FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Miller, FG Joffe, S AF Miller, Franklin G. Joffe, Steven TI Balancing Access and Evaluation in the Approval of New Cancer Drugs SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID ACCELERATED APPROVAL; CLINICAL-TRIALS C1 [Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Joffe, Steven] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Joffe, Steven] Childrens Hosp, Dept Med, Boston, MA 02115 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov OI Joffe, Steven/0000-0002-0667-7384 NR 10 TC 6 Z9 6 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 8 PY 2011 VL 305 IS 22 BP 2345 EP 2346 DI 10.1001/jama.2011.784 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 773YV UT WOS:000291349100029 PM 21642688 ER PT J AU Yamaguchi, T Wang, HL Li, XP Ng, TH Morales, M AF Yamaguchi, Tsuyoshi Wang, Hui-Ling Li, Xueping Ng, Tsz H. Morales, Marisela TI Mesocorticolimbic Glutamatergic Pathway SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; GABA-CONTAINING NEURONS; DOPAMINE NEURONS; NUCLEUS-ACCUMBENS; RAT-BRAIN; INTERFASCICULAR NUCLEUS; TYROSINE-HYDROXYLASE; IN-VITRO; SYNAPSES; TERMINALS AB The mesocorticolimbic dopamine (DA) system plays important roles in reward, motivation, learning, memory, and movement. This system arises from the A10 region, comprising the ventral tegmental area and three adjacent midline nuclei (caudal linear nucleus, interfascicular nucleus, and rostral linear nucleus of the raphe). DAergic and GABAergic neurons are intermingled in this region with recently discovered glutamatergic neurons expressing the vesicular glutamate transporter 2 (VGluT2). Here, we show by in situ hybridization and immunohistochemistry that there are two subpopulations of neurons expressing VGluT2mRNA in the A10 region: (1) a major subpopulation that expresses VGluT2 but lacks tyrosine hydroxylase (TH; VGluT2-only neurons), present in each nucleus of the A10 region, and (2) a smaller subpopulation that coexpresses VGluT2 and TH (VGluT2-TH neurons). By quantitative real-time PCR, we determined the mRNA copy numbers encoding VGluT2 or TH in samples of individual microdissected TH immunoreactive (IR) neurons. Data from both in situ hybridization and from mRNA quantification showed that VGluT2mRNA is not present in every TH-IR neuron, but restricted to a subset of TH-IR neurons located in the medial portion of the A10 region. By integration of tract tracing, in situ hybridization, and immunohistochemistry, we found that VGluT2-only neurons and VGluT2-TH neurons each innervate both the prefrontal cortex and the nucleus accumbens. These findings establish that in addition to the well-recognized mesocorticolimbic DA-only and GABA-only pathways, there exist parallel mesocorticolimbic glutamate-only and glutamate-DA pathways. C1 [Yamaguchi, Tsuyoshi; Wang, Hui-Ling; Li, Xueping; Ng, Tsz H.; Morales, Marisela] NIDA, Intramural Res Program, Neuronal Networks Sect, Baltimore, MD 21224 USA. RP Morales, M (reprint author), NIDA, Intramural Res Program, Neuronal Networks Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mmorales@intra.nida.nih.gov OI YAMAGUCHI, TSUYOSHI/0000-0002-0058-9244 FU National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse. We thank Dr. Roy Wise for discussions. NR 37 TC 116 Z9 116 U1 1 U2 13 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 8 PY 2011 VL 31 IS 23 BP 8476 EP 8490 DI 10.1523/JNEUROSCI.1598-11.2011 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 774LJ UT WOS:000291387200016 PM 21653852 ER PT J AU Chowell, G Cazelles, B Broutin, H Munayco, CV AF Chowell, Gerardo Cazelles, Bernard Broutin, Helene Munayco, Cesar V. TI The influence of geographic and climate factors on the timing of dengue epidemics in Peru, 1994-2008 SO BMC INFECTIOUS DISEASES LA English DT Article DE Dengue; dynamics; community size; wavelet analysis; wavelet coherence; epidemic timing; climatic factors; Peru ID HEMORRHAGIC-FEVER; AEDES-AEGYPTI; SPATIAL HIERARCHIES; TRAVELING-WAVES; COMMUNITY SIZE; TIME-SERIES; TRANSMISSION; MEASLES; VIRUS; DISPERSAL AB Background: Dengue fever is a mosquito-borne disease that affects between 50 and 100 million people each year. Increasing our understanding of the heterogeneous transmission patterns of dengue at different spatial scales could have considerable public health value by guiding intervention strategies. Methods: Based on the weekly number of dengue cases in Peru by province, we investigated the association between dengue incidence during the period 1994-2008 and demographic and climate factors across geographic regions of the country. Results: Our findings support the presence of significant differences in the timing of dengue epidemics between jungle and coastal regions, with differences significantly associated with the timing of the seasonal cycle of mean temperature. Conclusions: Dengue is highly persistent in jungle areas of Peru where epidemics peak most frequently around March when rainfall is abundant. Differences in the timing of dengue epidemics in jungle and coastal regions are significantly associated with the seasonal temperature cycle. Our results suggest that dengue is frequently imported into coastal regions through infective sparks from endemic jungle areas and/or cities of other neighboring endemic countries, where propitious environmental conditions promote year-round mosquito breeding sites. If jungle endemic areas are responsible for multiple dengue introductions into coastal areas, our findings suggest that curtailing the transmission of dengue in these most persistent areas could lead to significant reductions in dengue incidence in coastal areas where dengue incidence typically reaches low levels during the dry season. C1 [Chowell, Gerardo] Arizona State Univ, Math & Computat Modeling Sci Ctr, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. [Chowell, Gerardo; Broutin, Helene] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Cazelles, Bernard] UPMC, CNRS ENS, Ecole Normale Super, UMR 7625, F-75230 Paris 05, France. [Cazelles, Bernard] IRD UPMC, UMMISCO, UMI 209, F-93142 Bondy, France. [Broutin, Helene] UMR CNRS 5290 IRD 224 UM1 UM2, MIVEGEC, F-34394 Montpellier 5, France. [Munayco, Cesar V.] Minist Hlth, Direcc Gen Epidemiol, Jesus Maria Lima 11, Peru. RP Chowell, G (reprint author), Arizona State Univ, Math & Computat Modeling Sci Ctr, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. EM gchowell@asu.edu RI Munayco, Cesar/G-9990-2013; Chowell, Gerardo/F-5038-2012; Cazelles, Bernard/B-1572-2013 OI Munayco, Cesar/0000-0001-7872-8913; Chowell, Gerardo/0000-0003-2194-2251; Cazelles, Bernard/0000-0002-7972-361X FU Fogarty International Center, National Institutes of Health FX We would like to express our gratitude to the people of Direccion General de Epidemiologia and the national network of epidemiology for all their hard work conducting surveillance activities and providing the dengue data used in this study. We also thank Michael Golinski and Marcel Hurtado for their critical reading of the manuscript and Kamal Barely for assistance with graphic enhancement. HB was funded by the intramural research group of Fogarty International Center, National Institutes of Health. NR 44 TC 29 Z9 30 U1 3 U2 26 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JUN 8 PY 2011 VL 11 AR 164 DI 10.1186/1471-2334-11-164 PG 14 WC Infectious Diseases SC Infectious Diseases GA 783KS UT WOS:000292081800001 PM 21651779 ER PT J AU Schmid, P Flegel, WA AF Schmid, Pirmin Flegel, Willy A. TI Codon usage in vertebrates is associated with a low risk of acquiring nonsense mutations SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID NEIGHBOR BASE SEQUENCES; GC-CONTENT; HUMAN GENOME; DEOXYRIBONUCLEIC ACID; ENZYMATIC SYNTHESIS; ESCHERICHIA-COLI; BLOOD-DONORS; GENE; DNA; SUBSTITUTION AB Background: Codon usage in genomes is biased towards specific subsets of codons. Codon usage bias affects translational speed and accuracy, and it is associated with the tRNA levels and the GC content of the genome. Spontaneous mutations drive genomes to a low GC content. Active cellular processes are needed to maintain a high GC content, which influences the codon usage of a species. Loss-of-function mutations, such as nonsense mutations, are the molecular basis of many recessive alleles, which can greatly affect the genome of an organism and are the cause of many genetic diseases in humans. Methods: We developed an event based model to calculate the risk of acquiring nonsense mutations in coding sequences. Complete coding sequences and genomes of 40 eukaryotes were analyzed for GC and CpG content, codon usage, and the associated risk of acquiring nonsense mutations. We included one species per genus for all eukaryotes with available reference sequence. Results: We discovered that the codon usage bias detected in genomes of high GC content decreases the risk of acquiring nonsense mutations (Pearson's r = -0.95; P < 0.0001). In the genomes of all examined vertebrates, including humans, this risk was lower than expected (0.93 +/- 0.02; mean +/- SD) and lower than the risk in genomes of non-vertebrates (1.02 +/- 0.13; P = 0.019). Conclusions: While the maintenance of a high GC content is energetically costly, it is associated with a codon usage bias harboring a low risk of acquiring nonsense mutations. The reduced exposure to this risk may contribute to the fitness of vertebrates. C1 [Schmid, Pirmin; Flegel, Willy A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Flegel, WA (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM bill.flegel@nih.gov FU NIH Clinical Center; Swiss National Science Foundation (SNSF) [PBBEA-121056] FX We acknowledge the discussions with Franz F. Wagner in 1996 while working on Bombay blood group alleles [16] when the idea for this study was conceived. We thank Elizabeth Furlong and Michael J. Huvard for English editing. This research was supported by the Intramural Research Program of the NIH Clinical Center. PS was initially supported by a Swiss National Science Foundation fellowship (SNSF no. PBBEA-121056). The views expressed do not necessarily represent the view of the National Institutes of Health, the Department of Health and Human Services, or the U.S. Federal Government. NR 38 TC 1 Z9 1 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUN 8 PY 2011 VL 9 AR 87 DI 10.1186/1479-5876-9-87 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 785ZW UT WOS:000292272800001 PM 21651781 ER PT J AU Send, R Kaila, VRI Sundholm, D AF Send, Robert Kaila, Ville R. I. Sundholm, Dage TI Reduction of the virtual space for coupled-cluster excitation energies of large molecules and embedded systems SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID GAUSSIAN-BASIS SETS; ZETA-VALENCE QUALITY; EXCITED-STATES; CORRELATED CALCULATIONS; IDENTITY APPROXIMATION; VISUAL EXCITATION; ORBITAL SPACE; FROZEN CORE; MODEL CC2; DENSITY AB We investigate how the reduction of the virtual space affects coupled-cluster excitation energies at the approximate singles and doubles coupled-cluster level (CC2). In this reduced-virtual-space (RVS) approach, all virtual orbitals above a certain energy threshold are omitted in the correlation calculation. The effects of the RVS approach are assessed by calculations on the two lowest excitation energies of 11 biochromophores using different sizes of the virtual space. Our set of biochromophores consists of common model systems for the chromophores of the photoactive yellow protein, the green fluorescent protein, and rhodopsin. The RVS calculations show that most of the high-lying virtual orbitals can be neglected without significantly affecting the accuracy of the obtained excitation energies. Omitting all virtual orbitals above 50 eV in the correlation calculation introduces errors in the excitation energies that are smaller than 0.1 eV. By using a RVS energy threshold of 50 eV, the CC2 calculations using triple-zeta basis sets (TZVP) on protonated Schiff base retinal are accelerated by a factor of 6. We demonstrate the applicability of the RVS approach by performing CC2/TZVP calculations on the lowest singlet excitation energy of a rhodopsin model consisting of 165 atoms using RVS thresholds between 20 eV and 120 eV. The calculations on the rhodopsin model show that the RVS errors determined in the gas-phase are a very good approximation to the RVS errors in the protein environment. The RVS approach thus renders purely quantum mechanical treatments of chromophores in protein environments feasible and offers an ab initio alternative to quantum mechanics/molecular mechanics separation schemes. (c) 2011 American Institute of Physics. [doi:10.1063/1.3596729] C1 [Send, Robert] Karlsruher Inst Technol, Inst Phys Chem, D-76131 Karlsruhe, Germany. [Kaila, Ville R. I.; Sundholm, Dage] Univ Helsinki, Dept Chem, FIN-00014 Helsinki, Finland. [Kaila, Ville R. I.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Send, R (reprint author), Karlsruher Inst Technol, Inst Phys Chem, Kaiserstr 12, D-76131 Karlsruhe, Germany. EM Robert.Send@kit.edu; Ville.Kaila@nih.gov; Dage.Sundholm@helsinki.fi OI Sundholm, Dage Matts Borje/0000-0002-2367-9277 FU Academy of Finland; Center for Functional Nanostructures (CFN) of the Deutsche Forschungsgemeinschaft (DFG) [C3.9]; Sigrid Juselius Foundation; European Commission [228398]; European Molecular Biology Organization; National Institutes of Health, National Institute of Diabetes, and Digestive and Kidney Diseases FX We thank Reinhart Ahlrichs for helpful discussions on this project. This research has been supported by the Academy of Finland through its Centers of Excellence Programme 2006-2011. This work was also supported by the Center for Functional Nanostructures (CFN) of the Deutsche Forschungsgemeinschaft (DFG) within project C3.9, by the Sigrid Juselius Foundation, and the HPC-EUROPA2 project (Project No. 228398) with the support of the European Commission - Capacities Area - Research Infrastructures. CSC - the Finnish IT Center for Science is acknowledged for computer time and hosting this HPC-EUROPA2 project. V.R.I.K. acknowledges the European Molecular Biology Organization for Long-Term Fellowship, and the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes, and Digestive and Kidney Diseases for support. NR 53 TC 31 Z9 31 U1 3 U2 11 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD JUN 7 PY 2011 VL 134 IS 21 AR 214114 DI 10.1063/1.3596729 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 774RB UT WOS:000291402700015 PM 21663351 ER PT J AU Joergensen, A Broedbaek, K Weimann, A Semba, RD Ferrucci, L Joergensen, MB Poulsen, HE AF Joergensen, Anders Broedbaek, Kasper Weimann, Allan Semba, Richard D. Ferrucci, Luigi Joergensen, Martin B. Poulsen, Henrik E. TI Association between Urinary Excretion of Cortisol and Markers of Oxidatively Damaged DNA and RNA in Humans SO PLOS ONE LA English DT Article ID 8-OXO-7,8-DIHYDRO-2'-DEOXYGUANOSINE EXCRETION; DEPRESSIVE SYMPTOMS; CHRONIC STRESS; REPAIR; RISK; MORTALITY; CANCER; RATS; LIFE; DISORDERS AB Chronic psychological stress is associated with accelerated aging, but the underlying biological mechanisms are not known. Prolonged elevations of the stress hormone cortisol is suspected to play a critical role. Through its actions, cortisol may potentially induce oxidatively generated damage to cellular constituents such as DNA and RNA, a phenomenon which has been implicated in aging processes. We investigated the relationship between 24 h excretion of urinary cortisol and markers of oxidatively generated DNA and RNA damage, 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydroguanosine, in a sample of 220 elderly men and women (age 65 - 83 years). We found a robust association between the excretion of cortisol and the oxidation markers (R-2 = 0.15, P < 0.001 for both markers). Individuals in the highest quartile of cortisol excretion had a 57% and 61% higher median excretion of the DNA and RNA oxidation marker, respectively, than individuals in the lowest quartile. The finding adds support to the hypothesis that cortisol-induced damage to DNA/RNA is an explanatory factor in the complex relation between stress, aging and disease. C1 [Joergensen, Anders; Joergensen, Martin B.] Ctr Psychiat, Copenhagen, Denmark. [Broedbaek, Kasper; Weimann, Allan; Poulsen, Henrik E.] Rigshosp, Lab Clin Pharmacol Q7642, DK-2100 Copenhagen, Denmark. [Broedbaek, Kasper; Weimann, Allan; Poulsen, Henrik E.] Bispebjerg Hosp, Dept Clin Pharmacol, DK-2400 Copenhagen, Denmark. [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Poulsen, Henrik E.] