPR/TPR) are approaches that can be successful for developing ethical and effective research partnerships between academic institutions and Tribes and Native organizations. Objectives: The NIDA Clinical Trials Network funded a multi-site, exploratory study using CBPR/TPR to begin to better understand substance abuse issues of concern to some Tribes and Native organizations as well as strengths and resources that exist in these communities to address these concerns. Attention was paid to the development and maintenance of research partnerships in each of the sites. Methods: Each of the five partnerships is briefly described and common as well as unique challenges and successes are identified. Results: A summary of the common themes for developing these collaborative research efforts is provided. Conclusion: True, collaborative research partnerships require a great deal of time and effort in order to develop mutual trust, understanding, knowledge, and collaboration that will guide research that is rigorous as well as ethical, effective, and culturally appropriate. Scientific Significance: As AIAN communities become increasingly sophisticated partners in, and consumers of, research, CBPR and TPR are emerging as effective, ethical, culturally appropriate, and acceptable approaches. This can serve to improve the science we engage in with AIAN communities, add to the scarce literature regarding AIAN communities, and better serve AIAN communities in addressing health disparities and improving health. C1 [Thomas, Lisa Rey; Donovan, Dennis M.] Univ Washington, Alcohol & Drug Abuse Inst, Seattle, WA 98105 USA. [Rosa, Carmen] NIDA, Ctr Clin Trials Network, NIH, HHS, Rockville, MD USA. [Forcehimes, Alyssa] Univ New Mexico, Dept Psychol, Ctr Alcoholism Subst Abuse & Addict, Albuquerque, NM 87131 USA. RP Thomas, LR (reprint author), Univ Washington, Alcohol & Drug Abuse Inst, 1107 NE 45th St,Suite 120, Seattle, WA 98105 USA. EM lrthomas@u.washington.edu FU NCRR NIH HHS [UL1 RR025014]; NIDA NIH HHS [U10 DA015833-09, U10 DA013714-05, U10 DA013714, U10 DA015833] NR 14 TC 21 Z9 21 U1 3 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD SEP PY 2011 VL 37 IS 5 BP 333 EP 338 DI 10.3109/00952990.2011.596976 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 810HN UT WOS:000294116500009 PM 21854275 ER PT J AU Oden, NL VanVeldhuisen, PC Wakim, PG Trivedi, MH Somoza, E Lewis, D AF Oden, Neal L. VanVeldhuisen, Paul C. Wakim, Paul G. Trivedi, Madhukar H. Somoza, Eugene Lewis, Daniel TI Power of Automated Algorithms for Combining Time-Line Follow-Back and Urine Drug Screening Test Results in Stimulant-Abuse Clinical Trials SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE TLFB; UDS; stimulant abuse; clinical trial ID PLACEBO-CONTROLLED TRIAL; COCAINE DEPENDENCE; DOUBLE-BLIND; BENZOYLECGONINE; URINALYSIS AB Background: In clinical trials of treatment for stimulant abuse, researchers commonly record both Time-Line Follow-Back (TLFB) self-reports and urine drug screen (UDS) results. Objectives: To compare the power of self-report, qualitative (use vs. no use) UDS assessment, and various algorithms to generate self-report-UDS composite measures to detect treatment differences via t-test in simulated clinical trial data. Methods: We performed Monte Carlo simulations patterned in part on real data to model self-report reliability, UDS errors, dropout, informatively missing UDS reports, incomplete adherence to a urine donation schedule, temporal correlation of drug use, number of days in the study period, number of patients per arm, and distribution of drug-use probabilities. Investigated algorithms include maximum likelihood and Bayesian estimates, self-report alone, UDS alone, and several simple modifications of self-report (referred to here as ELCON algorithms) which eliminate perceived contradictions between it and UDS. Results: Among the algorithms investigated, simple ELCON algorithms gave rise to the most powerful t-tests to detect mean group differences in stimulant drug use. Conclusions: Further investigation is needed to determine if simple, naive procedures such as the ELCON algorithms are optimal for comparing clinical study treatment arms. But researchers who currently require an automated algorithm in scenarios similar to those simulated for combining TLFB and UDS to test group differences in stimulant use should consider one of the ELCON algorithms. Scientific Significance: This analysis continues a line of inquiry which could determine how best to measure outpatient stimulant use in clinical trials (NIDA. NIDA Monograph-57: Self-Report Methods of Estimating Drug Abuse: Meeting Current Challenges to Validity. NTIS PB 88248083. Bethesda, MD: National Institutes of Health, 1985; NIDA. NIDA Research Monograph 73: Urine Testing for Drugs of Abuse. NTIS PB 89151971. Bethesda, MD: National Institutes of Health, 1987; NIDA. NIDA Research Monograph 167: The Validity of Self-Reported Drug Use: Improving the Accuracy of Survey Estimates. NTIS PB 97175889. GPO 017-024-01607-1. Bethesda, MD: National Institutes of Health, 1997). C1 [Oden, Neal L.; VanVeldhuisen, Paul C.] EMMES Corp, Rockville, MD 20850 USA. [Wakim, Paul G.] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. [Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Somoza, Eugene; Lewis, Daniel] Univ Cincinnati, CinARC, Cincinnati, OH USA. [Somoza, Eugene] Univ Cincinnati, Cincinnati VA Med Ctr, Cincinnati, OH USA. RP Oden, NL (reprint author), EMMES Corp, 401 N Washington St,Suite 700, Rockville, MD 20850 USA. EM noden@emmes.com FU NIDA NIH HHS [U10 DA020024, 2U10DA020024-06, UG1 DA020024, 3U10DA020024-06S1, U10 DA013732-04, U10DA013732]; PHS HHS [HHSN271200900034C] NR 11 TC 5 Z9 5 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD SEP PY 2011 VL 37 IS 5 BP 350 EP 357 DI 10.3109/00952990.2011.601777 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 810HN UT WOS:000294116500011 PM 21854277 ER PT J AU Potter, JS Donovan, DM Weiss, RD Gardin, J Lindblad, R Wakim, P Dodd, D AF Potter, Jennifer Sharpe Donovan, Dennis M. Weiss, Roger D. Gardin, John Lindblad, Robert Wakim, Paul Dodd, Dorian TI Site Selection in Community-Based Clinical Trials for Substance Use Disorders: Strategies for Effective Site Selection SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE clinical trials; substance use disorders; methods; site selection; community-based research ID DRUG-ABUSE TREATMENT; NETWORK; EXPERIENCE; BELIEFS AB Background: The importance of conducting substance use disorder treatment research in real-world settings is now well recognized. While this approach to clinical trials research offers a variety of benefits, challenges also arise. Selecting high-quality sites to participate is critical to recruitment, retention, and overall trial performance when conducting multi-site, community-based clinical trials of treatments for substance use disorders. Objectives: Over the past 10 years, the National Institute on Drug Abuse-sponsored National Drug Abuse Treatment Clinical Trials Network (CTN) has strived to conduct high-quality, well-managed clinical trials. This includes developing methods for site selection to be used by investigators conducting CTN trials. Methods: We review site selection strategies from two community-based multi-site clinical trials conducted under the auspices of the National Drug Abuse Treatment Clinical Trials Network. Results: Issues relevant to site selection include the clinical trial design, availability of appropriate clinical population, and organizational attributes of potential clinical research sites. Site selection strategies include reviewing regional epidemiologic data, collecting standard site selection surveys, evaluating clinic data on existing patient populations, and site selection interviews and visits. Conclusion: This article describes considerations for selecting research sites and identifies specific strategies to employ when selecting community-based sites for participation in clinical trials. C1 [Potter, Jennifer Sharpe] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, Sch Med, Div Alcohol & Drug Abuse, San Antonio, TX 78232 USA. [Donovan, Dennis M.] Univ Washington, Inst Alcohol & Drug Abuse, Seattle, WA 98195 USA. [Donovan, Dennis M.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Weiss, Roger D.; Dodd, Dorian] Harvard Univ, Sch Med, McLean Hosp, Belmont, CA USA. [Gardin, John] ADAPT, Roseburg, OR USA. [Lindblad, Robert] EMMES Corp, Rockville, MD USA. [Wakim, Paul] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. RP Potter, JS (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, Sch Med, Div Alcohol & Drug Abuse, 7526 Louis Pasteur MC7733, San Antonio, TX 78232 USA. EM potterjs@uthscsa.edu RI Potter, Jennifer/C-6720-2008 OI Potter, Jennifer/0000-0002-7250-4422 FU NCRR NIH HHS [UL1 RR025014]; NIDA NIH HHS [K23 DA022297, K23 DA022297-05, K24 DA022288, K24 DA022288-05, U10 DA013036, U10 DA013036-10, U10 DA013714, U10 DA013714-10, U10 DA015831, U10 DA015831-10] NR 15 TC 4 Z9 4 U1 1 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD SEP PY 2011 VL 37 IS 5 BP 400 EP 407 DI 10.3109/00952990.2011.596975 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 810HN UT WOS:000294116500017 PM 21854283 ER PT J AU Donovan, DM Daley, DC Brigham, GS Hodgkins, CC Perl, HI Floyd, AS AF Donovan, Dennis M. Daley, Dennis C. Brigham, Gregory S. Hodgkins, Candace C. Perl, Harold I. Floyd, Anthony S. TI How Practice and Science Are Balanced and Blended in the NIDA Clinical Trials Network: The Bidirectional Process in the Development of the STAGE-12 Protocol as an Example SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE bidirectionality; research; clinical practice; internal validity; external validity; clinical trials network; protocol development ID COLLABORATIVE-COCAINE-TREATMENT; SUBSTANCE-ABUSE TREATMENT; SELF-HELP GROUPS; DEPENDENT PATIENTS; USE DISORDERS; FOLLOW-UP; INNOVATION ADOPTION; NATIONAL-INSTITUTE; DRINKING OUTCOMES; GROUP INVOLVEMENT AB Background: Bidirectional, collaborative partnerships between academic researchers and practitioners have been a fundamental vehicle to achieve the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) goal of improving outcomes of community-based drug treatment. These partnerships blend clinical perspectives of practitioners and methodological expertise of researchers working together to address clinically meaningful issues through randomized clinical trials conducted in community treatment settings. Objectives: Bidirectionality is a guiding principle of the CTN, but its operationlization at the practical level in protocol development and implementation has not been articulated. This descriptive article presents the development of one protocol as an example and model of this bidirectional, collaborative, iterative partnership between researchers and practitioners. Methods: This article illuminates several specific issues encountered while developing STAGE-12, a behavioral intervention to facilitate 12-step mutual support group involvement, as well as the rationale for decisions taken to resolve each. Results: The STAGE-12 protocol was successfully developed through a series of decisions taking into account both design factors and clinical practice needs and realities, thus maintaining a balance between methodological rigor and generalizability. Conclusion: The review demonstrates the process by which research and practice have been blended in protocol development, exemplifying the underlying principle of bidirectionality, a key element in the success of the NIDA CTN. Scientific Significance: Bidirectional partnerships as derived in the CTN, employing a hybrid model of efficacy-effectiveness research, are capable of designing and implementing protocols that are both methodologically rigorous and clinically meaningful, thus increasing likelihood of adoption and eventual improvement in public health. C1 [Donovan, Dennis M.] Univ Washington, Inst Alcohol & Drug Abuse, Seattle, WA 98105 USA. [Donovan, Dennis M.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98105 USA. [Daley, Dennis C.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Daley, Dennis C.] Western Psychiat Inst & Clin, Pittsburgh, PA USA. [Brigham, Gregory S.] Maryhaven Inc, Res Inst, Columbus, OH USA. [Hodgkins, Candace C.] Gateway Community Serv Inc, Jacksonville, FL USA. [Perl, Harold I.] NIDA, Bethesda, MD 20892 USA. RP Donovan, DM (reprint author), Univ Washington, Inst Alcohol & Drug Abuse, 1107 NE,45th St,Suite 120, Seattle, WA 98105 USA. EM ddonovan@u.washington.edu OI Brigham, Gregory/0000-0003-1150-4493 FU NCRR NIH HHS [UL1 RR025014]; NIDA NIH HHS [5U10DA020036, U10 DA13732, U10 DA13714, U10 DA020036, U10 DA013714, 5U10DA013720, U10 DA013714-05, U10 DA013720, U10 DA013732] NR 59 TC 7 Z9 7 U1 5 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD SEP PY 2011 VL 37 IS 5 BP 408 EP 416 DI 10.3109/00952990.2011.596970 PG 9 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 810HN UT WOS:000294116500018 PM 21854284 ER PT J AU Bogenschutz, MP Donovan, DM Adinoff, B Crandall, C Forcehimes, AA Lindblad, R Mandler, RN Oden, NL Perl, HI Walker, R AF Bogenschutz, Michael P. Donovan, Dennis M. Adinoff, Bryon Crandall, Cameron Forcehimes, Alyssa A. Lindblad, Robert Mandler, Raul N. Oden, Neal L. Perl, Harold I. Walker, Robrina TI Design of NIDA CTN Protocol 0047: Screening, Motivational Assessment, Referral, and Treatment in Emergency Departments (SMART-ED) SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE brief intervention; clinical trial; design; emergency department; SBIRT ID SUBSTANCE-ABUSE TREATMENT; BRIEF INTERVENTIONS; PRIMARY-CARE; ALCOHOL-USE; DRUG-ABUSE; EPIDEMIOLOGIC SURVEYS; NICOTINE DEPENDENCE; RANDOMIZED-TRIAL; PROBLEM DRINKING; ILLICIT DRUG AB Background: Medical settings such as emergency departments (EDs) present an opportunity to identify and provide services for individuals with substance use problems who might otherwise never receive any form of assessment, referral, or intervention. Although screening, brief intervention, and referral to treatment models have been extensively studied and are considered effective for individuals with alcohol problems presenting in EDs and other medical settings, the efficacy of such interventions has not been established for drug users presenting in EDs. Objectives: This article describes the design of a NIDA Clinical Trials Network protocol testing the efficacy of an screening, brief intervention, and referral to treatment model in medical EDs, highlighting considerations that are pertinent to the design of other studies targeting substance use behaviors in medical treatment settings. Methods: The protocol is described, and critical design decisions are discussed. Results: Design challenges included defining treatment conditions, study population, and site characteristics; developing the screening process; choosing the primary outcome; balancing brevity and comprehensiveness of assessment; and selecting the strategy for statistical analysis. Conclusion: Many of the issues arising in the design of this study will be relevant to future studies of interventions for addictions in medical settings. Scientific Significance: Optimal trial design is critical to determining how best to integrate substance abuse interventions into medical care. C1 [Bogenschutz, Michael P.] Univ New Mexico, Dept Psychiat, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Bogenschutz, Michael P.; Forcehimes, Alyssa A.] Univ New Mexico, Ctr Alcoholism Subst Abuse & Addict, Albuquerque, NM 87131 USA. [Donovan, Dennis M.] Univ Washington, Inst Alcohol & Drug Abuse, Seattle, WA 98195 USA. [Donovan, Dennis M.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Adinoff, Bryon; Walker, Robrina] Univ Texas Dallas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. [Adinoff, Bryon] VA N Texas Hlth Care Syst, Dallas, TX USA. [Crandall, Cameron] Univ New Mexico, Dept Emergency Med, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Lindblad, Robert; Oden, Neal L.] EMMES Corp, Rockville, MD USA. [Mandler, Raul N.; Perl, Harold I.] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. RP Bogenschutz, MP (reprint author), Univ New Mexico, Dept Psychiat, Hlth Sci Ctr, Albuquerque, NM 87131 USA. EM mbogenschutz@salud.unm.edu OI Bogenschutz, Michael/0000-0003-4530-3470 FU NCRR NIH HHS [UL1 RR025014]; NIDA NIH HHS [U10 DA013714, U10 DA015833, U10 DA015833-06, U10 DA020024, U10DA013714, U10DA015833, U10DA020024, UG1 DA020024] NR 53 TC 11 Z9 11 U1 2 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD SEP PY 2011 VL 37 IS 5 BP 417 EP 425 DI 10.3109/00952990.2011.596971 PG 9 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 810HN UT WOS:000294116500019 PM 21854285 ER PT J AU Wakim, PG Rosa, C Kothari, P Michel, ME AF Wakim, Paul G. Rosa, Carmen Kothari, Prasad Michel, Mary Ellen TI Relation of Study Design to Recruitment and Retention in CTN Trials SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE primary outcome; treatment exposure; case report form (CRF); trial design characteristics ID PLACEBO-CONTROLLED TRIAL; DRUG-ABUSE TREATMENT; CLINICAL-TRIAL; DEPENDENCE AB Background: Recruitment and retention in randomized clinical trials are difficult in general and particularly so in trials of substance abuse treatments. Understanding trial design characteristics that could affect recruitment and retention rates would help in the design of future trials. Objective: To test whether any of the following factors are associated with recruitment or retention: type of intervention, type of therapy, duration of treatment, total duration of trial, number of treatment sessions, number of follow-up visits, number of primary assessments, timing of primary assessments, number of case report form (CRF) pages at baseline, and number of CRF pages for the entire trial. Methods: Recruitment and retention data from 24 Clinical Trials Network (CTN) trials conducted and completed between 2001 and 2010 were analyzed using single-factor analysis of variance and single-predictor regression methods to test their association with trial design characteristics. Results: Almost all of the analyses performed did not show statistically significant patterns between recruitment and retention rates and the trial design characteristics considered. Conclusion: In CTN trials, the relationship between assessment burden on participants and length of trial, on the one hand, and recruitment and retention, on the other, is not as strong and direct as expected. Other factors must impinge on the conduct of the trial to influence trial participation. Scientific Significance: Researchers may deem slightly more justifiable to permit inclusion of some of the design features that previously were assumed to have a strong, negative influence on recruitment and retention, and should consider other strategies that may have a stronger, more direct effect on trial participation. C1 [Wakim, Paul G.; Rosa, Carmen; Michel, Mary Ellen] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. [Kothari, Prasad] Synergy Enterprises Inc, Silver Spring, MD USA. RP Wakim, PG (reprint author), NIDA, Ctr Clin Trials Network, 6001 Executive Blvd, Bethesda, MD 20892 USA. EM pwakim@nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 14 TC 2 Z9 2 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD SEP PY 2011 VL 37 IS 5 BP 426 EP 433 DI 10.3109/00952990.2011.596972 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 810HN UT WOS:000294116500020 PM 21854286 ER PT J AU Lindblad, R Campanella, M Styers, D Kothari, P Sparenborg, S Rosa, C AF Lindblad, Robert Campanella, Maria Styers, David Kothari, Prasad Sparenborg, Steve Rosa, Carmen TI Strategies for Safety Reporting in Substance Abuse Trials SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE safety reporting; substance use disorder; serious adverse events; adverse events; behavioral intervention; participant safety ID CLINICAL-TRIALS; ADVERSE EVENTS; RANDOMIZED-TRIALS; BUPRENORPHINE-NALOXONE; NATIONAL-INSTITUTE; INTERVENTION; COMMUNITY; NETWORK; EXPERIENCE AB Background: Reporting all adverse events (AEs) and serious adverse events (SAEs) in substance use disorder (SUD) clinical trials has yielded limited relevant safety information and has been burdensome to research sites. Objective: This article describes a new strategy utilizing standard data elements for AE and SAEs that defines a threshold to reduce unnecessary safety reporting burden in SUD clinical trials and describes retrospective review and prospective preliminary data on the strategy's safety reporting impact. Methods: We developed a new strategy to standardize safety reporting and tailor reporting to the trial intervention risk. Protocols and safety data from 17 SUD clinical trials were reviewed. Retrospective analysis of five of these studies and prospective application to new studies is described. Results: Across the 17 previously completed trials, a total of 11,220 AEs and 1330 SAEs were reported in the 6737 participants. Wide variability in AE and SAE reporting rates were noted based on trial type and inconsistent reporting strategies. Application of the new, tailored safety strategy retrospectively and prospectively reduces reporting burden of irrelevant safety events. Conclusion: Comparison of the previous reporting strategies used in SUD trials to the new strategy demonstrates a more consistent safety system with a reduction in safety reporting burden while maintaining appropriate safety monitoring. Scientific Significance: Safety assessments should be tailored to the participant risks based on the trial intervention. The current strategies could be applied to safety assessments across all clinical trials in SUDs. C1 [Lindblad, Robert; Campanella, Maria; Styers, David] EMMES Corp, Rockville, MD USA. [Lindblad, Robert; Kothari, Prasad] Synergy Enterprises Inc, Silver Spring, MD USA. [Sparenborg, Steve; Rosa, Carmen] NIDA, Bethesda, MD 20892 USA. RP Lindblad, R (reprint author), EMMES Corp, Rockville, MD USA. EM rlindblad@emmes.com NR 27 TC 2 Z9 2 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD SEP PY 2011 VL 37 IS 5 BP 440 EP 445 DI 10.3109/00952990.2011.602996 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 810HN UT WOS:000294116500022 PM 21854288 ER PT J AU Caban-Martinez, AJ Lee, DJ Fleming, LE Arheart, KL LeBlanc, WG McCollister, KE Tancredi, DJ Christ, SL Louie, GH Muennig, PA AF Caban-Martinez, Alberto J. Lee, David J. Fleming, Lora E. Arheart, Kristopher L. LeBlanc, William G. McCollister, Kathryn E. Tancredi, Daniel J. Christ, Sharon L. Louie, Grant H. Muennig, Peter A. TI Arthritis, Occupational Class, and the Aging US Workforce SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID HEALTH INTERVIEW SURVEY; QUALITY-OF-LIFE; RHEUMATOID-ARTHRITIS; ACTIVITY LIMITATIONS; WORK DISABILITY; PERSPECTIVE; PROJECTIONS; PREVALENCE; STATES; JOB AB Objectives. The working poor sometimes delay retirement to survive. However, their higher risk of disease and disability threatens both their financial survival and their ability to work through the retirement years. We used the burden of disease attributable to arthritis by occupational class to illustrate the challenges faced by the older poor. Methods. We merged data from the National Health Interview Survey, Medical Expenditure Panel Survey, and the National Death Index into a single database. We then calculated and compared age- and occupational class specific quality-adjusted life years (QALYs) between workers with and without arthritis by using unabridged life tables. Results. White-collar workers have a higher overall health-related quality of life than do other workers, and suffer fewer QALYs lost to arthritis at all ages. For instance, whereas 65-year-old white-collar workers without arthritis look forward to 17 QALYs of future life, blue-collar workers with arthritis experience only 11, and are much less likely to remain in the workforce than are those in service, farming, or white-collar jobs. Conclusions. To meet the needs of the aging workforce, more extensive health and disability insurance will be needed. (Am J Public Health. 2011;101:1729-1734. doi:10.2105/AJPH.2011.300173) C1 [Caban-Martinez, Alberto J.; Lee, David J.; Fleming, Lora E.; Arheart, Kristopher L.; LeBlanc, William G.; McCollister, Kathryn E.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Tancredi, Daniel J.] Univ Calif, Davis Hlth Syst, Ctr Healthcare Policy & Res, Sacramento, CA USA. [Christ, Sharon L.] Purdue Univ, Dept Child Dev & Family Studies & Stat, W Lafayette, IN 47907 USA. [Louie, Grant H.] NIAMSD, Intramural Res Program, US NIH, Bethesda, MD 20892 USA. [Muennig, Peter A.] Columbia Univ, Dept Hlth Policy & Management, Mailman Sch Publ Hlth, New York, NY USA. RP Caban-Martinez, AJ (reprint author), Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Clin Res Bldg,Room 1075,1120 NW 14th St,10th Floo, Miami, FL 33136 USA. EM acaban@med.miami.edu RI Tancredi, Daniel/O-3381-2013; Osborne, Nicholas/N-4915-2015 OI Caban-Martinez, Alberto/0000-0002-5960-1308; Tancredi, Daniel/0000-0002-3884-7907; Muennig, Peter/0000-0002-4234-0498; Osborne, Nicholas/0000-0002-6700-2284 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [F31AR057687]; National Institute for Occupational Safety and Health [R0I OH003915] FX This study was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant F31AR057687) and the National Institute for Occupational Safety and Health (grant R0I OH003915). NR 43 TC 18 Z9 18 U1 0 U2 9 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 SEP PY 2011 VL 101 IS 9 BP 1729 EP 1734 DI 10.2105/AJPH.2011.300173 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 809XR UT WOS:000294090500030 PM 21778483 ER PT J AU Schwope, DM Scheidweiler, KB Huestis, MA AF Schwope, David M. Scheidweiler, Karl B. Huestis, Marilyn A. TI Direct quantification of cannabinoids and cannabinoid glucuronides in whole blood by liquid chromatography-tandem mass spectrometry SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE THC; Cannabinoid glucuronides; LC-MS/MS; Whole blood ID SOLID-PHASE EXTRACTION; ORAL FLUID; GC-MS; 11-NOR-DELTA(9)-TETRAHYDROCANNABINOL-9-CARBOXYLIC ACID; DELTA(9)-TETRAHYDROCANNABINOL THC; GAS-CHROMATOGRAPHY; HEPATIC MICROSOMES; HUMAN-URINE; METABOLITES; TETRAHYDROCANNABINOL AB The first method for quantifying cannabinoids and cannabinoid glucuronides in whole blood by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated. Solid-phase extraction followed protein precipitation with acetonitrile. High-performance liquid chromatography separation was achieved in 16 min via gradient elution. Electrospray ionization was utilized for cannabinoid detection; both positive (Delta(9)-tetrahydrocannabinol [THC] and cannabinol [CBN]) and negative (11-hydroxy-THC [11-OH-THC], 11-nor-9-carboxy-THC [THCCOOH], cannabidiol [CBD], THC-glucuronide, and THCCOOH-glucuronide) polarity were employed with multiple reaction monitoring. Calibration by linear regression analysis utilized deuterium-labeled internal standards and a 1/x (2) weighting factor, yielding R (2) values > 0.997 for all analytes. Linearity ranged from 0.5 to 50 mu g/L (THC-glucuronide), 1.0-100 mu g/L (THC, 11-OH-THC, THCCOOH, CBD, and CBN), and 5.0-250 mu g/L (THCCOOH-glucuronide). Imprecision was < 10.5% CV, recovery was > 50.5%, and bias within +/- 13.1% of target for all analytes at three concentrations across the linear range. No carryover and endogenous or exogenous interferences were observed. This new analytical method should be useful for quantifying cannabinoids in whole blood and further investigating cannabinoid glucuronides as markers of recent cannabis intake. C1 [Schwope, David M.