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark. RP Joergensen, A (reprint author), Ctr Psychiat, Copenhagen, Denmark. EM anders.01.joergensen@regionh.dk RI Brodbak, Kasper/G-5115-2012; Jorgensen, Martin Balslev/K-5758-2012 OI Jorgensen, Martin Balslev/0000-0002-1321-8901 FU Psychiatric Center Copenhagen; Research Committee at Copenhagen University Hospital, Rigshospitalet, National Institute on Aging [R01 AG027012, R01 AG029148, R01 HL094507]; Italian Ministry of Health [ICS110.1/RF97.71]; NIA [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]; Intramural Research Program, National Institute on Aging, National Institutes of Health FX This study was supported by funding from Psychiatric Center Copenhagen, the Research Committee at Copenhagen University Hospital, Rigshospitalet, National Institute on Aging Grants R01 AG027012, R01 AG029148, R01 HL094507, 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, and the Intramural Research Program, National Institute on Aging, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 27 Z9 27 U1 3 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 JUN 7 PY 2011 VL 6 IS 6 AR e20795 DI 10.1371/journal.pone.0020795 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 777HR UT WOS:000291607000022 PM 21687734 ER PT J AU Kawut, SM Lima, JAC Barr, RG Chahal, H Jain, A Tandri, H Praestgaard, A Bagiella, E Kizer, JR Johnson, WC Kronmal, RA Bluemke, DA AF Kawut, Steven M. Lima, Joao A. C. Barr, R. Graham Chahal, Harjit Jain, Aditya Tandri, Harikrishna Praestgaard, Amy Bagiella, Emilia Kizer, Jorge R. Johnson, W. Craig Kronmal, Richard A. Bluemke, David A. TI Sex and Race Differences in Right Ventricular Structure and Function The Multi-Ethnic Study of Atherosclerosis-Right Ventricle Study SO CIRCULATION LA English DT Article DE hypertension, pulmonary; heart ventricles; magnetic resonance imaging; pulmonary heart disease; sex ID CARDIOVASCULAR MAGNETIC-RESONANCE; PULMONARY ARTERIAL-HYPERTENSION; GENDER-DIFFERENCES; EJECTION FRACTION; REFERENCE VALUES; BODY-SIZE; PRESSURE-OVERLOAD; HEART-FAILURE; SYSTOLIC FUNCTION; MASS AB Background-Right ventricular (RV) morphology is an important predictor of outcomes in heart and lung disease; however, determinants of RV anatomy have not been well studied. We examined the demographic factors associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease. Methods and Results-In the Multi-Ethnic Study of Atherosclerosis (MESA), cardiac magnetic resonance imaging was performed on 5098 participants. Right ventricular volumes and mass were available for 4204 participants. Normative equations for RV parameters were derived with an allometric approach. The study sample (n=4123) was 61.5 +/- 10.1 years of age and 47.5% men. Older age was associated with lower RV mass (approximate to 5% lower mass per decade), with larger age-related decrements in men than in women (P<0.05 for interaction). Older age was also associated with higher RV ejection fraction, an association that differed between races/ethnicities (P <= 0.01 for interaction). Overall, men had greater RV mass (approximate to 8%) and larger RV volumes than women, but had lower RV ejection fraction (4% in absolute terms; P<0.001). Blacks had lower RV mass than whites (P <= 0.002), whereas Hispanics had higher RV mass (P <= 0.02). When the derived normative equations were used, 7.3% (95% confidence interval, 6.5 to 8.1) met the criteria for RV hypertrophy, and 5.9% (95% confidence interval, 5.2 to 6.6) had RV dysfunction. Conclusion-Age, sex, and race are associated with significant differences in RV mass, RV volumes, and RV ejection fraction, potentially explaining distinct responses of the RV to cardiopulmonary disease. (Circulation. 2011;123:2542-2551.) C1 [Kawut, Steven M.] Univ Penn, Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Kawut, Steven M.; Praestgaard, Amy] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Lima, Joao A. C.; Chahal, Harjit; Jain, Aditya; Tandri, Harikrishna] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Barr, R. Graham] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA. [Barr, R. Graham] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Bagiella, Emilia] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Kizer, Jorge R.] Weill Cornell Med Ctr, Dept Med, New York, NY USA. [Kizer, Jorge R.] Weill Cornell Med Ctr, Dept Publ Hlth, New York, NY USA. [Johnson, W. Craig; Kronmal, Richard A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD USA. RP Kawut, SM (reprint author), 718 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM kawut@upenn.edu OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [R01-HL086719, R01-HL077612, N01-HC95159, HC95165, N01-HC95169] FX This work was supported by National Institutes of Health R01-HL086719, R01-HL077612, N01-HC95159 through HC95165, and N01-HC95169. NR 47 TC 81 Z9 85 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 7 PY 2011 VL 123 IS 22 BP 2542 EP U116 DI 10.1161/CIRCULATIONAHA.110.985515 PG 52 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 773KR UT WOS:000291306600016 PM 21646505 ER PT J AU McDermott, MM Liu, KA Ferrucci, L Tian, L Guralnik, JM Liao, YH Criqui, MH AF McDermott, Mary M. Liu, Kiang Ferrucci, Luigi Tian, Lu Guralnik, Jack M. Liao, Yihua Criqui, Michael H. TI Greater Sedentary Hours and Slower Walking Speed Outside the Home Predict Faster Declines in Functioning and Adverse Calf Muscle Changes in Peripheral Arterial Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE intermittent claudication; modifiable behaviors; peripheral arterial disease; physical activity; physical functioning ID ANKLE-BRACHIAL INDEX; PHYSICAL-ACTIVITY; DAILY-LIFE; OCCLUSIVE DISEASE; MORTALITY; EXERCISE; CLASSIFICATION; OSTEOARTHRITIS; ASSOCIATION; CRITERIA AB Objectives In participants with peripheral arterial disease (PAD), we determined whether more sedentary behavior and slower outdoor walking speed were associated with faster functional decline and more adverse changes in calf muscle characteristics over time. Background Modifiable behaviors associated with faster functional decline in lower-extremity PAD are understudied. Methods Participants were 384 men and women with an ankle brachial index <0.90 followed for a median of 47 months. At baseline, participants reported the number of hours they spent sitting per day and their walking speeds outside their homes. Participants underwent baseline and annual measures of objective functional performance. Calf muscle characteristics were measured with computed tomography at baseline and every 2 years subsequently. Analyses were adjusted for age, sex, race, comorbidities, ankle brachial index, and other confounders. Results Slower walking speed outside the home was associated with faster annual decline in calf muscle density (brisk/striding pace -0.32 g/cm(3), average pace -0.46 g/cm(3), casual strolling -1.03 g/cm(3), no walking at all -1.43 g/cm(3), p trend <0.001). Greater hours sitting per day were associated with faster decline in 6-min walk (<4 h: -35.8 feet/year; 4 to <7 h: -41.1 feet/year; 8 to <11 h: -68.7 feet; >= 12 h: -78.0 feet; p trend = 0.008). Similar associations were observed for greater hours sitting per day and faster declines in fast-paced (p trend = 0.018) and usual-paced (p trend < 0.001) 4-m walking velocity. Conclusions Greater sedentary hours per day and slower outdoor walking speed are modifiable behaviors that are associated with faster functional decline and greater decline in calf muscle density, respectively, in patients with PAD. (J Am Coll Cardiol 2011;57:2356-64) (C) 2011 by the American College of Cardiology Foundation C1 [McDermott, Mary M.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. [Tian, Lu] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Guralnik, Jack M.] NIA, Bethesda, MD 20892 USA. [Criqui, Michael H.] Univ Calif San Diego, Sch Med, Dept Family & Prevent Med, San Diego, CA 92103 USA. RP McDermott, MM (reprint author), Northwestern Univ, Dept Med, Feinberg Sch Med, 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU National Heart, Lung and Blood Institute [R01-HL58099, R01-HL64739, R01-HL071223, R01-HL076298]; National Center for Research Resources, National Institutes of Health [RR-00048]; National Institute on Aging FX This work was supported by grants R01-HL58099, R01-HL64739, R01-HL071223, and R01-HL076298 from the National Heart, Lung and Blood Institute, by grant RR-00048 from the National Center for Research Resources, National Institutes of Health, and in part by the Intramural Research Program, National Institute on Aging. The authors have reported that they have no relationships to disclose. Mehdi H. Shishehbor, DO, MPH, served as Guest Editor for this paper. NR 28 TC 24 Z9 26 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 7 PY 2011 VL 57 IS 23 BP 2356 EP 2364 DI 10.1016/j.jacc.2010.12.038 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 771HG UT WOS:000291147200009 PM 21636037 ER PT J AU Boura, E Rozycki, B Herrick, DZ Chung, HS Vecer, J Eaton, WA Cafiso, DS Hummer, G Hurley, JH AF Boura, Evzen Rozycki, Bartosz Herrick, Dawn Z. Chung, Hoi Sung Vecer, Jaroslav Eaton, William A. Cafiso, David S. Hummer, Gerhard Hurley, James H. TI Solution structure of the ESCRT-I complex by small-angle X-ray scattering, EPR, and FRET spectroscopy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hybrid methods; protein sorting; vesicle budding; multiprotein assemblies; ensemble refinement ID SINGLE-MOLECULE FRET; UBIQUITIN-BINDING; SORTING COMPLEX; TERMINAL DOMAIN; TSG101; MACHINERY; PROTEIN; CYTOKINESIS; TRAFFICKING; RECOGNITION AB ESCRT-I is required for the sorting of integral membrane proteins to the lysosome, or vacuole in yeast, for cytokinesis in animal cells, and for the budding of HIV-1 from human macrophages and T lymphocytes. ESCRT-I is a heterotetramer of Vps23, Vps28, Vps37, and Mvb12. The crystal structures of the core complex and the ubiquitin E2 variant and Vps28 C-terminal domains have been determined, but internal flexibility has prevented crystallization of intact ESCRT-I. Here we have characterized the structure of ESCRT-I in solution by simultaneous structural refinement against small-angle X-ray scattering and double electron-electron resonance spectroscopy of spin-labeled complexes. An ensemble of at least six structures, comprising an equally populated mixture of closed and open conformations, was necessary to fit all of the data. This structural ensemble was cross-validated against single-molecule FRET spectroscopy, which suggested the presence of a continuum of open states. ESCRT-I in solution thus appears to consist of an approximately 50% population of one or a few related closed conformations, with the other 50% populating a continuum of open conformations. These conformations provide reference points for the structural pathway by which ESCRT-I induces membrane buds. C1 [Rozycki, Bartosz; Chung, Hoi Sung; Eaton, William A.; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Boura, Evzen; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Herrick, Dawn Z.; Cafiso, David S.] Univ Virginia, Dept Chem, Biophys Program, Charlottesville, VA 22904 USA. [Herrick, Dawn Z.; Cafiso, David S.] Univ Virginia, Ctr Membrane Biol, Charlottesville, VA 22904 USA. [Vecer, Jaroslav] Charles Univ Prague, Inst Phys, Fac Math & Phys, CR-12116 Prague, Czech Republic. RP Hummer, G (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM hummer@helix.nih.gov; hurley@helix.nih.gov RI Chung, Hoi Sung/C-2624-2009; Rozycki, Bartosz/B-7005-2009; Boura, Evzen/I-2626-2012; Hummer, Gerhard/A-2546-2013; Boura, Evzen/G-5275-2014 OI Rozycki, Bartosz/0000-0001-5938-7308; Hummer, Gerhard/0000-0001-7768-746X; FU Department of Energy, Office of Biological and Environmental Research; National Institutes of Health, National Center for Research Resources; European Community; National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases; Office of the Director, NIH; NIH [GM072694]; Ministry of Education, Youth and Sports of the Czech Republic [MSM0021620835] FX We thank B. Beach and M. Kostelansky for preparing the Cys-free ESCRT-I construct and A. Bax for discussions. SAXS data were collected at the Stanford Synchrotron Radiation Laboratory (SSRL), a national user facility operated by Stanford University on behalf of the US Department of Energy, Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the Department of Energy, Office of Biological and Environmental Research, and by the National Institutes of Health, National Center for Research Resources, Biomedical Technology Program. B. R. was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme. This work was supported by the Intramural Program of the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (to W. A. E., G. H., and J.H.H.), the Intramural AIDS Targeted Anti-viral Program of the Office of the Director, NIH (to J.H.H.), NIH Grant GM072694 (to D. S. C.), and the Ministry of Education, Youth and Sports of the Czech Republic Grant MSM0021620835 (to J.V.). NR 34 TC 40 Z9 40 U1 1 U2 29 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 7 PY 2011 VL 108 IS 23 BP 9437 EP 9442 DI 10.1073/pnas.1101763108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773WE UT WOS:000291341400029 PM 21596998 ER PT J AU Wang, L Yu, CR Kim, HP Liao, W Telford, WG Egwuagu, CE Leonard, WJ AF Wang, Lu Yu, Cheng-Rong Kim, Hyoung-Pyo Liao, Wei Telford, William G. Egwuagu, Charles E. Leonard, Warren J. TI Key role for IL-21 in experimental autoimmune uveitis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID T-CELL-ACTIVATION; RECEPTOR-BETA; DISEASE; MICE; DIFFERENTIATION; INTERLEUKIN-21; MODEL; CHAIN; IMMUNODEFICIENCY; UVEORETINITIS AB IL-21 is a pleiotropic type 1 cytokine that shares the common cytokine receptor gamma-chain, gamma(c), with IL-2, IL-4, IL-7, IL-9, and IL-15. IL-21 is most homologous to IL-2. These cytokines are encoded by adjacent genes, but they are functionally distinct. Whereas IL-2 promotes development of regulatory T cells and confers protection from autoimmune disease, IL-21 promotes differentiation of Th17 cells and is implicated in several autoimmune diseases, including type 1 diabetes and systemic lupus erythematosus. However, the roles of IL-21 and IL-2 in CNS autoimmune diseases such as multiple sclerosis and uveitis have been controversial. Here, we generated Il21-mCherry/Il2-emGFP dual-reporter transgenic mice and showed that development of experimental autoimmune uveitis (EAU) correlated with the presence of T cells coexpressing IL-21 and IL-2 into the retina. Furthermore, Il21r(-/-) mice were more resistant to EAU development than wild-type mice, and adoptive transfer of Il21r(-/-) T cells induced much less severe EAU, underscoring the need for IL-21 in the development of this disease and suggesting that blocking IL-21/gamma(c)-signaling pathways may provide a means for controlling CNS auto-inflammatory diseases. C1 [Yu, Cheng-Rong; Egwuagu, Charles E.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Wang, Lu; Kim, Hyoung-Pyo; Liao, Wei; Leonard, Warren J.] NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. [Kim, Hyoung-Pyo] Yonsei Univ, Coll Med, Inst Trop Med, Dept Environm Med Biol, Seoul 120752, South Korea. [Kim, Hyoung-Pyo] Yonsei Univ, Coll Med, Brain Korea Project Med Sci 21, Seoul 120752, South Korea. [Telford, William G.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov; wjl@helix.nih.gov FU Divisions of Intramural Research, National Heart, Lung, and Blood Institute and National Eye Institute; Ministry of Education, Science and Technology [2010-0010483] FX We thank Dr. Robert Fariss and Mercedes Campos for help with confocal microscopy, Barbara J. Taylor for help with FACS analysis, Dr. Yunsang Lee and Yongjun Lee for help with immunization of mice and fundoscopy, and Drs. Jian-Xin Lin, Yrina Rochman, and Rosanne Spolski, National Heart, Lung, and Blood Institute, for valuable discussions and critical comments. This work was supported by the Divisions of Intramural Research, National Heart, Lung, and Blood Institute and National Eye Institute and by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (Grant 2010-0010483 to H.-P.K.). NR 38 TC 21 Z9 23 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 7 PY 2011 VL 108 IS 23 BP 9542 EP 9547 DI 10.1073/pnas.1018182108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773WE UT WOS:000291341400048 PM 21593413 ER PT J AU Behnke, MS Khan, A Wootton, JC Dubey, JP Tang, KL Sibley, LD AF Behnke, Michael S. Khan, Asis Wootton, John C. Dubey, Jitender P. Tang, Keliang Sibley, L. David TI Virulence differences in Toxoplasma mediated by amplification of a family of polymorphic pseudokinases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE copy-number variation; parasite; quantitative trait locus mapping; genetic mapping ID PARASITOPHOROUS VACUOLE; CLONAL EXPANSION; GONDII; KINASES; RECOMBINATION; MIGRATION; GENES; ROP2 AB The population structure of Toxoplasma gondii includes three highly prevalent clonal lineages referred to as types I, II, and III, which differ greatly in virulence in the mouse model. Previous studies have implicated a family of serine/threonine protein kinases found in rhoptries (ROPs) as important in mediating virulence differences between strain types. Here, we explored the genetic basis of differences in virulence between the highly virulent type I lineage and moderately virulent type II based on successful genetic cross between these lineages. Genome-wide association revealed that a single quantitative trait locus controls the dramatic difference in lethality between these strain types. Neither ROP16 nor ROP18, previously implicated in virulence of T. gondii, was found to contribute to differences between types I and II. Instead, the major virulence locus contained a tandem cluster of polymorphic alleles of ROP5, which showed similar protein expression between strains. ROP5 contains a conserved serine/threonine protein kinase domain that includes only part of the catalytic triad, and hence, all members are considered to be pseudokinases. Genetic disruption of the entire ROP5 locus in the type I lineage led to complete attenuation of acute virulence, and complementation with ROP5 restored lethality to WT levels. These findings reveal that a locus of polymorphic pseudokinases plays an important role in pathogenesis of toxoplasmosis in the mouse model. C1 [Behnke, Michael S.; Khan, Asis; Tang, Keliang; Sibley, L. David] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Wootton, John C.] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Dubey, Jitender P.] ARS, Anim Parasit Dis Lab, Anim & Nat Resources Inst, USDA, Beltsville, MD 20705 USA. RP Sibley, LD (reprint author), Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. EM sibley@borcim.wustl.edu RI Behnke, Michael/R-8839-2016 OI Behnke, Michael/0000-0002-4668-8109 FU National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health; US Department of Agriculture, Agriculture Research Service, Current Research Information System (CRIS) [1265-32000-076]; National Institutes of Health [AI082423, AI036629] FX We are grateful to John Boothroyd, Jon Boyle, and Michael Reese for discussions of unpublished data; David Roos, David Kulp, and Amit Bahl for their design of the Toxoplasma gene chip; Julie Nawas and Jennifer Barks for expert technical assistance; Mae Huynh and Vern Carruthers for the Delta ku80-deficient parasite line; Paul H. Davis for guidance with gDNA preparation; Kate McInnerney for hybridization of the ToxoGeneChip micro-arrays; and the public databases provided at http://ToxoDB.org and http://www.ncbi.nlm.nih.gov/Traces/trace.cgi. J.C.W is supported by the Intramural Program of National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health. J.P.D. was partially supported by US Department of Agriculture, Agriculture Research Service, Current Research Information System (CRIS) 1265-32000-076. This work was supported by National Institutes of Health Grants AI082423 and AI036629 (to L. D. S.). NR 39 TC 99 Z9 106 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 7 PY 2011 VL 108 IS 23 BP 9631 EP 9636 DI 10.1073/pnas.1015338108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773WE UT WOS:000291341400063 PM 21586633 ER PT J AU Bennuru, S Meng, ZJ Ribeiro, JMC Semnani, RT Ghedin, E Chan, K Lucas, DA Veenstra, TD Nutman, TB AF Bennuru, Sasisekhar Meng, Zhaojing Ribeiro, Jose M. C. Semnani, Roshanak Tolouei Ghedin, Elodie Chan, King Lucas, David A. Veenstra, Timothy D. Nutman, Thomas B. TI Stage-specific proteomic expression patterns of the human filarial parasite Brugia malayi and its endosymbiont Wolbachia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE filaria; nematode ID EXCRETORY-SECRETORY PRODUCTS; MIGRATION INHIBITORY FACTOR; AMINO-ACID REPEATS; PROTEIN ANTIGENS; SURFACE-PROTEINS; IMMUNE EVASION; IN-VITRO; NEMATODE; HOMOLOG; GENES AB Global proteomic analyses of pathogens have thus far been limited to unicellular organisms (e. g., protozoa and bacteria). Proteomic analyses of most eukaryotic pathogens (e. g., helminths) have been restricted to specific organs, specific stages, or secretomes. We report here a large-scale proteomic characterization of almost all the major mammalian stages of Brugia malayi, a causative agent of lymphatic filariasis, resulting in the identification of more than 62% of the products predicted from the Bm draft genome. The analysis also yielded much of the proteome of Wolbachia, the obligate endosymbiont of Bm that also expressed proteins in a stage-specific manner. Of the 11,610 predicted Bm gene products, 7,103 were definitively identified from adult male, adult female, blood-borne and uterine microfilariae, and infective L3 larvae. Among the 4,956 gene products (42.5%) inferred from the genome as "hypothetical," the present study was able to confirm 2,336 (47.1%) as bona fide proteins. Analysis of protein families and domains coupled with stage-specific expression highlight the important pathways that benefit the parasite during its development in the host. Gene set enrichment analysis identified extracellular matrix proteins and those with immunologic effects as enriched in the microfilarial and L3 stages. Parasite sex-and stage-specific protein expression identified those pathways related to parasite differentiation and demonstrates stage-specific expression by the Bm endosymbiont Wolbachia as well. C1 [Bennuru, Sasisekhar; Semnani, Roshanak Tolouei; Nutman, Thomas B.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Meng, Zhaojing; Chan, King; Lucas, David A.; Veenstra, Timothy D.] SAIC Frederick, Lab Prote & Analyt Technol, Adv Technol Program, Frederick, MD 21702 USA. [Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Ghedin, Elodie] Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Dept Computat & Syst Biol, Pittsburgh, PA 15261 USA. RP Bennuru, S (reprint author), NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. EM bennurus@niaid.nih.gov OI Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); National Cancer Institute, NIH [HHSN261200800001E] FX This project was funded primarily by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), and in part with federal funds from the National Cancer Institute, NIH, under Contract HHSN261200800001E. NR 47 TC 50 Z9 51 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 7 PY 2011 VL 108 IS 23 BP 9649 EP 9654 DI 10.1073/pnas.1011481108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773WE UT WOS:000291341400066 PM 21606368 ER PT J AU Colaneri, A Staffa, N Fargo, DC Gao, Y Wang, TY Peddada, SD Birnbaumer, L AF Colaneri, Alejandro Staffa, Nickolas Fargo, David C. Gao, Yuan Wang, Tianyuan Peddada, Shyamal D. Birnbaumer, Lutz TI Expanded methyl-sensitive cut counting reveals hypomethylation as an epigenetic state that highlights functional sequences of the genome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE methylome; single CpG; genome-wide; functional annotation; repetitive ID CPG-ISLANDS; DNA METHYLATION; CYTOSINE METHYLATION; MOUSE; SITES; LIVER; IDENTIFICATION; CHROMATIN; PATTERNS; PROMOTER AB Methyl-sensitive cut counting (MSCC) with the HpaII methylation-sensitive restriction enzyme is a cost-effective method to pinpoint unmethylated CpGs at single base-pair resolution. However, it has the drawback of addressing only CpGs in the context of the CCGG site, leaving out the remainder of the possible 16 XCGX tetranucleotides in which CpGs are found. We expanded MSCC to include three additional enzymes to address a total of 5 of the 16 XCGX combinations. This allowed us to survey methylation at about one-third of all a mammalian genome's CpGs. Applied to mouse liver DNA, we correctly confirmed data reported with other methods showing hypomethylation to be concentrated at promoters and in CpG islands (CGIs), with gene bodies and intergenic regions being mostly methylated. Grouping unmethylated CpGs, characterized by high MSCC scores (7% false discovery rate), we found a large number of unmethylated regions not qualifying as CGIs located in intergenic and intronic regions, which are highly enriched in functional DNA sequences (open regulatory annotation database) as well as in noncoding yet highly conserved mammalian sequences thought to be important but with as yet unknown function. About 50% of MSCC-defined unmethylated regions do not overlap algorithm-defined CGIs and offer a novel search space in which new functionalities of DNA may be found in health and disease. C1 [Colaneri, Alejandro; Staffa, Nickolas; Wang, Tianyuan; Birnbaumer, Lutz] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Fargo, David C.] NIEHS, Lib & Informat Serv, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Peddada, Shyamal D.] NIEHS, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Gao, Yuan] Johns Hopkins Univ, Div Gen Epigen & Bioinformat, Baltimore, MD 21205 USA. [Gao, Yuan] Johns Hopkins Univ, Lieber Inst Brain Dev & Neuroregenerat, Baltimore, MD 21205 USA. [Gao, Yuan] Johns Hopkins Univ, Inst Cell Engn, Stem Cell Program, Baltimore, MD 21205 USA. RP Colaneri, A (reprint author), NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM colaneria@niehs.nih.gov; birnbau1@niehs.nih.gov RI Gao, Yuan/E-1706-2011; Peddada, Shyamal/D-1278-2012 FU National Institutes of Health [Z01 ES101643] FX This study was supported by the Intramural Research Program of the National Institutes of Health (2009 National Institutes of Health Director's Challenge Award and Project Z01 ES101643 to L.B.). NR 29 TC 15 Z9 16 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 7 PY 2011 VL 108 IS 23 BP 9715 EP 9720 DI 10.1073/pnas.1105713108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773WE UT WOS:000291341400077 PM 21602498 ER PT J AU Wang, RJ Ilangovan, U Leal, BZ Robinson, AK Amann, BT Tong, CV Berg, JM Hinck, AP Kim, CA AF Wang, Renjing Ilangovan, Udayar Leal, Belinda Z. Robinson, Angela K. Amann, Barbara T. Tong, Corey V. Berg, Jeremy M. Hinck, Andrew P. Kim, Chongwoo A. TI Identification of Nudeic Acid Binding Residues in the FCS Domain of the Polycomb Group Protein Polyhomeotic SO BIOCHEMISTRY LA English DT Article ID MAGNETIC-RESONANCE RELAXATION; EMBRYONIC STEM-CELLS; MODEL-FREE APPROACH; DEVELOPMENTAL REGULATORS; NONCODING RNAS; X-INACTIVATION; DNA-BINDING; RECOGNITION; COMPLEX; MACROMOLECULES AB Polycomb group (PcG) proteins maintain the silent state of developmentally important genes. Recent evidence indicates that noncoding RNAs also play an important role in targeting PcG proteins to chromatin and PcG-mediated chromatin organization, although the molecular basis for how PcG and RNA function in concert remains unclear. The Phe-Cys-Ser (FCS) domain, named for three consecutive residues conserved in this domain, is a 30-40-residue Zn(2+) binding motif found in a number of PcG proteins. The FCS domain has been shown to bind RNA in a non-sequence specific manner, but how it does so is not known. Here, we present the three-dimensional structure of the FCS domain from human Polyhomeotic homologue 1 (HPH1, also known as PHC1) determined using multidimensional nuclear magnetic resonance methods. Chemical shift perturbations upon addition of RNA and DNA resulted in the identification of Lys 816 as a potentially important residue required for nucleic acid binding. The role played by this residue in Polyhomeotic function was demonstrated in a transcription assay conducted in Drosophila S2 cells. Mutation of the Arg residue to Ala in the Drosophila Polyhomeotic (Ph) protein, which is equivalent to Lys 816 in HPH1, was unable to repress transcription of a reporter gene to the level of wild-type Ph. These results suggest that direct interaction between the Ph FCS domain and nucleic acids is required for Ph-mediated repression. C1 [Wang, Renjing; Ilangovan, Udayar; Leal, Belinda Z.; Robinson, Angela K.; Tong, Corey V.; Hinck, Andrew P.; Kim, Chongwoo A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Amann, Barbara T.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Berg, Jeremy M.] NIDDK, Natl Inst Gen Med Sci, NIH, Bethesda, MD 20892 USA. RP Kim, CA (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, MSC 7760,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM chong@biochem.uthscsa.edu FU American Heart Association [0830111N]; American Cancer Society [RSG-08-285-01-GMC]; Department of Defense Breast Cancer Research [BC075278]; University of Texas Health Science Center at San Antonio (UTHSCSA); National Institutes of Health [NCI P30 CA54174] FX This work was supported by the American Heart Association (0830111N), the American Cancer Society (RSG-08-285-01-GMC), and the Department of Defense Breast Cancer Research Program (BC075278) (C.A.K.). Support for the NMR facility was provided by the University of Texas Health Science Center at San Antonio (UTHSCSA) and National Institutes of Health Grant NCI P30 CA54174 (CTRC at UTHSCSA). NR 42 TC 3 Z9 3 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 7 PY 2011 VL 50 IS 22 BP 4998 EP 5007 DI 10.1021/bi101487s PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 768ZG UT WOS:000290978200017 PM 21351738 ER PT J AU Dieffenbach, CW Fauci, AS AF Dieffenbach, Carl W. Fauci, Anthony S. TI Thirty Years of HIV and AIDS: Future Challenges and Opportunities SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; NEUTRALIZING ANTIBODIES; POTENT NEUTRALIZATION; DISEASE PROGRESSION; DOUBLE-BLIND; T-CELLS; INFECTION; VACCINE; PREVENTION; TRANSMISSION AB As the third decade since AIDS was first recognized comes to an end, extraordinary advances have occurred in the understanding, treatment, and prevention of HIV infection and AIDS. As a result of these successes, it is now time to focus on future challenges. Paramount among these is reaching the goal of truly controlling and ultimately ending the HIV and AIDS pandemic. To that end, AIDS researchers and public health personnel worldwide are aggressively pursuing 3 key areas of scientific research. Given the availability of highly effective therapeutic regimens for HIV infection, the first challenge is efficiently identifying a maximum number of HIV-infected persons through voluntary HIV testing and initiating antiretroviral therapy (ART). Second, scientists are trying to develop a cure for HIV infection, which would alleviate the need for lifelong ART. Finally, preventing new cases of HIV infection, which currently number approximately 2.6 million per year globally, is critical to any attempt to end this pandemic. This article addresses each of these challenges and provides directions for the future. C1 [Dieffenbach, Carl W.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Dieffenbach, CW (reprint author), NIAID, Div Aids, NIH, 6700 Rockledge Dr,MSC 7620, Bethesda, MD 20892 USA. EM cdieffenba@niaid.nih.gov NR 58 TC 67 Z9 68 U1 1 U2 5 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 7 PY 2011 VL 154 IS 11 BP 766 EP 771 DI 10.7326/0003-4819-154-11-201106070-00345 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 773MV UT WOS:000291312300008 PM 21628350 ER PT J AU Katz, JD Mamyrova, G Agarwal, S Jones, OY Bollar, H Huber, AM Rider, LG White, PH AF Katz, James D. Mamyrova, Gulnara Agarwal, Shilpi Jones, Olcay Y. Bollar, Harriet Huber, Adam M. Rider, Lisa G. White, Patience H. TI Parents' perception of self-advocacy of children with myositis: an anonymous online survey SO PEDIATRIC RHEUMATOLOGY LA English DT Article ID ADULT CARE; HEALTH-CARE; TRANSITION; ADOLESCENTS; ILLNESS; PATIENT; DISEASE AB Background: Children with complex medical issues experience barriers to the transition of care from pediatric to adult providers. We sought to identify these barriers by elucidating the experiences of patients with idiopathic inflammatory muscle disorders. Methods: We collected anonymous survey data using an online website. Patients and their families were solicited from the US and Canada through established clinics for children with idiopathic inflammatory muscle diseases as well as with the aid of a nonprofit organization for the benefit of such individuals. The parents of 45 older children/young adults suffering from idiopathic inflammatory muscle diseases were surveyed. As a basis of comparison, we similarly collected data from the parents of 207 younger children with inflammatory muscle diseases. The survey assessed transition of care issues confronting families of children and young adults with chronic juvenile myositis. Results: Regardless of age of the patient, respondents were unlikely to have a designated health care provider assigned to aid in transition of care and were unlikely to be aware of a posted policy concerning transition of care at their pediatrician's office. Additionally, regardless of age, patients and their families were unlikely to have a written plan for moving to adult care. Conclusions: We identified deficiencies in the health care experiences of families as pertain to knowledge, self-advocacy, policy, and vocational readiness. Moreover, as children with complex medical issues grow up, parents attribute less self-advocacy to their children's level of independence. C1 [Katz, James D.; Mamyrova, Gulnara; White, Patience H.] George Washington Univ, Div Rheumatol, Washington, DC 20052 USA. [Rider, Lisa G.] NIEHS, NIH, Bethesda, MD 20892 USA. [Jones, Olcay Y.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Huber, Adam M.] Dalhousie Univ, Halifax, NS B3H 4R2, Canada. [Huber, Adam M.] IWK Hlth Ctr, Halifax, NS B3H 4R2, Canada. [Agarwal, Shilpi] Glendale Adventist Family Med Residency, Glendale, CA 91205 USA. [Bollar, Harriet] Cure JM, Wilmette, IL 60091 USA. RP Katz, JD (reprint author), George Washington Univ, Div Rheumatol, Washington, DC 20052 USA. EM jkatz@mfa.gwu.edu OI Rider, Lisa/0000-0002-6912-2458 NR 20 TC 2 Z9 2 U1 2 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1546-0096 J9 PEDIATR RHEUMATOL JI Pediatr. Rheumatol. PD JUN 7 PY 2011 VL 9 AR 10 DI 10.1186/1546-0096-9-10 PG 6 WC Pediatrics; Rheumatology SC Pediatrics; Rheumatology GA 780PQ UT WOS:000291871000001 PM 21649897 ER PT J AU Fields, RD AF Fields, R. Douglas TI Imaging single photons and intrinsic optical signals for studies of vesicular and non-vesicular ATP release from axons SO FRONTIERS IN NEUROANATOMY LA English DT Article DE neuron-glia interactions; axon volume; intrinsic optical signals; activity-dependent development; synaptic-vesicle release; neurotransmitter release; axon swelling; luciferase ID REAL-TIME MEASUREMENT; DORSAL-ROOT GANGLIA; SPINAL-CORD SLICES; ACTION-POTENTIALS; MECHANICAL CHANGES; STRUCTURAL-CHANGES; NERVE-FIBERS; ADENOSINE TRIPHOSPHATE; FIREFLY LUCIFERASE; LIGHT-SCATTERING AB The temporal and spatial dynamics of neurotransmitter release are fundamental to understanding activity-dependent signaling between axons and other cells, including neurons, glia, and vascular cells. A microscopic imaging technique is described that enables studying release of the neurotransmitter ATP from axons in response to action potentials. The method combines imaging single-photons, intrinsic optical signal imaging, and high magnification time-lapse microscopy to enable investigations of action potential-induced ATP release together with cell morphology and activity- dependent axon swelling. ATP released from axons catalyzes a chemiluminescent reaction between luciferin and luciferase that generates single photons that can be imaged individually. In addition to vesicular release. ATP release through membrane channels activated by axon swelling was monitored simultaneously with intrinsic optical signals. Repeated emissions of photons were observed from localized 15 mu m regions of axons, with a frequency distribution that differed from a normal distribution and from the frequency of emissions outside these localized regions. C1 NICHHD, Nervous Syst Dev & Plast Sect, NIH, Bethesda, MD 20892 USA. RP Fields, RD (reprint author), NICHHD, Nervous Syst Dev & Plast Sect, NIH, Bldg 35,Room 2A211,MSC 3713,35 Lincoln Dr, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov FU NICHD FX The author wishes to thank Larry Phillips and Jim Sims, formerly of Universal Imaging Corporation, for technical advice on single-photon imaging instrumentation and software for image acquisition and analysis. This research was supported by NICHD funds for intramural research. NR 67 TC 9 Z9 9 U1 0 U2 3 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5129 J9 FRONT NEUROANAT JI Front. Neuroanat. PD JUN 6 PY 2011 VL 5 AR 32 DI 10.3389/fnana.2011.00032 PG 11 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA 886PY UT WOS:000299867500001 PM 21852965 ER PT J AU Ren, DB Yu, SQ Gao, S Peng, DX Petralia, RS Muszynski, A Carlson, RW Robbins, JB Tsai, CM Lim, DJ Gu, XX AF Ren, Dabin Yu, Shengqing Gao, Song Peng, Daxin Petralia, Ronald S. Muszynski, Artur Carlson, Russell W. Robbins, John B. Tsai, Chao-Ming Lim, David J. Gu, Xin-Xing TI Mutant lipooligosaccharide-based conjugate vaccine demonstrates a broad-spectrum effectiveness against Moraxella catarrhalis SO VACCINE LA English DT Article DE Moraxella catarrhalis; Lipooligosaccharide mutant; Conjugate vaccine; Cross-reactivity; Conserved antigen ID OUTER-MEMBRANE PROTEIN; BRANHAMELLA-CATARRHALIS; PULMONARY CLEARANCE; SEROTYPE-A; DETOXIFIED LIPOOLIGOSACCHARIDE; LIPOPOLYSACCHARIDE ANTIGENS; IMMUNOLOGICAL-PROPERTIES; MUCOSAL PATHOGENS; MOLECULAR MIMICRY; OTITIS-MEDIA AB There is no licensed vaccine available against Moraxella catarrhalis, an exclusive human pathogen responsible for otitis media in children and respiratory infections in adults. We previously developed conjugate vaccine candidates based on lipooligosaccharides (LOSs) of M. catarrhalis serotypes A, B, and C, each of which was shown to cover a portion of the clinical strains. To generate conserved LOS antigens and eliminate a potential autoimmune response to a similar epitope between M. catarrhalis LOS moiety Gal alpha 1-4Gal beta 1-4Glc and human P(k) antigen, two LOS mutants from strain O35E were constructed. Mutant O35Elgt5 or O35EgalE revealed a deletion of one or two terminal galactose residues of wild type O35E LOS. Each LOS molecule was purified, characterized, detoxified, and coupled to tetanus toxoid (IT) to form conjugates, namely dLOS-TT. Three subcutaneous immunizations using dLOS-TT from O35Elgt5 or O35EgalE elicited significant increases (a 729- or 1263-fold above the preimmune serum levels) of serum immunoglobulin (Ig)G against O35E LOS in rabbits with an adjuvant or without an adjuvant (an 140- or 140-fold above the preimmune serum levels). Rabbit antisera demonstrated elevated complement-mediated bactericidal activities against the wild type strain O35E. The rabbit sera elicited by O35Elgt5 dLOS-TT were further examined and showed cross bactericidal activity against all additional 19 M. catarrhalis strains and clinical isolates studied. Moreover, the rabbit sera displayed cross-reactivity not only among three serotype strains but also clinical isolates in a whole-cell enzyme-linked immunosorbent assay (ELISA), which was further confirmed under transmission electron microscopy. In conclusion, O35Elgt5 dLOs-TT may act as a vaccine against most M. catarrhalis strains and therefore can be used for further in vivo efficacy studies. Published by Elsevier Ltd. C1 [Ren, Dabin; Yu, Shengqing; Gao, Song; Peng, Daxin; Gu, Xin-Xing] Natl Inst Deafness & Other Commun Disorders NIDCD, Vaccine Res Sect, NIH, Rockville, MD 20850 USA. [Petralia, Ronald S.] NIDCD, Sect Neurotransmitter Receptor Biol, NIH, Bethesda, MD 20892 USA. [Muszynski, Artur; Carlson, Russell W.] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. [Robbins, John B.] NICHHD, NIH, Bethesda, MD 20892 USA. [Tsai, Chao-Ming] US FDA, Div Bacterial Parasit & Allergen Prod, Bethesda, MD 20892 USA. [Lim, David J.] House Ear Res Inst, Sect Pathogenesis Ear Dis, Los Angeles, CA 90057 USA. RP Gu, XX (reprint author), NIH, 6610 Rockledge Dr,Room 3200, Bethesda, MD 20817 USA. EM guxx@mail.nih.gov RI Ren, Dabin/H-6263-2013; OI Muszynski, Artur/0000-0003-3497-9977 FU National Institute on Deafness and Other Communication Disorders (NIDCD), NIH FX We are grateful to Eric J. Hansen at University of Texas, Dallas, TX and Goro Mogi (deceased) at Oita Medical University, Oita, Japan for providing strains. We thank Anup Datta at Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California for the composition and structure analyses of LOSs. We thank the NIH Fellows Editorial Board for carefully reviewing and providing critical comments during the preparation of the manuscript. This research was supported by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD), NIH. NR 44 TC 10 Z9 10 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 6 PY 2011 VL 29 IS 25 BP 4210 EP 4217 DI 10.1016/j.vaccine.2011.03.102 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 779KY UT WOS:000291777700008 PM 21501641 ER PT J AU Price, RA Koshiol, J Kobrin, S Tiro, JA AF Price, Rebecca Anhang Koshiol, Jill Kobrin, Sarah Tiro, Jasmin A. TI Knowledge and intention to participate in cervical cancer screening after the human papillomavirus vaccine SO VACCINE LA English DT Article DE Human papillomavirus (HPV); Cervical cancer; Cancer screening; Disparities ID HEALTH INTERVIEW SURVEY; UNITED-STATES; YOUNG-WOMEN; SOCIETY GUIDELINE; ADOLESCENT GIRLS; COVERAGE; CARE; US; INSURANCE; EFFICACY AB Background: If women who receive the human papillomavirus (HPV) vaccine are unduly reassured about the cancer prevention benefits of vaccination, they may choose not to participate in screening, thereby increasing their risk for cervical cancer. This study assesses adult women's knowledge of the need to continue cervical cancer screening after HPV vaccination, describes Pap test intentions of vaccinated young adult women, and evaluates whether knowledge and intentions differ across groups at greatest risk for cervical cancer. Methods: Data were from the 2008 Health Information National Trends Survey (HINTS) and the 2008 National Health Interview Survey (NHIS), which initiated data collection approximately 18 months after the first FDA approval of an HPV vaccine. We calculated associations between independent variables and the outcomes using chi-square tests. Results: Of 1586 female HINTS respondents ages 18 through 74,95.6% knew that HPV-vaccinated women should continue to receive Pap tests. This knowledge did not vary significantly by race/ethnicity, education, income, or healthcare access. Among 1101 female NHIS respondents ages 18-26 who had ever received a Pap test, the proportion (12.7%; n=139) who reported receipt of the HPV vaccine were more likely than those not vaccinated to plan to receive a Pap test within three years (98.1% vs. 92.5%, p < 0.001). Conclusions: US adult women possess high knowledge and intention to participate in Pap testing after HPV vaccination. The vast majority of young adult women who received the HPV vaccine within its first two years on the market intend to participate in cervical cancer screening in the near future. Future studies are needed to examine whether those vaccinated in adolescence will become aware of, and adhere to, screening guidelines as they become eligible. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Price, Rebecca Anhang] NCI, SAIC Frederick Inc, Clin Monitoring Res Program, Frederick, MD 21702 USA. [Price, Rebecca Anhang] RAND Corp, Frederick, MD 21702 USA. [Koshiol, Jill] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. [Kobrin, Sarah] NCI, Appl Canc Screening Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20852 USA. [Tiro, Jasmin A.] Univ Texas SW Med Ctr Dallas, Div Behav & Commun Sci, Dept Clin Sci, Dallas, TX 75390 USA. RP Price, RA (reprint author), RAND Corp, 1200 S Hayes St,Room 7139, Arlington, VA 22202 USA. EM ranhangp@rand.org; koshiolj@mail.nih.gov; kobrins@mail.nih.gov; jtiro@utsouthwestern.edu OI Tiro, Jasmin/0000-0001-8300-0441 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract 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 38 TC 15 Z9 15 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 6 PY 2011 VL 29 IS 25 BP 4238 EP 4243 DI 10.1016/j.vaccine.2011.03.076 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 779KY UT WOS:000291777700012 ER PT J AU Rerks-Ngarm, S Premsri, N Namwat, C Khamboonruang, C Kunasol, P Pitisuttithum, P Kaewkungwal, J Nitayaphan, S Eamsila, C Benenson, MW Paris, R Kim, JH Chunsuttiwat, S Thongcharoen, P Bussaratid, V Maek-a-Nantawat, W Dhitavat, J Suntharasamai, P Pungpak, S Vanijanonta, S Khamsiriwatchara, A Jarujareet, P Tabprasit, S Morgan, P de Souza, M Brown, AE Trichavaroj, R Gurunathan, S Tartaglia, J McNeil, JG Francis, D Heyward, W Gurwith, M Chiu, J Robb, ML Michael, NL Birx, DL Milazzo, M Bolen, A AF Rerks-Ngarm, Supachai Premsri, Nakorn Namwat, Chawetsan Khamboonruang, Chirasak Kunasol, Prayura Pitisuttithum, Punnee Kaewkungwal, Jaranit Nitayaphan, Sorachai Eamsila, Chirapa Benenson, Michael W. Paris, Robert Kim, Jerome H. Chunsuttiwat, Supamit Thongcharoen, Prasert Bussaratid, Valai Maek-a-Nantawat, Wirach Dhitavat, Jittima Suntharasamai, Pravan Pungpak, Swangjai Vanijanonta, Sirivan Khamsiriwatchara, Amnat Jarujareet, Pawinee Tabprasit, Sutchana Morgan, Patricia de Souza, Mark Brown, Arthur E. Trichavaroj, Rapee Gurunathan, Sanjay Tartaglia, Jim McNeil, John G. Francis, Donald Heyward, William Gurwith, Marc Chiu, Joseph Robb, Merlin L. Michael, Nelson L. Birx, Deborah L. Milazzo, Mark Bolen, Aimee CA Minist Public Hlth-Thai Aids Vacci TI Screening and evaluation of potential volunteers for a phase III trial in Thailand of a candidate preventive HIV vaccine (RV148) SO VACCINE LA English DT Article DE HIV-1; Vaccine trial; Thailand; Screening; Phase III; Prime-boost; ALVAC-HIV; AIDSVAX; gp120; RV144; RV148 ID IMMUNODEFICIENCY-VIRUS TYPE-1; SUBTYPE-E; RISK-FACTORS; DOUBLE-BLIND; INFECTION; IMMUNOGENICITY; EFFICACY; SAFETY; PRIME; BOOST AB Screening for the community-based, phase III, prime-boost HIV vaccine trial conducted in Thailand (also referred to as "RV144") began in September 2003 and concluded in December 2005 in Rayong and Chon Buri provinces. During this period 26,676 persons were consented and screened for vaccine trial eligibility in a separate protocol ("RV148") at 47 screening sites, of which 26,548 were tested for HIV, and 16,402 were ultimately enrolled in RV144 and received at least one vaccination or corresponding placebo injection. Fifty-eight percent of those enrolled in RV148 were men and roughly half of the men and women were married. A slight majority was born in the provinces in which the study was conducted. The median age was 23 (IQR 20-26) and most had achieved a level of education that was higher than grade 9, which is compulsory for Thai citizens. The prevalence of confirmed HIV infection was 1.6%; among persons who did not return for confirmatory testing, it was 2.0%. Eighty-three percent were infected with CRF01 AE strains (formerly subtype E) as determined by serological typing. The estimated incidence of HIV infection using a capture EIA assay was 0.19 per 100 person-years. Female sex, older age, single marital status, and lower educational attainment were associated with HIV infection. Persons who reported working in the fishing or sex-work industries were more frequently infected (2.4% and 4.1%, respectively), but accounted for a small percent of the tested population in RV148 (0.7% and 0.6%, respectively), reflecting the overall low-risk of HIV in this study. Those screened for eligibility but did not participate in the vaccine trial were not substantially different from enrolled vaccine trial subjects. Published by Elsevier Ltd. C1 [Rerks-Ngarm, Supachai; Premsri, Nakorn; Namwat, Chawetsan; Khamboonruang, Chirasak; Kunasol, Prayura; Chunsuttiwat, Supamit; Thongcharoen, Prasert] Minist Publ Hlth, Dept Dis Control, Nonthaburi, Thailand. [Pitisuttithum, Punnee; Bussaratid, Valai; Maek-a-Nantawat, Wirach; Dhitavat, Jittima; Suntharasamai, Pravan; Pungpak, Swangjai; Vanijanonta, Sirivan] Mahidol Univ, Fac Trop Med, Vaccine Trials Ctr, Bangkok, Thailand. [Kaewkungwal, Jaranit; Khamsiriwatchara, Amnat; Jarujareet, Pawinee] Mahidol Univ, Fac Trop Med, Data Management Unit, Bangkok, Thailand. [Nitayaphan, Sorachai; Eamsila, Chirapa; Tabprasit, Sutchana] Royal Thai Army, Armed Forces Res Inst Med Sci, Bangkok, Thailand. [Benenson, Michael W.; Paris, Robert; Morgan, Patricia; de Souza, Mark; Brown, Arthur E.; Trichavaroj, Rapee] US Army Component, Armed Forces Res Inst Med Sci, Bangkok, Thailand. [Gurunathan, Sanjay; Tartaglia, Jim; McNeil, John G.] Sanofi Pasteur, Swiftwater, PA USA. [Francis, Donald; Heyward, William; Gurwith, Marc] Global Solut Infect Dis, San Francisco, CA USA. [Chiu, Joseph] NIAID, Div Aids, Bethesda, MD 20892 USA. [Kim, Jerome H.; Robb, Merlin L.; Michael, Nelson L.; Birx, Deborah L.; Milazzo, Mark; Bolen, Aimee] Walter Reed Army Inst Res, US Mil HIV Res Program, Div Retrovirol, Rockville, MD USA. [Kim, Jerome H.; Robb, Merlin L.; Michael, Nelson L.; Birx, Deborah L.; Milazzo, Mark; Bolen, Aimee] USA, Med Mat Dev Agcy, USAMRMC, Rockville, MD USA. FU USAMRMC [DAMD-W81XWH-07-2-0067, Y1-AI-5026-01/MRMC 05-0005]; Henry M. Jackson Foundation for the Advancement of Military Medicine [DAMD-W81XWH-07-2-0067]; Division of AIDS, National Institute of Allergy and Infectious Diseases FX This work is supported by DAMD-W81XWH-07-2-0067 between USAMRMC and the Henry M. Jackson Foundation for the Advancement of Military Medicine.; Funding for this work has also been provided by the Division of AIDS, National Institute of Allergy and Infectious Diseases and USAMRMC through an interagency agreement Y1-AI-5026-01/MRMC 05-0005. NR 26 TC 6 Z9 6 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUN 6 PY 2011 VL 29 IS 25 BP 4285 EP 4292 DI 10.1016/j.vaccine.2011.03.014 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 779KY UT WOS:000291777700018 ER PT J AU Petersen, I Eastman, R Lanzer, M AF Petersen, Ines Eastman, Richard Lanzer, Michael TI Drug-resistant malaria: Molecular mechanisms and implications for public health SO FEBS LETTERS LA English DT Review DE Drug resistance; Antimalarial drug; pfcrt; pfmdr1; Plasmodium falciparum; Plasmodium vivax ID PLASMODIUM-FALCIPARUM MALARIA; IN-VITRO SUSCEPTIBILITY; P-GLYCOPROTEIN HOMOLOG; TRANSMEMBRANE PROTEIN PFCRT; EXCHANGER PFNHE-1 GENE; CHLOROQUINE RESISTANCE; ANTIMALARIAL-DRUG; NA+/H+ EXCHANGER; DIHYDROFOLATE-REDUCTASE; ARTEMETHER-LUMEFANTRINE AB Resistance to antimalarial drugs has often threatened malaria elimination efforts and historically has led to the short-term resurgence of malaria incidences and deaths. With concentrated malaria eradication efforts currently underway, monitoring drug resistance in clinical settings complemented by in vitro drug susceptibility assays and analysis of resistance markers, becomes critical to the implementation of an effective antimalarial drug policy. Understanding of the factors, which lead to the development and spread of drug resistance, is necessary to design optimal prevention and treatment strategies. This review attempts to summarize the unique factors presented by malarial parasites that lead to the emergence and spread of drug resistance, and gives an overview of known resistance mechanisms to currently used antimalarial drugs. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved. C1 [Petersen, Ines; Lanzer, Michael] Univ Klinikum Heidelberg, Dept Infect Dis, D-69120 Heidelberg, Germany. [Eastman, Richard] NIAID, Malaria Funct Genom Sect, Lab Malaria & Vector Res, DIR,NIH, Rockville, MD 20852 USA. RP Petersen, I (reprint author), Univ Klinikum Heidelberg, Dept Infect Dis, Neuenheimer Feld 324, D-69120 Heidelberg, Germany. EM i.petersen@uni-heidelberg.de; michael_lanzer@med.uni-heidelberg.de FU Deutsche Forschungsgemeinschaft FX We thank Marcel Deponte and Sophie Adjalley for their constructive comments and suggestions on the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft under the portfolio of the Special Research Focus "Control of Tropical Infectious Diseases". M.L. is a member of the German Excellence Cluster "Cellnetworks" and the European Network of Excellence "EviMalaR". NR 151 TC 105 Z9 109 U1 3 U2 31 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 6 PY 2011 VL 585 IS 11 BP 1551 EP 1562 DI 10.1016/j.febslet.2011.04.042 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 769MY UT WOS:000291020300009 PM 21530510 ER PT J AU Campino, S Auburn, S Kivinen, K Zongo, I Ouedraogo, JB Mangano, V Djimde, A Doumbo, OK Kiara, SM Nzila, A Borrmann, S Marsh, K Michon, P Mueller, I Siba, P Jiang, HY Su, XZ Amaratunga, C Socheat, D Fairhurst, RM Imwong, M Anderson, T Nosten, F White, NJ Gwilliam, R Deloukas, P MacInnis, B Newbold, CI Rockett, K Clark, TG Kwiatkowski, DP AF Campino, Susana Auburn, Sarah Kivinen, Katja Zongo, Issaka Ouedraogo, Jean-Bosco Mangano, Valentina Djimde, Abdoulaye Doumbo, Ogobara K. Kiara, Steven M. Nzila, Alexis Borrmann, Steffen Marsh, Kevin Michon, Pascal Mueller, Ivo Siba, Peter Jiang, Hongying Su, Xin-Zhuan Amaratunga, Chanaki Socheat, Duong Fairhurst, Rick M. Imwong, Mallika Anderson, Timothy Nosten, Francois White, Nicholas J. Gwilliam, Rhian Deloukas, Panos MacInnis, Bronwyn Newbold, Christopher I. Rockett, Kirk Clark, Taane G. Kwiatkowski, Dominic P. TI Population Genetic Analysis of Plasmodium falciparum Parasites Using a Customized Illumina GoldenGate Genotyping Assay SO PLOS ONE LA English DT Article ID MULTIPLE DISPLACEMENT AMPLIFICATION; ANTIMALARIAL-DRUG RESISTANCE; MALARIA; GENOME; DIVERSITY; MICROSATELLITE; IDENTIFICATION; SEQUENCE; PCR AB The diversity in the Plasmodium falciparum genome can be used to explore parasite population dynamics, with practical applications to malaria control. The ability to identify the geographic origin and trace the migratory patterns of parasites with clinically important phenotypes such as drug resistance is particularly relevant. With increasing single-nucleotide polymorphism (SNP) discovery from ongoing Plasmodium genome sequencing projects, a demand for high SNP and sample throughput genotyping platforms for large-scale population genetic studies is required. Low parasitaemias and multiple clone infections present a number of challenges to genotyping P. falciparum. We addressed some of these issues using a custom 384-SNP Illumina GoldenGate assay on P. falciparum DNA from laboratory clones (long-term cultured adapted parasite clones), short-term cultured parasite isolates and clinical (non-cultured isolates) samples from East and West Africa, Southeast Asia and Oceania. Eighty percent of the SNPs (n = 306) produced reliable genotype calls on samples containing as little as 2 ng of total genomic DNA and on whole genome amplified DNA. Analysis of artificial mixtures of laboratory clones demonstrated high genotype calling specificity and moderate sensitivity to call minor frequency alleles. Clear resolution of geographically distinct populations was demonstrated using Principal Components Analysis (PCA), and global patterns of population genetic diversity were consistent with previous reports. These results validate the utility of the platform in performing population genetic studies of P. falciparum. C1 [Campino, Susana; Auburn, Sarah; Kivinen, Katja; Gwilliam, Rhian; Deloukas, Panos; MacInnis, Bronwyn; Newbold, Christopher I.; Rockett, Kirk; Clark, Taane G.; Kwiatkowski, Dominic P.] Wellcome Trust Sanger Inst, Hinxton, England. [Auburn, Sarah] Charles Darwin Univ, Menzies Sch Hlth Res, Global Hlth Div, Darwin, NT 0909, Australia. [Zongo, Issaka; Ouedraogo, Jean-Bosco] Inst Rech Sci Sante, Direct Reg Ouest, Bobo Dioulasso, Burkina Faso. [Mangano, Valentina] Univ Roma La Sapienza, Dept Publ Hlth Sci, Sect Parasitol, Rome, Italy. [Djimde, Abdoulaye; Doumbo, Ogobara K.] Univ Bamako, Malaria Res & Training Ctr, Fac Med Pharm & Odontostomatol, Bamako, Mali. [Kiara, Steven M.; Nzila, Alexis; Borrmann, Steffen; Marsh, Kevin] KEMRI Wellcome Trust Res Program, Kilifi, Kenya. [Michon, Pascal; Siba, Peter] Papua New Guinea Inst Med Res, Goroka, Papua N Guinea. [Michon, Pascal; Mueller, Ivo] Divine Word Univ, Fac Hlth Sci, Madang, Papua N Guinea. [Jiang, Hongying; Su, Xin-Zhuan; Amaratunga, Chanaki; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Socheat, Duong] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Imwong, Mallika] Mahidol Univ, Fac Trop Med, Dept Clin Trop Med, Bangkok, Thailand. [Imwong, Mallika] Mahidol Univ, Fac Trop Med, Dept Mol Trop Med & Genet, Bangkok, Thailand. [Anderson, Timothy] SW Fdn Biomed Res, San Antonio, TX 78284 USA. [Nosten, Francois] Shoklo Malaria Res Unit, Mae Sot, Thailand. [White, Nicholas J.] Mahidol Oxford Univ, Res Unit, Fac Trop Med, Bangkok, Thailand. [White, Nicholas J.; Newbold, Christopher I.] John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DU, England. [Rockett, Kirk; Kwiatkowski, Dominic P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Clark, Taane G.] Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England. RP Campino, S (reprint author), Wellcome Trust Sanger Inst, Hinxton, England. EM sc11@sanger.ac.uk RI mangano, valentina/I-2456-2012; White, Nicholas/I-4629-2012; Deloukas, Panos/B-2922-2013; Mueller, Ivo/C-7251-2013; Borrmann, Steffen/G-1838-2013; OI Kwiatkowski, Dominic/0000-0002-5023-0176; Deloukas, Panos/0000-0001-9251-070X; Mueller, Ivo/0000-0001-6554-6889; Borrmann, Steffen/0000-0001-9189-4393; Newbold, Chris/0000-0002-9274-3789; Mangano, Valentina D/0000-0002-2021-6162; Nosten, Francois/0000-0002-7951-0745; Su, Xinzhuan/0000-0003-3246-3248; Auburn, Sarah/0000-0002-4638-536X FU Bill and Melinda Gates Foundation; Wellcome Trust; Medical Research Council-UK; European Developing Countries Clinical Trials Partnership; Division of Intramural Research of the National Institutes of Health and National Institute of Allergy and Infectious Diseases-USA; National Health and Medical Research Council-Australia; National Malaria Control Program; National Budget of the Institut de Recherche en Sciences de le Sante-Burkina Faso; Howard Hughes Medical Institution International Scholarship FX Funding: This work was in part funded by the Bill and Melinda Gates Foundation, Wellcome Trust, Medical Research Council-UK, European Developing Countries Clinical Trials Partnership, Division of Intramural Research of the National Institutes of Health and National Institute of Allergy and Infectious Diseases-USA, the National Health and Medical Research Council-Australia, The National Malaria Control Program and the National Budget of the Institut de Recherche en Sciences de le Sante-Burkina Faso. A. A. D. is supported by European and Developing Countries Clinical Trial Partnership Senior Fellowship and Howard Hughes Medical Institution International Scholarship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 11 Z9 12 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 6 PY 2011 VL 6 IS 6 AR e20251 DI 10.1371/journal.pone.0020251 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 774BN UT WOS:000291356400003 PM 21673999 ER PT J AU Adamou, A Dao, A Timbine, S Kassogue, Y Yaro, AS Diallo, M Traore, SF Huestis, DL Lehmann, T AF Adamou, Abdoulaye Dao, Adama Timbine, Seydou Kassogue, Yaya Yaro, Alpha Seydou Diallo, Moussa Traore, Sekou F. Huestis, Diana L. Lehmann, Tovi TI The contribution of aestivating mosquitoes to the persistence of Anopheles gambiae in the Sahel SO MALARIA JOURNAL LA English DT Article ID DRY SEASON; MALARIA TRANSMISSION; POPULATION-SIZE; MOLECULAR-FORMS; WEST-AFRICA; VILLAGE; MALI; ARABIENSIS; SURVIVAL; COMPLEX AB Background: Persistence of African anophelines throughout the long dry season (4-8 months) when no surface waters are available remains one of the enduring mysteries of medical entomology. Recent studies demonstrated that aestivation (summer diapause) is one mechanism that allows the African malaria mosquito, Anopheles gambiae, to persist in the Sahel. However, migration from distant localities - where reproduction continues year-round might also be involved. Methods: To assess the contribution of aestivating adults to the buildup of populations in the subsequent wet season, two villages subjected to weekly pyrethrum sprays throughout the dry season were compared with two nearby villages, which were only monitored. If aestivating adults are the main source of the subsequent wet-season population, then the subsequent wet-season density in the treated villages will be lower than in the control villages. Moreover, since virtually only M-form An. gambiae are found during the dry season, the reduction should be specific to the M form, whereas no such difference is predicted for S-form An. gambiae or Anopheles arabiensis. On the other hand, if migrants arriving with the first rain are the main source, no differences between treated and control villages are expected across all members of the An. gambiae complex. Results: The wet-season density of the M form in treated villages was 30% lower than that in the control (P < 10(-4), permutation test), whereas no significant differences were detected in the S form or An. arabiensis. Conclusions: These results support the hypothesis that the M form persist in the arid Sahel primarily by aestivation, whereas the S form and An. arabiensis rely on migration from distant locations. Implications for malaria control are discussed. C1 [Huestis, Diana L.; Lehmann, Tovi] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Adamou, Abdoulaye; Dao, Adama; Timbine, Seydou; Kassogue, Yaya; Yaro, Alpha Seydou; Diallo, Moussa; Traore, Sekou F.] Malaria Res & Training Ctr MRTC, Fac Med Pharm & Odontostomatol, Bamako, Mali. RP Lehmann, T (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM tlehmann@niaid.nih.gov OI Huestis, Diana/0000-0001-6649-4785 FU NIH, NIAID FX We are grateful to the residents of the villages who accommodated our studies and for their hospitality. We thank Drs. Guha Dharmarajan and Robert Gwadz for valuable suggestions on earlier versions of this ms. This study was supported by the Intramural Research Program in NIH, NIAID. NR 26 TC 26 Z9 26 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUN 6 PY 2011 VL 10 AR 151 DI 10.1186/1475-2875-10-151 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 784ZO UT WOS:000292197400001 PM 21645385 ER PT J AU Duke-Sylvester, SM Bolzoni, L Real, LA AF Duke-Sylvester, Scott M. Bolzoni, Luca Real, Leslie A. TI Strong seasonality produces spatial asynchrony in the outbreak of infectious diseases SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE seasonality; infectious disease; spatial dynamics; spatial synchronization; rabies; latitudinal gradient ID EPIZOOTIC RABIES; MEASLES DYNAMICS; HOUSE FINCHES; CHAOS; POPULATION; EXTINCTION; EPIDEMICS; METAPOPULATIONS; HIERARCHIES; COMPLEXITY AB Models for infectious diseases usually assume a fixed demographic structure. Yet, a disease can spread over a region encountering different local demographic variations that may significantly alter local dynamics. Spatial heterogeneity in the resulting dynamics can lead to important differences in the design of surveillance and control strategies. We illustrate this by exploring the north-south gradient in the seasonal demography of raccoon rabies over the eastern USA. We find that the greater variance in the timing of spring births characteristic of southern populations can lead to the spatial synchronization of southern epidemics, while the narrow birth-pulse associated with northern populations can lead to an irregular patchwork of epidemics. These results indicate that surveillance in the southern states can be reduced relative to northern locations without loss of detection ability. This approach could yield significant savings in vaccination programmes. The importance of seasonality in many widely distributed diseases indicates that our findings will find applications beyond raccoon rabies. C1 [Duke-Sylvester, Scott M.] Emory Univ, Dept Biol, Atlanta, GA 30322 USA. [Duke-Sylvester, Scott M.; Real, Leslie A.] Emory Univ, Ctr Dis Ecol, Atlanta, GA 30322 USA. [Duke-Sylvester, Scott M.] Univ Louisiana Lafayette, Dept Biol, Lafayette, LA 70504 USA. [Bolzoni, Luca] Univ Parma, Dipartimento Sci Ambientali, I-43100 Parma, Italy. [Real, Leslie A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Duke-Sylvester, SM (reprint author), Emory Univ, Dept Biol, 1510 Clifton Rd, Atlanta, GA 30322 USA. EM smd3729@louisiana.edu RI Bolzoni, Luca/F-5061-2011 FU NIH [RO1 AI047498]; RAPIDD Programme of the Science and Technology Directorate, Department of Homeland Security; Forgarty International Center, National Institutes of Health FX We would like to thank Roman Biek, Lance Waller, Juliet Pullium, Michael Fuller and Katie Hampson for comments and discussion of the manuscript. This research was supported by NIH grant RO1 AI047498 to L. A. R. and the RAPIDD Programme of the Science and Technology Directorate, Department of Homeland Security and the Forgarty International Center, National Institutes of Health. All computer simulations were performed on the Emory High Performance Computer Cluster. NR 51 TC 16 Z9 16 U1 2 U2 14 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD JUN 6 PY 2011 VL 8 IS 59 BP 817 EP 825 DI 10.1098/rsif.2010.0475 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 752EL UT WOS:000289672200006 PM 20961894 ER PT J AU Watts, NR Conway, JF Cheng, NQ Stahl, SJ Steven, AC Wingfield, PT AF Watts, Norman R. Conway, James F. Cheng, Naiqian Stahl, Stephen J. Steven, Alasdair C. Wingfield, Paul T. TI Role of the Propeptide in Controlling Conformation and Assembly State of Hepatitis B Virus e-Antigen SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HBeAg; HBcAg; thermal stability; circular dichroism; cryo-EM ID CORE ANTIGEN; CAPSID PROTEIN; CRYOELECTRON MICROSCOPY; CIRCULAR-DICHROISM; VIRAL REPLICATION; ESCHERICHIA-COLI; PRECORE PROTEIN; EXPRESSION; PARTICLES; PEPTIDE AB Hepatitis B virus "e-antigen" (HBeAg) is thought to be a soluble dimeric protein that is associated with chronic infection. It shares 149 residues with the viral capsid protein "core-antigen" (HBcAg), but has an additional 10-residue, hydrophobic, cysteine-containing amino-terminal propeptide whose presence correlates with physical, serological, and immunological differences between the two proteins. In HBcAg dimers, the subunits pair by forming a four-helix bundle stabilized by an intermolecular disulfide bond. The structure of HBeAg is probably similar but, instead, has two intramolecular disulfide bonds involving the propeptide. To compare the proteins directly and thereby clarify the role of the propeptide, we identified mutations and solution conditions that render both proteins as either soluble dimers or assembled capsids. Thermally induced unfolding monitored by circular dichroism, and electrophoresis of oxidized and reduced dimers, showed that the propeptide has a destabilizing effect and that the intramolecular disulfide bond forms preferentially and blocks the formation of the intermolecular disulfide bond that otherwise stabilizes the dimer. The HBeAg capsids are less regular than the HBcAg capsids; nevertheless, cryo-electron microscopy reconstructions confirm that they are constructed of dimers resembling those of HBcAg capsids. In them, a portion of the propeptide is visible near the dimer interface, suggesting that it intercalates there, consistent with the known formation of a disulfide bond between C(-7) in the propeptide and C61 in the dimer interface. However, this intercalation distorts the dimer into an assembly-reluctant conformation. Published by Elsevier Ltd. C1 [Watts, Norman R.; Stahl, Stephen J.; Wingfield, Paul T.] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [Conway, James F.] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA. [Cheng, Naiqian; Steven, Alasdair C.] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wingfield, PT (reprint author), NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. EM pelpw@helix.