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health FX The authors thank Allan Barnes, Erin Karschner, Teresa Gray, Amanda Rigdon, and the clinical staff of the NIDA Intramural Research Program for technical assistance. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 36 TC 41 Z9 41 U1 1 U2 38 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD SEP PY 2011 VL 401 IS 4 BP 1273 EP 1283 DI 10.1007/s00216-011-5197-7 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 804CW UT WOS:000293632700022 PM 21727996 ER PT J AU King, JR Yogev, R Jean-Philippe, P Graham, B Wiznia, A Britto, P Carey, V Hazra, R Acosta, EP AF King, Jennifer R. Yogev, Ram Jean-Philippe, Patrick Graham, Bobbie Wiznia, Andrew Britto, Paula Carey, Vincent Hazra, Rohan Acosta, Edward P. CA P1058 Protocol Team TI Steady-State Pharmacokinetics of Tenofovir-Based Regimens in HIV-Infected Pediatric Patients SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID REVERSE-TRANSCRIPTASE INHIBITORS; DISOPROXIL FUMARATE; ATAZANAVIR-RITONAVIR; COMBINATION THERAPY; RANDOMIZED-TRIAL; EFAVIRENZ; CHILDREN AB HIV-infected children are treated with tenofovir in combination with other, potentially interacting, antiretroviral agents. We report the pharmacokinetic parameters of tenofovir in combination with efavirenz, darunavir-ritonavir, or atazanavir-ritonavir in HIV-infected children. HIV-infected patients 8 to 18 years of age receiving a tenofovir (300 mg)-based regimen containing efavirenz (300 or 600 mg) once daily (group 1), darunavir (300 or 600 mg)-ritonavir (100 mg) twice daily (group 2), or atazanavir (150 to 400 mg)-ritonavir (100 mg) once daily (group 3) were enrolled. Plasma samples were collected over a 24-h time interval. The 90% confidence intervals (90% CI) of the geometric means for the area under the plasma concentration-time curve (AUC) and the minimum concentration of drug in serum (C(min)) of each antiretroviral were computed and checked for overlap with intervals bracketing published values obtained in adult or pediatric studies demonstrating safety and/or efficacy. Group 1 efavirenz plasma concentrations were observed to be higher in patients receiving fixed-dose combination tablets compared with subjects receiving the individual formulation. In group 2, tenofovir and darunavir exposure was observed to be lower than expected. In group 3, tenofovir and atazanavir administered concomitantly produced exposures similar to those published for adult patients. The 90% CI of AUC and C(min) for tenofovir overlapped the target range for all combinations. Informal comparisons of treatment groups did not indicate any advantage to any combination with respect to tenofovir exposure. Further study of exposures achieved with antiretrovirals administered in combination is warranted. C1 [King, Jennifer R.] Univ Alabama, Div Clin Pharmacol, Dept Pharmacol & Toxicol, Birmingham, AL 35294 USA. [Yogev, Ram] Northwestern Univ, Childrens Mem Hosp, Dept Pediat, Feinberg Sch Med, Chicago, IL 60614 USA. [Jean-Philippe, Patrick] NIH, Div Aids, Int Maternal Adolescent Pediat Branch, Bethesda, MD USA. [Graham, Bobbie] Frontier Sci & Technol, Amherst, NY USA. [Wiznia, Andrew] Jacobi Med Ctr, Brooklyn, NY USA. [Britto, Paula; Carey, Vincent] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. RP King, JR (reprint author), Univ Alabama, Div Clin Pharmacol, Dept Pharmacol & Toxicol, 1530 3rd Ave S,Shelby 1170, Birmingham, AL 35294 USA. EM jennifer.king@ccc.uab.edu FU National Institute of Allergy and Infectious Diseases [U01AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [N01-DK-9-001/HHSN267200800001C]; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C] FX The project described was supported by grant number U01AI068632 from the National Institute of Allergy and Infectious Diseases and contract number N01-DK-9-001/HHSN267200800001C from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).; Statistical support was provided by the Statistical and Data Analysis Center at Harvard School of Public Health, under National Institute of Allergy and Infectious Diseases cooperative agreement # 1 U01 AI068616 with the IMPAACT Group. Support for P.J.-P. was provided with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272200800014C. NR 17 TC 7 Z9 7 U1 0 U2 2 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 SEP PY 2011 VL 55 IS 9 BP 4290 EP 4294 DI 10.1128/AAC.01334-10 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 808CW UT WOS:000293953900046 PM 21670182 ER PT J AU Gao, JL Schneider, EH Dimitrov, EL Haun, F Pham, TM Mohammed, AH Usdin, TB Murphy, PM AF Gao, Ji-Liang Schneider, Erich H. Dimitrov, Eugene L. Haun, Forrest Pham, Therese M. Mohammed, Abdul H. Usdin, Ted B. Murphy, Philip M. TI Reduced Fear Memory and Anxiety-like Behavior in Mice Lacking Formylpeptide Receptor 1 SO BEHAVIOR GENETICS LA English DT Article DE Chemoattractant receptor; Fpr1; Behavior; Anxiety; Knockout mice; Corticosterone ID FORMYL-PEPTIDE RECEPTOR; TARGETED DELETION; GENE; GLUCOCORTICOIDS; SYSTEM; EMOTIONALITY; SECRETION; ANNEXIN-1; RESPONSES; FAMILY AB N-formylpeptide receptor 1 (FPR1) is a G protein-coupled receptor that mediates pro-inflammatory chemotactic responses by phagocytic leukocytes to N-formylpeptides produced by bacteria or mitochondria. Mice lacking Fpr1 (Fpr1 (-/-) mice) have increased susceptibility to challenge with certain bacteria. FPR1 is also a receptor for annexin-1, which mediates the anti-inflammatory effects of glucocorticoids as well as negative feedback by glucocorticoids of the hypothalamic-pituitary-adrenocortical axis. However, homeostatic functions of FPR1 in the neuroendocrine system have not previously been defined. Here we show that in systematic behavioral testing Fpr1 (-/-) mice exhibited increased exploratory activity, reduced anxiety-like behavior, and impaired fear memory, but normal spatial memory and learning capacity. Consistent with this, the homeostatic serum level of corticosterone in Fpr1 (-/-) mice was significantly lower compared with wild-type mice. The data implicate Fpr1 in modulation of anxiety-like behavior and fear memory by regulating glucocorticoid production. C1 [Gao, Ji-Liang; Schneider, Erich H.; Murphy, Philip M.] NIAID, Mol Signalling Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Dimitrov, Eugene L.; Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, NIH, Bethesda, MD 20892 USA. [Haun, Forrest; Mohammed, Abdul H.] Neuro Detect Int Inc, Wyncote, PA 19095 USA. [Pham, Therese M.; Mohammed, Abdul H.] Karolinska Inst, Alzheimers Dis Res Ctr, Dept NVS, Stockholm, Sweden. RP Gao, JL (reprint author), NIAID, Mol Signalling Sect, Lab Mol Immunol, NIH, Bldg 10,Room 11N107, Bethesda, MD 20892 USA. EM jgao@niaid.nih.gov RI Schneider, Erich/B-9051-2016 OI Schneider, Erich/0000-0002-7905-4276 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 36 TC 8 Z9 8 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD SEP PY 2011 VL 41 IS 5 BP 724 EP 733 DI 10.1007/s10519-011-9467-0 PG 10 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 812MI UT WOS:000294297200011 PM 21484271 ER PT J AU Odet, F Gabel, SA Williams, J London, RE Goldberg, E Eddy, EM AF Odet, Fanny Gabel, Scott A. Williams, Jason London, Robert E. Goldberg, Erwin Eddy, Edward M. TI Lactate Dehydrogenase C and Energy Metabolism in Mouse Sperm SO BIOLOGY OF REPRODUCTION LA English DT Article DE ATP; flagellum; gamete biology; glycolysis; isozyme; nuclear magnetic resonance; null mutation/knockout; sperm hyperactivation; transgenic/knockout model ID TESTIS-SPECIFIC ISOZYMES; FIBROUS SHEATH; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; MAMMALIAN SPERMATOZOA; GLYCOLYTIC-ENZYMES; MALE-FERTILITY; GERM-CELLS; MOTILITY; GLUCOSE; PROTEIN AB We demonstrated previously that disruption of the germ cell-specific lactate dehydrogenase C gene (Ldhc) led to male infertility due to defects in sperm function, including a rapid decline in sperm ATP levels, a decrease in progressive motility, and a failure to develop hyperactivated motility. We hypothesized that lack of LDHC disrupts glycolysis by feedback inhibition, either by causing a defect in renewal of the NAD(+) cofactor essential for activity of glyceraldehyde 3-phosphate dehydrogenase, sperm (GAPDHS), or an accumulation of pyruvate. To test these hypotheses, nuclear magnetic resonance analysis was used to follow the utilization of labeled substrates in real time. We found that in sperm lacking LDHC, glucose consumption was disrupted, but the NAD:NADH ratio and pyruvate levels were unchanged, and pyruvate was rapidly metabolized to lactate. Moreover, the metabolic disorder induced by treatment with the lactate dehydrogenase (LDH) inhibitor sodium oxamate was different from that caused by lack of LDHC. This supported our earlier conclusion that LDHA, an LDH isozyme present in the principal piece of the flagellum, is responsible for the residual LDH activity in sperm lacking LDHC, but suggested that LDHC has an additional role in the maintenance of energy metabolism in sperm. By coimmunoprecipitation coupled with mass spectrometry, we identified 27 proteins associated with LDHC. A majority of these proteins are implicated in ATP synthesis, utilization, transport, and/or sequestration. This led us to hypothesize that in addition to its role in glycolysis, LDHC is part of a complex involved in ATP homeostasis that is disrupted in sperm lacking LDHC. C1 [Odet, Fanny; Eddy, Edward M.] NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Gabel, Scott A.; Williams, Jason; London, Robert E.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Goldberg, Erwin] Northwestern Univ, Dept Mol Biosci, Evanston, IL USA. RP Eddy, EM (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM eddy@niehs.nih.gov FU National Institutes of Health (NIH) [HD05863]; National Institute of Environmental Health Sciences (NIEHS) [ES070076] FX Supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) ES070076 (E.M.E.) and by NIH HD05863 (E.G.). A preliminary description of these studies was presented in a poster at the 42nd Annual Meeting of the Society for the Study of Reproduction, 1822, July 2009, Pittsburgh, Pennsylvania. NR 40 TC 41 Z9 47 U1 6 U2 19 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 SEP PY 2011 VL 85 IS 3 BP 556 EP 564 DI 10.1095/biolreprod.111.091546 PG 9 WC Reproductive Biology SC Reproductive Biology GA 810FH UT WOS:000294110400016 PM 21565994 ER PT J AU Villasenor, A Ambs, A Ballard-Barbash, R Baumgartner, KB McTiernan, A Ulrich, CM Neuhouser, ML AF Villasenor, Adriana Ambs, Anita Ballard-Barbash, Rachel Baumgartner, Kathy B. McTiernan, Anne Ulrich, Cornelia M. Neuhouser, Marian L. TI Dietary fiber is associated with circulating concentrations of C-reactive protein in breast cancer survivors: the HEAL study SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Dietary fiber; Breast cancer; C-reactive protein; Serum amyloid A; Inflammation ID PHYSICAL-ACTIVITY LEVELS; NF-KAPPA-B; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME; WOMENS HEALTH; SYSTEMIC INFLAMMATION; GUT MICROBIOTA; WEIGHT-LOSS; RISK; MARKERS AB Inflammation is a suspected risk factor for breast cancer and its subsequent prognosis. The extent to which dietary and lifestyle factors might influence inflammation is important to examine. Specifically, dietary fiber may reduce systemic inflammation, but this relationship has not been examined among breast cancer survivors. We examined associations between dietary fiber and serum concentrations of C-reactive protein (CRP) and serum amyloid A (SAA), among 698 female breast cancer survivors from the Health, Eating, Activity, and Lifestyle (HEAL) Study. Data are from interviews and clinical visits conducted 24-months post-study enrollment. Multivariate-adjusted linear regression estimated associations of total, soluble, and insoluble fiber with serum concentrations of CRP and SAA. Logistic regression estimated the odds of elevated CRP (defined as > 3.0 mg/l) across tertiles of dietary fiber intake. Mean total dietary fiber intake was 13.9 +/- A 6.4 g/day. Mean CRP and SAA were 3.32 +/- A 3.66 and 7.73 +/- A 10.23 mg/l, respectively. We observed a multivariate-adjusted inverse association between total dietary fiber intake and CRP concentrations (beta, -0.029; 95% CI, -0.049, -0.008). Results for insoluble fiber were similar (beta, -0.039; 95% CI, -0.064, -0.013). Among survivors who consumed > 15.5 g/day of insoluble dietary fiber, a 49% reduction in the likelihood of having elevated CRP concentrations (OR, 0.51; 95% CI, 0.27, 0.95) was observed compared to those who consumed < 5.4 g/day (P = 0.053). Our results suggest that diets high in fiber may benefit breast cancer survivors via reductions in systemic inflammation; elevated inflammation may be prognostic for reduced survival. C1 [Villasenor, Adriana; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. [Ambs, Anita; Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Baumgartner, Kathy B.] Univ Louisville, Dept Epidemiol & Populat Hlth, Louisville, KY 40202 USA. [McTiernan, Anne; Ulrich, Cornelia M.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98109 USA. RP Villasenor, A (reprint author), Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1100 Fairview Ave N,M3-B232, Seattle, WA 98109 USA. EM avillase@fhcrc.org FU National Cancer Institute [NO1-CN-75036-20, NO1-CN-05228, NO1-PC-67010, U54-CA116847, R25-CA094880]; National Institutes of Health [MO1-RR-0037]; University of New Mexico [NCRR MO1-RR-0997]; National Institute of Child Health and Human Development [N01-HD-3-3175]; California Department of Health Services [050Q-8709-S1528] FX The Authors would like to thank the HEAL participants for their ongoing dedication to this study and Gloria D. Coronado, PhD and Sandi L. Navarro, MS for their expertise and assistance. This study was supported through National Cancer Institute contracts NO1-CN-75036-20, NO1-CN-05228, NO1-PC-67010, U54-CA116847 and training grant R25-CA094880. A portion of this study was conducted through the Clinical Research Center at the University of Washington and supported by the National Institutes of Health grant MO1-RR-0037, and University of New Mexico grant, NCRR MO1-RR-0997. Data collection for the Women's CARE Study at the University of Southern California was supported by contract N01-HD-3-3175 from the National Institute of Child Health and Human Development, and patient identification was supported in part by contract 050Q-8709-S1528 from the California Department of Health Services. NR 62 TC 10 Z9 10 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD SEP PY 2011 VL 129 IS 2 BP 485 EP 494 DI 10.1007/s10549-011-1474-6 PG 10 WC Oncology SC Oncology GA 804DI UT WOS:000293634000017 PM 21455669 ER PT J AU Nyante, SJ Gammon, MD Kaufman, JS Bensen, JT Lin, DY Barnholtz-Sloan, JS Hu, YJ He, QC Luo, JC Millikan, RC AF Nyante, Sarah J. Gammon, Marilie D. Kaufman, Jay S. Bensen, Jeannette T. Lin, Dan Yu Barnholtz-Sloan, Jill S. Hu, Yijuan He, Qianchuan Luo, Jingchun Millikan, Robert C. TI Common genetic variation in adiponectin, leptin, and leptin receptor and association with breast cancer subtypes SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Adiponectin; Leptin; Leptin receptor; Breast cancer; Subtypes; Single nucleotide polymorphism ID BASAL-LIKE SUBTYPE; GENOME-WIDE ASSOCIATION; CARCINOMA IN-SITU; SERUM ADIPONECTIN; POPULATION STRATIFICATION; ENVIRONMENT INTERACTIONS; MOLECULAR SUBTYPES; ESTROGEN-RECEPTOR; AFRICAN-AMERICAN; DUCTAL CARCINOMA AB Adipocytokines are produced by visceral fat, and levels may be associated with breast cancer risk. We investigated whether single nucleotide polymorphisms (SNPs) in adipocytokine genes adiponectin (ADIPOQ), leptin (LEP), and the leptin receptor (LEPR) were associated with basal-like or luminal A breast cancer subtypes. 104 candidate and tag SNPs were genotyped in 1776 of 2022 controls and 1972 (200 basal-like, 679 luminal A) of 2311 cases from the Carolina Breast Cancer Study (CBCS), a population-based case-control study of whites and African Americans. Breast cancer molecular subtypes were determined by immunohistochemistry. Genotype odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Haplotype ORs and 95% CIs were estimated using Hapstat. Interactions with waist-hip ratio were evaluated using a multiplicative interaction term. Ancestry was estimated from 144 ancestry informative markers (AIMs), and included in models to control for population stratification. Candidate SNPs LEPR K109R (rs1137100) and LEPR Q223R (rs1137101) were positively associated with luminal A breast cancer, whereas ADIPOQ +45 T/G (rs2241766), ADIPOQ +276 G/T (rs1501299), and LEPR K656N (rs8129183) were not associated with either subtype. Few patterns were observed among tag SNPs, with the exception of 3 LEPR SNPs (rs17412175, rs9436746, and rs9436748) that were in moderate LD and inversely associated with basal-like breast cancer. However, no SNP associations were statistically significant after adjustment for multiple comparisons. Haplotypes in LEP and LEPR were associated with both basal-like and luminal A subtypes. There was no evidence of interaction with waist-hip ratio. Data suggest associations between LEPR candidate SNPs and luminal A breast cancer in the CBCS and LEPR intron 2 tag SNPs and basal-like breast cancer. Replication in additional studies where breast cancer subtypes have been defined is necessary to confirm these potential associations. C1 [Nyante, Sarah J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Nyante, Sarah J.; Gammon, Marilie D.; Bensen, Jeannette T.; Millikan, Robert C.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Nyante, Sarah J.; Gammon, Marilie D.; Bensen, Jeannette T.; Lin, Dan Yu; Luo, Jingchun; Millikan, Robert C.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Kaufman, Jay S.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Lin, Dan Yu; Hu, Yijuan; He, Qianchuan] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Barnholtz-Sloan, Jill S.] Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH USA. RP Nyante, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM sarah.nyante@nih.gov OI Kaufman, Jay/0000-0003-1606-401X FU Lineberger Cancer Center [R25 CA57726]; UNC [NIH/NCI P50-CA58223]; Lineberger Comprehensive Cancer Center [P30-CA16086] FX The authors wish to thank Patricia Basta, Michael Andre, and Amanda Beaty for their work in preparing the DNA samples and conducting the genotyping. The authors also thank Jessica Tse for advice and statistical support. Sarah J. Nyante was supported by the Lineberger Cancer Center Cancer Control Education Program Predoctoral Fellowship (R25 CA57726). The Carolina Breast Cancer Study was funded by the Specialized Program of Research Excellence (SPORE) in Breast Cancer at UNC (NIH/NCI P50-CA58223) and the Lineberger Comprehensive Cancer Center Core Grant (P30-CA16086). NR 67 TC 26 Z9 27 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD SEP PY 2011 VL 129 IS 2 BP 593 EP 606 DI 10.1007/s10549-011-1517-z PG 14 WC Oncology SC Oncology GA 804DI UT WOS:000293634000029 PM 21516303 ER PT J AU Gameiro, SR Caballero, JA Higgins, JP Apelian, D Hodge, JW AF Gameiro, Sofia R. Caballero, Jorge A. Higgins, Jack P. Apelian, David Hodge, James W. TI Exploitation of differential homeostatic proliferation of T-cell subsets following chemotherapy to enhance the efficacy of vaccine-mediated antitumor responses SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE NSCLC; Non-small-cell lung cancer; Cisplatin; Vinorelbine; Adjuvant chemotherapy; Immunotherapy ID PHASE-III TRIAL; HUMAN CARCINOEMBRYONIC ANTIGEN; CISPLATIN PLUS VINORELBINE; LUNG-CANCER; POPULATION PHARMACOKINETICS; ADJUVANT CHEMOTHERAPY; IMMUNE-RESPONSES; DOUBLE-BLIND; STAGE-IB; IN-VIVO AB The 5-year survival rate for stage IB-III non-small-cell lung cancer (NSCLC) remains 15%. Surgical resection followed by adjuvant chemotherapy with cisplatin and vinorelbine is one standard-of-care. We sought to determine in a preclinical model whether (a) the combination of cisplatin and vinorelbine could positively modulate components of the immune system independent of antitumor activity, and (b) there were synergistic effects of this drug combination and vaccine immunotherapy. We examined the effect of cisplatin/vinorelbine on gene expression, cell-surface phenotype, and CTL-mediated cytolysis of murine lung carcinoma cells in vitro; we also assessed the effects of cisplatin/vinorelbine on immune subsets and function of Tregs in vivo. Finally, we evaluated the potential synergy between chemotherapy and a recombinant yeast-CEA vaccine in a murine model transgenic for CEA with mice bearing lung tumors. These studies demonstrate that exposure of lung tumor cells to the platinum doublet cisplatin/vinorelbine modulates tumor cell phenotype and increases sensitivity to CTL-mediated cytolysis. These studies also demonstrate that cisplatin/vinorelbine (a) induces sub-myeloablative leucopenia that differentially modulates reconstitution of Treg versus effector T-cell subsets and (b) can be employed synergistically with vaccine, exploiting homeostatic peripheral expansion of T cells. Antitumor studies show for the first time that cisplatin/vinorelbine combined with vaccine increases the survival of mice with established NSCLC. These findings provide the rationale for the potential clinical benefit of the combined use of vaccine with cisplatin/vinorelbine chemotherapy regimens. C1 [Gameiro, Sofia R.; Caballero, Jorge A.; Higgins, Jack P.; Hodge, James W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Apelian, David] GlobeImmune Inc, Louisville, KY USA. RP Hodge, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B13, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The authors thank Marion Taylor for excellent technical assistance, and Bonnie L. Casey for editorial assistance in the preparation of this manuscript. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 68 TC 31 Z9 31 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD SEP PY 2011 VL 60 IS 9 BP 1227 EP 1242 DI 10.1007/s00262-011-1020-8 PG 16 WC Oncology; Immunology SC Oncology; Immunology GA 811MQ UT WOS:000294215600003 PM 21544650 ER PT J AU Ostrand-Rosenberg, S Celis, E Cohen, P Eshher, Z Gendler, S Hoelzinger, D Hurwitz, A Pease, L Sherman, L AF Ostrand-Rosenberg, Suzanne Celis, Esteban Cohen, Peter Eshher, Zelig Gendler, Sandra Hoelzinger, Dominique Hurwitz, Arthur Pease, Larry Sherman, Linda CA Lustgarten Lab Members TI Obituary: Joseph Lustgarten, 1963-2011 SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Biographical-Item C1 [Ostrand-Rosenberg, Suzanne] Univ Maryland, Baltimore, MD 21250 USA. [Celis, Esteban] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Cohen, Peter; Gendler, Sandra; Hoelzinger, Dominique] Mayo Clin, Scottsdale, AZ 85259 USA. [Eshher, Zelig] Weizmann Inst Sci, IL-76100 Rehovot, Israel. [Hurwitz, Arthur] NCI, NIH, Rockville, MD 20852 USA. [Pease, Larry] Mayo Clin, Rochester, MN 55905 USA. [Sherman, Linda] Scripps Res Inst, La Jolla, CA 92037 USA. RP Ostrand-Rosenberg, S (reprint author), Univ Maryland, Baltimore, MD 21250 USA. EM srosenbe@umbc.edu NR 1 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD SEP PY 2011 VL 60 IS 9 BP 1357 EP 1358 DI 10.1007/s00262-011-1080-9 PG 2 WC Oncology; Immunology SC Oncology; Immunology GA 811MQ UT WOS:000294215600014 ER PT J AU White, MD Bosio, CM Duplantis, BN Nano, FE AF White, Matthew D. Bosio, Catharine M. Duplantis, Barry N. Nano, Francis E. TI Human body temperature and new approaches to constructing temperature-sensitive bacterial vaccines SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Essential gene; Psychrophile; Vaccine; Temperature-sensitive; Body temperature ID TRANSPOSON MUTANT LIBRARY; INFLUENZA-VIRUS VACCINE; ADJUSTABLE SET-POINT; PSITTACI VAR-OVIS; ESSENTIAL GENES; BACILLUS-SUBTILIS; DENDRITIC CELLS; MYCOPLASMA-SYNOVIAE; ESCHERICHIA-COLI; ATTENUATION PHENOTYPES AB Many of the live human and animal vaccines that are currently in use are attenuated by virtue of their temperature-sensitive (TS) replication. These vaccines are able to function because they can take advantage of sites in mammalian bodies that are cooler than the core temperature, where TS vaccines fail to replicate. In this article, we discuss the distribution of temperature in the human body, and relate how the temperature differential can be exploited for designing and using TS vaccines. We also examine how one of the coolest organs of the body, the skin, contains antigen-processing cells that can be targeted to provoke the desired immune response from a TS vaccine. We describe traditional approaches to making TS vaccines, and highlight new information and technologies that are being used to create a new generation of engineered TS vaccines. We pay particular attention to the recently described technology of substituting essential genes from Arctic bacteria for their homologues in mammalian pathogens as a way of creating TS vaccines. C1 [Duplantis, Barry N.; Nano, Francis E.] Univ Victoria, Dept Biochem & Microbiol, Victoria, BC V8W 3P6, Canada. [White, Matthew D.] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Bosio, Catharine M.] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Nano, FE (reprint author), Univ Victoria, Dept Biochem & Microbiol, POB 3055, Victoria, BC V8W 3P6, Canada. EM matt@sfu.ca; dupi@uvic.ca; fnano@uvic.ca FU Intramural NIH HHS [ZIA AI001013-05] NR 86 TC 5 Z9 5 U1 0 U2 12 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD SEP PY 2011 VL 68 IS 18 BP 3019 EP 3031 DI 10.1007/s00018-011-0734-2 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 811ZY UT WOS:000294258700003 PM 21626408 ER PT J AU Zoerner, AA Stichtenoth, DO Engeli, S Batkai, S Winkler, C Schaumann, F Janke, J Holz, O Krug, N Tsikas, D Jordan, J Hohlfeld, JM AF Zoerner, A. A. Stichtenoth, D. O. Engeli, S. Batkai, S. Winkler, C. Schaumann, F. Janke, J. Holz, O. Krug, N. Tsikas, D. Jordan, J. Hohlfeld, J. M. TI Allergen Challenge Increases Anandamide in Bronchoalveolar Fluid of Patients With Allergic Asthma SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID RECEPTOR-SELECTIVE AGONIST; GUINEA-PIGS; ENDOCANNABINOID SYSTEM; INFLAMMATION; ACTIVATION; ACID; EXPRESSION; ENDOTOXIN; MARIHUANA; PATHWAY AB Preclinical studies suggest that the endocannabinoid anandamide restrains allergic airway obstruction and inflammation. Therefore, we applied saline or allergens via bronchoscopy into different lung segments of patients with allergic asthma. Twenty-four hours later, anandamide concentrations in bronchoalveolar lavage fluids had increased more than fourfold. Anandamide concentrations correlated with severity of airway inflammation. These observations suggest that allergen exposure specifically activates the pulmonary endocannabinoid system (ECS) in patients with allergic asthma. C1 [Zoerner, A. A.; Stichtenoth, D. O.; Engeli, S.; Batkai, S.; Tsikas, D.; Jordan, J.] Hannover Med Sch, Inst Clin Pharmacol, D-3000 Hannover, Germany. [Batkai, S.] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. [Winkler, C.; Schaumann, F.; Holz, O.; Krug, N.; Hohlfeld, J. M.] Fraunhofer Inst Toxicol & Expt Med, Dept Clin Airway Res, Hannover, Germany. [Janke, J.] Charite, Expt & Clin Res Ctr, Berlin, Germany. RP Jordan, J (reprint author), Hannover Med Sch, Inst Clin Pharmacol, D-3000 Hannover, Germany. EM jordan.jens@mh-hannover.de RI Batkai, Sandor/H-7983-2014; OI Hohlfeld, Jens/0000-0003-2646-6186 FU Deutsche Forschungsgemeinschaft [SFB 587/B8, B9] FX We thank Maria-Theresia Suchy and Frank-Mathias Gutzki for their skillful technical assistance and the team members of the Department of Clinical Airway Research for the excellent manner in which they conducted the clinical study. This work was funded by Deutsche Forschungsgemeinschaft SFB 587/B8, B9. NR 31 TC 10 Z9 10 U1 0 U2 6 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 SEP PY 2011 VL 90 IS 3 BP 388 EP 391 DI 10.1038/clpt.2011.94 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 811WM UT WOS:000294247900012 PM 21716266 ER PT J AU Yoon, YH Chen, CM Yi, HY Moss, HB AF Yoon, Young-Hee Chen, Chiung M. Yi, Hsiao-ye Moss, Howard B. TI Effect of comorbid alcohol and drug use disorders on premature death among unipolar and bipolar disorder decedents in the United States, 1999 to 2006 SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID SUBSTANCE USE DISORDERS; NATIONAL EPIDEMIOLOGIC SURVEY; CAUSE-SPECIFIC MORTALITY; EXCESS MORTALITY; MENTAL-DISORDERS; PSYCHIATRIC-DISORDERS; SURVEY REPLICATION; MAJOR DEPRESSION; ILLNESS; PREVALENCE AB Objective: The aim of this study was to quantify the effect of comorbid alcohol and drug use disorders on premature death, as reflected by the manner of death (suicide and other unnatural death versus natural death) and the age at death, among decedents with unipolar and bipolar disorders. Methods: This study is based on the US Multiple Cause of Death public-use data files for 1999 to 2006. Secondary data analysis was conducted comparing decedents with unipolar/bipolar disorders and decedents with all other causes of death, based on the death records of 19 052 468 decedents in the Multiple Cause of Death data files who died at 15 years and older. Poisson regression models were used to derive prevalence ratios to assess the effect of comorbid substance use disorders (SUD) on the risks for being an unnatural death among mood disorder deaths. Multiple-cause life table analysis and mean age at death were used to quantify the effect of comorbid SUDs on premature mortality among mood disorder deaths. Results: Prevalence of comorbid SUDs was higher among unipolar and bipolar disorder deaths than that among all other deaths. Among unipolar and bipolar disorder deaths, comorbid SUDs were associated with elevated risks for suicide and other unnatural death in both men and women (prevalence ratios ranging 1.49-9.46, P < .05). They also were associated with reductions in mean ages at death (ranging 11.7-33.8 years, P < .05). In general, these effects were much stronger for drug use disorders than for alcohol use disorders. Both SUDs had stronger effects on suicide among women, whereas their effects on other unnatural deaths were stronger among men. Conclusions: This study is among the first to provide population mortality-based evidence to further establish comorbid SUD as one of the key risk factors for premature death among individuals with unipolar or bipolar disorders in the United States. Clinicians need to be aware of the potentially lethal risk associated with these comorbid conditions. (C) 2011 Elsevier Inc. All rights reserved. C1 [Yoon, Young-Hee; Chen, Chiung M.; Yi, Hsiao-ye] CSR Inc, Alcohol Epidemiol Data Syst, Arlington, VA 22201 USA. [Moss, Howard B.] NIAAA, NIH, Bethesda, MD USA. RP Yoon, YH (reprint author), CSR Inc, Alcohol Epidemiol Data Syst, Arlington, VA 22201 USA. EM yhyoon@csrincorporated.com FU National Institute on Alcohol Abuse and Alcoholism [HHSN267200800023C] FX This study was conducted for the Alcohol Epidemiologic Data System project funded by the National Institute on Alcohol Abuse and Alcoholism through Contract (Contract No. HHSN267200800023C) to CSR, Inc. NR 52 TC 22 Z9 22 U1 3 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X J9 COMPR PSYCHIAT JI Compr. Psychiat. PD SEP-OCT PY 2011 VL 52 IS 5 BP 453 EP 464 DI 10.1016/j.comppsych.2010.10.005 PG 12 WC Psychiatry SC Psychiatry GA 812GB UT WOS:000294278000001 PM 21146814 ER PT J AU Katragkou, A Simitsopoulou, M Chatzimoschou, A Georgiadou, E Walsh, TJ Roilides, E AF Katragkou, Aspasia Simitsopoulou, Maria Chatzimoschou, Athanasios Georgiadou, Elpiniki Walsh, Thomas J. Roilides, Emmanuel TI Effects of interferon-gamma and granulocyte colony-stimulating factor on antifungal activity of human polymorphonuclear neutrophils against Candida albicans grown as biofilms or planktonic cells SO CYTOKINE LA English DT Article DE Biofilm; Candida albicans; IFN-gamma; G-CSF; Neutrophils ID IFN-GAMMA; INFECTIONS; ACTIVATION; EXPRESSION; CYTOKINES; THERAPY AB Candida albicans is a leading cause of biofilm-related infections. As Candida biofilms are recalcitrant to host defenses, we sought to determine the effects of interferon-gamma and granulocyte colony-stimulating factor, two pro-inflammatory cytokines, on the antifungal activities of human polymorphonuclear neutrophils (PMNs) against C albicans biofilms, using an in vitro biofilm model. Priming of PMNs by these cytokines augmented fungal damage of planktonic cells; however, priming of PMNs did not have the same effect against Candida biofilms. Biofilm phenotype appears to play an important role in protecting C. albicans from the innate immune system. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Katragkou, Aspasia; Simitsopoulou, Maria; Chatzimoschou, Athanasios; Georgiadou, Elpiniki; Roilides, Emmanuel] Aristotle Univ Thessaloniki, Hippokrat Hosp, Dept Pediat 3, Infect Dis Lab,Sch Med, GR-54642 Thessaloniki, Greece. [Walsh, Thomas J.; Roilides, Emmanuel] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Walsh, Thomas J.] Cornell Univ, Weill Cornell Med Coll, Transplantat Oncol Infect Dis Program, New York, NY 10065 USA. [Walsh, Thomas J.] New York Presbyterian Hosp, New York, NY 10065 USA. RP Roilides, E (reprint author), Aristotle Univ Thessaloniki, Hippokrat Hosp, Dept Pediat 3, Infect Dis Lab,Sch Med, Konstantinoupoleos 49, GR-54642 Thessaloniki, Greece. EM roilides@med.auth.gr FU Aristotle University, Thessaloniki, Greece; European Society of Pediatric Infectious Diseases; Pfizer [GA900095] FX This study was partially supported by the Aristotle University, Thessaloniki, Greece, by a grant from the European Society of Pediatric Infectious Diseases (2006-2007 Small Grant Awards) and by a grant from Pfizer (GA900095). NR 22 TC 10 Z9 10 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2011 VL 55 IS 3 BP 330 EP 334 DI 10.1016/j.cyto.2011.05.007 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 809EH UT WOS:000294034100002 PM 21641233 ER PT J AU Buzas, K Oppenheim, JJ Howard, OMZ AF Buzas, Krisztina Oppenheim, Joost J. Howard, O. M. Zack TI Myeloid cells migrate in response to IL-24 SO CYTOKINE LA English DT Article DE IL-24; Mda-7; Monocyte; Neutrophil; Migration ID DIFFERENTIATION-ASSOCIATED GENE-7; GROWTH-FACTOR; IN-VIVO; MELANOMA; IL-10; MDA-7/IL-24; RECEPTORS; APOPTOSIS; EXPRESSION; CYTOKINE AB IL-24 (melanoma differentiation associated gene 7 product) is a member of the IL-10 cytokine family that has been reported to possess anti-tumor activity. IL-24 is produced by immune tissues and its expression can be induced in human peripheral blood mononuclear cells by pathogen-associated molecules. While immune cells are known to produce IL-24, the response of immune cells to IL-24 is unclear. Using recombinant human IL-24, we demonstrated that IL-24 induces human monocyte and neutrophil migration, in vitro. An in vivo chemotaxis model showed that IL-24 attracted CD11b positive myeloid cells. To further characterize the chemotactic IL-24 response and type(s) of receptor(s) utilized by IL-24, we treated monocytes with signaling pathway inhibitors. IL-24-induced migration was reduced by pertussis toxin treatment, thus implicating G-protein coupled receptors in this process. Additionally, MEK and JAK inhibitors markedly decreased monocyte migration toward IL-24. These results suggest that IL-24 activates several signaling cascades in immune cells eliciting migration of myeloid cells, which may contribute to the known anti-cancer effects of IL-24. Published by Elsevier Ltd. C1 [Buzas, Krisztina; Oppenheim, Joost J.; Howard, O. M. Zack] Natl Canc Inst Frederick, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Howard, OMZ (reprint author), 1050 Boyles St,POB B,Bld 560 Rm 31-19, Frederick, MD 21702 USA. EM howardz@mail.nih.gov RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 FU NIH, National Cancer Institute, Center for Cancer Research; UICC FX This Research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.; In vivo chemotaxis assays has been supported by a UICC International Cancer Technology Transfer Fellowship. NR 38 TC 6 Z9 7 U1 1 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2011 VL 55 IS 3 BP 429 EP 434 DI 10.1016/j.cyto.2011.05.018 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 809EH UT WOS:000294034100016 PM 21703864 ER PT J AU Ocak, I Lacomis, JM Deible, CR Turkbey, B Knollmann, F AF Ocak, Iclal Lacomis, Joan M. Deible, Christopher R. Turkbey, Baris Knollmann, Friedrich TI Prevalence of aortic root dilation in patients with CT angiography of the aorta SO DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY LA English DT Article DE aortic root dilation; CT angiography; thoracic aorta ID MULTIDETECTOR-ROW CT; ASCENDING AORTA; REGURGITATION; DILATATION; RECONSTRUCTION; HYPERTENSION; ANEURYSM AB PURPOSE To investigate the prevalence of aortic root dilation in patients who underwent CT angiography of the thoracic aorta. MATERIALS AND METHODS In 95 patients, 64-slice multislice computed tomography was performed for evaluation of the thoracic aorta. Measurements of the annulus, sinuses of valsalva (SOV), sinotubular junction (STD, and maximum ascending aorta (AAo) were made by double oblique multiplanar reformation (MPR). For the AAo, STJ, and SOV, dilation was defined as greater than 40 mm; for annulus, the dilation criterion was greater than 27 mm. RESULTS Overall, 52 patients were diagnosed with a dilated AAo. Of those patients with dilated AAo, 28 patients had a dilated annulus, 27 patients had dilated SOV, and 11 patients had STJ dilation. Forty-three patients presented with normal AAo; 12 patients had annulus dilation; 12 patients had SOV dilation; and 4 patients had STJ dilation. In patients with dilated AAo, 38% also had a dilated annulus, 52% showed SOV dilation, and 21% presented with STJ dilation, compared to 28% annulus dilation, 28% SOV dilation, and 9% STJ dilation in patients with an AAo of normal caliber. CONCLUSION Our data indicate a higher prevalence of aortic root dilation among patients with dilated AAo. C1 [Ocak, Iclal; Lacomis, Joan M.; Deible, Christopher R.; Knollmann, Friedrich] Univ Pittsburgh, Dept Radiol, Med Ctr, Thorac Imaging Div, Pittsburgh, PA 15260 USA. [Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Ocak, I (reprint author), Univ Pittsburgh, Dept Radiol, Med Ctr, Thorac Imaging Div, Pittsburgh, PA 15260 USA. EM ocaki@upmc.edu RI Knollmann, Friedrich/H-1404-2011 OI Knollmann, Friedrich/0000-0001-6730-4090 NR 19 TC 2 Z9 2 U1 0 U2 0 PU TURKISH SOC RADIOLOGY PI ANKARA PA HOSDERE CAD, GUZELKENT SOK, CANKAYA EVLERI, F-2, ANKARA, 06540, TURKEY SN 1305-3825 J9 DIAGN INTERV RADIOL JI Diagn. Interv. Radiol. PD SEP PY 2011 VL 17 IS 3 BP 272 EP 276 DI 10.4261/1305-3825.DIR.3437-10.1 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 811HL UT WOS:000294197400015 PM 20725902 ER PT J AU Chen, M Mema, E Kelleher, J Nemechek, N Berger, A Wang, J Xie, T Gavrilova, O Drucker, DJ Weinstein, LS AF Chen, Min Mema, Eralda Kelleher, James Nemechek, Nicholas Berger, Alta Wang, Jie Xie, Tao Gavrilova, Oksana Drucker, Daniel J. Weinstein, Lee S. TI Absence of the Glucagon-Like Peptide-1 Receptor Does Not Affect the Metabolic Phenotype of Mice with Liver-Specific G(s)alpha Deficiency SO ENDOCRINOLOGY LA English DT Article ID ALPHA-CELL HYPERPLASIA; HEPATIC GLUCONEOGENESIS; MODULATES GLUCONEOGENESIS; GLUCOSE-TOLERANCE; COACTIVATOR PGC-1; GENE-EXPRESSION; KNOCKOUT MICE; MASS; HYPERGLUCAGONEMIA; HYPOGLYCEMIA AB The stimulatory G protein alpha-subunit (G(s)alpha) couples hormone and other receptors to the generation of intracellular cAMP. We previously showed that mice with liver-specific G(s)alpha deficiency [liver-specific G(s)alpha knockout (LGsKO) mice] had reduced adiposity and improved glucose tolerance associated with increased glucose-stimulated insulin secretion, pancreatic islet hyperplasia, and very high serum glucagon and glucagon-like peptide 1 (GLP-1) levels. Because GLP-1 is known to stimulate insulin secretion and to have effects on energy balance, we mated LGsKO mice with germline GLP-1 receptor (GLP-1R) knockout mice (Glp1r(-/-)) and compared LGsKO to double-knockout (LGs/Glp1r(-/-)) mice to determine the contribution of excess GLP-1R signaling to the LGsKO phenotype. Loss of the GLP-1R failed to reverse most of the metabolic features of LGsKO mice, including reduced fat mass, increased glucose tolerance, and second-phase glucose-stimulated insulin secretion, islet cell hyperplasia, and very high glucagon and GLP-1 levels. However, loss of GLP-1R impaired first-phase insulin secretion in mice with or without liver-specific G(s)alpha deficiency. Thus, excess GLP-1 action (or at least through GLP-1R) does not contribute to the LGsKO metabolic phenotype, and other unknown factors involved in the cross talk between the liver G(s)alpha/cAMP pathway and pancreatic islet function need to be further elucidated. (Endocrinology 152: 3343-3350, 2011) C1 [Chen, Min; Mema, Eralda; Kelleher, James; Nemechek, Nicholas; Berger, Alta; Wang, Jie; Xie, Tao; Weinstein, Lee S.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD 20892 USA. [Drucker, Daniel J.] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Med, Toronto, ON M5G 1X5, Canada. RP Chen, M (reprint author), NIDDKD, Metab Dis Branch, NIH, Bldg 10,Room 8C101, Bethesda, MD 20892 USA. EM minc@intra.niddk.nih.gov RI Drucker, Daniel/A-4092-2010 FU National Institute for Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services; Canadian Institutes of Health Research [93749, 82700] FX This work was supported by the Intramural Research Program of the National Institute for Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services and by Canadian Institutes of Health Research Grants 93749 and 82700 (to D.J.D.). NR 32 TC 10 Z9 10 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD SEP PY 2011 VL 152 IS 9 BP 3343 EP 3350 DI 10.1210/en.2011-0012 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 810WX UT WOS:000294161000007 PM 21771891 ER PT J AU Beaty, TH Ruczinski, I Murray, JC Marazita, ML Munger, RG Hetmanski, JB Murray, T Redett, RJ Fallin, MD Liang, KY Wu, T Patel, PJ Jin, SC Zhang, TX Schwender, H Wu-Chou, YH Chen, PK Chong, SS Cheah, F Yeow, V Ye, XQ Wang, H Huang, SZ Jabs, EW Shi, B Wilcox, AJ Lie, RT Jee, SH Christensen, K Doheny, KF Pugh, EW Ling, H Scott, AF AF Beaty, Terri H. Ruczinski, Ingo Murray, Jeffrey C. Marazita, Mary L. Munger, Ronald G. Hetmanski, Jacqueline B. Murray, Tanda Redett, Richard J. Fallin, M. Daniele Liang, Kung Yee Wu, Tao Patel, Poorav J. Jin, Sheng-Chih Zhang, Tian Xiao Schwender, Holger Wu-Chou, Yah Huei Chen, Philip K. Chong, Samuel S. Cheah, Felicia Yeow, Vincent Ye, Xiaoqian Wang, Hong Huang, Shangzhi Jabs, Ethylin W. Shi, Bing Wilcox, Allen J. Lie, Rolv T. Jee, Sun Ha Christensen, Kaare Doheny, Kimberley F. Pugh, Elizabeth W. Ling, Hua Scott, Alan F. TI Evidence for Gene-Environment Interaction in a Genome Wide Study of Nonsyndromic Cleft Palate SO GENETIC EPIDEMIOLOGY LA English DT Article DE gene-environment interaction; cleft palate; genome wide association studies ID ORAL CLEFTS; MATERNAL SMOKING; BIRTH-DEFECTS; ASSOCIATION; POPULATION; RISK; METAANALYSIS; VARIANTS; POLYMORPHISM; TESTS AB Nonsyndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome-wide association study (GWAS) using 550 case-parent trios, ascertained through a CP case collected in an international consortium. Family-based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption, and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene-environment (G x E) interaction simultaneously, plus a separate 1 df test for G x E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome-wide significance when considered alone, markers in several genes attained or approached genome-wide significance when G x E interaction was included. Among these, MLLT3 and SMC2 on chromosome 9 showed multiple SNPs resulting in an increased risk if the mother consumed alcohol during the peri-conceptual period (3 months prior to conception through the first trimester). TBK1 on chr. 12 and ZNF236 on chr. 18 showed multiple SNPs associated with higher risk of CP in the presence of maternal smoking. Additional evidence of reduced risk due to G x E interaction in the presence of multivitamin supplementation was observed for SNPs in BAALC on chr. 8. These results emphasize the need to consider G x E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as nonsyndromic CP. Genet. Epidemiol. 35: 469-478, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Beaty, Terri H.] Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Murray, Jeffrey C.] Univ Iowa, Childrens Hosp, Iowa City, IA USA. [Marazita, Mary L.] Univ Pittsburgh, Sch Dent Med, Ctr Craniofacial & Dent Genet, Pittsburgh, PA USA. [Munger, Ronald G.] Utah State Univ, Logan, UT 84322 USA. [Liang, Kung Yee] Natl Yang Ming Univ, Taipei 112, Taiwan. [Wu-Chou, Yah Huei; Chen, Philip K.] Chang Gung Mem Hosp, Tao Yuan, Taiwan. [Chong, Samuel S.; Cheah, Felicia] Natl Univ Singapore, Singapore 117548, Singapore. [Yeow, Vincent] KK Womens & Childrens Hosp, Singapore, Singapore. [Wang, Hong] Peking Univ, Hlth Sci Ctr, Beijing 100871, Peoples R China. [Ye, Xiaoqian] Wuhan Univ, Sch Stomatol, Wuhan 430072, Peoples R China. [Huang, Shangzhi] Peking Union Med Coll, Beijing 100021, Peoples R China. [Ye, Xiaoqian; Jabs, Ethylin W.] Mt Sinai Sch Med, New York, NY USA. [Shi, Bing] Sichuan Univ, W China Coll Stomatol, State Key Lab Oral Dis, Chengdu 610064, Peoples R China. [Wilcox, Allen J.] NIEHS NIH, Epidemiol Branch, Durham, NC USA. [Lie, Rolv T.] Univ Bergen, Bergen, Norway. [Jee, Sun Ha] Yonsei Univ, Seoul 120749, South Korea. [Christensen, Kaare] Univ So Denmark, Odense, Denmark. [Doheny, Kimberley F.; Pugh, Elizabeth W.; Ling, Hua] Johns Hopkins Univ, Sch Med, Ctr Inherited Dis Res, Baltimore, MD 21205 USA. RP Beaty, TH (reprint author), Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM tbeaty@jhsph.edu RI Liang, Kung-Yee/F-8299-2011; Chong, Samuel/D-8098-2015; Christensen, Kaare/C-2360-2009; OI Christensen, Kaare/0000-0002-5429-5292; Wilcox, Allen/0000-0002-3376-1311; Jabs, Ethylin/0000-0001-8983-5466 FU NIH, National Institute of Environmental Health Sciences; National Human Genome Research Institute [R01-DE-014581, R01-DE-016148, P50-DE-016215, R21-DE-016930, R01-DE-09886, R37-DE-08559, R37-DE-0-8559, U01-DE-020057, R01-DE-012472, R01-DE-0106877, U01-DE-018993] FX Contract grant sponsors: Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; National Human Genome Research Institute; Contract grant numbers: R01-DE-014581; R01-DE-016148; P50-DE-016215; R21-DE-016930; R01-DE-09886; R37-DE-08559; U01-DE-020057; R37-DE-0-8559; U01-DE-020057; R01-DE-012472; R01-DE-0106877; U01-DE-018993.; We sincerely thank all of the families at each recruitment site for participating in this international study, and we gratefully acknowledge the invaluable assistance of clinical, field, and laboratory staff who contributed to making this work possible. We are particularly grateful to K. Durda and J. L'Heureux of the University of Iowa for assistance with samples and phenotype data: L. Henkle for technical assistance; J. Resick, C. Brandon, and K. Bardi of the University of Pittsburgh for assistance with recruitment; W. Carricato, K. Deeley, and J. Ruff of the University of Pittsburgh for sample handling. We also thank Dr. Christoph Lange for providing guidance in using the PBAT software. Funding to support data collection, genotyping and analysis came from several sources, some to individual investigators (R01-DE-014581, R01-DE016148, P50-DE-016215, R21-DE-016930, R01-DE-09886, R37-DE-08559, U01-DE-020057, R37-DE-0-8559, U01-DE020057, R01-DE-012472, R01-DE-0106877) and some to the cleft consortium itself (U01-DE-018993); part of this research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. This project was part of the Gene, Environment Association Studies (GENEVA) Consortium funded by the National Human Genome Research Institute (NHGRI) to enhance communication and collaboration among researchers conducting genome-wide studies of complex diseases. Our group benefited greatly from the work and efforts of the entire consortium, especially the Coordinating Center (directed by B. Weir and C. Laurie of the University of Washington; U01HG004446) in data cleaning and preparation for submission to the Database for Genotypes and Phenotypes (dbGaP). We also acknowledge the leadership of T. Manolio of NHGRI and E. Harris of National Institute of Dental and Craniofacial Research (NIDCR). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). NR 23 TC 56 Z9 59 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD SEP PY 2011 VL 35 IS 6 BP 469 EP 478 DI 10.1002/gepi.20595 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 811BW UT WOS:000294177900005 PM 21618603 ER PT J AU Zhang, H Wacholder, S Qin, J Hildesheim, A Yu, K AF Zhang, Hong Wacholder, Sholom Qin, Jing Hildesheim, Allan Yu, Kai TI Improved Genetic Association Tests for an Ordinal Outcome Representing the Disease Progression Process SO GENETIC EPIDEMIOLOGY LA English DT Article DE cervical cancer; maximal score test; ordinal response; proportional odds model; P-value combination test ID HUMAN-PAPILLOMAVIRUS; CERVICAL-CANCER; PERSISTENCE; VARIANTS; RISK AB We are interested in detecting genetic variants that influence transition between discrete stages of a disease progression process, such as the natural history of progression to cervical cancer with the following four stages: (1) normal-human papillomavirus (HPV) exposed, (2) persistent infection with oncogenic HPV, (3) cervical intraepithelial neoplasia grades 2 or 3 (CIN2/3), and (4) cervical cancer. Standard statistical tests derived from the proportional odds model or polytomous regression model can be used to study this type of ordinal outcome. But these methods are either too sensitive to the proportion odds assumption or fail to take advantage of the restriction on the parameter space for the genetic variants. Two alternative tests, the maximum score test (MAX) and the adaptive P-value combination test (Adapt-P), are proposed with the aim of striking a balance between efficiency and robustness. A simulation study demonstrates that MAX and Adapt-P have the most robust performance among all considered tests under various realistic scenarios. As a demonstration, we applied the considered tests to a genetic association study of cervical cancer. Genet. Epidemiol. 35: 499-505, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Yu, Kai] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Zhang, Hong] Fudan Univ, Inst Biostat, Shanghai 200433, Peoples R China. [Qin, Jing] NIAID, Div Clin Res, Bethesda, MD 20892 USA. RP Yu, K (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S,Room 5064, Bethesda, MD 20892 USA. EM yuka@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NIH, National Cancer Institute; NIH; National Cancer Institute FX Contract grant sponsor: NIH, National Cancer Institute.; This research utilized the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, Maryland (http://biowulf.nih.gov). The work of H. Zhang, S. Wacholder, A. Hildesheim, and K. Yu was supported in part by the Intramural Program of the NIH and the National Cancer Institute. NR 13 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD SEP PY 2011 VL 35 IS 6 BP 499 EP 505 DI 10.1002/gepi.20599 PG 7 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 811BW UT WOS:000294177900008 PM 21618605 ER PT J AU Machiela, MJ Chen, CY Chen, C Chanock, SJ Hunter, DJ Kraft, P AF Machiela, Mitchell J. Chen, Chia-Yen Chen, Constance Chanock, Stephen J. Hunter, David J. Kraft, Peter TI Evaluation of Polygenic Risk Scores for Predicting Breast and Prostate Cancer Risk SO GENETIC EPIDEMIOLOGY LA English DT Article DE single nucleotide polymorphisms; genome-wide association study; human genetics ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CONFER SUSCEPTIBILITY; COMMON VARIANTS; IDENTIFICATION; ALLELES; GENE; 8Q24 AB Recently, polygenic risk scores (PRS) have been shown to be associated with certain complex diseases. The approach has been based on the contribution of counting multiple alleles associated with disease across independent loci, without requiring compelling evidence that every locus had already achieved definitive genome-wide statistical significance. Whether PRS assist in the prediction of risk of common cancers is unknown. We built PRS from lists of genetic markers prioritized by their association with breast cancer (BCa) or prostate cancer (PCa) in a training data set and evaluated whether these scores could improve current genetic prediction of these specific cancers in independent test samples. We used genome-wide association data on 1,145 BCa cases and 1,142 controls from the Nurses' Health Study and 1,164 PCa cases and 1,113 controls from the Prostate Lung Colorectal and Ovarian Cancer Screening Trial. Ten-fold cross validation was used to build and evaluate PRS with 10 to 60,000 independent single nucleotide polymorphisms (SNPs). For both BCa and PCa, the models that included only published risk alleles maximized the cross-validation estimate of the area under the ROC curve (0.53 for breast and 0.57 for prostate). We found no significant evidence that PRS using common variants improved risk prediction for BCa and PCa over replicated SNP scores. Genet. Epidemiol. 