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health; Commonwealth of Pennsylvania [SAP 4100031302] FX We wish to thank Dr. Adam Zlotnick for helpful discussions, Joshua Kaufman and Ira Palmer for technical assistance, and Philip Greer and Douglas Bevan for aid with computer resources. This research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program of the National Institutes of Health and by the Commonwealth of Pennsylvania grant SAP 4100031302 (J.F.C.). NR 51 TC 10 Z9 10 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 3 PY 2011 VL 409 IS 2 BP 202 EP 213 DI 10.1016/j.jmb.2011.03.049 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 776FO UT WOS:000291520100010 PM 21463641 ER PT J AU Kryndushkin, DS Wickner, RB Tycko, R AF Kryndushkin, Dmitry S. Wickner, Reed B. Tycko, Robert TI The Core of Ure2p Prion Fibrils Is Formed by the N-Terminal Segment in a Parallel Cross-beta Structure: Evidence from Solid-State NMR SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE amyloid structure; yeast prions; dipolar recoupling; magic-angle spinning ID NUCLEAR-MAGNETIC-RESONANCE; YEAST SACCHAROMYCES-CEREVISIAE; FORMATION IN-VITRO; SHEET STRUCTURE; LIMITED PROTEOLYSIS; SECONDARY-STRUCTURE; MAMMALIAN PRIONS; PROTEIN FIBRILS; ROTATING SOLIDS; AMYLOID FIBRILS AB Intracellular fibril formation by Ure2p produces the non-Mendelian genetic element [URE3] in Saccharomyces cerevisiae, making Ure2p a prion protein. We show that solid-state NMR spectra of full-length Ure2p fibrils, seeded with infectious prions from a specific [URE3] strain and labeled with uniformly (15)N-(13)C-enriched Be, include strong, sharp signals from Be residues in the globular C-terminal domain (CTD) with both helical and nonhelical (13)C chemical shifts. Treatment with proteinase K eliminates these CTD signals, leaving only nonhelical signals from the Gln-rich and Asn-rich N-terminal segment, which are also observed in the solid-state NMR spectra of Ile-labeled fibrils formed by residues 1-89 of Ure2p. Thus, the N-terminal segment, or "prion domain" (PD), forms the fibril core, while CTD units are located outside the core. We additionally show that, after proteinase K treatment, Ile-labeled Ure2p fibrils formed without prion seeding exhibit a broader set of solid-state NMR signals than do prion-seeded fibrils, consistent with the idea that structural variations within the PD core account for prion strains. Measurements of (13)C-(13)C magnetic dipole-dipole couplings among (13)C-labeled Be carbonyl sites in full-length Ure2p fibrils support an in-register parallel p-sheet structure for the PD core of Ure2p fibrils. Finally, we show that a model in which CTD units are attached rigidly to the parallel beta-sheet core is consistent with steric constraints. Published by Elsevier Ltd. C1 [Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Kryndushkin, Dmitry S.; Wickner, Reed B.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. We thank Eric Anderson for mass spectrometry measurements, Frank Shewmaker for assistance with electron microscopy, and Charles Schwieters for assistance with molecular modeling. Computational facilities of the Helix systems at the National Institutes of Health were used in this work. NR 57 TC 30 Z9 31 U1 1 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 3 PY 2011 VL 409 IS 2 BP 263 EP 277 DI 10.1016/j.jmb.2011.03.067 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 776FO UT WOS:000291520100015 PM 21497604 ER PT J AU Bernier, M Paul, RK Martin-Montalvo, A Scheibye-Knudsen, M Song, SM He, HJ Armour, SM Hubbard, BP Bohr, VA Wang, LL Zong, YP Sinclair, DA de Cabo, R AF Bernier, Michel Paul, Rajib K. Martin-Montalvo, Alejandro Scheibye-Knudsen, Morten Song, Shaoming He, Hua-Jun Armour, Sean M. Hubbard, Basil P. Bohr, Vilhelm A. Wang, Lili Zong, Yaping Sinclair, David A. de Cabo, Rafael TI Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FACTOR-KAPPA-B; SERINE PHOSPHORYLATION; SIGNAL TRANSDUCER; CALORIE RESTRICTION; SER-727 PHOSPHORYLATION; MITOCHONDRIAL STAT3; DEPENDENT PATHWAY; DIRECT ACTIVATOR; CELLS; ACETYLATION AB In mammals, the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) is regulated by the deacetylase SIRT1. However, whether the newly described non-genomic actions of STAT3 toward mitochondrial oxidative phosphorylation are dependent on SIRT1 is unclear. In this study, Sirt1 gene knock-out murine embryonic fibroblast (MEF) cells were used to delineate the role of SIRT1 in the regulation of STAT3 mitochondrial function. Here, we show that STAT3 mRNA and protein levels and the accumulation of serine-phosphorylated STAT3 in mitochondria were increased significantly in Sirt1-KO cells as compared with wild-type MEFs. Various mitochondrial bioenergetic parameters, such as the oxygen consumption rate in cell cultures, enzyme activities of the electron transport chain complexes in isolated mitochondria, and production of ATP and lactate, indicated that Sirt1-KO cells exhibited higher mitochondrial respiration as compared with wildtype MEFs. Two independent approaches, including ectopic expression of SIRT1 and siRNA-mediated knockdown of STAT3, led to reduction in intracellular ATP levels and increased lactate production in Sirt1-KO cells that were approaching those of wild-type controls. Comparison of profiles of phospho-antibody array data indicated that the deletion of SirT1 was accompanied by constitutive activation of the proinflammatory NF-kappa B pathway, which is key for STAT3 induction and increased cellular respiration in Sirt1-KO cells. Thus, SIRT1 appears to be a functional regulator of NF-kappa B-dependent STAT3 expression that induces mitochondrial biogenesis. These results have implications for understanding the interplay between STAT3 and SIRT1 in pro-inflammatory conditions. C1 [Bernier, Michel] NIA, Clin Invest Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [He, Hua-Jun; Wang, Lili] Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. [Paul, Rajib K.; Martin-Montalvo, Alejandro; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Scheibye-Knudsen, Morten; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Armour, Sean M.; Hubbard, Basil P.; Sinclair, David A.] Harvard Univ, Sch Med, Dept Pathol, Paul F Glenn Labs, Boston, MA 02115 USA. [Zong, Yaping] Full Moon Biosyst Inc, Sunnyvale, CA 94085 USA. RP Bernier, M (reprint author), NIA, Clin Invest Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd,Ste 100, Baltimore, MD 21224 USA. EM Bernierm@mail.nih.gov; deCaboRa@grc.nia.nih.gov RI Sanders, Susan/G-1957-2011; de Cabo, Rafael/J-5230-2016; Martin-Montalvo, Alejandro/C-2031-2017; OI , rafael/0000-0003-2830-5693; de Cabo, Rafael/0000-0002-3354-2442; Martin-Montalvo, Alejandro/0000-0002-3886-5355; Bernier, Michel/0000-0002-5948-368X; Scheibye-Knudsen, Morten/0000-0002-6637-1280; Sinclair, David/0000-0002-9936-436X FU National Institutes of Health NIA FX This work was supported, in whole or in part, by National Institutes of Health NIA Intramural Research Program. NR 72 TC 46 Z9 50 U1 2 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 3 PY 2011 VL 286 IS 22 BP 19270 EP 19279 DI 10.1074/jbc.M110.200311 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 769OZ UT WOS:000291027700009 PM 21467030 ER PT J AU Patterson, AD Bonzo, JA Li, F Krausz, KW Eichler, GS Aslam, S Tigno, X Weinstein, JN Hansen, BC Idle, JR Gonzalez, FJ AF Patterson, Andrew D. Bonzo, Jessica A. Li, Fei Krausz, Kristopher W. Eichler, Gabriel S. Aslam, Sadaf Tigno, Xenia Weinstein, John N. Hansen, Barbara C. Idle, Jeffrey R. Gonzalez, Frank J. TI Metabolomics Reveals Attenuation of the SLC6A20 Kidney Transporter in Nonhuman Primate and Mouse Models of Type 2 Diabetes Mellitus SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOENOLPYRUVATE-CARBOXYKINASE GENE; PEROXISOME BIOGENESIS DISORDERS; NUCLEAR-MAGNETIC-RESONANCE; GLYCINE BETAINE EXCRETION; LIQUID-CHROMATOGRAPHY; SKELETAL-MUSCLE; RHESUS-MONKEYS; METABONOMIC ANALYSIS; MASS-SPECTROMETRY; PIPECOLIC ACID AB To enhance understanding of the metabolic indicators of type 2 diabetes mellitus (T2DM) disease pathogenesis and progression, the urinary metabolomes of well characterized rhesus macaques (normal or spontaneously and naturally diabetic) were examined. High-resolution ultra-performance liquid chromatography coupled with the accurate mass determination of time-of-flight mass spectrometry was used to analyze spot urine samples from normal (n = 10) and T2DM (n = 11) male monkeys. The machine-learning algorithm random forests classified urine samples as either from normal or T2DM monkeys. The metabolites important for developing the classifier were further examined for their biological significance. Random forests models had a misclassification error of less than 5%. Metabolites were identified based on accurate masses (<10 ppm) and confirmed by tandem mass spectrometry of authentic compounds. Urinary compounds significantly increased (p < 0.05) in the T2DM when compared with the normal group included glycine betaine (9-fold), citric acid (2.8-fold), kynurenic acid (1.8-fold), glucose (68-fold), and pipecolic acid (6.5-fold). When compared with the conventional definition of T2DM, the metabolites were also useful in defining the T2DM condition, and the urinary elevations in glycine betaine and pipecolic acid (as well as proline) indicated defective re-absorption in the kidney proximal tubules by SLC6A20, a Na(+)-dependent transporter. The mRNA levels of SLC6A20 were significantly reduced in the kidneys of monkeys with T2DM. These observations were validated in the db/db mouse model of T2DM. This study provides convincing evidence of the power of metabolomics for identifying functional changes at many levels in the omics pipeline. C1 [Patterson, Andrew D.; Bonzo, Jessica A.; Li, Fei; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Eichler, Gabriel S.; Weinstein, John N.] NCI, Genom & Bioinformat Grp, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Aslam, Sadaf; Tigno, Xenia; Hansen, Barbara C.] Univ S Florida, Dept Internal Med, Tampa, FL 33612 USA. [Aslam, Sadaf; Tigno, Xenia; Hansen, Barbara C.] Univ S Florida, Dept Pediat, Tampa, FL 33612 USA. [Idle, Jeffrey R.] Univ Bern, Dept Clin Pharmacol, CH-3010 Bern, Switzerland. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov RI Patterson, Andrew/G-3852-2012; Hansen, Barbara/J-8723-2012; Li, Fei/F-6849-2013; OI Patterson, Andrew/0000-0003-2073-0070; Hansen, Barbara/0000-0001-9646-3525; Idle, Jeff/0000-0002-6143-1520 FU National Institutes of Health [NO1-AG-3-1012, AG-42100, HHSN26300800022C]; National Cancer Institute; NIGMS, National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grants NO1-AG-3-1012 (to B. C. H.), AG-42100 (to B. C. H.), and HHSN26300800022C and the National Cancer Institute, Intramural Research Program.; Supported by Pharmacology Research Associate in Training Fellowships from the NIGMS, National Institutes of Health. NR 75 TC 37 Z9 38 U1 0 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 3 PY 2011 VL 286 IS 22 BP 19511 EP 19522 DI 10.1074/jbc.M111.221739 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 769OZ UT WOS:000291027700034 PM 21487016 ER PT J AU Kurotani, R Okumura, S Matsubara, T Yokoyama, U Buckley, JR Tomita, T Kezuka, K Nagano, T Esposito, D Taylor, TE Gillette, WK Ishikawa, Y Abe, H Ward, JM Kimura, S AF Kurotani, Reiko Okumura, Satoshi Matsubara, Tsutomu Yokoyama, Utako Buckley, John R. Tomita, Takeshi Kezuka, Kyohei Nagano, Tomokazu Esposito, Dominic Taylor, Troy E. Gillette, William K. Ishikawa, Yoshihiro Abe, Hiroyuki Ward, Jerrold M. Kimura, Shioko TI Secretoglobin 3A2 Suppresses Bleomycin-induced Pulmonary Fibrosis by Transforming Growth Factor beta Signaling Down-regulation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UTEROGLOBIN-RELATED PROTEIN-1; ALLERGIC AIRWAY INFLAMMATION; INDUCED LUNG FIBROSIS; INTERFERON-GAMMA; IFN-GAMMA; GENE-EXPRESSION; BREAST-CANCER; MOUSE; INHIBITION; RECEPTOR AB With increasing worldwide rates of morbidity and mortality of pulmonary fibrosis, the development of effective therapeutics for this disease is of great interest. Secretoglobin (SCGB) 3A2, a novel cytokine-like molecule predominantly expressed in pulmonary airways epithelium, exhibits anti-inflammatory and growth factor activities. In the current study SCGB3A2 was found to inhibit TGF beta-induced differentiation of fibroblasts to myofibroblasts, a hallmark of the fibrogenic process, using pulmonary fibroblasts isolated from adult mice. This induction was through increased phosphorylation of STAT1 and expression of SMAD7 and decreased phosphorylation of SMAD2 and SMAD3. To demonstrate the effect of SCGB3A2 on the TGF beta signaling in vivo, a bleomycin-induced pulmonary fibrosis mouse model was used. Mice were administered bleomycin intratracheally followed by intravenous injection of recombinant SCGB3A2. Histological examination in conjunction with inflammatory cell counts in bronchoalveolar lavage fluids demonstrated that SCGB3A2 suppressed bleomycin-induced pulmonary fibrosis. Microarray analysis was carried out using RNAs from lungs of bleomycin-treated mice with or without SCGB3A2 and normal mice treated with SCGB3A2. The results demonstrated that SCGB3A2 affects TGF beta signaling and reduces the expression of genes involved in fibrosis. This study suggests the potential utility of SCGB3A2 for targeting TGF beta signaling in the treatment of pulmonary fibrosis. C1 [Kurotani, Reiko; Matsubara, Tsutomu; Buckley, John R.; Tomita, Takeshi; Nagano, Tomokazu; Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Kurotani, Reiko; Okumura, Satoshi; Yokoyama, Utako; Kezuka, Kyohei; Ishikawa, Yoshihiro] Yokohama City Univ, Cardiovasc Res Inst, Yokohama, Kanagawa 2360004, Japan. [Kurotani, Reiko; Abe, Hiroyuki] Yamagata Univ, Fac Engn, Yamagata 9928510, Japan. [Esposito, Dominic; Taylor, Troy E.; Gillette, William K.] NCI, Prot Express Lab, Adv Technol Program, SAIC Frederick Inc,NIH, Frederick, MD 21701 USA. [Ishikawa, Yoshihiro] Univ Med & Dent New Jersey, New Jersey Med Sch, Cardiovasc Res Inst, Dept Cell Biol & Mol Med & Med Cardiol, Newark, NJ 07103 USA. [Ward, Jerrold M.] Global VetPathol, Montgomery Village, MD 20866 USA. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bldg 37,Rm 3106, Bethesda, MD 20892 USA. EM kimuras@mail.nih.gov FU National Institutes of Health, Center for Cancer Research (NCI; NIH) [0010190305, Z01 BC010449-06]; [21790207] FX This work was supported by the National Institutes of Health, Center for Cancer Research (Intramural Research Program of the NCI; NIH 0010190305 and Z01 BC010449-06, to S. K.). This work was also supported by Grant-in-aid for Young Scientists (B) (21790207, to R. K.). NR 50 TC 15 Z9 16 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 3 PY 2011 VL 286 IS 22 BP 19682 EP 19692 DI 10.1074/jbc.M111.239046 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 769OZ UT WOS:000291027700051 PM 21478551 ER PT J AU Kang, YH Park, CH Kim, TS Soung, NK Bang, JK Kim, BY Park, JE Lee, KS AF Kang, Young H. Park, Chi-Hoon Kim, Tae-Sung Soung, Nak-Kyun Bang, Jeong K. Kim, Bo Y. Park, Jung-Eun Lee, Kyung S. TI Mammalian Polo-like Kinase 1-dependent Regulation of the PBIP1-CENP-Q Complex at Kinetochores SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BOX DOMAIN; PLK1-PBIP1 INTERACTION; PLK1 LOCALIZATION; PROTEIN-KINASE; CENP-A; POLO-LIKE-KINASE-1; CYTOKINESIS; PHOSPHORYLATION; STABILITY; REVEALS AB Mammalian polo-like kinase 1 (Plk1) plays a pivotal role during M-phase progression. Plk1 localizes to specific subcellular structures through the targeting activity of the C-terminal polobox domain (PBD). Disruption of the PBD function results in improper bipolar spindle formation, chromosome missegregation, and cytokinesis defect that ultimately lead to the generation of aneuploidy. It has been shown that Plk1 recruits itself to centromeres by phosphorylating and binding to a centromere scaffold, PBIP1 (also called MLF1IP and CENP-U[ 50]) through its PBD. However, how PBIP1 itself is targeted to centromeres and what roles it plays in the regulation of Plk1-dependent mitotic events remain unknown. Here, we demonstrated that PBIP1 directly interacts with CENP-Q, and this interaction was mutually required not only for their stability but also for their centromere localization. Plk1 did not appear to interact with CENP-Q directly. However, Plk1 formed a ternary complex with PBIP1 and CENP-Q through a self-generated p-T78 motif on PBIP1. This complex formation was central for Plk1-dependent phosphorylation of PBIP1-bound CENP-Q and delocalization of the PBIP1-CENP-Q complex from mitotic centromeres. This study reveals a unique mechanism of how PBIP1 mediates Plk1-dependent phosphorylation event onto a third protein, and provides new insights into the mechanism of how Plk1 and its recruitment scaffold, PBIP1-CENP-Q complex, are localized to and delocalized from centromeres. C1 [Kang, Young H.; Park, Chi-Hoon; Kim, Tae-Sung; Soung, Nak-Kyun; Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bang, Jeong K.] Korean Basic Sci Inst, Div Magnet Resonance, Ochang 363883, Chung Buk, South Korea. [Soung, Nak-Kyun; Kim, Bo Y.] Korea Res Inst Biosci & Biotechnol, Chem Biol Res Ctr, Ochang 363883, Chung Buk, South