35: 506-514, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Machiela, Mitchell J.; Chen, Chia-Yen; Chen, Constance; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kraft, P (reprint author), 655 Huntington Ave,Bldg 2,Room 207, Boston, MA 02115 USA. EM pkraft@hsph.harvard.edu RI Machiela, Mitchell/F-9781-2013 OI Machiela, Mitchell/0000-0001-6538-9705 FU [CA09001-34]; [T32GM074897] FX Contract grant sponsor: Meir Stampfer; Contract grant number: CA09001-34; Contract grant sponsor: Xihong Lin; Contract grant number: T32GM074897. NR 34 TC 26 Z9 26 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD SEP PY 2011 VL 35 IS 6 BP 506 EP 514 DI 10.1002/gepi.20600 PG 9 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 811BW UT WOS:000294177900009 PM 21618606 ER PT J AU Hoskins, E Rodriguez-Canales, J Hewitt, SM Elmasri, W Han, J Han, S Davidson, B Kohn, EC AF Hoskins, Ebony Rodriguez-Canales, Jaime Hewitt, Stephen M. Elmasri, Wafic Han, Jasmine Han, Shing Davidson, Ben Kohn, Elise C. TI Paracrine SLPI secretion upregulates MMP-9 transcription and secretion in ovarian cancer cells SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; SLPI; MMP-9; Metalloproteinase ID LEUKOCYTE PROTEASE INHIBITOR; MATRIX-DEGRADING PROTEINASES; LEUCOPROTEASE INHIBITOR; GELATINASE-A; IN-VITRO; METALLOPROTEINASES; EXPRESSION; ACTIVATION; PACLITAXEL; PROTEOMICS AB Objectives. Secretory leukocyte protease inhibitor (SLPI) is amplified in serous ovarian cancer. We have dissected its function, showing it is a survival factor for ovarian cancer and promotes tumorigenesis and paclitaxel-resistance. We hypothesized that the protease inhibitory function was responsible for modulating SIPI's invasive capacity. Methods. Stable HEYA8 ovarian cancer transfectants expressing vector, wild type SIP!, and protease inhibitor null (F-)SLPI were examined in vitro and in xenografts. Invasion, enzyme activity, and MMP production and function assays were applied. SLPI and MMP immunoexpression was graded on tissue microarray and clinical samples. Statistical comparisons used unpaired t test and ANOVA, where appropriate. Results. SLPI and F-SLPI cells caused greater parenchymal and peritoneal dissemination over control cells in xenografts and invasion assays (p < 0.001). MMP-9 protease activity was increased in SLPI and F-SLPI cells over control. SLPI, but not F-SLPI, inhibited plasmin activity, necessary for MMP-9 activation and release, and inhibited activation of MMP-9. However, paradoxically, both induced quantitative MMP-9 transcription ( p <0.05) and protein (p < 0.008), yielding an increased net MMP-9 activity in the face of plasmin inhibition. SLPI and MMP-9 expression were strongly correlated in serous ovarian cancers (r(2) = 0.986) and a set of ovarian cancers (p < 0.02). SLPI expression was greater in serous than endometrioid ovarian cancers (p = 0.04). Conclusions. SLPI stimulates ovarian cancer invasion, modulated in part by its serine protease inhibitory activity attenuating MMP-9 release. However, SIPI induction of MMP-9, independent of protease inhibition activity, is greater yielding a net pro-invasive behavior. These findings further support SLPI as a molecular target for ovarian cancer. Published by Elsevier Inc. C1 [Hoskins, Ebony; Elmasri, Wafic; Han, Jasmine; Kohn, Elise C.] NCI, Mol Signaling Sect, Med Oncol Branch, Bethesda, MD 20892 USA. [Rodriguez-Canales, Jaime; Hewitt, Stephen M.; Han, Shing] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Davidson, Ben] Univ Oslo, Fac Med, N-0316 Oslo, Norway. [Davidson, Ben] Oslo Univ Hosp, Norwegian Radium Hosp, Div Pathol, Oslo, Norway. RP Kohn, EC (reprint author), 10 Ctr Dr,MSC1906, Bethesda, MD 20892 USA. EM kohne@mail.nih.gov OI Rodriguez-Canales, Jaime/0000-0002-0885-2377; Hewitt, Stephen/0000-0001-8283-1788 FU NIH, National Cancer Institute, Center for Cancer Research; Norwegian Cancer Society; Health Region of South-Eastern Norway FX The authors thank Mr. Tim Clair for his guidance and collaboration. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by grants from the Norwegian Cancer Society and the Health Region of South-Eastern Norway (BD). NR 39 TC 7 Z9 9 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD SEP PY 2011 VL 122 IS 3 BP 656 EP 662 DI 10.1016/j.ygyno.2011.04.052 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 810TY UT WOS:000294151200035 PM 21676452 ER PT J AU Wu, T Long, XY Wang, L Hallett, M Zang, YF Li, KC Chan, P AF Wu, Tao Long, Xiangyu Wang, Liang Hallett, Mark Zang, Yufeng Li, Kuncheng Chan, Piu TI Functional Connectivity of Cortical Motor Areas in the Resting State in Parkinson's Disease SO HUMAN BRAIN MAPPING LA English DT Article DE Parkinson's disease; functional connectivity; resting state; rostral supplementary motor area; primary motor cortex ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; TRANSCRANIAL MAGNETIC STIMULATION; EXTERNALLY TRIGGERED MOVEMENTS; BASAL GANGLIA; PREFRONTAL CORTEX; PREMOTOR CORTEX; CINGULATE CORTEX; FRONTAL-CORTEX; BRAIN NETWORKS AB Parkinson's disease (PD) patients have difficulty in initiating movements. Previous studies have suggested that the abnormal brain activity may happen not only during performance of self-initiated movements but also in the before movement (baseline or resting) state. In the current study, we investigated the functional connectivity of brain networks in the resting state in PD. We chose the rostral supplementary motor area (pre-SMA) and bilateral primary motor cortex (M1) as "seed" regions, because the pre-SMA is important in motor preparation, whereas the M1 is critical in motor execution. FMRIs were acquired in 18 patients and 18 matched controls. We found that in the resting state, the pattern of connectivity with both the pre-SMA or the M1 was changed in PD. Connectivity with the pre-SMA in patients with PD compared to normal subjects was increased connectivity to the right M1 and decreased to the left putamen, right insula, right premotor cortex, and left inferior parietal lobule. We only found stronger connectivity in the M1 with its own local region in patients with PD compared to controls. Our findings demonstrate that the interactions of brain networks are abnormal in PD in the resting state. There are more connectivity changes of networks related to motor preparation and initiation than to networks of motor execution in PD. We postulate that these disrupted connections indicate a lack of readiness for movement and may be partly responsible for difficulty in initiating movements in PD. Hum Brain Mapp 32:1443-1457, 2011. (C) 2010Wiley-Liss, Inc. C1 [Wu, Tao; Chan, Piu] Capital Med Univ, Dept Neurobiol, Key Lab Neurodegenerat Disorders, Beijing Inst Geriatr,Minist Educ,Xuanwu Hosp, Beijing 100053, Peoples R China. [Long, Xiangyu; Zang, Yufeng] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. [Wang, Liang; Li, Kuncheng] Capital Med Univ, Xuanwu Hosp, Dept Radiol, Beijing 100053, Peoples R China. [Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Wu, T (reprint author), Capital Med Univ, Dept Neurobiol, Key Lab Neurodegenerat Disorders, Beijing Inst Geriatr,Minist Educ,Xuanwu Hosp, Beijing 100053, Peoples R China. EM wutao69@gmail.com RI ZANG, Yu-Feng/J-1558-2012 OI ZANG, Yu-Feng/0000-0003-1833-8010 FU National Science Foundation of China [30870693]; Ministry of Science and Technology [2006AA02A408] FX Contract grant sponsor: National Science Foundation of China; Contract grant number: 30870693; Contract grant sponsor: Ministry of Science and Technology; Contract grant number: 2006AA02A408. NR 116 TC 66 Z9 69 U1 4 U2 20 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD SEP PY 2011 VL 32 IS 9 BP 1443 EP 1457 DI 10.1002/hbm.21118 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 811DR UT WOS:000294182900008 PM 20740649 ER PT J AU Bolton, ML Siminiceanu, RI Bass, EJ AF Bolton, Matthew L. Siminiceanu, Radu I. Bass, Ellen J. TI A Systematic Approach to Model Checking Human-Automation Interaction Using Task Analytic Models SO IEEE TRANSACTIONS ON SYSTEMS MAN AND CYBERNETICS PART A-SYSTEMS AND HUMANS LA English DT Article DE Formal methods; human-automation interaction; model checking; task analysis ID OPERATOR FUNCTION; FORMAL METHODS; METHODOLOGY; DESIGN AB Formal methods are typically used in the analysis of complex system components that can be described as "automated" (digital circuits, devices, protocols, and software). Humanautomation interaction has been linked to system failure, where problems stem from human operators interacting with an automated system via its controls and information displays. As part of the process of designing and analyzing human-automation interaction, human factors engineers use task analytic models to capture the descriptive and normative human operator behavior. In order to support the integration of task analyses into the formal verification of larger system models, we have developed the enhanced operator function model (EOFM) as an Extensible Markup Language-based, platform-and analysis-independent language for describing task analytic models. We present the formal syntax and semantics of the EOFM and an automated process for translating an instantiated EOFM into the model checking language Symbolic Analysis Laboratory. We present an evaluation of the scalability of the translation algorithm. We then present an automobile cruise control example to illustrate how an instantiated EOFM can be integrated into a larger system model that includes environmental features and the human operator's mission. The system model is verified using model checking in order to analyze a potentially hazardous situation related to the human-automation interaction. C1 [Bolton, Matthew L.] San Jose State Univ, Res Fdn, Natl Aeronaut & Space Adm, Ames Res Ctr, Mountain View, CA 94043 USA. [Siminiceanu, Radu I.] NIA, Hampton, VA 23666 USA. [Bass, Ellen J.] Univ Virginia, Dept Syst & Informat Engn, Charlottesville, VA 22904 USA. RP Bolton, ML (reprint author), San Jose State Univ, Res Fdn, Natl Aeronaut & Space Adm, Ames Res Ctr, Mountain View, CA 94043 USA. EM mlb4b@virginia.edu; radu@nianet.org; ejb4n@virginia.edu RI Bolton, Matthew/G-5199-2012; Bolton, Matthew/A-6390-2016 FU National Library of Medicine [T15LM009462]; National Aeronautics and Space Administration (NASA) Cooperative Agreement [NCC1002043]; NASA [NNA10DE79C] FX Manuscript received January 11, 2010; revised August 17, 2010; accepted November 26, 2010. Date of publication March 22, 2011; date of current version August 23, 2011. This work was supported in part by the National Library of Medicine under Grant T15LM009462, by the National Aeronautics and Space Administration (NASA) Cooperative Agreement NCC1002043, and by the NASA Contract NNA10DE79C. This paper was recommended by Associate Editor M. Dorneich. NR 60 TC 27 Z9 27 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1083-4427 EI 1558-2426 J9 IEEE T SYST MAN CY A JI IEEE Trans. Syst. Man Cybern. Paart A-Syst. Hum. PD SEP PY 2011 VL 41 IS 5 SI SI BP 961 EP 976 DI 10.1109/TSMCA.2011.2109709 PG 16 WC Computer Science, Cybernetics; Computer Science, Theory & Methods SC Computer Science GA 810OJ UT WOS:000294134300013 ER PT J AU Rahman, MM Antani, SK Thoma, GR AF Rahman, M. M. Antani, S. K. Thoma, G. R. TI A query expansion framework in image retrieval domain based on local and global analysis SO INFORMATION PROCESSING & MANAGEMENT LA English DT Article DE Image retrieval; Vector space model; Support vector machine; Relevance feedback; Query expansion ID RELEVANCE FEEDBACK; CLASSIFICATION; SYSTEMS AB We present an image retrieval framework based on automatic query expansion in a concept feature space by generalizing the vector space model of information retrieval. In this framework, images are represented by vectors of weighted concepts similar to the keyword-based representation used in text retrieval. To generate the concept vocabularies, a statistical model is built by utilizing Support Vector Machine (SVM)-based classification techniques. The images are represented as "bag of concepts" that comprise perceptually and/or semantically distinguishable color and texture patches from local image regions in a multi-dimensional feature space. To explore the correlation between the concepts and overcome the assumption of feature independence in this model, we propose query expansion techniques in the image domain from a new perspective based on both local and global analysis. For the local analysis, the correlations between the concepts based on the co-occurrence pattern, and the metrical constraints based on the neighborhood proximity between the concepts in encoded images, are analyzed by considering local feedback information. We also analyze the concept similarities in the collection as a whole in the form of a similarity thesaurus and propose an efficient query expansion based on the global analysis. The experimental results on a photographic collection of natural scenes and a biomedical database of different imaging modalities demonstrate the effectiveness of the proposed framework in terms of precision and recall. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Rahman, M. M.; Antani, S. K.; Thoma, G. R.] NIH, US Natl Lib Med, Bethesda, MD 20892 USA. RP Rahman, MM (reprint author), NIH, US Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM rahmanmm@mail.nih.gov OI Antani, Sameer/0000-0002-0040-1387 FU National Institutes of Health (NIH), National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) FX This research is supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM), and Lister Hill National Center for Biomedical Communications (LHNCBC). The authors would like to thank the CLEF organizers2 for making the databases available for the experiments. NR 40 TC 7 Z9 8 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4573 J9 INFORM PROCESS MANAG JI Inf. Process. Manage. PD SEP PY 2011 VL 47 IS 5 BP 676 EP 691 DI 10.1016/j.ipm.2010.12.001 PG 16 WC Computer Science, Information Systems; Information Science & Library Science SC Computer Science; Information Science & Library Science GA 809WM UT WOS:000294087400006 PM 21822350 ER PT J AU Ellis, RJ Kaminsky, DA Zhou, EH Fu, PF Chen, WD Brelin, A Faulhaber, PF Bodner, D AF Ellis, Rodney J. Kaminsky, Deborah A. Zhou, Esther H. Fu, Pingfu Chen, Wei-Dong Brelin, Alaina Faulhaber, Peter F. Bodner, Donald TI TEN-YEAR OUTCOMES: THE CLINICAL UTILITY OF SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY/COMPUTED TOMOGRAPHY CAPROMAB PENDETIDE (PROSTASCINT) IN A COHORT DIAGNOSED WITH LOCALIZED PROSTATE CANCER SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Capromab pendetide; Prostascint; Prostate-specific membrane antigen; Staging; Image-guided radiotherapy ID BIOCHEMICAL FAILURE; BRACHYTHERAPY; RADIOTHERAPY; PREDICTS; THERAPY; DISEASE; ANTIGEN; FUSION; SCAN; MEN AB Purpose: To evaluate the clinical utility of capromab pendetide imaging with single photon emission computed tomography coregistration with computed tomography (SPECT/CT) in primary prostate cancer (CaP) for pretreatment prognostic staging and localization of biologic target volumes (WIN) for individualized image-guided radiotherapy close escalation (IGRT-DE). Methods and Materials: Patients consecutively presenting for primary radiotherapy (February 1997 to December 2002), having a clinical diagnosis of localized CaP, were evaluated for tumor stage using conventional staging and SPECT/CT (N = 239). Distant metastatic uptake (mets) were identified by SPECT/CT in 22 (9.2%). None of the suspected mets could be clinically confirmed. Thus, all subjects were followed without alteration in disease management. The SPECT/CT pelvic images defined WIN for IGRT-DE (+150% brachytherapy dose) without (n = 150) or with (n = 89) external radiation of 45 Gy. The National Comprehensive Cancer Network criteria defined risk groups (RC). The median survivor follow-up was 7 years. Biochemical disease-free survival (bDFS) was reported by clinical nadir +2 ng/mL (CN+2) criteria. Statistical analyses included Kaplan-Meier, multivariate analysis, and Concordance-index models. Results: At 10-year analyses, overall survival was 84.8% and bDFS was 84.6%. With stratification by RC, CN+2 bDFS was 93.5% for the low-RG (n = 116), 78.7% for the intermediate-RC (n = 94), and 68.8% for the high-RG (n = 29), p = 0.0002. With stratification by pretreatment SPECT/CT findings, WE'S was 65.5% in patients with suspected mets (n = 22) vs. 86.6% in patients with only localized uptake (n = 217), p = 0.0014. Call disease-specific survival (DSS) was 97.7% for the cohort. With stratification by SPECT/CT findings, DSS was 86.4% (with suspected mets) vs. 99.0% (localized only), p = 0.0001. Using multivariate analysis, the DSS hazard ratio for SPECT/CT findings (mets vs. localized) was 3.58 (p = 0.0026). Concordance-index tests, based on all data, by CN+2 bDFS criteria were 0.710 for RG alone and 0.773 for SPECT/CT + RG. Conclusions: Through long-term outcomes we demonstrate statistically significant bDFS and DSS predictive value for pretreatment capromab pendetide SPECT/CT imaging in primary CaP. Dual clinical utility is demonstrated, using SPECT/CT to define BTV for individualized IGRT-DE. (C) 2011 Elsevier Inc. C1 [Ellis, Rodney J.] Univ Hosp Cleveland, Dept Radiat Oncol, Case Med Ctr, Cleveland, OH 44106 USA. [Fu, Pingfu] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Ellis, Rodney J.] Northeastern Ohio Univ Coll Med & Pharm, Coll Med, Dept Radiol, Rootstown, OH 44272 USA. [Kaminsky, Deborah A.] Aultman Hosp, Div Radiat Therapy, Canton, OH USA. [Zhou, Esther H.] USA Food & Drug Adm, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Chen, Wei-Dong] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chen, Wei-Dong] Natl Naval Med Ctr, Bethesda, MD USA. [Faulhaber, Peter F.] Univ Hosp Cleveland, Dept Radiol, Case Med Ctr, Cleveland, OH 44106 USA. [Bodner, Donald] Univ Hosp Cleveland, Dept Urol, Case Med Ctr, Cleveland, OH 44106 USA. RP Ellis, RJ (reprint author), Univ Hosp Cleveland, Dept Radiat Oncol, Case Med Ctr, 11000 Euclid Ave, Cleveland, OH 44106 USA. EM rodney.ellis@case.edu RI CHEN, WEI-DONG/F-4521-2014 OI CHEN, WEI-DONG/0000-0003-2264-5515 FU Cytogen Corporation, Princeton, NJ; EUSA Pharma, Longhorne, PA FX Supported by educational grants from the Cytogen Corporation, Princeton, NJ, and EUSA Pharma, Longhorne, PA. NR 29 TC 20 Z9 20 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD SEP 1 PY 2011 VL 81 IS 1 BP 29 EP 34 DI 10.1016/j.ijrobp.2010.05.053 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 809YT UT WOS:000294093300005 PM 20961696 ER PT J AU Scheidweiler, KB Ladenheim, B Barnes, AJ Cadet, JL Huestis, MA AF Scheidweiler, Karl B. Ladenheim, Bruce Barnes, Allan J. Cadet, Jean Lud Huestis, Marilyn A. TI (+/-)-3,4-Methylenedioxymethamphetamine and Metabolite Disposition in Plasma and Striatum of Wild-Type and Multidrug Resistance Protein la Knock-Out Mice SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID METHYLENEDIOXYMETHAMPHETAMINE MDMA; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; NONLINEAR PHARMACOKINETICS; THIOETHER METABOLITES; SQUIRREL-MONKEYS; MAIN METABOLITES; P-GLYCOPROTEIN; DESIGNER DRUGS; RAT-BRAIN; ECSTASY C1 [Scheidweiler, Karl B.; Barnes, Allan J.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. [Ladenheim, Bruce; Cadet, Jean Lud] NIDA, Mol Neuropsychiat Branch, Intramural Res Program, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH,Biomed Res Ctr, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institutes of Health, National Institute on Drug Abuse FX This research was supported by funds from the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse. NR 47 TC 7 Z9 7 U1 0 U2 2 PU PRESTON PUBL INC PI NILES PA 6600 W TOUHY AVE, NILES, IL 60714-4588 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD SEP PY 2011 VL 35 IS 7 SI SI BP 470 EP 480 PG 11 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 811TV UT WOS:000294239900011 PM 21871156 ER PT J AU Chou, WYS Liu, BM Post, S Hesse, B AF Chou, Wen-ying Sylvia Liu, Benmei Post, Samantha Hesse, Bradford TI Health-related Internet use among cancer survivors: data from the Health Information National Trends Survey, 2003-2008 SO JOURNAL OF CANCER SURVIVORSHIP-RESEARCH AND PRACTICE LA English DT Article DE Internet; Web 2.0 technologies; Cancer survivors; Cancer communication; Health behavior ID E-MAIL; PATIENT; NEEDS; COMMUNICATE; SUPPORT; HINTS AB Introduction Increasing prevalence of Internet and new technologies are changing the communication pattern for patients and caregivers across the cancer care continuum. To date, little is known on how cancer survivors in the USA utilize the Internet for health-related purposes. This knowledge is crucial in developing effective communication programs to achieve quality and equitable cancer care. Methods Data from 2003, 2005, and 2008 iterations of the NCI-sponsored Health Information National Trends Survey(HINTS) were analyzed to: (1) compare health-related Internet use (hereafter HRIU) between individuals with and without a cancer diagnosis, (2) report trends, prevalence, and user profiles of HRIU, including support group participation, emailing provider, buying medicine online, and cancer information seeking on the Internet. Descriptive analyses and weighted multivariate logistic regression analyses were performed. Results While Internet penetration is growing over the years across the USA, cancer survivors access the Internet at a lower rate than general population (49.4% to 56.4% vs. 63.1% to 66.3%). Once on the Internet, they are more likely to use it for health-related purposes. Disparities in Internet access persists, as higher likelihood of Internet access is associated with younger age, higher education, non-Hispanic White race/ethnicity, metropolitan residence, and better self-rated health. On the other hand, among Internet-accessing survivors, socio-demographic, and health factors do not play a significant role in determining the pattern of HRIU. Conclusions The study identifies an increasing trend in HRIU among survivors, though the digital divide remains in Internet access. The findings also point to opportunities for narrowing the divide and using Internet to better serve survivors' needs, as individuals from wide-ranging backgrounds and experiences are equally engaging in health-related activities on the Internet. Implications for survivors To increase equity and effectiveness in communication and cancer care, Internet access, functions, and technology literacy are important factors to be considered. C1 [Chou, Wen-ying Sylvia; Hesse, Bradford] NCI, Hlth Commun & Informat Res Branch, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Liu, Benmei] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Post, Samantha] NCI, Basic & Biobehav Res Branch, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Chou, WYS (reprint author), NCI, Hlth Commun & Informat Res Branch, Div Canc Control & Populat Sci, NIH, 6130 Execut Blvd, Bethesda, MD 20892 USA. EM chouws@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 NR 29 TC 56 Z9 57 U1 1 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD SEP PY 2011 VL 5 IS 3 BP 263 EP 270 DI 10.1007/s11764-011-0179-5 PG 8 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA 811AV UT WOS:000294174700006 PM 21505861 ER PT J AU Harlan, LC Lynch, CF Keegan, THM Hamilton, AS Wu, XC Kato, I West, MM Cress, RD Schwartz, SM Smith, AW Deapen, D Stringer, SM Potosky, AL AF Harlan, Linda C. Lynch, Charles F. Keegan, Theresa H. M. Hamilton, Ann S. Wu, Xiao-Cheng Kato, Ikuko West, Michele M. Cress, Rosemary D. Schwartz, Stephen M. Smith, Ashley W. Deapen, Dennis Stringer, Sonja M. Potosky, Arnold L. CA AYA HOPE Study Collaborative Grp TI Recruitment and follow-up of adolescent and young adult cancer survivors: the AYA HOPE Study SO JOURNAL OF CANCER SURVIVORSHIP-RESEARCH AND PRACTICE LA English DT Article DE Adolescent cancer; Young adult cancer; Survey; Response rates; Medical records; Consent forms ID CLINICAL-TRIALS; RESPONSE RATE; QUALITY; OPTION; RATES; MAIL AB Introduction Cancer is rare in adolescents and young adults (AYA), but these patients have seen little improvement in survival in contrast to most other age groups. Furthermore, participation in research by AYAs is typically low. We conducted a study to examine the feasibility of recruiting a population-based sample of AYA survivors to examine issues of treatment and health outcomes. Methods Individuals diagnosed in 2007-08 and age 15-39 at the time of diagnosis with acute lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, germ cell cancer or sarcoma were identified by 7 Surveillance, Epidemiology, and End-Results (SEER) cancer registries, mailed surveys within 14 months after diagnosis and again a year later, and had medical records reviewed. Results 525 (43%) of the eligible patients responded, 39% refused and 17% were lost to follow-up. Extensive efforts were required for most potential respondents (87%). 76% of respondents completed the paper rather than online survey version. In a multivariate model, age, cancer site, education and months from diagnosis to the first mailing of the survey were not associated with participation, although males (p < 0.01), Hispanics and non-Hispanic blacks (p < 0.001) were less likely to participate. 91% of survivors completing the initial survey completed the subsequent survey. Discussion Despite the response rate, those who participated adequately reflected the population of AYA cancer survivors. The study demonstrates that cancer registries are valuable foundations for conducting observational, longitudinal population-based research on AYA cancer survivors. Implications for Cancer Survivors Achieving a reasonable response rate in this population is possible, but requires extensive resources. C1 [Harlan, Linda C.] NCI, Bethesda, MD 20892 USA. [Lynch, Charles F.; West, Michele M.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Keegan, Theresa H. M.] Canc Prevent Inst Calif, Fremont, CA USA. [Keegan, Theresa H. M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Hamilton, Ann S.; Deapen, Dennis] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Wu, Xiao-Cheng] Louisiana State Univ, Hlth Sci Ctr, Program Epidemiol, Louisiana Tumor Registry,Sch Publ Hlth, New Orleans, LA USA. [Kato, Ikuko] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI USA. [Kato, Ikuko] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI USA. [Cress, Rosemary D.] UC Davis Sch Med, Dept Publ Hlth Sci, Davis, CA USA. [Cress, Rosemary D.] Calif Canc Registry, Inst Publ Hlth, Sacramento, CA USA. [Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stringer, Sonja M.] Kelly Serv, Sci Resources, Rockville, MD USA. [Potosky, Arnold L.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Harlan, LC (reprint author), NCI, 6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM lh50w@nih.gov NR 16 TC 51 Z9 52 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD SEP PY 2011 VL 5 IS 3 BP 305 EP 314 DI 10.1007/s11764-011-0173-y PG 10 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA 811AV UT WOS:000294174700010 PM 21274648 ER PT J AU Mongeon, R Walogorsky, M Urban, J Mandel, G Ono, F Brehm, P AF Mongeon, Rebecca Walogorsky, Michael Urban, Jason Mandel, Gail Ono, Fumihito Brehm, Paul TI An acetylcholine receptor lacking both gamma and epsilon subunits mediates transmission in zebrafish slow muscle synapses SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID CHANNEL OPEN TIME; NEUROMUSCULAR-JUNCTION; DELTA-SUBUNIT; SKELETAL-MUSCLE; XENOPUS MUSCLE; SYNAPTIC CURRENTS; ALPHA-SUBUNIT; GARTER SNAKE; FIBERS; FROG AB Fast and slow skeletal muscle types in larval zebrafish can be distinguished by a fivefold difference in the time course of their synaptic decay. Single-channel recordings indicate that this difference is conferred through kinetically distinct nicotinic acetylcholine receptor (AChR) isoforms. The underlying basis for this distinction was explored by cloning zebrafish muscle AChR subunit cDNAs and expressing them in Xenopus laevis oocytes. Measurements of single-channel conductance and mean open burst duration assigned alpha(2)beta delta epsilon to fast muscle synaptic current. Contrary to expectations, receptors composed of only alpha beta delta subunits (presumed to be alpha(2)beta delta(2) receptors) recapitulated the kinetics and conductance of slow muscle single-channel currents. Additional evidence in support of gamma/epsilon-less receptors as mediators of slow muscle synapses was reflected in the inward current rectification of heterologously expressed alpha(2)beta delta(2) receptors, a property normally associated with neuronal-type nicotinic receptors. Similar rectification was reflected in both single-channel and synaptic currents in slow muscle, distinguishing them from fast muscle. The final evidence for alpha(2)beta delta(2) receptors in slow muscle was provided by our ability to convert fast muscle synaptic currents to those of slow muscle by knocking down. subunit expression in vivo. Thus, for the first time, muscle synaptic function can be ascribed to a receptor isoform that is composed of only three different subunits. The unique functional features offered by the alpha(2)beta delta(2) receptor likely play a central role in mediating the persistent contractions characteristic to this muscle type. C1 [Mongeon, Rebecca; Walogorsky, Michael; Mandel, Gail; Brehm, Paul] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. [Mongeon, Rebecca; Mandel, Gail] Oregon Hlth & Sci Univ, Howard Hughes Med Inst, Portland, OR 97239 USA. [Urban, Jason; Ono, Fumihito] NIAAA, NIH, Rockville, MD 20852 USA. RP Brehm, P (reprint author), Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. EM brehmp@ohsu.edu FU National Institutes of Health [NS-18205]; Howard Hughes Medical Institute FX Support was provided by National Institutes of Health (grant NS-18205 to P. Brehm) and Howard Hughes Medical Institute (G. Mandel). NR 52 TC 9 Z9 9 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD SEP PY 2011 VL 138 IS 3 BP 353 EP 366 DI 10.1085/jgp.201110649 PG 14 WC Physiology SC Physiology GA 812YL UT WOS:000294330700008 PM 21844221 ER PT J AU Lakhani, NA Shaw, KM Thompson, T Yaroch, AL Glanz, K Hartman, AM Saraiya, M AF Lakhani, Naheed A. Shaw, Kate M. Thompson, Trevor Yaroch, Amy L. Glanz, Karen Hartman, Anne M. Saraiya, Mona TI Prevalence and predictors of total-body skin examination among US adults: 2005 National Health Interview Survey SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Lakhani, Naheed A.; Shaw, Kate M.; Thompson, Trevor; Saraiya, Mona] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Yaroch, Amy L.] Ctr Human Nutr, Omaha, NE USA. [Glanz, Karen] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Glanz, Karen] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Hartman, Anne M.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. RP Saraiya, M (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Hwy,Mailstop K-55, Atlanta, GA 30341 USA. EM MSaraiya@cdc.gov NR 4 TC 7 Z9 7 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD SEP PY 2011 VL 65 IS 3 BP 645 EP 648 DI 10.1016/j.jaad.2011.02.028 PG 4 WC Dermatology SC Dermatology GA 810QK UT WOS:000294142000023 PM 21839321 ER PT J AU Inzitari, M Arnold, AM Patel, KV Mercer, LD Karlamangla, A Ding, JZ Psaty, BM Williamson, JD Kuller, LH Newman, AB AF Inzitari, Marco Arnold, Alice M. Patel, Kushang V. Mercer, Laina D. Karlamangla, Arun Ding, Jingzhong Psaty, Bruce M. Williamson, Jeff D. Kuller, Lewis H. Newman, Anne B. TI Subclinical Vascular Disease Burden and Risk for Death and Cardiovascular Events in Older Community Dwellers SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Epidemiology; Aging; Atherosclerosis; Cardiovascular disease; Mortality ID CORONARY-ARTERY CALCIFICATION; ANKLE-ARM INDEX; MYOCARDIAL-INFARCTION; MEDIA THICKNESS; ADULTS; HEALTH; MORTALITY; PREVALENCE; PREDICTORS; INTIMA AB Individual measures and previous composite measures of subclinical vascular disease defined high risk for cardiovascular events, but did not detect low and modest risk. A different approach might better describe the spectrum from low to high risk. In the Cardiovascular Health Study, 3,252 participants without history of clinical cardiovascular disease (M +/- SD 74.3 years +/- 5.1, 63% women, 17% African Americans) had noninvasive vascular assessments in 1992-1993. We assigned a score of 0, 1, or 2 (no, mild, or severe abnormalities) to ankle-arm index, electrocardiogram, and common carotid intima-media thickness, based on clinical cutoffs. A summary index (range 0-6, absent to severe disease) summed individual scores. Abdominal aortic ultrasound and brain magnetic resonance imaging were collected in a subsample. Mortality and incident cardiovascular events were identified through June 2008. Event and death rates increased across index grades. Comparing grades 1 to 5+ with absent disease, and adjusting for demographics, hazard ratios for cardiovascular events within 8 years ranged from 1.1 (95% confidence interval 0.8-1.6) to 4.7 (3.4-6.9) and, for mortality, from 1.5 (1.0-2.3) to 5.0 (3.3-7.7) (p for trend across grades <.001 for both outcomes). Adjustment for cardiovascular risk factors did not substantially change the associations. The index improved mortality risk classification over demographics and risk factors in participants who did not die during the follow-up. Including in the index the aortic ultrasound and the brain magnetic resonance imaging further improved risk classification. Older adults with minimal subclinical vascular disease had low cardiovascular events risk and mortality. This approach might more fully account for vascular burden. C1 [Inzitari, Marco] Autonomous Univ Barcelona, Pere Virgili Hosp, Barcelona 08023, Spain. [Inzitari, Marco; Newman, Anne B.] Univ Pittsburgh, Dept Med, Div Geriatr Med, Pittsburgh, PA 15260 USA. [Inzitari, Marco; Kuller, Lewis H.; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Inzitari, Marco; Arnold, Alice M.; Mercer, Laina D.] Autonomous Univ Barcelona, Inst Aging, E-08193 Barcelona, Spain. [Patel, Kushang V.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Karlamangla, Arun] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Ding, Jingzhong; Williamson, Jeff D.] Univ Calif Los Angeles, Div Geriatr, Los Angeles, CA 90024 USA. [Psaty, Bruce M.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Psaty, Bruce M.] Wake Forest Univ, Bowman Gray Sch Med, Oristano Program Cardiovasc Res, Winston Salem, NC USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. RP Inzitari, M (reprint author), Autonomous Univ Barcelona, Pere Virgili Hosp, C Esteve Terrades 30, Barcelona 08023, Spain. EM minzitari@perevirgili.catsalut.net RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU "Gianandrea Pugi" Foundation (Florence, Italy); CHS All Stars Study [R-01 AG-023629]; National Heart, Lung, and Blood Institute [N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079, N01-HC-85086, N01 HC-15103, N01 HC-55222, U01 HL080295]; National Institute on Aging, NIH; Oristano Program for Cardiovascular Disease Research FX M. I. was a research scholar at the Pepper Older Americans Independence Center of the University of Pittsburgh (P30 AG024827) and was supported by an educational grant from the "Gianandrea Pugi" Foundation (Florence, Italy) and from the CHS All Stars Study (R-01 AG-023629). This study was also supported by contracts N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079 through N01-HC-85086, N01 HC-15103, N01 HC-55222, and U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of participating investigators and institutions in the CHS is at http://chs3.chs.biostat.washington.edu/chs/. This research was supported in part by the Intramural Research Program of the National Institute on Aging, NIH (K.V.P.). The "Oristano Program for Cardiovascular Disease Research" supported part of this work. The National Heart, Lung, and Blood Institute approved the manuscript before submission. All the other sponsors had no role in the collection, analysis, or interpretation of the data or in the decision to submit the study for publication. NR 22 TC 8 Z9 8 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD SEP PY 2011 VL 66 IS 9 BP 986 EP 993 DI 10.1093/gerona/glr069 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 809OP UT WOS:000294066900008 PM 21705627 ER PT J AU Tan, E Weiss, BM Mena, E Korde, N Choyke, PL Landgren, O AF Tan, Esther Weiss, Brendan M. Mena, Esther Korde, Neha Choyke, Peter L. Landgren, Ola TI Current and future imaging modalities for multiple myeloma and its precursor states SO LEUKEMIA & LYMPHOMA LA English DT Review DE Multiple myeloma; monoclonal gammopathy of undetermined significance; smoldering multiple myeloma; skeletal survey; PET/CT; DCE MRI ID POSITRON-EMISSION-TOMOGRAPHY; BONE-MARROW ANGIOGENESIS; UNDETERMINED SIGNIFICANCE MGUS; HIGH-RISK MYELOMA; MONOCLONAL GAMMOPATHY; STAGING SYSTEM; PROGNOSTIC-SIGNIFICANCE; MICROVESSEL DENSITY; MULTIDETECTOR CT; WORKING GROUP AB Traditionally, the skeletal survey has been the standard modality for the detection of osteolytic bone disease in multiple myeloma. In addition to its poor sensitivity for the detection of osteolytic lesions, this modality is not able to identify extramedullary lesions and focal bone marrow involvement, nor measure response to therapy. The application of novel imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and molecular imaging such as fluorine-18 fluorodeoxyglucose positron emission tomography CT (F-18-FDG PET/CT) and fluorine-18 sodium fluoride positron emission tomography CT (F-18-NaF PET/CT) has the potential to overcome these limitations as well as provide prognostic information in precursor states and multiple myeloma. Also promising is the use of dynamic contrast enhanced magnetic resonance imaging (DCE MRI) to measure vascular permeability, an important feature of myelomagenesis. This review summarizes the current status and possible future role of novel imaging modalities in multiple myeloma and its precursor states. C1 [Tan, Esther; Weiss, Brendan M.] Walter Reed Army Med Ctr, Hematol Oncol Serv, Dept Med, Washington, DC 20307 USA. [Tan, Esther; Weiss, Brendan M.; Korde, Neha; Landgren, Ola] NCI, Multiple Myeloma Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Mena, Esther; Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Tan, E (reprint author), Walter Reed Army Med Ctr, Hematol Oncol Serv, Dept Med, 6900 Georgia Ave, Washington, DC 20307 USA. EM esther.tan@us.army.mil; landgreo@mail.nih.gov FU Intramural NIH HHS [Z01 BC010654-04] NR 58 TC 20 Z9 20 U1 1 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD SEP PY 2011 VL 52 IS 9 BP 1630 EP 1640 DI 10.3109/10428194.2011.573036 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 811QM UT WOS:000294228100007 PM 21649546 ER PT J AU Herishanu, Y Gibellini, F Njuguna, N Hazan-Halevy, I Farooqui, M Bern, S Keyvanfar, K Lee, E Wilson, W Wiestner, A AF Herishanu, Yair Gibellini, Federica Njuguna, Ndegwa Hazan-Halevy, Inbal Farooqui, Mohammed Bern, Sarah Keyvanfar, Keyvan Lee, Elinor Wilson, Wyndham Wiestner, Adrian TI Activation of CD44, a receptor for extracellular matrix components, protects chronic lymphocytic leukemia cells from spontaneous and drug induced apoptosis through MCL-1 SO LEUKEMIA & LYMPHOMA LA English DT Article DE CLL; CD44; MCL-1 ID ADHESION MOLECULE EXPRESSION; B-CELLS; IN-VITRO; PHOSPHOINOSITIDE 3-KINASE/AKT; PROGNOSTIC MARKERS; SURVIVAL PATHWAY; CARCINOMA CELLS; RESISTANCE; LIGATION; GX15-070 AB Survival of chronic lymphocytic leukemia (CLL) cells in vivo is supported by the tissue microenvironment, which includes components of the extracellular matrix. Interactions between tumor cells and the extracellular matrix are in part mediated by CD44, whose principal ligand is hyaluronic acid. Here, we show that CD44 is more highly expressed on CLL cells of the clinically more progressive immunglobulin heavy chain variable gene (IGHV)-unmutated subtype than on cells of the IGHV-mutated type. Engagement of CD44 activated the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK)/ERK pathways and increased myeloid cell leukemia sequence 1 (MCL-1) protein expression. Consistent with the induction of these anti-apoptotic mechanisms, CD44 protected CLL cells from spontaneous and fludarabine-induced apoptosis. Obatoclax, an antagonist of MCL-1, blocked the pro-survival effect of CD44. In addition, obatoclax synergized with fludarabine to induce apoptosis of CLL cells. In conclusion, components of the extracellular matrix may provide survival signals to CLL cells through engagement of CD44. Inhibition of MCL-1 is a promising strategy to reduce the anti-apoptotic effect of the microenvironment on CLL cells. C1 [Herishanu, Yair; Gibellini, Federica; Njuguna, Ndegwa; Farooqui, Mohammed; Bern, Sarah; Keyvanfar, Keyvan; Lee, Elinor; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wilson, Wyndham] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hazan-Halevy, Inbal] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov FU NIH, the National Cancer Institute, and the National, Heart, Lung, and Blood Institute FX This research was supported by the Intramural Research Program of the NIH, the National Cancer Institute, and the National, Heart, Lung, and Blood Institute. NR 51 TC 44 Z9 44 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD SEP PY 2011 VL 52 IS 9 BP 1758 EP 1769 DI 10.3109/10428194.2011.569962 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA 811QM UT WOS:000294228100022 PM 21649540 ER PT J AU Kelly, RJ Sharon, E Hassan, R AF Kelly, Ronan Joseph Sharon, Elad Hassan, Raffit TI Chemotherapy and targeted therapies for unresectable malignant mesothelioma SO LUNG CANCER LA English DT Review DE Mesothelioma; Chemotherapy; Targeted therapy; Immunotherapy; MORAb-009; SS1P ID I CLINICAL-TRIAL; HISTONE DEACETYLASE INHIBITORS; METASTATIC PLEURAL EFFUSIONS; PEMETREXED PLUS CARBOPLATIN; SOUTHWEST-ONCOLOGY-GROUP; MULTICENTER PHASE-II; FRONT-LINE THERAPY; BETA GENE-TRANSFER; CELL LUNG-CANCER; LEUKEMIA GROUP-B AB The global burden of mesothelioma is expected to increase in the coming decades. As a result the development of more effective therapies with an emphasis on personalized treatments based on validated prognostic and predictive biomarkers is an essential requirement. Progress has been made in the last decade with the development of newer generation anti-folates leading to the current standard of care of pemetrexed and cisplatin in patients with unresectable disease. However, the median overall survival of patients with this combination treatment is only 12 months. There is no consensus regarding second line therapy for patients who have progressed or not responded to pemetrexed based therapies although gemcitabine in combination with a platinum compound or single agent vinorelbine is a reasonable option. The development of effective targeted agents that are active in mesothelioma has to date been disappointing. Strategies involving the addition of bevacizumab to pemetrexed and cisplatin in the frontline setting, the histone deacetylase inhibitor vorinostat as second line therapy and studies evaluating the utility of maintenance therapy in mesothelioma are all ongoing and appear promising. In addition clinical trials investigating immunotherapy and gene therapy in combination with chemotherapy could potentially improve the prognosis of patients with mesothelioma. Published by Elsevier Ireland Ltd. C1 [Hassan, Raffit] NCI, Mol Biol Lab, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, Med Oncol Branch, Ctr Canc Res, 37 Convent Dr,Room 5116, Bethesda, MD 20892 USA. EM hassanr@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 81 TC 28 Z9 29 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD SEP PY 2011 VL 73 IS 3 BP 256 EP 263 DI 10.1016/j.lungcan.2011.04.014 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 810BS UT WOS:000294101000002 PM 21620512 ER PT J AU Au, AYM Hackl, T Yeager, TR Cohen, SB Pass, HI Harris, CC Reddel, RR AF Au, Amy Y. M. Hackl, Torben Yeager, Thomas R. Cohen, Scott B. Pass, Harvey I. Harris, Curtis C. Reddel, Roger R. TI Telomerase activity in pleural malignant mesotheliomas SO LUNG CANCER LA English DT Article DE Malignant mesothelioma; Telomerase; Alternative lengthening of telomeres; Immortalisation; Telomere maintenance mechanism; Pleura ID CANCER CELLS; MECHANISMS; IMMORTALIZATION; ASBESTOS; HTERT; SV40; CARCINOGENESIS; THERAPEUTICS; ASSOCIATION; INHIBITION AB New treatments are needed for malignant pleural mesothelioma (MPM), which currently has a poor prognosis. Cellular immortalisation, one of the hallmarks of cancer, depends on the activity of a telomere length maintenance mechanism (TMM) - either telomerase or alternative lengthening of telomeres (ALT). The TMMs are widely regarded as potential targets for cancer therapies and telomerase inhibitors have entered clinical trials. The aim of this study was to determine what proportion of MPMs use ALT and/or telomerase. Forty-three MPMs from 42 patients were examined for telomerase and ALT activity. Telomerase activity was detected by immunoaffinity purification followed by the telomere repeat amplification protocol (TRAP), and ALT activity was determined by the C-circle assay and by assessing telomere lengths using terminal restriction fragment analyses. We found that 43 of 43 MPMs were telomerase-positive[+] and ALT-negative[-]. Therefore, to investigate whether pleural mesothelial cells are unusually susceptible to activation of telomerase, we examined activation of the TMMs in an in vitro model of cellular immortalisation, in which normal pleural mesothelial cells were transduced with simian virus 40 (SV40) oncogenes. We found that normal mesothelial cells were TMM-negative, and that expression of the SV40 oncogenes did not directly activate telomerase or ALT. Immortalisation, which in this experimental system results from additional genetic changes that have not yet been identified, was accompanied by activation of either TMM. Therefore, pleural mesothelial cells are capable of activating either TMM in vitro, and the observation that 100% of MPMs were telomerase[+] suggests that there are factors in vivo that select for telomerase activity during oncogenesis of this tumour type. We conclude that MPM is a tumour that could be considered for anti-telomerase therapy. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Au, Amy Y. M.; Hackl, Torben; Yeager, Thomas R.; Cohen, Scott B.; Reddel, Roger R.] Childrens Med Res Inst, Westmead, NSW 2145, Australia. [Cohen, Scott B.; Reddel, Roger R.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Pass, Harvey I.] NYU, Sch Med, Dept Cardiothorac Surg, New York, NY 10016 USA. [Harris, Curtis C.] NIH, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Reddel, RR (reprint author), Childrens Med Res Inst, 214 Hawkesbury Rd, Westmead, NSW 2145, Australia. EM rreddel@cmri.org.au RI Reddel, Roger/A-6635-2014 OI Reddel, Roger/0000-0002-6302-6107 FU Cancer Institute NSW; Cancer Council NSW; NIH FX This research was supported by a Cancer Institute NSW Early Career Development Award and Cancer Council NSW Program Grant, and in part by the Intramural Research Program of the NIH. NR 33 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 J9 LUNG CANCER JI Lung Cancer PD SEP PY 2011 VL 73 IS 3 BP 283 EP 288 DI 10.1016/j.lungcan.2010.12.023 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 810BS UT WOS:000294101000006 PM 21277646 ER PT J AU Bhuvanendran, S Hussin, HM Meran, LP Anthony, AA Zhang, LL Burch, LH Phua, KK Ismail, A Balaram, P AF Bhuvanendran, Saatheeyavaane Hussin, Hani M. Meran, Lila P. Anthony, Amy A. Zhang, Leilei Burch, Lauranell H. Phua, Kia K. Ismail, Asma Balaram, Prabha TI Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and typhoid susceptibility in Asian Malay population in Malaysia SO MICROBES AND INFECTION LA English DT Article DE Typhoid fever; TLR4 polymorphisms; Malay ethnicity ID PULMONARY TUBERCULOSIS; INFECTIOUS-DISEASES; SALMONELLA-TYPHI; TLR4; GENE; TOLL-LIKE-RECEPTOR-4; MUTATIONS; FEVER; HYPORESPONSIVENESS; VARIANTS AB Typhoid fever is a major health problem with frequent outbreaks in Kelantan, Malaysia. Prevalence of TLR4 gene polymorphisms varies with ethnic groups (0-20%) and predisposean individual to gram-negative infections. The prevalence rate of TLR4 Asp299Gly and Thr399lle polymorphisms in the Malay population or the influence of these on typhoid fever susceptibility is not yet reported. 250 normal and 304 susceptible Malay individuals were investigated for these polymorphisms using allele-specific PCR and analysed for its association with typhoid fever susceptibility. The total prevalence of polymorphisms in the normal population was 4.8% in comparison to 12.5% in the susceptible population (p = 0.002). An increased frequency of both polymorphisms was observed in the susceptible population (p < 0.01) with no homozygous mutants observed. Co-segregation was observed in 2% of controls and 3.6% of the susceptible individuals. This study, for the first time, reports the prevalence of TLR4 gene polymorphisms in the Malay population and suggests that these polymorphisms confer a higher risk for typhoid, infection. The higher incidence of typhoid fever in Kelantan could be attributed to the higher percentage of Malays (95%) in this state. In order to reduce the incidence of this disease, people with these polymorphisms, can be prioritised for prophylactic strategies. (C) 2011 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. C1 [Bhuvanendran, Saatheeyavaane; Anthony, Amy A.; Phua, Kia K.; Ismail, Asma; Balaram, Prabha] Univ Sains Malaysia, Inst Res Mol Med INFORMM, Kubang Kerian 16150, Kelantan, Malaysia. [Hussin, Hani M.; Meran, Lila P.] Minist Hlth, Kelantan State Hlth Dept, Kota Baharu 15590, Kelantan, Malaysia. [Zhang, Leilei; Burch, Lauranell H.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Balaram, P (reprint author), Univ Sains Malaysia, Inst Res Mol Med INFORMM, Hlth Campus, Kubang Kerian 16150, Kelantan, Malaysia. EM prabhabalaram@yahoo.co.in RI Balaram, Prabha/A-7026-2010; Ismail, Asma/A-5688-2010; Phua, Kia-Kien/A-7598-2010; OI PHUA, KIA KIEN/0000-0001-8999-028X FU Universiti Sains Malaysia [1001/CIPPM/8130131]; NIH, National Institute of Environmental Health Sciences FX This study was funded by Grant No. 1001/CIPPM/8130131 from Universiti Sains Malaysia and student fellowship (Ms. Saatheeyavaane) from USM. This study was also supported (in part) by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 44 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD SEP PY 2011 VL 13 IS 10 BP 844 EP 851 DI 10.1016/j.micinf.2011.04.007 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 809ZZ UT WOS:000294096500007 PM 21612766 ER PT J AU Srikantan, S Abdelmohsen, K Lee, EK Tominaga, K Subaran, SS Kuwano, Y Kulshrestha, R Panchakshari, R Kim, HH Yang, XL Martindale, JL Marasa, BS Kim, MM Wersto, RP Indig, FE Chowdhury, D Gorospe, M AF Srikantan, Subramanya Abdelmohsen, Kotb Lee, Eun Kyung Tominaga, Kumiko Subaran, Sarah S. Kuwano, Yuki Kulshrestha, Ritu Panchakshari, Rohit Kim, Hyeon Ho Yang, Xiaoling Martindale, Jennifer L. Marasa, Bernard S. Kim, Mihee M. Wersto, Robert P. Indig, Fred E. Chowdhury, Dipanjan Gorospe, Myriam TI Translational Control of TOP2A Influences Doxorubicin Efficacy SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DNA TOPOISOMERASE-II; RNA-BINDING PROTEINS; CANCER-CHEMOTHERAPY; ANIMAL DEVELOPMENT; MAMMALIAN-CELLS; HUR; EXPRESSION; REPRESSION; STRESS; PHOSPHORYLATION AB The cellular abundance of topoisomerase II alpha (TOP2A) critically maintains DNA topology after replication and determines the efficacy of TOP2 inhibitors in chemotherapy. Here, we report that the RNA-binding protein HuR, commonly overexpressed in cancers, binds to the TOP2A 3'-untranslated region (3'UTR) and increases TOP2A translation. Reducing HuR levels triggered the recruitment of TOP2A transcripts to RNA-induced silencing complex (RISC) components and to cytoplasmic processing bodies. Using a novel MS2-tagged RNA precipitation method, we identified microRNA miR-548c-3p as a mediator of these effects and further uncovered that the interaction of miR-548c-3p with the TOP2A 3'UTR repressed TOP2A translation by antagonizing the action of HuR. Lowering TOP2A by silencing HuR or by overexpressing miR-548c-3p selectively decreased DNA damage after treatment with the chemotherapeutic agent doxorubicin. In sum, HuR enhances TOP2A translation by competing with miR-548c-3p; their combined actions control TOP2A expression levels and determine the effectiveness of doxorubicin. C1 [Srikantan, Subramanya; Abdelmohsen, Kotb; Lee, Eun Kyung; Tominaga, Kumiko; Kuwano, Yuki; Kim, Hyeon Ho; Yang, Xiaoling; Martindale, Jennifer L.; Marasa, Bernard S.; Kim, Mihee M.; Gorospe, Myriam] NIA, LMBI, IRP, NIH, Baltimore, MD 21224 USA. [Subaran, Sarah S.; Wersto, Robert P.; Indig, Fred E.] NIA, Res Resources Branch, IRP, NIH, Baltimore, MD 21224 USA. [Subaran, Sarah S.; Kulshrestha, Ritu; Panchakshari, Rohit; Chowdhury, Dipanjan] Harvard Univ, Dana Farber Canc Inst, Dept Radiat Oncol, Sch Med, Boston, MA 02118 USA. [Kim, Hyeon Ho] Sungkyunkwan Univ, Samsung Biomed Res Inst, Sch Med, Seoul, South Korea. RP Gorospe, M (reprint author), NIA, LMBI, IRP, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM Dipanjan_Chowdhury@dfci.harvard.edu; myriam-gorospe@nih.gov OI srikantan, subramanya/0000-0003-1810-6519; abdelmohsen, Kotb/0000-0001-6240-5810 FU NIA-IRP, NIH; Barr Award; NCI [R01CA142698] FX This research was supported by the NIA-IRP, NIH. R. K., R. P., and D. C. were supported by the Barr Award and NCI R01CA142698. NR 39 TC 46 Z9 48 U1 0 U2 1 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 SEP PY 2011 VL 31 IS 18 BP 3790 EP 3801 DI 10.1128/MCB.05639-11 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 811WE UT WOS:000294246700011 PM 21768308 ER PT J AU Itsko, M Schaaper, RM AF Itsko, Mark Schaaper, Roel M. TI The dgt gene of Escherichia coli facilitates thymine utilization in thymine-requiring strains SO MOLECULAR MICROBIOLOGY LA English DT Article ID DEOXYGUANOSINE TRIPHOSPHATE TRIPHOSPHOHYDROLASE; BIOCHEMICAL-CHARACTERIZATION; DEOXYNUCLEOSIDE KINASES; SALMONELLA-TYPHIMURIUM; WILD-TYPE; REPLICATION; MUTANTS; DEATH; DEOXYCYTIDINE; METABOLISM AB The Escherichia coli dGTP triphosphohydrolase (dGTPase) encoded by the dgt gene catalyses the hydrolysis of dGTP to deoxyguanosine and triphosphate. The recent discovery of a mutator effect associated with deletion of dgt indicated participation of the triphosphohydrolase in preventing mutagenesis. Here, we have investigated the possible involvement of dgt in facilitating thymine utilization through its ability to provide intracellular deoxyguanosine, which is readily converted by the DeoD phosphorylase to deoxyribose-1-phosphate, the critical intermediate that enables uptake and utilization of thymine. Indeed, we observed that the minimal amount of thymine required for growth of thymine-requiring (thyA) strains decreased with increased expression level of the dgt gene. As expected, this dgt-mediated effect was dependent on the DeoD purine nucleoside phosphorylase. We also observed that thyA strains experience growth difficulties upon nutritional shift-up and that the dgt gene facilitates adaptation to the new growth conditions. Blockage of the alternative yjjG (dUMP phosphatase) pathway for deoxyribose-1-phosphate generation greatly exacerbated the severity of thymine starvation in enriched media, and under these conditions the dgt pathway becomes crucial in protecting the cells against thymineless death. Overall, our results suggest that the dgt-dependent pathway for deoxyribose-1-phosphate generation may operate under various cell conditions to provide deoxyribosyl donors. C1 [Itsko, Mark; Schaaper, Roel M.] Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Schaaper, RM (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM schaaper@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [ES101905] FX We thank Drs S. Covo and M. Young of the NIEHS for their critical reading of the manuscript for this article and helpful comments. We thank Dr J. Drake (NIEHS) for providing the bacteriophage T4 and E. coli optA1 strains, and the National Institute of Genetics, Japan, for strain JD20450. This research was supported by project number ES101905 of the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 52 TC 6 Z9 6 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD SEP PY 2011 VL 81 IS 5 BP 1221 EP 1232 DI 10.1111/j.1365-2958.2011.07756.x PG 12 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 811MC UT WOS:000294214100009 PM 21736641 ER PT J AU Raznahan, A Lee, Y Long, R Greenstein, D Clasen, L Addington, A Rapoport, JL Giedd, JN AF Raznahan, A. Lee, Y. Long, R. Greenstein, D. Clasen, L. Addington, A. Rapoport, J. L. Giedd, J. N. TI Common functional polymorphisms of DISC1 and cortical maturation in typically developing children and adolescents SO MOLECULAR PSYCHIATRY LA English DT Article DE DISC1; cortical thickness; schizophrenia; autism; genetic; neuroimaging ID HUMAN CEREBRAL-CORTEX; CHILDHOOD-ONSET SCHIZOPHRENIA; GRAY-MATTER; SPECTRUM DISORDERS; POSITIVE SYMPTOMS; BRAIN-DEVELOPMENT; MAJOR DEPRESSION; ASSOCIATION; RISK; THICKNESS AB Disrupted-in-schizophrenia-1 (DISC1), contains two common non-synonymous single-nucleotide polymorphisms (SNPs)-Leu607Phe and Ser704Cys-that modulate (i) facets of DISC1 molecular functioning important for cortical development, (ii) fronto-temporal cortical anatomy in adults and (iii) risk for diverse psychiatric phenotypes that often emerge during childhood and adolescence, and are associated with altered fronto-temporal cortical development. It remains unknown, however, if Leu607Phe and Ser704Cys influence cortical maturation before adulthood, and whether each SNP shows unique or overlapping effects. Therefore, we related genotype at Leu607Phe and Ser704Cys to cortical thickness (CT) in 255 typically developing individuals aged 9-22 years on whom 598 magnetic resonance imaging brain scans had been acquired longitudinally. Rate of cortical thinning varied with DISC1 genotype. Specifically, the rate of cortical thinning was attenuated in Phe-carrier compared with Leu-homozygous groups (in bilateral superior frontal and left angular gyri) and accelerated in Ser-homozygous compared with Cys-carrier groups (in left anterior cingulate and temporal cortices). Both SNPs additively predicted fixed differences in right lateral temporal CT, which were maximal between Phe-carrier/Ser-homozygous (thinnest) vs Leu-homozygous/Cys-carrier (thickest) groups. Leu607Phe and Ser704Cys genotype interacted to predict the rate of cortical thinning in right orbitofrontal, middle temporal and superior parietal cortices, wherein a significantly reduced rate of CT loss was observed in Phe-carrier/ Cys-carrier participants only. Our findings argue for further examination of Leu607Phe and Ser704Cys interactions at a molecular level, and suggest that these SNPs might operate (in concert with other genetic and environmental factors) to shape risk for diverse phenotypes by impacting on the early maturation of frontotemporal cortices. Molecular Psychiatry (2011) 16, 917-926; doi:10.1038/mp.2010.72; published online 13 July 2010 C1 [Raznahan, A.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Raznahan, A.] Kings Coll London, Dept Child & Adolescent Psychiat, Inst Psychiat, London WC2R 2LS, England. RP Raznahan, A (reprint author), NIMH, Child Psychiat Branch, NIH, 10 Ctr Dr,Bldg 10,Room 3N202, Bethesda, MD 20892 USA. EM raznahana@mail.nih.gov RI Giedd, Jay/A-3080-2008; 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 FU National Institutes of Health, National Institute of Health Intramural Research; UK Medical Research Council [AR-G0701370] FX This study was funded through the National Institutes of Health, National Institute of Health Intramural Research, and a UK Medical Research Council Clinical Research Training Fellowship (author AR-G0701370). We thank the participants who took part in this study. We are also grateful to the reviewers of this paper for their helpful comments. Dr Raznahan would like to thank Ms Shirley V Rojas for her tireless support on both sides of the laboratory door. NR 73 TC 23 Z9 24 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2011 VL 16 IS 9 BP 917 EP 926 DI 10.1038/mp.2010.72 PG 10 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 811VX UT WOS:000294245600007 PM 20628343 ER PT J AU Lipkowitz, S Weissman, AM AF Lipkowitz, Stanley Weissman, Allan M. TI RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis SO NATURE REVIEWS CANCER LA English DT Review ID GROWTH-FACTOR RECEPTOR; FANCONI-ANEMIA PATHWAY; ANAPHASE-PROMOTING COMPLEX; HIPPEL-LINDAU PROTEIN; NF-KAPPA-B; HYPOXIA-INDUCIBLE FACTOR; RENAL-CELL CARCINOMA; SMALL-MOLECULE RITA; C-CBL; NEGATIVE REGULATION AB The ubiquitin-proteasome system has numerous crucial roles in physiology and pathophysiology. Fundamental to the specificity of this system are ubiquitin-protein ligases (E3s). Of these, the majority are RING finger and RING finger-related E3s. Many RING finger E3s have roles in processes that are central to the maintenance of genomic integrity and cellular homeostasis, such as the anaphase promoting complex/cyclosome (APC/C), the SKP1-cullin 1-F-box protein (SCF) E3s, MDM2, BRCA1, Fanconi anaemia proteins, CBL proteins, von Hippel-Lindau tumour suppressor (VHL) and SIAH proteins. As a result, many RING finger E3s are implicated in either the suppression or the progression of cancer. This Review summarizes current knowledge in this area. C1 [Lipkowitz, Stanley] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. [Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. RP Lipkowitz, S (reprint author), NCI, Cellular & Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM lipkowis@mail.nih.gov; amw@nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research, USA FX The authors apologize to the many scientists whose contributions to this extensive and exponentially growing field of research could not be directly cited because of space limitations. They are indebted to their colleagues whose outstanding reviews on individual RING finger E3s and RING finger E3 families summarize and cite much of this important research. The authors thank R. Das (Structural Biophysics Laboratory, National Cancer Institute, USA) for invaluable assistance in generating the RING finger-E2 ribbon diagram. The authors' research programmes are supported by the National Institutes of Health, National Cancer Institute, Center for Cancer Research, USA. NR 192 TC 147 Z9 154 U1 1 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD SEP PY 2011 VL 11 IS 9 BP 629 EP 643 DI 10.1038/nrc3120 PG 15 WC Oncology SC Oncology GA 811IZ UT WOS:000294203400011 PM 21863050 ER PT J AU Forlino, A Cabral, WA Barnes, AM Marini, JC AF Forlino, Antonella Cabral, Wayne A. Barnes, Aileen M. Marini, Joan C. TI New perspectives on osteogenesis imperfecta SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Review ID EHLERS-DANLOS-SYNDROME; CARBOXYL-TERMINAL PROPEPTIDE; CARTILAGE-ASSOCIATED PROTEIN; TELOPEPTIDE LYSYL HYDROXYLASE; TRANSCRIPTION FACTOR OSTERIX; HYPEROSTOSIS CAFFEY-DISEASE; EMBRYONIC LETHAL MUTATION; PROCOLLAGEN N-PROTEINASE; ALPHA-1(I) COLLAGEN GENE; GROWTH-HORMONE TREATMENT AB A new paradigm has emerged for osteogenesis imperfecta as a collagen-related disorder. The more prevalent autosomal dominant forms of osteogenesis imperfecta are caused by primary defects in type I collagen, whereas autosomal recessive forms are caused by deficiency of proteins which interact with type I procollagen for post-translational modification and/or folding. Factors that contribute to the mechanism of dominant osteogenesis imperfecta include intracellular stress, disruption of interactions between collagen and noncollagenous proteins, compromised matrix structure, abnormal cell-cell and cell-matrix interactions and tissue mineralization. Recessive osteogenesis imperfecta is caused by deficiency of any of the three components of the collagen prolyl 3-hydroxylation complex. Absence of 3-hydroxylation is associated with increased modification of the collagen helix, consistent with delayed collagen folding. Other causes of recessive osteogenesis imperfecta include deficiency of the collagen chaperones FKBP10 or Serpin H1. Murine models are crucial to uncovering the common pathways in dominant and recessive osteogenesis imperfecta bone dysplasia. Clinical management of osteogenesis imperfecta is multidisciplinary, encompassing substantial progress in physical rehabilitation and surgical procedures, management of hearing, dental and pulmonary abnormalities, as well as drugs, such as bisphosphonates and recombinant human growth hormone. Novel treatments using cell therapy or new drug regimens hold promise for the future. C1 [Forlino, Antonella; Cabral, Wayne A.; Barnes, Aileen M.; Marini, Joan C.] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. [Forlino, Antonella] Univ Pavia, Dept Biochem, Sect Med & Pharm, I-27100 Pavia, Italy. RP Marini, JC (reprint author), NICHD, Bone & Extracellular Matrix Branch, NIH, Bldg 10,Room 10N260,9000 Rockville Pike, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov RI Forlino, Antonella/H-5385-2015 OI Forlino, Antonella/0000-0002-6385-1182 FU Intramural NIH HHS [Z99 HD999999] NR 215 TC 224 Z9 236 U1 11 U2 76 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 EI 1759-5037 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD SEP PY 2011 VL 7 IS 9 BP 540 EP 557 DI 10.1038/nrendo.2011.81 PG 18 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 810FL UT WOS:000294111000009 PM 21670757 ER PT J AU Weissman, AM Shabek, N Ciechanover, A AF Weissman, Allan M. Shabek, Nitzan Ciechanover, Aaron TI The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID ANAPHASE-PROMOTING COMPLEX; RETICULUM-ASSOCIATED DEGRADATION; PEROXISOMAL IMPORT RECEPTOR; POLYCOMB PROTEIN RING1B; ENDOPLASMIC-RETICULUM; DEUBIQUITINATING ENZYME; 26S PROTEASOME; E3 LIGASE; IN-VITRO; S-PHASE AB Ubiquitylation (also known as ubiquitination) regulates essentially all of the intracellular processes in eukaryotes through highly specific modification of numerous cellular proteins, which is often tightly regulated in a spatial and temporal manner. Although most often associated with proteasomal degradation, ubiquitylation frequently serves non-proteolytic functions. In light of its central roles in cellular regulation, it has not been surprising to find that many of the components of the ubiquitin system itself are regulated by ubiquitylation. This observation has broad implications for pathophysiology. C1 [Weissman, Allan M.] NCI, Lab Prot Dynam & Signalling, Frederick, MD 21702 USA. [Shabek, Nitzan; Ciechanover, Aaron] Technion Israel Inst Technol, Canc & Vasc Biol Res Ctr, Rappaport Fac Med, IL-31096 Haifa, Israel. [Shabek, Nitzan; Ciechanover, Aaron] Technion Israel Inst Technol, Res Inst, IL-31096 Haifa, Israel. RP Weissman, AM (reprint author), NCI, Lab Prot Dynam & Signalling, Frederick, MD 21702 USA. EM amw@nih.gov; c_tzachy@netvision.net.il FU US National Institutes of Health National Cancer Institute and Center for Cancer Research; Miriam and Sheldon Adelson Foundation for Medical Research; Israel Science Foundation; German-Israeli Foundation for Research and Scientific Development; Deutsch-Israelische Projektkooperation; Rubicon - the European Union Network of Excellence FX Space constrains do not allow us to cite many of the studies in this evolving, yet already prolific, research area, and we apologize for that. Research in the laboratory of A.M.W. is supported by the US National Institutes of Health National Cancer Institute and Center for Cancer Research. Research in the laboratory of A.C. is supported by grants from the Miriam and Sheldon Adelson Foundation for Medical Research, the Israel Science Foundation, the German-Israeli Foundation for Research and Scientific Development, the Deutsch-Israelische Projektkooperation and Rubicon - the European Union Network of Excellence Studying the Role of Ubiquitin and Ubiquitin-like Modifiers in Cellular Regulation. A.C. is an Israel Cancer Research Fund USA Professor. NR 157 TC 136 Z9 140 U1 1 U2 36 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 EI 1471-0080 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD SEP PY 2011 VL 12 IS 9 BP 605 EP 620 DI 10.1038/nrm3173 PG 16 WC Cell Biology SC Cell Biology GA 810XX UT WOS:000294164700014 PM 21860393 ER PT J AU Yoon, JS Mughal, MR Mattson, MP AF Yoon, Jeong Seon Mughal, Mohamed R. Mattson, Mark P. TI Energy Restriction Negates NMDA Receptor Antagonist Efficacy in Ischemic Stroke SO NEUROMOLECULAR MEDICINE LA English DT Article DE Cerebral ischemia; Diabetes; Dizocilpine; Excitotoxicity; MK-801; Obesity ID CALORIC RESTRICTION; DIABETIC MICE; BRAIN; NEURONS; STRESS; SYSTEM AB Preclinical evaluation of drugs for neurological disorders is usually performed on overfed rodents, without consideration of how metabolic state might affect drug efficacy. Using a widely employed mouse model of focal ischemic stroke, we found that that the NMDA receptor antagonist dizocilpine (MK-801) reduces brain damage and improves functional outcome in mice on the usual ad libitum diet, but exhibits little or no therapeutic efficacy in mice maintained on an energy-restricted diet. Thus, NMDA receptor activation plays a central role in the mechanism by which a high dietary energy intake exacerbates ischemic brain injury. These findings suggest that inclusion of subjects with a wide range of energy intakes in clinical trials for stroke may mask a drug benefit in the overfed/obese subpopulation of subjects. C1 [Yoon, Jeong Seon; Mughal, Mohamed R.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institute on Aging. NR 16 TC 3 Z9 3 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD SEP PY 2011 VL 13 IS 3 BP 175 EP 178 DI 10.1007/s12017-011-8145-y PG 4 WC Neurosciences SC Neurosciences & Neurology GA 809PH UT WOS:000294068700002 PM 21660587 ER PT J AU Ossola, B Schendzielorz, N Chen, SH Bird, GS Tuominen, RK Mannisto, PT Hong, JS AF Ossola, Bernardino Schendzielorz, Nadia Chen, Shih-Heng Bird, Gary S. Tuominen, Raimo K. Mannisto, Pekka T. Hong, Jau-Shyong TI Amantadine protects dopamine neurons by a dual action: Reducing activation of microglia and inducing expression of GNDF in astroglia SO NEUROPHARMACOLOGY LA English DT Article DE Parkinson's disease; In vitro model; Neurodegenerative disease; Neuroinflammation; Neuroprotection; MPP(+); LPS ID NMDA RECEPTOR ANTAGONISTS; PARKINSONS-DISEASE; NEUROTROPHIC FACTOR; MEDIATED NEUROTOXICITY; ALZHEIMERS-DISEASE; MEMANTINE; RATS; DEGENERATION; TOXICITY; EXCITOTOXICITY AB Amantadine is commonly given to alleviate L-DOPA-induced dyskinesia of Parkinson's disease (PD) patients. Animal and human evidence showed that amantadine may also exert neuroprotection in several neurological disorders. Additionally, it is generally believed that this neuroprotection results from the ability of amantadine to inhibit glutamatergic NMDA receptor. However, several lines of evidence questioned the neuroprotective capacity of NMDA receptor antagonists in animal models of PD. Thus the cellular and molecular mechanism of neuroprotection of amantadine remains unclear. Using primary cultures with different composition of neurons, microglia, and astroglia we investigated the direct role of these glial cell types in the neuroprotective effect of amantadine. First, amantadine protected rat midbrain cultures from either MPP+ or lipopolysaccharide (LPS), two toxins commonly used as PD models. Second, our studies revealed that amantadine reduced both LPS- and MPP(+)-induced toxicity of dopamine neurons through 1) the inhibition of the release of microglial pro-inflammatory factors, 2) an increase in expression of neurotrophic factors such as GDNF from astroglia. Lastly, differently from the general view on amantadine's action, we provided evidence suggesting that NMDA receptor inhibition was not crucial for the neuroprotective effect of amantadine. In conclusion, we report that amantadine protected dopamine neurons in two PD models through a novel dual mechanism, namely reducing the release of pro-inflammatory factors from activated microglia and increasing the expression of GNDF in astroglia. Published by Elsevier Ltd. C1 [Ossola, Bernardino; Schendzielorz, Nadia; Chen, Shih-Heng; Hong, Jau-Shyong] NIEHS, Lab Toxicol & Pharmacol, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Ossola, Bernardino; Schendzielorz, Nadia; Tuominen, Raimo K.; Mannisto, Pekka T.] Univ Helsinki, Fac Pharm, Div Pharmacol & Toxicol, FIN-00014 Helsinki, Finland. [Bird, Gary S.] NIEHS, Lab Signal Transduct, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Hong, JS (reprint author), NIEHS, Toxicol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Bernardino.ossola@helsinki.fi; Nadia.Schendzielorz@helsinki.f; Chens3@niehs.nih.gov; bird@niehs.nih.gov; raimo.tuominen@helsinki.fi; pekka.mannisto@helsinki.fi; hong3@niehs.nih.gov FU Finnish Parkinson Foundation; Ella and Georg Ehrnrooth Foundation; National Institute of Health, National Institute of Environmental Health Sciences FX We thank Mr. John Petranka and Jeff Tucker for helping to setup the measurement of Ca2+ signals. We thank Dr. Qingshan Wang for helping with the p47 and p67 translocation study. We thank Dr. Huiming Gao for valuable discussions about the preparation of the different cultures. This work was supported by the Finnish Parkinson Foundation and Ella and Georg Ehrnrooth Foundation. This research was also supported in part by the Intramural Research Program of the National Institute of Health, National Institute of Environmental Health Sciences. The funding sources had no involvement in this study. NR 41 TC 27 Z9 28 U1 0 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2011 VL 61 IS 4 BP 574 EP 582 DI 10.1016/j.neuropharm.2011.04.030 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 809XN UT WOS:000294090100004 PM 21586298 ER PT J AU Varner, MW Murguia, M Anderson, B Tolosa, JE Sheffield, J Spong, CY Saade, G Peaceman, AM Louis, JM Wapner, RJ Tita, ATN Sorokin, Y Blackwell, SC Prasad, M Thorp, JM Naresh, A Van Dorsten, JP AF Varner, Michael W. Murguia, Madeline Rice Anderson, Brenna Tolosa, Jorge E. Sheffield, Jeanne Spong, Catherine Y. Saade, George Peaceman, Alan M. Louis, Judette M. Wapner, Ronald J. Tita, Alan T. N. Sorokin, Yoram Blackwell, Sean C. Prasad, Mona Thorp, John M., Jr. Naresh, Amber Van Dorsten, J. Peter CA Eunice Kennedy Shriver Natl Inst TI Influenza-Like Illness in Hospitalized Pregnant and Postpartum Women During the 2009-2010 H1N1 Pandemic SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID VIRUS-INFECTION; OUTCOMES AB OBJECTIVE: To estimate characteristics and outcomes of pregnant and immediately postpartum women hospitalized with influenza-like illness during the 2009-2010 influenza pandemic and the factors associated with more severe illness. METHODS: An observational cohort in 28 hospitals of pregnant and postpartum (within 2 weeks of delivery) women hospitalized with influenza-like illness. Influenza-like illness was defined as clinical suspicion of influenza and either meeting the Centers for Disease Control and Prevention definition of influenza-like illness (fever 100.0 degrees F or higher, cough, sore throat) or a positive influenza test. RESULTS: Of 356 women meeting eligibility criteria, 35 (9.8%) were admitted to the intensive care unit (ICU) and four (1.1%) died. Two hundred eighteen women (61.2%) were in the third trimester and 10 (2.8%) were postpartum. More than half (55.3%) were admitted in October and 25.0% in November with rapidly decreasing numbers thereafter. Antiviral therapy was administered to 10.1% of the women before hospitalization and to 88.5% during hospitalization. Factors associated with an increased likelihood of ICU admission included cigarette smoking (29.4% compared with 13.4%; odds ratio [OR] 2.77, 95% confidence interval [CI] 1.19-6.45) and chronic hypertension (17.1% compared with 3.1%; OR 6.86, 95% CI 2.19-21.51). Antiviral treatment within 2 days of symptom onset decreased the likelihood of ICU admission (31.4% compared with 56.6%, OR 0.36, 95% CI 0.16-0.77). CONCLUSION: Comorbidities, including chronic hypertension and smoking in pregnancy, increase the likelihood of ICU admission in influenza-like illness hospitalizations, whereas early antiviral treatment may reduce its frequency. C1 [Varner, Michael W.] Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. Brown Univ, Providence, RI 02912 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ Texas Med Branch, Galveston, TX USA. Northwestern Univ, Chicago, IL 60611 USA. Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH USA. Columbia Univ, New York, NY USA. Univ Alabama, Birmingham, AL USA. Wayne State Univ, Detroit, MI USA. Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. Ohio State Univ, Columbus, OH 43210 USA. Univ N Carolina, Chapel Hill, NC USA. Univ Pittsburgh, Pittsburgh, PA USA. Med Univ S Carolina, Charleston, SC 29425 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Varner, MW (reprint author), Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, 30 N 1900 E,Room 2A226, Salt Lake City, UT 84132 USA. EM michael.varner@hsc.utah.edu RI Louis, Judette/E-5130-2013; Varner, Michael/K-9890-2013 OI Louis, Judette/0000-0002-1336-7886; Peaceman, Alan/0000-0002-4515-4850; Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD40544, HD40500, HD53118, HD53097, HD40512, HD40560, HD34208, HD27917, HD40545, HD27915, HD34116, HD40485, HD21410, HD36801, HD27869, 5UL1RR025777] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD40544, HD40500, HD53118, HD53097, HD40512, HD40560, HD34208, HD27917, HD40545, HD27915, HD34116, HD40485, HD21410, HD36801, HD27869 and 5UL1RR025777). Its contents do not necessarily represent the official view of NICHD or the National Institutes of Health. NR 19 TC 17 Z9 17 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2011 VL 118 IS 3 BP 593 EP 600 DI 10.1097/AOG.0b013e318229e484 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 810VP UT WOS:000294156200014 PM 21860288 ER PT J AU Hou, QZ Barr, T Gee, L Vickers, J Wymer, J Borsani, E Rodella, L Getsios, S Burdo, T Eisenberg, E Guha, U Lavker, R Kessler, J Chittur, S Fiorino, D Rice, F Albrecht, P AF Hou, Quanzhi Barr, Travis Gee, Lucy Vickers, Jeff Wymer, James Borsani, Elisa Rodella, Luigi Getsios, Spiro Burdo, Trisha Eisenberg, Elan Guha, Udayan Lavker, Robert Kessler, John Chittur, Sridar Fiorino, Dennis Rice, Frank Albrecht, Phillip TI Keratinocyte expression of calcitonin gene-related peptide beta: Implications for neuropathic and inflammatory pain mechanisms SO PAIN LA English DT Article DE Sensory transduction; Cutaneous innervation; BMP-4; Noggin; Skin; Dermatology ID PRIMARY AFFERENT NEURONS; PERMEABILITY BARRIER RECOVERY; LECTIN-BINDING ANALYSIS; DORSAL-ROOT GANGLION; SENSING ION-CHANNEL; CGRP MESSENGER-RNA; SENSORY NEURONS; IN-VITRO; NEUROGENIC INFLAMMATION; SUBSTANCE-P AB Calcitonin gene-related peptide (CGRP) is a vasodilatory peptide that has been detected at high levels in the skin, blood, and cerebrospinal fluid (CSF) under a variety of inflammatory and chronic pain conditions, presumably derived from peptidergic C and Ad innervation. Herein, CGRP immunolabeling (IL) was detected in epidermal keratinocytes at levels that were especially high and widespread in the skin of humans from locations afflicted with postherpetic neuralgia (PHN) and complex region pain syndrome type 1 (CRPS), of monkeys infected with simian immunodeficiency virus, and of rats subjected to L5/L6 spinal nerve ligation, sciatic nerve chronic constriction, and subcutaneous injection of complete Freund's adjuvant. Increased CGRP-IL was also detected in epidermal keratinocytes of transgenic mice with keratin-14 promoter driven overexpression of noggin, an antagonist to BMP-4 signaling. Transcriptome microarray, quantitative Polymerase Chain Reaction (qPCR), and Western blot analyses using laser-captured mouse epidermis from transgenics, monolayer cultures of human and mouse keratinocytes, and multilayer human keratinocyte organotypic cultures, revealed that keratinocytes express predominantly the beta isoform of CGRP. Cutaneous peptidergic innervation has been shown to express predominantly the alpha isoform of CGRP. Keratinocytes also express the cognate CGRP receptor components, Calcitonin receptor-like receptor (CRLR), Receptor activity-modifying protein 1 (RAMP1), CGRP-receptor component protein (RCP) consistent with known observations that CGRP promotes several functional changes in keratinocytes, including proliferation and cytokine production. Our results indicate that keratinocyte-derived CGRP beta may modulate epidermal homeostasis through autocrine/paracrine signaling and may contribute to chronic pain under pathological conditions. (C) 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Hou, Quanzhi; Barr, Travis; Gee, Lucy; Vickers, Jeff; Rice, Frank; Albrecht, Phillip] Albany Med Coll, Ctr Neuropharmacol & Neurosci, Albany, NY 12208 USA. [Wymer, James] Albany Med Coll, Dept Neurol, Albany, NY 12208 USA. [Borsani, Elisa; Rodella, Luigi] Univ Brescia, Div Human Anat, Dept Biomed Sci & Biotechnol, Brescia, Italy. [Getsios, Spiro; Lavker, Robert] Northwestern Univ, Dept Dermatol, Feinberg Sch Med, Chicago, IL 60611 USA. [Burdo, Trisha] Boston Coll, Dept Biol, Chestnut Hill, MA 02167 USA. [Eisenberg, Elan] Technion Israel Inst Technol, Fac Med, Rambam Med Ctr, Haifa, Israel. [Guha, Udayan] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Kessler, John] Northwestern Univ, Dept Neurol, Feinberg Sch Med, Chicago, IL 60611 USA. [Chittur, Sridar] SUNY Albany, Ctr Funct Genom, Rensselaer, NY USA. [Fiorino, Dennis] Vertex Pharmaceut, Vivo Pharmacol, San Diego, CA USA. [Rice, Frank; Albrecht, Phillip] Integrated Tissue Dynam LLC, Rensselaer, NY USA. RP Albrecht, P (reprint author), Albany Med Coll, Ctr Neuropharmacol & Neurosci, Albany, NY 12208 USA. EM philalbrecht@intidyn.com OI Rodella, Luigi Fabrizio/0000-0002-9497-4708 FU AMC [NIDA DA07307] FX The authors thank Dr. I. Silos-Santiago for facilitating the PHN and diabetic neuropathy portions of this research; Dr. L. B. Hough, Albany Medical College, for assistance in producing the SNL rats; Dr. K. Ren, University of Maryland, for providing CFA-injected rat tissues; Dr. K. C. Williams, Boston College, for providing SIV monkey tissues; Dr. A. Miller for obtaining rhesus palmar skin from SIV-infected macaques; Dr. B. Herron, Wadsworth Center, for providing primary mouse cell cultures; Dr. M. DiPersio, Albany Medical College, for providing MK116 cells; Dr. S. Temple, New York State Neural Stem Cell Institute, for providing primary mouse fibroblasts; Dr. R. Ferland and Dr. L. Jacobsen, Albany Medical College, for providing trigeminal ganglia tissue; Dr. R. Keller, Albany Medical College, for expert assistance with qPCR experiments; Dr. Y. Huang, Albany Medical College, for assistance with Western blotting experiments; Mrs. Marilyn Dockum, Albany Medical College, for assistance in processing tissues; and Ms. Jennifer Jewitt, Northwestern University, for assistance with transgenic mice tissue. We also thank the Northwestern University Skin Disease Research Center Keratinocyte Core Facility (NIH/NIAMS-1P30AR057216-01). Portions of this research study were supported by an AMC training grant (NIDA DA07307). The authors declare that there are no real or percieved conflicts of interest associated with the research data presented. NR 119 TC 40 Z9 41 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD SEP PY 2011 VL 152 IS 9 BP 2036 EP 2051 DI 10.1016/j.pain.2011.04.033 PG 16 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 810GF UT WOS:000294113100018 PM 21641113 ER PT J AU Capitini, CM Gottschalk, S Brenner, M Cooper, LJN Handgretinger, R Mackall, CL AF Capitini, Christian M. Gottschalk, Stephen Brenner, Malcolm Cooper, Laurence J. N. Handgretinger, Rupert Mackall, Crystal L. TI Highlights of the Second International Conference on "Immunotherapy in Pediatric Oncology" SO PEDIATRIC HEMATOLOGY AND ONCOLOGY LA English DT Review DE HSCT; immunotherapy; immunology; oncology (target therapy); phase I/II studies ID ACUTE LYMPHOBLASTIC-LEUKEMIA; STEM-CELL TRANSPLANTATION; NATURAL-KILLER-CELLS; CD8(+) T-CELLS; I CLINICAL-TRIAL; ADOPTIVE IMMUNOTHERAPY; PHASE-I; NEUROBLASTOMA PATIENTS; IMMUNE RECONSTITUTION; GENETIC-MODIFICATION AB The Second International Conference on Immunotherapy in Pediatric Oncology was held in Houston, Texas, USA, October 11-12, 2010, to discuss the progress and challenges that have occurred in cutting edge immunotherapeutic strategies currently being developed for pediatric oncology. Major topics included immune targeting of acute lymphoblastic leukemia and pediatric solid tumors, chimeric antigen receptors (CARs) for hematologic malignancies and solid tumors, enhancing graft-versus-leukemia for pediatric cancers, overcoming hurdles of immunotherapy, strategies to active the innate immune system, and moving immunotherapy beyond phase I studies. Significant progress has been made in the last 2 years both in the development of novel immunobiologics such as CARs, and in establishing survival benefits of an anti-GD2 monoclonal antibody in randomized studies. Although there is much excitement going forward, a great deal of laboratory and regulatory challenges lie ahead in improving the efficacy of each of these modalities as well as getting them to patients in a timely and cost-effective fashion. The resulting discussions will hopefully lead to new collaborations and insight for further translational and clinical studies. C1 [Capitini, Christian M.; Mackall, Crystal L.