Korea. RP Lee, KS (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Rm 3118, Bethesda, MD 20892 USA. EM kyunglee@mail.nih.gov FU NCI, National Institutes of Health [Z01 BC 010520]; Korea Basic Science Institute [T3022B]; Ministry of Education, Science and Technology of Korea FX This work was supported, in whole or in part, by NCI, National Institutes of Health intramural Grant Z01 BC 010520 (to K. S. L.), the Korea Basic Science Institute's high field NMR Research Program Grant T3022B (to J. K. B.), and the World Class Institute research program of the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology of Korea (to B. Y. K.). NR 33 TC 15 Z9 15 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 3 PY 2011 VL 286 IS 22 BP 19744 EP 19757 DI 10.1074/jbc.M111.224105 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 769OZ UT WOS:000291027700057 PM 21454580 ER PT J AU Park, BH Lee, SB Stolz, DB Lee, YJ Lee, BC AF Park, Bae-Hang Lee, Sean-Bong Stolz, Donna B. Lee, Yong J. Lee, Byeong-Chel TI Synergistic Interactions between Heregulin and Peroxisome Proliferator-activated Receptor-gamma (PPAR gamma) Agonist in Breast Cancer Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LIGAND TROGLITAZONE; HYDROGEN-PEROXIDE; INDUCED APOPTOSIS; CARCINOMA CELLS; TUMOR-CELLS; DNA-DAMAGE; PHASE-II; IN-VIVO; AUTOPHAGY; GROWTH AB Here, we demonstrate that troglitazone (Rezulin), a peroxisome proliferator-activated receptor agonist, acted in synergy with heregulin to induce massive cell death in breast cancer cells. Although the combination of heregulin and troglitazone (HRG/TGZ) induced both apoptosis and necrosis, the main mode of cell death was caspase-independent and occurred via necrosis. This combination increased generation of superoxide in mitochondria, which in turn destabilized mitochondria potential. Pretreatment with N-acetyl-L-cysteine and catalase expression ameliorated cell death induced by the combination treatment, indicating a role of oxidative stress in mediating HRG/TGZ-induced cell death. Notably, pretreatment with pyruvate significantly prevented the cell death, suggesting a potential mechanistic link between metabolic stress and HRG/TGZ-induced cell death. The activation of the HRG signaling axis has been considered as a poor prognostic factor in breast cancer and confers resistance to gefitinib (Iressa) and tamoxifen. However, our data presented here paradoxically suggest that HRG expression can actually be beneficial when it comes to treating breast cancer with peroxisome proliferator-activated receptor-gamma ligands. Taken together, the combination of HRG and TGZ may provide a basis for the development of a novel strategy in the treatment of apoptosis-resistant and/or hormone-refractory breast cancer. C1 [Lee, Byeong-Chel] Univ Pittsburgh, Sch Med, Hillman Canc Ctr, Univ Pittsburgh Canc Inst, Pittsburgh, PA 15213 USA. [Park, Bae-Hang; Lee, Byeong-Chel] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol & Oncol, Pittsburgh, PA 15213 USA. [Lee, Sean-Bong] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Stolz, Donna B.] Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. [Lee, Yong J.] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. RP Lee, BC (reprint author), Univ Pittsburgh, Sch Med, Hillman Canc Ctr, Univ Pittsburgh Canc Inst, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM leeb4@upmc.edu FU National Institutes of Health [CA140554]; Department of Defense [W81XWH-09-1-0350]; University of Pittsburgh Cancer Institute; Hillman Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grant CA140554 (to Y. J. L.). This work was also supported by Department of Defense Grant W81XWH-09-1-0350 and University of Pittsburgh Cancer Institute (to B.-C. L.).; Recipient of a research scholar grant from The Hillman Foundation. To whom correspondence should be addressed: University of Pittsburgh Cancer Institute, Hillman Cancer Center, 5117 Centre Ave., Pittsburgh, PA 15213. Tel.: 412-623-2285; Fax: 412-623-7828; E-mail: leeb4@upmc.edu. NR 56 TC 10 Z9 10 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 3 PY 2011 VL 286 IS 22 BP 20087 EP 20099 DI 10.1074/jbc.M110.191718 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 769OZ UT WOS:000291027700085 PM 21467033 ER PT J AU Terrazas, M Avino, A Siddiqui, MA Marquez, VE Eritja, R AF Terrazas, Montserrat Avino, Anna Siddiqui, Maqbool A. Marquez, Victor E. Eritja, Ramon TI A Direct, Efficient Method for the Preparation of siRNAs Containing Ribo-like North Bicyclo[3.1.0]hexane Pseudosugars SO ORGANIC LETTERS LA English DT Article ID SMALL INTERFERING RNA; MAMMALIAN-CELLS; STEREOSELECTIVE-SYNTHESIS; BIOLOGICAL-ACTIVITY; CHEMICAL-SYNTHESIS; PROTECTING GROUPS; SUGAR RING; NUCLEOSIDES; NUCLEOTIDES; ANALOGS AB An efficient method for the preparation of siRNAs modified with ribo-like North bicyclo[3.1.0]hexane pseudosugars is described. The combined use of 2'-O-(2-cyanoethoxymethyl) (CEM) and 2'-O-TBDMS protection was successfully employed for RNA synthesis with the added advantage that both groups were efficiently removed in a single step. The resulting North ribo-methanocarba-modified siRNAs are compatible with the intracellular RNAi machinery and can mediate specific degradation of target mRNA. C1 [Siddiqui, Maqbool A.; Marquez, Victor E.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Terrazas, Montserrat; Avino, Anna; Eritja, Ramon] Spanish Res Council CSIC, Inst Res Biomed IRB Barcelona, Networking Ctr Bioengn Biomat & Nanomed CIBER BBN, E-08028 Barcelona, Spain. Spanish Res Council CSIC, Inst Adv Chem Catalonia IQAC, E-08028 Barcelona, Spain. RP Marquez, VE (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM marquezv@mail.nih.gov; recgma@cid.csic.es RI eritja, ramon/B-5613-2008; Avino, Anna/N-5223-2015 OI eritja, ramon/0000-0001-5383-9334; Avino, Anna/0000-0003-3047-738X FU Spanish Ministry of Education [BFU2007-63287, CTQ2010-20541-C03-01]; Generalitat de Catalunya [2009/SGR/208]; Instituto de Salud Carlos III; Center for Cancer Research, National Cancer Institute, NIH; MICINN, Spain FX This research was supported by the Spanish Ministry of Education (BFU2007-63287 and CTQ2010-20541-C03-01) and the Generalitat de Catalunya (2009/SGR/208) and the Instituto de Salud Carlos III. This work was funded in part by the Center for Cancer Research, National Cancer Institute, NIH. M.T. acknowledges the Juan de la Cierva contract (MICINN, Spain) for financial support. NR 43 TC 7 Z9 7 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD JUN 3 PY 2011 VL 13 IS 11 BP 2888 EP 2891 DI 10.1021/ol200909j PG 4 WC Chemistry, Organic SC Chemistry GA 771AB UT WOS:000291128500024 PM 21553811 ER PT J AU Hathcock, KS Farrington, L Ivanova, I Livak, F Selimyan, R Sen, R Williams, J Tai, XG Hodes, RJ AF Hathcock, Karen S. Farrington, Lila Ivanova, Irina Livak, Ferenc Selimyan, Roza Sen, Ranjan Williams, Joy Tai, Xuguang Hodes, Richard J. TI The Requirement for Pre-TCR during Thymic Differentiation Enforces a Developmental Pause That Is Essential for V-DJ beta Rearrangement SO PLOS ONE LA English DT Article ID T-CELL-RECEPTOR; CHAIN GENE REARRANGEMENT; ALLELIC EXCLUSION; V(D)J RECOMBINATION; THYMOCYTE DEVELOPMENT; IMMATURE THYMOCYTES; DEFICIENT MICE; HISTONE H3; CD3-EPSILON-MEDIATED SIGNALS; TRANSCRIPTIONAL REGULATION AB T cell development occurs in the thymus and is critically dependent on productive TCR beta rearrangement and pre-TCR expression in DN3 cells. The requirement for pre-TCR expression results in the arrest of thymocytes at the DN3 stage (beta checkpoint), which is uniquely permissive for V-DJ beta recombination; only cells expressing pre-TCR survive and develop beyond the DN3 stage. In addition, the requirement for TCR beta rearrangement and pre-TCR expression enforces suppression of TCR beta rearrangement on a second allele, allelic exclusion, thus ensuring that each T cell expresses only a single TCR beta product. However, it is not known whether pre-TCR expression is essential for allelic exclusion or alternatively if allelic exclusion is enforced by developmental changes that can occur in the absence of pre-TCR. We asked if thymocytes that were differentiated without pre-TCR expression, and therefore without pause at the beta checkpoint, would suppress all V-DJ beta rearrangement. We previously reported that premature CD28 signaling in murine CD4(-)CD8(-) (DN) thymocytes supports differentiation of CD4(+)CD8(+) (DP) cells in the absence of pre-TCR expression. The present study uses this model to define requirements for TCR beta rearrangement and allelic exclusion. We demonstrate that if cells exit the DN3 developmental stage before TCR beta rearrangement occurs, V-DJ beta rearrangement never occurs, even in DP cells that are permissive for D-J beta and TCR alpha rearrangement. These results demonstrate that pre-TCR expression is not essential for thymic differentiation to DP cells or for V-DJ beta suppression. However, the requirement for pre-TCR signals and the exclusion of alternative stimuli such as CD28 enforce a developmental "pause" in early DN3 cells that is essential for productive TCR beta rearrangement to occur. C1 [Hathcock, Karen S.; Farrington, Lila; Williams, Joy; Tai, Xuguang; Hodes, Richard J.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Ivanova, Irina; Selimyan, Roza; Sen, Ranjan; Hodes, Richard J.] NIA, Lab Cellular & Mol Biol, NIH, Baltimore, MD 21224 USA. [Livak, Ferenc] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Hathcock, KS (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hathcock@exchange.nih.gov FU National Institutes of Health (NIH), National Cancer Institute; National Institute on Aging FX All research was funded by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute and National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 3 PY 2011 VL 6 IS 6 AR e20639 DI 10.1371/journal.pone.0020639 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 774BE UT WOS:000291355500029 PM 21673984 ER PT J AU Ivashkevich, AN Martin, OA Smith, AJ Redon, CE Bonner, WM Martin, RF Lobachevsky, PN AF Ivashkevich, Alesia N. Martin, Olga A. Smith, Andrea J. Redon, Christophe E. Bonner, William M. Martin, Roger F. Lobachevsky, Pavel N. TI gamma H2AX foci as a measure of DNA damage: A computational approach to automatic analysis SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE DNA damage; Gamma-H2AX foci; Ionising radiation; Fluorescence microscopy; Automated image analysis ID DOUBLE-STRAND BREAKS; IONIZING-RADIATION EXPOSURE; PHOSPHORYLATED HISTONE H2AX; PRIMARY HUMAN FIBROBLASTS; NORMAL-TISSUES; IN-VIVO; BIOLOGICAL DOSIMETRY; RESIDUAL GAMMA-H2AX; BLOOD-LYMPHOCYTES; PULSED-FIELD AB The gamma H2AX focus assay represents a fast and sensitive approach for the detection of one of the critical types of DNA damage - double-strand breaks (DSB) induced by various cytotoxic agents including ionising radiation. Apart from research applications, the assay has a potential in clinical medicine/pathology, such as assessment of individual radiosensitivity, response to cancer therapies, as well as in biodosimetry. Given that generally there is a direct relationship between numbers of microscopically visualised gamma H2AX foci and DNA DSB in a cell, the number of foci per nucleus represents the most efficient and informative parameter of the assay. Although computational approaches have been developed for automatic focus counting, the tedious and time consuming manual focus counting still remains the most reliable way due to limitations of computational approaches. We suggest a computational approach and associated software for automatic focus counting that minimises these limitations. Our approach, while using standard image processing algorithms, maximises the automation of identification of nuclei/cells in complex images, offers an efficient way to optimise parameters used in the image analysis and counting procedures, optionally invokes additional procedures to deal with variations in intensity of the signal and background in individual images, and provides automatic batch processing of a series of images. We report results of validation studies that demonstrated correlation of manual focus counting with results obtained using our computational algorithm for mouse jejunum touch prints, mouse tongue sections and human blood lymphocytes as well as radiation dose response of gamma H2AX focus induction for these biological specimens. (C) 2011 Elsevier B.V. All rights reserved. C1 [Ivashkevich, Alesia N.; Smith, Andrea J.; Martin, Roger F.; Lobachevsky, Pavel N.] Peter MacCallum Canc Ctr, Trescowthick Res Labs, Melbourne, Vic 3002, Australia. [Martin, Olga A.; Redon, Christophe E.; Bonner, William M.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. RP Lobachevsky, PN (reprint author), Peter MacCallum Canc Ctr, Trescowthick Res Labs, St Andrews Pl, Melbourne, Vic 3002, Australia. EM pavel.lobachevsky@petermac.org FU Sirtex Medical Inc; Peter MacCallum Cancer Centre; National Cancer Institute, National Institutes of Health FX The research was supported by a licensing agreement between Sirtex Medical Inc and Peter MacCallum Cancer Centre and by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 45 TC 44 Z9 45 U1 0 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 EI 1873-135X J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 3 PY 2011 VL 711 IS 1-2 SI SI BP 49 EP 60 DI 10.1016/j.mrfmmm.2010.12.015 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 781EZ UT WOS:000291914700006 PM 21216255 ER PT J AU Wilson, DM Kim, D Berquist, BR Sigurdson, AJ AF Wilson, David M., III Kim, Daemyung Berquist, Brian R. Sigurdson, Alice J. TI Variation in base excision repair capacity SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Review DE DNA repair capacity; Base excision; Pathway assay; Polymorphism; Disease susceptibility ID DNA-POLYMERASE-BETA; STRAND BREAK REPAIR; MUTYH-ASSOCIATED POLYPOSIS; GENOME-WIDE ASSOCIATION; AMYOTROPHIC-LATERAL-SCLEROSIS; ACID SUBSTITUTION VARIANTS; CANCER SUSCEPTIBILITY LOCI; INDUCED CYTIDINE DEAMINASE; CLASS-SWITCH RECOMBINATION; HYPER-IGM SYNDROME AB The major DNA repair pathway for coping with spontaneous forms of DNA damage, such as natural hydrolytic products or oxidative lesions, is base excision repair (BER). In particular, BER processes mutagenic and cytotoxic DNA lesions such as non-bulky base modifications, abasic sites, and a range of chemically distinct single-strand breaks. Defects in BER have been linked to cancer predisposition, neurodegenerative disorders, and immunodeficiency. Recent data indicate a large degree of sequence variability in DNA repair genes and several studies have associated BER gene polymorphisms with disease risk, including cancer of several sites. The intent of this review is to describe the range of BER capacity among individuals and the functional consequences of BER genetic variants. We also discuss studies that associate BER deficiency with disease risk and the current state of BER capacity measurement assays. Published by Elsevier B.V. C1 [Wilson, David M., III; Berquist, Brian R.