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gottschalk, Stephen; Brenner, Malcolm] Texas Childrens Hosp, Ctr Cell & Gene Therapy, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Gottschalk, Stephen; Brenner, Malcolm] Baylor Coll Med, Houston, TX 77030 USA. [Cooper, Laurence J. N.] Univ Texas MD Anderson Canc Ctr, Div Pediat, Houston, TX 77030 USA. [Handgretinger, Rupert] Univ Tubingen, Dept Pediat Hematol Oncol, Childrens Univ Hosp, Tubingen, Germany. RP Capitini, CM (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,MSC 1104, Bethesda, MD 20892 USA. EM capitinic@mail.nih.gov OI Capitini, Christian/0000-0002-2276-6731 FU National Institutes of Health FX This work was funded by the intramural research program at the National Institutes of Health. NR 81 TC 4 Z9 4 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0888-0018 J9 PEDIATR HEMAT ONCOL JI Pediatr. Hematol. Oncol. PD SEP PY 2011 VL 28 IS 6 BP 459 EP U21 DI 10.3109/08880018.2011.596615 PG 18 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 809OF UT WOS:000294065900001 PM 21854215 ER PT J AU Venkatesan, AM Kadoury, S Abi-Jaoudeh, N Levy, EB Maass-Moreno, R Krucker, J Dalal, S Xu, S Glossop, N Wood, BJ AF Venkatesan, Aradhana M. Kadoury, Samuel Abi-Jaoudeh, Nadine Levy, Elliot B. Maass-Moreno, Roberto Kruecker, Jochen Dalal, Sandeep Xu, Sheng Glossop, Neil Wood, Bradford J. TI Real-time FDG PET Guidance during Biopsies and Radiofrequency Ablation Using Multimodality Fusion with Electromagnetic Navigation SO RADIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; F-18-FDG PET; CANCER; REGISTRATION; FEASIBILITY; EXPERIENCE; TRACKING; LESIONS AB Purpose: To assess the feasibility of combined electromagnetic device tracking and computed tomography (CT)/ultrasonography (US)/fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) fusion for real-time feedback during percutaneous and intraoperative biopsies and hepatic radiofrequency (RF) ablation. Materials and Methods: In this HIPAA-compliant, institutional review board-approved prospective study with written informed consent, 25 patients (17 men, eight women) underwent 33 percutaneous and three intraoperative biopsies of 36 FDG-avid targets between November 2007 and August 2010. One patient underwent biopsy and RF ablation of an FDG-avid hepatic focus. Targets demonstrated heterogeneous FDG uptake or were not well seen or were totally inapparent at conventional imaging. Preprocedural FDG PET scans were rigidly registered through a semiautomatic method to intraprocedural CT scans. Coaxial biopsy needle introducer tips and RF ablation electrode guider needle tips containing electromagnetic sensor coils were spatially tracked through an electromagnetic field generator. Real-time US scans were registered through a fiducial-based method, allowing US scans to be fused with intraprocedural CT and preacquired FDG PET scans. A visual display of US/CT image fusion with overlaid coregistered FDG PET targets was used for guidance; navigation software enabled real-time biopsy needle and needle electrode navigation and feedback. Results: Successful fusion of real-time US to coregistered CT and FDG PET scans was achieved in all patients. Thirty-one of 36 biopsies were diagnostic (malignancy in 18 cases, benign processes in 13 cases). RF ablation resulted in resolution of targeted FDG avidity, with no local treatment failure during short follow-up (56 days). Conclusion: Combined electromagnetic device tracking and image fusion with real-time feedback may facilitate biopsies and ablations of focal FDG PET abnormalities that would be challenging with conventional image guidance. (C) RSNA, 2011 C1 [Venkatesan, Aradhana M.; Abi-Jaoudeh, Nadine; Levy, Elliot B.; Wood, Bradford J.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Kadoury, Samuel; Kruecker, Jochen; Dalal, Sandeep; Xu, Sheng] Philips Res, Briarcliff Manor, NY USA. [Maass-Moreno, Roberto] NIH, Div Nucl Med, Bethesda, MD 20892 USA. [Glossop, Neil] Focused Ultrasound Surg Fdn, Charlottesville, VA USA. RP Venkatesan, AM (reprint author), NIH, Ctr Intervent Oncol Radiol & Imaging Sci, 10 Ctr Dr,Bldg 10,Room 1C369,MSC 1182, Bethesda, MD 20892 USA. EM VenkatesanA@cc.nih.gov FU National Institutes of Health (NIH) Center for Interventional Oncology; NIH Intramural Research Program; NIH Center for Interventional Oncology and Philips Research (Briarcliff, NY); Traxtal (Toronto, Ontario, Canada), now Philips Healthcare FX Supported in part by the National Institutes of Health (NIH) Center for Interventional Oncology, NIH Intramural Research Program, and Cooperative Research and Development Agreements between the NIH Center for Interventional Oncology and Philips Research (Briarcliff, NY), and Traxtal (Toronto, Ontario, Canada), now Philips Healthcare. NR 25 TC 44 Z9 45 U1 0 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2011 VL 260 IS 3 BP 848 EP 856 DI 10.1148/radiol.11101985 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 808AI UT WOS:000293944700028 PM 21734159 ER PT J AU Ilias, I Divgi, C Pacak, K AF Ilias, Ioannis Divgi, Chaitanya Pacak, Karel TI Current Role of Metaiodobenzylguanidine in the Diagnosis of Pheochromocytoma and Medullary Thyroid Cancer SO SEMINARS IN NUCLEAR MEDICINE LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; I-123 METAIODOBENZYLGUANIDINE; METASTATIC PHEOCHROMOCYTOMA; PROCEDURE GUIDELINES; MIBG SCINTIGRAPHY; PARAGANGLIOMAS; LOCALIZATION; I-123-METAIODOBENZYLGUANIDINE; THERAPY; PHARMACOKINETICS AB Despite early reports of excellent diagnostic characteristics of [(131)I]/[(231)I]-metaiodobenzylguanidine (MIBG) in the evaluation of pheochromocytomas/paragangliornas (PHEOs/PGLs) or medullary thyroid cancer as experience with it was accumulated, the sensitivity dropped. Nevertheless, this modality is still useful in the diagnostic work-up of PHEOs/PGLs because it is widely available, and in case of positive scans it might indicate patients who are potential candidates for [(131)I]MIBG therapy. Semin Nucl Med 41:364-368. Published by Elsevier Inc. C1 [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, CRC, Bethesda, MD 20892 USA. [Ilias, Ioannis] E Venizelou Hosp, Dept Endocrinol, Athens, Greece. [Divgi, Chaitanya] Columbia Univ, Kreitchman PET Ctr, New York, NY USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, CRC, Bldg 10,Room 1E-3140,10 Ctr Dr MSC-1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Eunice Shriver Kennedy National Institute of Child Health and Development FX Support for this work was provided in part by the intramural research program of the Eunice Shriver Kennedy National Institute of Child Health and Development. I.I. and K.P. would like to thank Ms Millie Whatley, CNMT for her assistance in preparing this manuscript. I.I. would like to thank Dr M. Kesse-Elias for her critical review of the manuscript. NR 45 TC 14 Z9 14 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 0001-2998 J9 SEMIN NUCL MED JI Semin. Nucl. Med. PD SEP PY 2011 VL 41 IS 5 BP 364 EP 368 DI 10.1053/j.semnuclmed.2011.03.003 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 810CR UT WOS:000294103500006 PM 21803186 ER PT J AU Kumar, M Bhadoria, DP Dutta, K Singh, S Gupta, J Kumar, R Chhillar, AK Yadav, V Singh, B Sharma, GL AF Kumar, Manish Bhadoria, D. P. Dutta, Koushik Singh, Seema Gupta, Jyotsana Kumar, Ram Chhillar, Anil K. Yadav, Vibha Singh, Bharat Sharma, G. L. TI Combinatorial effect of TIMP-1 and alpha(1)AT gene polymorphisms on development of chronic obstructive pulmonary disease SO CLINICAL BIOCHEMISTRY LA English DT Article DE Alpha-1 antitrypsin; Tissue inhibitor of metalloproteinase-1; Gene interaction; Chronic obstructive pulmonary disease AB Objective: To study the role of alpha(1)AT and TIMP-1 gene polymorphisms in development of COPD. Design and methods: Blood samples from total 408 subjects (217 COPD patients and 191 controls) were used for genotyping and estimating biolevels of alpha(1)AT, TIMP-1 and inflammatory cytokines. Data was analyzed to determine the role of interaction of TIMP-1 and alpha(1)AT genes; and interplay between various genotypes and biolevels of alpha(1)AT, TIMP-1 and inflammatory cytokines in development of COPD. Results: Significantly low levels of alpha(1)AT and TIMP-1 were observed in COPD patients as compared to controls (P = 0.001), where as the inflammatory cytokines were found to be increased in patients. PIM3 allele of alpha(1)AT gene in COPD patients was found to be associated with low levels of alpha(1)AT (P = 0.001), the effect being more pronounced when PIM3 combined with rs6609533 of TIMP-1 gene (P = 0.0001). Combination of genotypes rs6609533 of TIMP-1 and PIM3 of alpha(1)AT containing the risk alleles was over-represented in patients (P = 0.005). Conclusion: The SNP rs6609533 of TIMP-1 gene interacted with PIM3 of alpha(1)AT to make a possible risk combination for development of COPD. (C) 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. C1 [Kumar, Manish; Singh, Seema; Kumar, Ram; Singh, Bharat; Sharma, G. L.] Inst Genom & Integrat Biol, Delhi 110007, India. [Bhadoria, D. P.; Dutta, Koushik] Maulana Azad Med Coll, New Delhi 110002, India. [Bhadoria, D. P.; Dutta, Koushik] Lok Nayak Jaiprakash Narayan Hosp, New Delhi 110002, India. [Kumar, Manish; Singh, Seema] Univ Pune, Dept Biotechnol, Pune 411007, Maharashtra, India. [Gupta, Jyotsana] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ H3G 1A4, Canada. [Chhillar, Anil K.] Maharshi Dayanand Univ, Ctr Biotechnol, Rohtak 124001, Haryana, India. [Yadav, Vibha] NIH, Bethesda, MD 20892 USA. RP Sharma, GL (reprint author), Inst Genom & Integrat Biol, Univ Campus,Mall Rd, Delhi 110007, India. EM manishkumarteo@gmail.com; dharampbhadoria@yahoo.co.in; sriduttakoushik@yahoo.com; seema.acbrdu@gmail.com; jyotsanagupta4@gmail.com; ramkumarbu@gmail.com; anil.chhillar@gmail.com; vibhabio@gmail.com; bharatsingh1601@gmail.com; drglsharma@hotmail.com FU University Grants Commission; Council of Scientific and Industrial Research, Govt. of India FX Manish Kumar is highly thankful to University Grants Commission and Council of Scientific and Industrial Research, Govt. of India for providing financial assistance. MK is also thankful to Director, Institute of Genomics and Integrative Biology for providing necessary research facilities at the Institute. NR 40 TC 8 Z9 8 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 EI 1873-2933 J9 CLIN BIOCHEM JI Clin. Biochem. PD SEP PY 2011 VL 44 IS 13 BP 1067 EP 1073 DI 10.1016/j.clinbiochem.2011.06.986 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA V31BA UT WOS:000208857900008 PM 21763297 ER PT J AU Koup, RA Douek, DC AF Koup, Richard A. Douek, Daniel C. TI Vaccine Design for CD8 T Lymphocyte Responses SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article AB Vaccines are arguably the most powerful medical intervention in the fight against infectious diseases. The enormity of the global human immunodeficiency virus type 1 (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic makes the development of an AIDS vaccine a scientific and humanitarian priority. Research on vaccines that induce T-cell immunity has dominated much of the recent development effort, mostly because of disappointing efforts to induce neutralizing antibodies through vaccination. Whereas T cells are known to limit HIV and other virus infections after infection, their role in protection against initial infection is much less clear. In this article, we will review the rationale behind a T-cell-based vaccine approach, provide an overview of the methods and platforms that are being applied, and discuss the impact of recent vaccine trial results on the future direction of T-cell vaccine research. C1 [Koup, Richard A.; Douek, Daniel C.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Koup, RA (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM rkoup@mail.nih.gov NR 118 TC 43 Z9 44 U1 3 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD SEP PY 2011 VL 1 IS 1 AR a007252 DI 10.1101/cshperspect.a007252 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA V27OZ UT WOS:000208623800007 PM 22229122 ER PT J AU Kwong, PD Mascola, JR Nabel, GJ AF Kwong, Peter D. Mascola, John R. Nabel, Gary J. TI Rational Design of Vaccines to Elicit Broadly Neutralizing Antibodies to HIV-1 SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article AB The development of a highly effective AIDS vaccine will likely depend on success in designing immunogens that elicit broadly neutralizing antibodies to naturally circulating strains of HIV-1. Although the antibodies induced after natural infection with HIV-1 are often directed to strain-specific or nonneutralizing determinants, it is now evident that 10%-25% of HIV-infected individuals generate neutralizing antibody responses of considerable breadth. In the past, only four broadly neutralizing monoclonal antibodies had been defined, but more than a dozen monoclonal antibodies of substantial breadth have more recently been isolated. An understanding of their recognition sites, the structural basis of their interaction with the HIV Env, and their development pathways provides new opportunities to design vaccine candidates that will elicit broadly protective antibodies against this virus. C1 [Kwong, Peter D.; Mascola, John R.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gnabel@nih.gov NR 102 TC 64 Z9 65 U1 1 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD SEP PY 2011 VL 1 IS 1 AR a007278 DI 10.1101/cshperspect.a007278 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA V27OZ UT WOS:000208623800008 PM 22229123 ER PT J AU Grant, C Dunleavy, K Eberle, FC Pittaluga, S Wilson, WH Jaffe, ES AF Grant, Cliona Dunleavy, Kieron Eberle, Franziska C. Pittaluga, Stefania Wilson, Wyndham H. Jaffe, Elaine S. TI Primary Mediastinal Large B-Cell Lymphoma, Classic Hodgkin Lymphoma Presenting in the Mediastinum, and Mediastinal Gray Zone Lymphoma: What is the Oncologist To Do? SO CURRENT HEMATOLOGIC MALIGNANCY REPORTS LA English DT Article DE Hodgkin lymphoma; Hodgkin's disease; Mediastinal lymphomas; Primary mediastinal large B-cell lymphoma; Thymic lymphoma; Diffuse large B-cell lymphoma; DLBCL; Gray zone lymphoma; Grey zone lymphoma; Epigenetics; Gene expression profiling; Radiation therapy; Chemotherapy; Immunophenotyping; Microenvironment ID REED-STERNBERG CELLS; RADIATION-THERAPY; TRANSCRIPTION FACTORS; ABVD CHEMOTHERAPY; CD23 EXPRESSION; DISEASE; FEATURES; IMMUNOGLOBULIN; BOB.1/OBF.1; EXPERIENCE AB In recent years, an overlap in biologic and clinical features has been identified between classic Hodgkin lymphoma (CHL) and primary mediastinal large B-cell lymphoma (PMBL). Further strengthening this relationship is the identification of lymphomas with clinical and morphologic features transitional between the two, known as gray zone lymphomas (GZL). However, this diagnostic gray zone is not just of theoretical interest: it presents a practical problem, as the treatment approaches for CHL traditionally differ from those for aggressive B-cell lymphomas. This article reviews the treatment approach for mediastinal lymphomas, including CHL of the nodular sclerosis subtype (CHL-NS), PMBL, and mediastinal GZL. Though several trials have evaluated different regimens with or without radiation in PMBL and CHL-NS, there is a lack of prospective experience in treating GZL because of the rarity of these tumors. Historical data indicate that they have done poorly with traditional approaches developed for the treatment of either CHL or diffuse large B-cell lymphoma. C1 [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Grant, Cliona; Dunleavy, Kieron; Wilson, Wyndham H.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Eberle, Franziska C.] Univ Tubingen, Dept Dermatol, Tubingen, Germany. [Pittaluga, Stefania] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. EM ejaffe@mail.nih.gov OI Jaffe, Elaine/0000-0003-4632-0301 NR 49 TC 25 Z9 25 U1 0 U2 4 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1558-8211 J9 CURR HEMATOL MALIG R JI Curr. Hematol. Malig. Rep. PD SEP PY 2011 VL 6 IS 3 BP 157 EP 163 DI 10.1007/s11899-011-0090-1 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 023BP UT WOS:000310008200002 PM 21590365 ER PT J AU Yewdell, JW AF Yewdell, Jonathan W. TI Viva la revolucion: rethinking influenza A virus antigenic drift SO CURRENT OPINION IN VIROLOGY LA English DT Article ID MONOCLONAL-ANTIBODIES; INFECTED CELLS; STEM REGION; HEMAGGLUTININ; BINDING; VARIANTS; MICE; NEUTRALIZATION; IMMUNITY; EPITOPE AB Rapid antigenic evolution of the influenza A virus hemagglutinin has precluded developing vaccines that provide durable protection. The yearly costs of influenza (circa $10(11) in the USA alone) easily justify investments in better understanding the interaction of influenza with antibodies and other inducible elements of the immune system that potentially limit or circumvent antigenic variation. Here, I summarize exciting new findings that offer the possibility of a quantum improvement in vaccine efficacy, focusing on studies clearly documenting robust neutralizing antibody responses to the conserved stem region of the hemagglutinin. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@nih.gov FU Intramural NIH HHS [ZIA AI001055-02, ZIA AI001104-01] NR 57 TC 14 Z9 14 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD SEP PY 2011 VL 1 IS 3 BP 177 EP 183 DI 10.1016/j.coviro.2011.05.005 PG 7 WC Virology SC Virology GA 051FR UT WOS:000312112100004 PM 22034587 ER PT J AU Nishimura, Y Martin, MA AF Nishimura, Yoshiaki Martin, Malcolm A. TI The acute HIV infection: implications for intervention, prevention and development of an effective AIDS vaccine SO CURRENT OPINION IN VIROLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CD4(+) T-CELLS; HIV-1/SIV CHIMERIC VIRUS; RHESUS-MONKEYS; SIV INFECTION; IN-VIVO; INTRAVAGINAL INOCULATION; NEUTRALIZING ANTIBODIES; ANTIRETROVIRAL THERAPY; VAGINAL TRANSMISSION AB Effective preventive measures against HIV must function near the time of virus transmission to prevent the establishment of a chronic infection. Low-dose SIV/SHIV infections by multiple routes lead to remarkably rapid systemic dissemination of virus and large numbers of infected cells during the initial weeks of the acute infection. Here we describe the narrow time-frame during which potent post-exposure interventions such as anti-retroviral therapy or the administration of high-titered neutralizing antibodies can block the establishment of the in vivo infection. This short window of opportunity is applicable to HIV infections and represents a formidable challenge for developing effective chemoprophylaxis and vaccine approaches. C1 [Nishimura, Yoshiaki; Martin, Malcolm A.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM malm@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Our work is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 47 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD SEP PY 2011 VL 1 IS 3 BP 204 EP 210 DI 10.1016/j.coviro.2011.05.007 PG 7 WC Virology SC Virology GA 051FR UT WOS:000312112100007 PM 21909345 ER PT J AU Cleary, P Braffett, B Maynard, J Cowie, C Gubitosi-Klug, R Orchard, T AF Cleary, P. Braffett, B. Maynard, J. Cowie, C. Gubitosi-Klug, R. Orchard, T. TI Association of skin intrinsic fluorescence with cumulative glycaemic exposure in the DCCT/EDIC study SO DIABETOLOGIA LA English DT Meeting Abstract CT 47th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 12-16, 2011 CL Lisbon, PORTUGAL SP European Assoc Study Diabet (EASD) C1 [Cleary, P.; Braffett, B.] George Washington Univ, Rockville, MD USA. [Maynard, J.] VeraLight, Albuquerque, NM USA. [Cowie, C.] NIDDK, Bethesda, MD USA. [Gubitosi-Klug, R.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Orchard, T.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2011 VL 54 SU 1 MA 339 BP S146 EP S146 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 990ZT UT WOS:000307671300340 ER PT J AU Deters, N Stokes, RA Ho, K Lau, S Cheng, K Scott, C Lau, S Girgis, C Adams, M Cha, K Gonzalez, F Gunton, JE AF Deters, N. Stokes, R. A. Ho, K. Lau, S. Cheng, K. Scott, C. Lau, S. Girgis, C. Adams, M. Cha, K. Gonzalez, F. Gunton, J. E. TI It's between the ears: role of hypoxia inducible factor 1alpha (HIF1alpha) activity in obesity SO DIABETOLOGIA LA English DT Meeting Abstract CT 47th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 12-16, 2011 CL Lisbon, PORTUGAL SP European Assoc Study Diabet (EASD) C1 [Deters, N.; Stokes, R. A.; Ho, K.; Lau, S.; Cheng, K.; Scott, C.; Lau, S.; Girgis, C.; Adams, M.; Cha, K.] St Vincents Hosp, Garvan Inst Med Res, Diabet & Transcript Factors Grp, Darlinghurst, NSW 2010, Australia. [Gonzalez, F.; Gunton, J. E.] NCI, Lab Metab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2011 VL 54 SU 1 MA 138 BP S64 EP S64 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 990ZT UT WOS:000307671300139 ER PT J AU Dicembrini, I Di Pasquale, G Raimondi, L Pagano, C Egan, JM Cozzi, A Cinci, L Manni, ME Morelli, A Baum, BJ Maggi, M Vettor, R Chiorini, JA Mannucci, E Rotella, CM AF Dicembrini, I. Di Pasquale, G. Raimondi, L. Pagano, C. Egan, J. M. Cozzi, A. Cinci, L. Manni, M. E. Morelli, A. Baum, B. J. Maggi, M. Vettor, R. Chiorini, J. A. Mannucci, E. Rotella, C. M. TI Sustained Exendin-4 secretion through gene therapy targeting salivary glands in Zucker fa/fa rats and high fat diet mice SO DIABETOLOGIA LA English DT Meeting Abstract CT 47th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 12-16, 2011 CL Lisbon, PORTUGAL SP European Assoc Study Diabet (EASD) C1 [Morelli, A.; Maggi, M.] Univ Florence, Androl Unit, I-50121 Florence, Italy. [Baum, B. J.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Pagano, C.; Vettor, R.] Univ Padua, I-35100 Padua, Italy. [Mannucci, E.] Careggi Teaching Hosp, Diabet Agcy, Florence, Italy. RI Raimondi, laura/A-9280-2013 NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2011 VL 54 SU 1 MA 512 BP S213 EP S213 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 990ZT UT WOS:000307671301167 ER PT J AU Gonzalez, N Ramos-Alvarez, I Martin-Duce, A Sanz, R Portal-Nunez, S Gutierrez-Rojas, I Acitores, A Moreno, P Jensen, RT Villanueva-Penacarrilo, ML AF Gonzalez, N. Ramos-Alvarez, I. Martin-Duce, A. Sanz, R. Portal-Nunez, S. Gutierrez-Rojas, I. Acitores, A. Moreno, P. Jensen, R. T. Villanueva-Penacarrilo, M. L. TI Key role of BRS-3 receptor in the glucose metabolism in human skeletal muscle SO DIABETOLOGIA LA English DT Meeting Abstract CT 47th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 12-16, 2011 CL Lisbon, PORTUGAL SP European Assoc Study Diabet (EASD) C1 [Gonzalez, N.; Ramos-Alvarez, I.; Sanz, R.; Portal-Nunez, S.; Gutierrez-Rojas, I.; Acitores, A.; Moreno, P.; Villanueva-Penacarrilo, M. L.] IIS Fdn Jimenez Diaz, Madrid, Spain. [Martin-Duce, A.] Univ Alcala de Henares, Madrid, Spain. [Jensen, R. T.] NIH, DDB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2011 VL 54 SU 1 MA 547 BP S226 EP S226 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 990ZT UT WOS:000307671301202 ER PT J AU Li, G Zhang, P Wang, J An, Y Gong, Q Gregg, EW Roglic, G Yang, W Zhang, B Hu, Y Bennett, PH AF Li, G. Zhang, P. Wang, J. An, Y. Gong, Q. Gregg, E. W. Roglic, G. Yang, W. Zhang, B. Hu, Y. Bennett, P. H. TI Modifiable predictors of cardiovascular disease and mortality in Chinese with impaired glucose tolerance: 23-year follow-up of the Daqing diabetes prevention study SO DIABETOLOGIA LA English DT Meeting Abstract CT 47th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 12-16, 2011 CL Lisbon, PORTUGAL SP European Assoc Study Diabet (EASD) C1 [Li, G.; An, Y.; Gong, Q.; Yang, W.; Zhang, B.] China Japan Friendship Hosp, Beijing, Peoples R China. [Zhang, P.; Gregg, E. W.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Wang, J.; Hu, Y.] Daqing First Hosp, Daqing, Peoples R China. [Roglic, G.] WHO, CH-1211 Geneva, Switzerland. [Bennett, P. H.] NIH, Phoenix Epidemiol & Clin Res Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2011 VL 54 SU 1 MA 306 BP S133 EP S133 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 990ZT UT WOS:000307671300307 ER PT J AU Ramos-Alvarez, I Martin-Duce, A Sanz, R Portal-Nunez, S Muguerza, J Rodriguez, A Gutierrez-Rojas, I Acitores, A Moreno, P Jensen, RT Villanueva-Penacarrilo, ML Gonzalez, N AF Ramos-Alvarez, I. Martin-Duce, A. Sanz, R. Portal-Nunez, S. Mugueerza, J. Rodriguez, A. Gutierrez-Rojas, I. Acitores, A. Moreno, P. Jensen, R. T. Villanueva-Penacarrilo, M. L. Gonzalez, N. TI Receptor subtype-3 (BRS-3): a candidate as therapeutic molecular target in obesity SO DIABETOLOGIA LA English DT Meeting Abstract CT 47th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 12-16, 2011 CL Lisbon, PORTUGAL SP European Assoc Study Diabet (EASD) C1 [Ramos-Alvarez, I.; Sanz, R.; Portal-Nunez, S.; Gutierrez-Rojas, I.; Acitores, A.; Moreno, P.; Villanueva-Penacarrilo, M. L.; Gonzalez, N.] IIS Fdn Jimenez Diaz, Madrid, Spain. [Martin-Duce, A.] Univ Alcala de Henares, Madrid, Spain. [Mugueerza, J.; Rodriguez, A.] Hosp Principe Asturias, Madrid, Spain. [Jensen, R. T.] NIH, DDB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2011 VL 54 SU 1 MA 548 BP S226 EP S227 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 990ZT UT WOS:000307671301203 ER PT J AU Scott, RA Manning, AK Hivert, MF Bouatia-Naji, N Grimsby, J Liu, CT Chen, H Bielak, LF Rasmussen-Torvik, L Wareham, NJ Watanabe, RM Florez, JC Langenberg, C Dupuis, J Meigs, JB AF Scott, R. A. Manning, A. K. Hivert, M. -F. Bouatia-Naji, N. Grimsby, J. Liu, C. -T. Chen, H. Bielak, L. F. Rasmussen-Torvik, L. Wareham, N. J. Watanabe, R. M. Florez, J. C. Langenberg, C. Dupuis, J. Meigs, J. B. TI Genome-wide joint meta-analysis of SNP by BMI interaction on fasting insulin: a MAGIC study SO DIABETOLOGIA LA English DT Meeting Abstract CT 47th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 12-16, 2011 CL Lisbon, PORTUGAL SP European Assoc Study Diabet (EASD) C1 [Scott, R. A.; Wareham, N. J.; Langenberg, C.] MRC Epidemiol Unit, Cambridge, England. [Manning, A. K.; Liu, C. -T.; Chen, H.; Dupuis, J.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Hivert, M. -F.] Univ Sherbrooke, Quebec City, PQ, Canada. [Bouatia-Naji, N.] Inst Pasteur, F-59019 Lille, France. [Grimsby, J.; Florez, J. C.; Meigs, J. B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bielak, L. F.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Rasmussen-Torvik, L.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Watanabe, R. M.] USC, Keck Sch Med, Los Angeles, CA USA. [Florez, J. C.; Meigs, J. B.] Harvard Univ, Sch Med, Boston, MA USA. [Dupuis, J.] NHLBI, Framingham Heart Study, Framingham, MA USA. RI BOUATIA-NAJI, NABILA/D-5863-2013 NR 0 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2011 VL 54 SU 1 MA 166 BP S76 EP S76 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 990ZT UT WOS:000307671300167 ER PT J AU Brown, EE Pelser, C Vitale, F Lauria, C Dipasquale, M Stella, S Manzella, L Amodio, E Gafa, L Messina, A Romano, N Goedert, JJ AF Brown, E. E. Pelser, C. Vitale, F. Lauria, C. Dipasquale, M. Stella, S. Manzella, L. Amodio, E. Gafa, L. Messina, A. Romano, N. Goedert, J. J. TI CONTROLLED CASE STUDY ON CLASSIC KAPOSI SARCOMA: IMMUNITY AND HEMATOLOGICAL PARAMETERS SO EPIDEMIOLOGIA & PREVENZIONE LA Italian DT Meeting Abstract C1 [Brown, E. E.; Pelser, C.; Goedert, J. J.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Vitale, F.; Amodio, E.; Romano, N.] Univ Palermo, Dipartimento Igiene & Microbiol Giuseppe DAlessan, I-90133 Palermo, Italy. [Lauria, C.; Dipasquale, M.; Gafa, L.] Lega Italiana Lotta Contro & Tumori, Sez Ragusa, Ragusa, Italy. [Stella, S.; Manzella, L.; Messina, A.] Univ Catania, Dipartimento Sci Biomed, I-95124 Catania, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFERENZE SCARL PI MILANO PA VIA RICCIARELLI N 29, MILANO, 20148, ITALY SN 1120-9763 J9 EPIDEMIOL PREV JI Epidemiol. Prev. PD SEP-DEC PY 2011 VL 35 IS 5-6 SU 1 MA 226 BP 137 EP 137 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V44YN UT WOS:000209784400142 ER PT J AU Sullivan, R Peppercorn, J Sikora, K Zalcberg, J Meropol, N Amir, E Khayat, D Boyle, P Tannock, I Fojo, T AF Sullivan, R. Peppercorn, J. Sikora, K. Zalcberg, J. Meropol, N. Amir, E. Khayat, D. Boyle, P. Tannock, I. Fojo, T. TI Delivering Affordable Cancer Care in High-income Countries: a Lancet Oncology Commission SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Sullivan, R.] Kings Coll London, Kings Hlth Partners Integrated Canc Ctr, London WC2R 2LS, England. [Peppercorn, J.] Duke Univ, Duke Canc Inst, Medicial Ctr, Durham, NC 27706 USA. [Sikora, K.] CancerPartnersUK, Head Off, London, England. [Zalcberg, J.] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Meropol, N.] Case Western Reserve Univ, Univ Hosp Seidman Canc Ctr, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Amir, E.; Tannock, I.] Princess Margaret Hosp, Div Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. [Amir, E.; Tannock, I.] Univ Toronto, Toronto, ON, Canada. [Khayat, D.] Hop La Pitie Salpetriere, Div Oncol, Paris, France. [Boyle, P.] Int Prevent Res Inst, Head Off, Lyon, France. [Fojo, T.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 2 MA 8LBA BP 6 EP 6 PG 1 WC Oncology SC Oncology GA V40HU UT WOS:000209470500015 ER PT J AU FitzGerald, MP DuBeau, CE Kraus, SR Johnson, HW Rahn, DD Mallett, V Stoddard, AM Zyczynski, HM AF FitzGerald, Mary P. DuBeau, Catherine E. Kraus, Stephen R. Johnson, Harry W., Jr. Rahn, David D. Mallett, Veronica Stoddard, Anne M. Zyczynski, Halina M. CA Urinary Incontinence Treatment Net TI Patient Expectations Did Not Predict Outcome of Drug and Behavioral Treatment of Urgency Urinary Incontinence SO FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY LA English DT Article DE urinary incontinence; urinary urgency incontinence; patient expectations AB Objectives: This study aimed to determine whether expectations of treatment outcomes in women participating in a drug and behavioral treatment trial for urge urinary incontinence are related to patient factors, demographics, health-related locus of control, and treatment outcomes. Methods: Baseline assessments included expectations (improvement in bladder condition, time to improvement in bladder condition, and duration of improvement) and the Medical Health Locus of Control (MHLC) scale. Outcomes were measured by the Patient Global Impression of Improvement scale (PGI-I) at the end of active treatment (10 weeks) and 8 months after trial start. Results: At baseline among 173 subjects, 114 (66%) believed their incontinence would get "very much better," 94 (55%) expected improvement by 1 month, and 111 (66%) expected improvement would last for the rest of their lives. There were no significant associations between baseline expectations or MHLC with the Patient Global Impression of Improvement scale at 10 weeks or 8 months. Conclusions: Expectations of treatment outcome and MHLC did not predict eventual patient-reported treatment outcome in this sample of women with urge-predominant urinary incontinence participating in a trial of drug and behavioral therapy. C1 [FitzGerald, Mary P.] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [DuBeau, Catherine E.] Univ Massachusetts, Sch Med, Mem Med Ctr, Boston, MA 02125 USA. [Kraus, Stephen R.] Univ Texas San Antonio, Hlth Sci Ctr, San Antonio, TX USA. [Johnson, Harry W., Jr.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Rahn, David D.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Mallett, Veronica] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Stoddard, Anne M.] New England Res Inst, Watertown, MA 02172 USA. [Zyczynski, Halina M.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Urinary Incontinence Treatment Net] NIDDK, Bethesda, MD USA. RP FitzGerald, MP (reprint author), Loyola Univ, Med Ctr, Div Female Pelv Med & Reconstruct Surg, 2160 S First Ave,Bldg 103,Room 1004, Maywood, IL 60153 USA. EM Mfitzg8@lumc.edu FU National Institutes of Health; William Beaumont Hospital [U01 DK58231]; Loyola University Medical Center [U01 DK60379]; University of Alabama, Birmingham, AL [U01 DK60380]; University of California, San Diego, CA [U01 DK60401]; University of Maryland, Baltimore, MD [U01 DK60397]; University of Pittsburgh, Pittsburgh, PA [U01 DK 58225]; University of Texas Southwestern, Dallas, TX [U01 DK60395]; University of Texas Health Sciences Center, San Antonio, TX [U01 DK58234]; University of Utah, Salt Lake City, UT [U01 DK60393]; New England Research Institutes, Watertown, MA [U01 DK58229] FX This study was financially supported by the National Institutes of Health; William Beaumont Hospital (U01 DK58231); Loyola University Medical Center (U01 DK60379); University of Alabama, Birmingham, AL (U01 DK60380); University of California, San Diego, CA (U01 DK60401); University of Maryland, Baltimore, MD (U01 DK60397); University of Pittsburgh, Pittsburgh, PA (U01 DK 58225); University of Texas Southwestern, Dallas, TX (U01 DK60395); University of Texas Health Sciences Center, San Antonio, TX (U01 DK58234); University of Utah, Salt Lake City, UT (U01 DK60393); and New England Research Institutes, Watertown, MA (U01 DK58229). NR 20 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2151-8378 J9 FEMALE PELVIC MED RE JI Female Pelvic Med. Reconstr. Surg. PD SEP-OCT PY 2011 VL 17 IS 5 BP 231 EP 237 DI 10.1097/SPV.0b013e31822dd10b PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA V35WQ UT WOS:000209176400006 PM 22453106 ER PT J AU Saenz, C AF Saenz, Carla TI AFFORDABILITY OF HEALTH CARE: A GENDER-RELATED PROBLEM AND A GENDER-RESPONSIVE SOLUTION SO INTERNATIONAL JOURNAL OF FEMINIST APPROACHES TO BIOETHICS LA English DT Article AB Evidence shows that women have greater difficulty than men in affording health care. But what is it to afford health care? According to the reasonable tradeoff account of affordability, individuals can afford health care if paying for it does not require them to make tradeoffs that are not reasonable that is, if in order to pay for health care they do not have to sacrifice something as important as having one's health covered. Unlike alternative accounts of affordability, which are empirically based and needs-based, the reasonable tradeoff account can solve the genuine affordability problems that both men and women experience, and close the gender gap in the affordability of health care. C1 [Saenz, Carla] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 1 U2 1 PU INDIANA UNIV PRESS PI BLOOMINGTON PA 601 N MORTON STREET, BLOOMINGTON, IN 47404-3797 USA SN 1937-4585 J9 INT J FEM APPROACHES JI Int. J. Fem. Approaches Bioeth. PD FAL PY 2011 VL 4 IS 2 BP 144 EP 153 PG 10 WC Ethics; Social Sciences, Biomedical; Women's Studies SC Social Sciences - Other Topics; Biomedical Social Sciences; Women's Studies GA V28CO UT WOS:000208659100007 ER PT J AU Polanco, FR Dominguez, DC Grady, C Stoll, P Ramos, C Mican, JM Miranda-Acevedo, R Morgan, M Aizvera, J Purdie, L Koziol, D Rivera-Goba, MV AF Polanco, Frinny R. Dominguez, Dinora C. Grady, Christine Stoll, Pamela Ramos, Catalina Mican, JoAnn M. Miranda-Acevedo, Robert Morgan, Marcela Aizvera, Jeasmine Purdie, Lori Koziol, Deloris Rivera-Goba, Migdalia V. TI Conducting HIV Research in Racial and Ethnic Minority Communities: Building a Successful Interdisciplinary Research Team SO JANAC-JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE LA English DT Article DE African American; clinical research; Hispanic; HIV; interdisciplinary; team building AB HIV infection occurs in disproportionately high rates among racial and ethnic minorities in the United States, making it imperative that individuals from these groups be included in research studies. However; it is often difficult to recruit HIV-infected Hispanics and African Americans in clinical trials, but a skilled interdisciplinary team that includes researchers with racial and ethnic diversity can help. This article describes a successful approach for building an interdisciplinary team that values the participation of racial and ethnic minorities in clinical trials and has the skills to work with these groups. The success of the Adelante (a Spanish word meaning forward) Team can be attributed to team members who actively participate in decision-making, are empowered, and function in a cohesive manner Successful research teams build relationships with research participants to increase the probability that racial and ethnic minorities will enroll and participate fully in research. Published by Elsevier Inc. on behalf of Association of Nurses in AIDS Care C1 [Polanco, Frinny R.; Stoll, Pamela; Purdie, Lori; Rivera-Goba, Migdalia V.] NIH, Nursing Serv, Ctr Clin, Bethesda, MD 20892 USA. [Polanco, Frinny R.; Stoll, Pamela; Purdie, Lori; Rivera-Goba, Migdalia V.] NIH, Patient Care Serv, Ctr Clin, Bethesda, MD 20892 USA. [Dominguez, Dinora C.] NIH, Patient Recruitment & Publ Liaison Sect, Ctr Clin, Bethesda, MD 20892 USA. [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Ramos, Catalina] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Mican, JoAnn M.] NIAID, Intramural Clin Management & Operat Branch, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Miranda-Acevedo, Robert] Natl Inst Deafness & Other Commun, Off Hlth Commun & Publ Liaison, NIH, Bethesda, MD USA. [Morgan, Marcela; Aizvera, Jeasmine] NIH, Dept Social Work, Ctr Clin, Bethesda, MD 20892 USA. [Koziol, Deloris] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Polanco, FR (reprint author), NIH, Nursing Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. FU Intramural Research Program of the NIH, Clinical Center FX This research was supported by the Intramural Research Program of the NIH, Clinical Center. NR 25 TC 7 Z9 7 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1055-3290 J9 J ASSOC NURSE AIDS C JI J. Assoc. Nurses Aids Care PD SEP-OCT PY 2011 VL 22 IS 5 BP 388 EP 396 DI 10.1016/j.jana.2010.10.008 PG 9 WC Nursing SC Nursing GA V28YP UT WOS:000208716400008 PM 21277228 ER PT J AU Brandt, DE Houtenville, AJ Huynh, MT Chan, L Rasch, EK AF Brandt, Diane E. Houtenville, Andrew J. Huynh, Minh T. Chan, Leighton Rasch, Elizabeth K. TI Connecting Contemporary Paradigms to the Social Security Administration's Disability Evaluation Process SO JOURNAL OF DISABILITY POLICY STUDIES LA English DT Article DE disability evaluation; Social Security Administration; impairment; functional ability ID HEALTH-STATUS ASSESSMENT; ITEM RESPONSE THEORY AB From 1998 to 2008, the Social Security Administration's (SSA) disability insurance program (DI) applications rose from 1.2 million to 2.3 million and exceeded 3 million in 2009. Given these large and growing numbers, even small changes in processing disability applications may reduce processing time, lower program costs, and improve performance of SSA's disability programs. A literature review examining current conceptual models of disability and SSA's disability evaluation process for adults was conducted. A gap exists between contemporary models of disability and how SSA defines and operationalizes disability. This is complicated by substantial variation in the timing, quantity, and quality of applicant functional information and workplace demands. A focus on impairment marginalizes more comprehensive assessment of function necessary to assess capacity for work. Novel assessment methodologies, such as computer adaptive testing to measure human functioning may hold promise for SSA's data collection methods and disability assessment. C1 [Rasch, Elizabeth K.] NIH, Epidemiol & Biostat Sect, Dept Rehabil Med, Clin Res Ctr, Bethesda, MD 20892 USA. [Houtenville, Andrew J.] Univ New Hampshire, Durham, NH 03824 USA. RP Brandt, DE (reprint author), NIH, Mark O Hatfield Clin Res Ctr, Dept Rehabil Med, 10 Ctr Dr,Room 1-1469,MSC 1604, Bethesda, MD 20892 USA. EM brandtdi@cc.nih.gov NR 64 TC 9 Z9 9 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1044-2073 EI 1538-4802 J9 J DISABIL POLICY STU JI J. Disabil. Policy Stud. PD SEP PY 2011 VL 22 IS 2 BP 116 EP 128 DI 10.1177/1044207310396509 PG 13 WC Rehabilitation SC Rehabilitation GA 054TV UT WOS:000312368000005 ER PT J AU Tinetti, ME McAvay, G Chang, SS Ning, YM Newman, AB Fitzpatrick, A Fried, TR Harris, TB Nevitt, MC Satterfield, S Yaffe, K Peduzzi, P AF Tinetti, Mary E. McAvay, Gail Chang, Sandy S. Ning, Yuming Newman, Anne B. Fitzpatrick, Annette Fried, Terri R. Harris, Tamara B. Nevitt, Michael C. Satterfield, Suzanne Yaffe, Kristine Peduzzi, Peter TI Effect of Chronic Disease-Related Symptoms and Impairments on Universal Health Outcomes in Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE chronic diseases; universal health outcomes; self-reported outcomes; clinical decision-making ID OBSTRUCTIVE PULMONARY-DISEASE; QUALITY-OF-LIFE; CARDIOVASCULAR HEALTH; HEART-FAILURE; SYSTOLIC FUNCTION; LUNG-FUNCTION; RISK-FACTORS; DISABILITY; MORTALITY; ASSOCIATION AB OBJECTIVES: To determine the extent to which disease-related symptoms and impairments, which constitute measures of disease severity or targets of therapy, account for the associations between chronic diseases and universal health outcomes. DESIGN: Cross-sectional. SETTING: The Cardiovascular Health Study (CHS) and the Health, Aging and Body Composition Study (Health ABC). PARTICIPANTS: Five thousand six hundred fifty-four CHS members and 2,706 Health ABC members. MEASUREMENTS: Diseases included heart failure (HF), chronic obstructive pulmonary disease (COPD), osteoarthritis, and cognitive impairment. The universal health outcomes included self-rated health, basic and instrumental activities of daily living (ADLs and IADLs), and death. Disease-related symptoms and impairments included HF symptoms and ejection fraction (EF) for HF, Dyspnea Scale and forced expiratory volume in 1 second for COPD, joint pain for osteoarthritis, and executive function for cognitive impairment. RESULTS: The diseases were associated with the universal health outcomes (P < .001) except osteoarthritis with death (both cohorts) and cognitive impairment with self-rated health (Health ABC). Symptoms and impairments accounted for 30% or more of each disease's effect on the universal health outcomes. In CHS, for example, HF was associated with one fewer (0.918) ADL and IADL performed without difficulty than no HF; HF symptoms accounted for 27% of this effect and EF for only 5%. The hazard ratio for death with HF was 6.5 (95% confidence interval = 4.7-8.9) with EF accounting for 40% and HF symptoms for only 14%. CONCLUSION: Disease-related symptoms and impairments accounted for much of the significant associations between the four chronic diseases and the universal health outcomes. Results support considering universal health outcomes as common metrics across diseases in clinical decision-making, perhaps by targeting the disease-related symptoms and impairments that contribute most strongly to the effect of the disease on the universal health outcomes. J Am Geriatr Soc 59: 1618-1627, 2011. C1 [Tinetti, Mary E.; McAvay, Gail; Chang, Sandy S.; Ning, Yuming; Fried, Terri R.] Yale Univ, Sch Med, Dept Med, New Haven, CT 06520 USA. [Tinetti, Mary E.; Peduzzi, Peter] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Fitzpatrick, Annette] Univ Washington, Sch Publ Hlth, Dept Epidemiol & Global Hlth, Seattle, WA 98195 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Nevitt, Michael C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. RP Tinetti, ME (reprint author), Yale Univ, Sch Med, Dept Internal Med Geriatr, POB 208025, New Haven, CT 06520 USA. EM mary.tinetti@yale.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging [R21 AG033, P30 AG021342244]; National Institutes of Health [UL1 RR024139]; NIH, National Institute on Aging; National Heart, Lung, and Blood Institute [N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295]; [N01AG-6-2101]; [N01AG-6-2103]; [N01AG-6-2106] FX This research was supported by R21 AG033244 and the Yale Pepper Center (P30 AG021342), both from the National Institute on Aging, and by a Clinical and Translational Science Award (UL1 RR024139) from the National Institutes of Health. Funding for Health study is from N01AG-6-2101, N01AG-6-2103, and N01AG-6-2106. This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging. CHS was supported by Contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and Grant U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. NR 56 TC 20 Z9 21 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2011 VL 59 IS 9 BP 1618 EP 1627 DI 10.1111/j.1532-5415.2011.03576.x PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 829WD UT WOS:000295615000007 PM 21883120 ER PT J AU Mens, H Kearney, M Wiegand, A Spindler, J Maldarelli, F Mellors, JW Coffin, JM AF Mens, Helene Kearney, Mary Wiegand, Ann Spindler, Jonathan Maldarelli, Frank Mellors, John W. Coffin, John M. TI Amplifying and Quantifying HIV-1 RNA in HIV Infected Individuals with Viral Loads Below the Limit of Detection by Standard Clinical Assays SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 55; single genome sequencing; SGS; real-time PCR; single-copy assay; SCA; HIV-1; ultra-sensitive; RNA extraction AB Amplifying viral genes and quantifying HIV-1 RNA in HIV-1 infected individuals with viral loads below the limit of detection by standard assays (below 50-75 copies/ml) is necessary to gain insight to viral dynamics and virus host interactions in patients who naturally control the infection and those who are on combination antiretroviral therapy (cART). Here we describe how to amplify viral genomes by single genome sequencing (the SGS protocol) (13, 19) and how to accurately quantify HIV-1 RNA in patients with low viral loads (the single-copy assay (SCA) protocol) (12, 20). The single-copy assay is a real-time PCR assay with sensitivity depending on the volume of plasma being assayed. If a single virus genome is detected in 7 ml of plasma, then the RNA copy number is reported to be 0.3 copies/ml. The assay has an internal control testing for the efficiency of RNA extraction, and controls for possible amplification from DNA or contamination. Patient samples are measured in triplicate. The single-genome sequencing assay (SGS), now widely used and considered to be non-labor intensive (3, 7, 12, 14, 15), is a limiting dilution assay, in which endpoint diluted cDNA product is spread over a 96-well plate. According to a Poisson distribution, when less than 1/3 of the wells give product, there is an 80% chance of the PCR product being resultant of amplification from a single cDNA molecule. SGS has the advantage over cloning of not being subjected to resampling and not being biased by PCR-introduced recombination (19). However, the amplification success of SCA and SGS depend on primer design. Both assays were developed for HIV-1 subtype B, but can be adapted for other subtypes and other regions of the genome by changing primers, probes, and standards. C1 [Mens, Helene; Kearney, Mary; Wiegand, Ann; Spindler, Jonathan; Maldarelli, Frank] NCI Frederick, Virol Core, HIV Drug Resistance Program, Bethesda, MD USA. [Mellors, John W.] Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA 15260 USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA USA. RP Mens, H (reprint author), NCI Frederick, Virol Core, HIV Drug Resistance Program, Bethesda, MD USA. EM Helene.mens@gmail.com FU F.M. Kirby Foundation FX J.M.C. was a Research Professor of the American Cancer Society with support from the F.M. Kirby Foundation. NR 20 TC 0 Z9 0 U1 1 U2 1 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD SEP PY 2011 IS 55 AR UNSP e2960 DI 10.3791/2960 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36OY UT WOS:000209222100008 ER PT J AU Xu, XH Jin, T AF Xu, Xuehua Jin, Tian TI Imaging G-protein Coupled Receptor (GPCR)-mediated Signaling Events that Control Chemotaxis of Dictyostelium Discoideum SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Molecular Biology; Issue 55; Chemotaxis; directional sensing; GPCR; PCR; G-proteins; signal transduction; Dictyostelium discoideum ID LEADING-EDGE; LIVING CELLS; CHEMOATTRACTANT; LOCALIZATION; ACTIVATION; GPCR AB Many eukaryotic cells can detect gradients of chemical signals in their environments and migrate accordingly (1). This guided cell migration is referred as chemotaxis, which is essential for various cells to carry out their functions such as trafficking of immune cells and patterning of neuronal cells (2, 3). A large family of G-protein coupled receptors (GPCRs) detects variable small peptides, known as chemokines, to direct cell migration in vivo (4). The final goal of chemotaxis research is to understand how a GPCR machinery senses chemokine gradients and controls signaling events leading to chemotaxis. To this end, we use imaging techniques to monitor, in real time, spatiotemporal concentrations of chemoattractants, cell movement in a gradient of chemoattractant, GPCR mediated activation of heterotrimeric G-protein, and intracellular signaling events involved in chemotaxis of eukaryotic cells (5-8). The simple eukaryotic organism, Dictyostelium discoideum, displays chemotaxic behaviors that are similar to those of leukocytes, and D. discoideum is a key model system for studying eukaryotic chemotaxis. As free-living amoebae, D. discoideum cells divide in rich medium. Upon starvation, cells enter a developmental program in which they aggregate through cAMP-mediated chemotaxis to form multicullular structures. Many components involved in chemotaxis to cAMP have been identified in D. discoideum. The binding of cAMP to a GPCR (cAR1) induces dissociation of heterotrimeric G-proteins into G gamma and G beta gamma subunits (7, 9, 10). G beta gamma subunits activate Ras, which in turn activates PI3K, converting PIP2 into PIP3 on the cell membrane (11-13). PIP3 serve as binding sites for proteins with pleckstrin Homology (PH) domains, thus recruiting these proteins to the membrane (14, 15). Activation of cAR1 receptors also controls the membrane associations of PTEN, which dephosphorylates PIP3 to PIP2 (16, 17). The molecular mechanisms are evolutionarily conserved in chemokine GPCR-mediated chemotaxis of human cells such as neutrophils (18). We present following methods for studying chemotaxis of D. discoideum cells. 1. Preparation of chemotactic component cells. 2. Imaging chemotaxis of cells in a cAMP gradient. 3. Monitoring a GPCR induced activation of heterotrimeric G-protein in single live cells. 4. Imaging chemoattractant-triggered dynamic PIP3 responses in single live cells in real time. Our developed imaging methods can be applied to study chemotaxis of human leukocytes. C1 [Xu, Xuehua; Jin, Tian] NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH, Bethesda, MD 26520 USA. RP Xu, XH (reprint author), NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH, Bethesda, MD 26520 USA. EM XXU@niaid.nih.gov OI xu, xuehua/0000-0002-3863-9593 FU NIAID, NIH FX This work is supported by the intramural fund from NIAID, NIH. NR 18 TC 1 Z9 1 U1 1 U2 5 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD SEP PY 2011 IS 55 AR UNSP e3128 DI 10.3791/3128 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36OY UT WOS:000209222100021 ER EF