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Kim, Daemyung] Cheongju Univ, Dept Genet Engn, Cheongju 360764, South Korea. [Sigurdson, Alice J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM wilsonda@mail.nih.gov FU National Institute on Aging, NIH; Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH FX As the reports on the various topics covered herein are enormous, we apologize in advance if relevant articles were missed or not cited. This research was supported by the Intramural Research Programs of the National Institute on Aging, NIH and the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. NR 147 TC 57 Z9 58 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 3 PY 2011 VL 711 IS 1-2 SI SI BP 100 EP 112 DI 10.1016/j.mrfmmm.2010.12.004 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 781EZ UT WOS:000291914700010 PM 21167187 ER PT J AU Baird, BJ Dickey, JS Nakamura, AJ Redon, CE Parekh, P Griko, YV Aziz, K Georgakilas, AG Bonner, WM Martin, OA AF Baird, Brandon J. Dickey, Jennifer S. Nakamura, Asako J. Redon, Christophe E. Parekh, Palak Griko, Yuri V. Aziz, Khaled Georgakilas, Alexandros G. Bonner, William M. Martin, Olga A. TI Hypothermia postpones DNA damage repair in irradiated cells and protects against cell killing SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Hypothermia; Radioprotective effect; Cell survival; DNA damage ID DOUBLE-STRAND BREAKS; INDUCED HAIR LOSS; SQUIRRELS CITELLUS-TRIDECEMLINEATUS; BASE EXCISION-REPAIR; IONIZING-RADIATION; GROUND SQUIRRELS; IN-VITRO; BLOOD-LYMPHOCYTES; SPACE EXPLORATION; TOPOISOMERASE-I AB Hibernation is an established strategy used by some homeothermic organisms to survive cold environments. In true hibernation, the core body temperature of an animal may drop to below 0 degrees C and metabolic activity almost cease. The phenomenon of hibernation in humans is receiving renewed interest since several cases of victims exhibiting core body temperatures as low as 13.7 degrees C have been revived with minimal lasting deficits. In addition, local cooling during radiotherapy has resulted in normal tissue protection. The experiments described in this paper were prompted by the results of a very limited pilot study, which showed a suppressed DNA repair response of mouse lymphocytes collected from animals subjected to 7-Gy total body irradiation under hypothermic (13 degrees C) conditions, compared to normothermic controls. Here we report that human BJ-hTERT cells exhibited a pronounced radioprotective effect on clonogenic survival when cooled to 13 degrees C during and 12h after irradiation. Mild hypothermia at 20 and 30 degrees C also resulted in some radioprotection. The neutral comet assay revealed an apparent lack on double strand break (DSB) rejoining at 13 degrees C. Extension of the mouse lymphocyte study to ex vivo-irradiated human lymphocytes confirmed lower levels of induced phosphorylated H2AX (gamma-H2AX) and persistence of the lesions at hypothermia compared to the normal temperature. Parallel studies of radiation-induced oxidatively clustered DNA lesions (0CDL5) revealed partial repair at 13 degrees C compared to the rapid repair at 37 degrees C. For both gamma-H2AX foci and OCDLs, the return of lymphocytes to 37 degrees C resulted in the resumption of normal repair kinetics. These results, as well as observations made by others and reviewed in this study, have implications for understanding the radiobiology and protective mechanisms underlying hypothermia and potential opportunities for exploitation in terms of protecting normal tissues against radiation. (C) 2011 Published by Elsevier B.V. C1 [Baird, Brandon J.; Dickey, Jennifer S.; Nakamura, Asako J.; Redon, Christophe E.; Parekh, Palak; Bonner, William M.; Martin, Olga A.] NCI, Mol Pharmacol Lab, CCR, Bethesda, MD 20892 USA. [Aziz, Khaled; Georgakilas, Alexandros G.] E Carolina Univ, Dept Biol, Greenville, NC 27858 USA. [Griko, Yuri V.] NASA, Ames Res Ctr, Radiat & Space Biotechnol Branch, Moffett Field, CA 94035 USA. RP Martin, OA (reprint author), Bldg 37,Room 5050,9000 Rockville Pike, Bethesda, MD USA. EM sedelnio@mail.nih.gov RI Parekh, Palak/B-7042-2015 OI Parekh, Palak/0000-0001-9201-5194 FU National Cancer Institute, Center for Cancer Research, National Institutes of Health; NASA [NNX08AB13A]; ECU FX This work was founded by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health; by the NASA Human Research Program and the NASA contract to the Carnegie Mellon University Silicon Valley #NNX08AB13A; and by funds provided to Dr. Georgakilas by a 2009/2010 ECU Research/Creative Activity Award. NR 64 TC 8 Z9 9 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 3 PY 2011 VL 711 IS 1-2 SI SI BP 142 EP 149 DI 10.1016/j.mrfmmm.2010.12.006 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 781EZ UT WOS:000291914700014 PM 21185842 ER PT J AU Kim, HK Kim, J Korolevich, S Choi, IJ Kim, CH Munroe, DJ Green, JE AF Kim, Hark Kyun Kim, Joseph Korolevich, Susie Choi, Il Ju Kim, Chang Hee Munroe, David J. Green, Jeffrey E. TI Distinctions in gastric cancer gene expression signatures derived from laser capture microdissection versus histologic macrodissection SO BMC MEDICAL GENOMICS LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; MICROARRAY ANALYSIS; AMPLIFICATION; PROGRESSION; ABERRATIONS; CARCINOMAS; PROFILES; SUBTYPES; BIAS; PCR AB Background: Gastric cancer samples obtained by histologic macrodissection contain a relatively high stromal content that may significantly influence gene expression profiles. Differences between the gene expression signature derived from macrodissected gastric cancer samples and the signature obtained from isolated gastric cancer epithelial cells from the same biopsies using laser-capture microdissection (LCM) were evaluated for their potential experimental biases. Methods: RNA was isolated from frozen tissue samples of gastric cancer biopsies from 20 patients using both histologic macrodissection and LCM techniques. RNA from LCM was subject to an additional round of T7 RNA amplification. Expression profiling was performed using Affymetrix HG-U133A arrays. Genes identified in the expression signatures from each tissue processing method were compared to the set of genes contained within chromosomal regions found to harbor copy number aberrations in the tumor samples by array CGH and to proteins previously identified as being overexpressed in gastric cancer. Results: Genes shown to have increased copy number in gastric cancer were also found to be overexpressed in samples obtained by macrodissection (LS P value < 10(-5)), but not in array data generated using microdissection. A set of 58 previously identified genes overexpressed in gastric cancer was also enriched in the gene signature identified by macrodissection (LS P < 10(-5)), but not in the signature identified by microdissection (LS P = 0.013). In contrast, 66 genes previously reported to be underexpressed in gastric cancer were enriched in the gene signature identified by microdissection (LS P < 10(-5)), but not in the signature identified by macrodissection (LS P = 0.89). Conclusions: The tumor sampling technique biases the microarray results. LCM may be a more sensitive collection and processing method for the identification of potential tumor suppressor gene candidates in gastric cancer using expression profiling. C1 [Kim, Hark Kyun; Kim, Joseph; Green, Jeffrey E.] NCI, Bethesda, MD 20892 USA. [Kim, Hark Kyun; Choi, Il Ju] Natl Canc Ctr, Goyang 410769, Gyeonggi, South Korea. [Korolevich, Susie; Kim, Chang Hee; Munroe, David J.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Green, JE (reprint author), NCI, Bethesda, MD 20892 USA. EM jegreen@nih.gov FU Center for Cancer Research, National Cancer Institute, Bethesda; Converging Research Center Program through the Korean Ministry of Education, Science and Technology [2010K001121]; Korean National Cancer Center [0910570]; NCI [HHSN261200800001E] FX The research was supported in part by the Intramural Program, Center for Cancer Research, National Cancer Institute, Bethesda; by the Converging Research Center Program through the Korean Ministry of Education, Science and Technology (2010K001121); by Korean National Cancer Center Grant 0910570; and by federal funds from the NCI 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 the mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 29 TC 10 Z9 10 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD JUN 2 PY 2011 VL 4 AR 48 DI 10.1186/1755-8794-4-48 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 795WQ UT WOS:000293009500001 PM 21635755 ER PT J AU Piekarz, RL Frye, R Prince, HM Kirschbaum, MH Zain, J Allen, SL Jaffe, ES Ling, A Turner, M Peer, CJ Figg, WD Steinberg, SM Smith, S Joske, D Lewis, I Hutchins, L Craig, M Fojo, AT Wright, JJ Bates, SE AF Piekarz, Richard L. Frye, Robin Prince, H. Miles Kirschbaum, Mark H. Zain, Jasmine Allen, Steven L. Jaffe, Elaine S. Ling, Alexander Turner, Maria Peer, Cody J. Figg, William D. Steinberg, Seth M. Smith, Sonali Joske, David Lewis, Ian Hutchins, Laura Craig, Michael Fojo, A. Tito Wright, John J. Bates, Susan E. TI Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma SO BLOOD LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; DEPSIPEPTIDE FR901228; CLINICAL-TRIALS; II TRIAL; FK228; DIFFERENTIATION; IDENTIFICATION; PRALATREXATE; MULTICENTER; INDUCERS AB Romidepsin (depsipeptide or FK228) is a histone deacetylase inhibitor, one of a new class of agents active in T-cell lymphoma. A phase 2 trial was conducted in cutaneous (CTCL) and peripheral (PTCL) T-cell lymphoma. Major and durable responses in CTCL supported the approval of romidepsin for CTCL. Forty-seven patients with PTCL of various subtypes including PTCL NOS, angioimmunoblastic, ALK-negative anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma were enrolled. All patients had received prior therapy with a median of 3 previous treatments (range 1-11); 18 (38%) had undergone stem-cell transplant. All patients were evaluated for toxicity; 2 patients discovered to be ineligible were excluded from response assessment. Common toxicities were nausea, fatigue, and transient thrombocytopenia and granulocytopenia. Complete responses were observed in 8 and partial responses in 9 of 45 patients, for an overall response rate of 38% (95% confidence interval 24%-53%). The median duration of overall response was 8.9 months (range 2-74). Responses were observed in various subtypes, with 6 responses among the 18 patients with prior stemcell transplant. The histone deacetylase inhibitor romidepsin has single agent clinical activity associated with durable responses in patients with relapsed PTCL. This study has been registered at clinical-trials. gov as NCT00007345. (Blood. 2011; 117(22): 5827-5834) C1 [Piekarz, Richard L.; Wright, John J.] NIH, Rockville, MD 20852 USA. [Frye, Robin; Jaffe, Elaine S.; Turner, Maria; Peer, Cody J.; Figg, William D.; Steinberg, Seth M.; Fojo, A. Tito; Bates, Susan E.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Prince, H. Miles] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Kirschbaum, Mark H.; Zain, Jasmine] City Hope Natl Canc Ctr, Duarte, CA USA. [Allen, Steven L.] Hoftra N Shore Long Isl Jewish Sch Med, Manhasset, NY USA. [Ling, Alexander] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Smith, Sonali] Univ Chicago, Chicago, IL 60637 USA. [Joske, David] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia. [Lewis, Ian] Royal Adelaide Hosp, Adelaide, SA 5000, Australia. [Hutchins, Laura] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Craig, Michael] W Virginia Univ, Morgantown, WV 26506 USA. RP Piekarz, RL (reprint author), NIH, 6130 Execut Blvd,Suite 7131 MSC 7426, Rockville, MD 20852 USA. EM rpiekarz@nih.gov RI Figg Sr, William/M-2411-2016; OI Allen, Steven/0000-0002-3482-3182; Jaffe, Elaine/0000-0003-4632-0301 FU NIH, NCI, Center for Cancer Research; Cooperative Research and Development Agreement with Gloucester Pharmaceuticals (and Celgene Corporation) FX This research was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research and by a Cooperative Research and Development Agreement with Gloucester Pharmaceuticals (and Celgene Corporation). NR 35 TC 196 Z9 204 U1 1 U2 12 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 JUN 2 PY 2011 VL 117 IS 22 BP 5827 EP 5834 DI 10.1182/blood-2010-10-312603 PG 8 WC Hematology SC Hematology GA 772BA UT WOS:000291203200010 PM 21355097 ER PT J AU Cohen, JI Jaffe, ES Dale, JK Pittaluga, S Heslop, HE Rooney, CM Gottschalk, S Bollard, CM Rao, VK Marques, A Burbelo, PD Turk, SP Fulton, R Wayne, AS Little, RF Cairo, MS El-Mallawany, NK Fowler, D Sportes, C Bishop, MR Wilson, W Straus, SE AF Cohen, Jeffrey I. Jaffe, Elaine S. Dale, Janet K. Pittaluga, Stefania Heslop, Helen E. Rooney, Cliona M. Gottschalk, Stephen Bollard, Catherine M. Rao, V. Koneti Marques, Adriana Burbelo, Peter D. Turk, Siu-Ping Fulton, Rachael Wayne, Alan S. Little, Richard F. Cairo, Mitchell S. El-Mallawany, Nader K. Fowler, Daniel Sportes, Claude Bishop, Michael R. Wilson, Wyndham Straus, Stephen E. TI Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; UMBILICAL-CORD BLOOD; CYTOTOXIC T-CELLS; EBV INFECTION; LYMPHOPROLIFERATIVE DISEASE; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; VIROLOGICAL CHARACTERISTICS; QUANTITATIVE-ANALYSIS; GENE-EXPRESSION AB Chronic active EBV disease (CAEBV) is a lymphoproliferative disorder characterized by markedly elevated levels of antibody to EBV or EBV DNA in the blood and EBV RNA or protein in lymphocytes in tissues. We present our experience with CAEBV during the last 28 years, including the first 8 cases treated with hematopoietic stem cell transplantation in the United States. Most cases of CAEBV have been reported from Japan. Unlike CAEBV in Japan, where EBV is nearly always found in T or natural killer (NK) cells in tissues, EBV was usually detected in B cells in tissues from our patients. Most patients presented with lymphadenopathy and splenomegaly; fever, hepatitis, and pancytopenia were common. Most patients died of infection or progressive lymphoproliferation. Unlike cases reported from Japan, our patients often showed a progressive loss of B cells and hypogammaglobulinemia. Although patients with CAEBV from Japan have normal or increased numbers of NK cells, many of our patients had reduced NK-cell numbers. Although immunosuppressive agents, rituximab, autologous cytotoxic T cells, or cytotoxic chemotherapy often resulted in short-term remissions, they were not curative. Hematopoietic stem cell transplantation was often curative for CAEBV, even in patients with active lymphoproliferative disease that was unresponsive to chemotherapy. These studies are registered at http://www.clinicaltrials.gov as NCT00032513 for CAEBV, NCT00062868 and NCT00058812 for EBV-specific T-cell studies, and NCT00578539 for the hematopoietic stem cell transplantation protocol. (Blood. 2011; 117(22): 5835-5849) C1 [Cohen, Jeffrey I.; Dale, Janet K.; Rao, V. Koneti; Marques, Adriana; Turk, Siu-Ping; Fulton, Rachael; Straus, Stephen E.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Jaffe, Elaine S.; Pittaluga, Stefania] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Heslop, Helen E.; Rooney, Cliona M.; Gottschalk, Stephen; Bollard, Catherine M.] Methodist Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Heslop, Helen E.; Rooney, Cliona M.; Gottschalk, Stephen; Bollard, Catherine M.] Texas Childrens Hosp, Houston, TX 77030 USA. [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Lab Sensory Biol, NIH, Bethesda, MD USA. [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Little, Richard F.] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cairo, Mitchell S.; El-Mallawany, Nader K.] Columbia Univ, NY Presbyterian Morgan Stanley Childrens Hosp, Dept Pediat Med Pathol & Cell Biol, New York, NY USA. [Fowler, Daniel; Sportes, Claude; Bishop, Michael R.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Wilson, Wyndham] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr,Bldg 50,Rm 6134,MSC 8007, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov OI Jaffe, Elaine/0000-0003-4632-0301; El-Mallawany, Nader/0000-0001-6115-1046 FU National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Institute of Dental and Craniofacial Research [CA094237, P50CA126752] FX This work was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Institute of Dental and Craniofacial Research and extramural grants CA094237 and P50CA126752. NR 48 TC 57 Z9 74 U1 1 U2 10 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 JUN 2 PY 2011 VL 117 IS 22 BP 5835 EP 5849 DI 10.1182/blood-2010-11-316745 PG 15 WC Hematology SC Hematology GA 772BA UT WOS:000291203200011 PM 21454450 ER PT J AU Schwartz, S Vergoulidou, M Schreier, E Loddenkemper, C Reinwald, M Schmidt-Hieber, M Flegel, WA Thiel, E Schneider, T AF Schwartz, Stefan Vergoulidou, Maria Schreier, Eckart Loddenkemper, Christoph Reinwald, Mark Schmidt-Hieber, Martin Flegel, Willy A. Thiel, Eckhard Schneider, Thomas TI Norovirus gastroenteritis causes severe and lethal complications after chemotherapy and hematopoietic stem cell transplantation SO BLOOD LA English DT Article ID BLOOD GROUP ANTIGENS; AIRBORNE TRANSMISSION; HOSPITAL OUTBREAK; NORWALK VIRUS; RT-PCR; ILLNESS; INFECTIONS; MORBIDITY; CHILDREN; MUTATION AB Norovirus (NV) infections are a frequent cause of gastroenteritis (GE), but data on this disease in immunocompromised patients are limited. We analyzed an NV outbreak, which affected immunosuppressed patients in the context of chemotherapy or HSCT. On recognition, 7 days after admission of the index patient, preventive measures were implemented. Attack rates were only 3% (11/334) and 10% (11/105) among patients and staff members, respectively. The median duration of symptoms was 7 days in patients compared with only 3 days in staff members (P =.02). Three patients died of the NV infection. Commonly used clinical diagnostic criteria (Kaplan-criteria) were unsuitable because they applied to 11 patients with proven NV-GE but also to 15 patients without NV-GE. With respect to the therapeutic management, it is important to differentiate intestinal GVHD from NV-GE. Therefore, we analyzed the histopathologic patterns in duodenal biopsies, which were distinctive in both conditions. Stool specimens in patients remained positive for NV-RNA for a median of 30 days, but no transmission was observed beyond an asymptomatic interval of 48 hours. NV-GE is a major threat to patients with chemotherapy or HSCT, and meticulous measures are warranted to prevent transmission of NV to these patients. (Blood. 2011; 117(22): 5850-5856) C1 [Schwartz, Stefan; Vergoulidou, Maria; Reinwald, Mark; Schmidt-Hieber, Martin; Thiel, Eckhard] Charite, Med Klin 3, D-12200 Berlin, Germany. [Schreier, Eckart] Robert Koch Inst, D-1000 Berlin, Germany. [Loddenkemper, Christoph] Charite Campus Benjamin Franklin, Inst Pathol, Berlin, Germany. [Flegel, Willy A.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. [Schneider, Thomas] Charite Campus Benjamin Franklin, Med Klin 1, Berlin, Germany. RP Schwartz, S (reprint author), Charite, Med Klin 3, Campus Benjamin Franklin,Hindenburgdamm 30, D-12200 Berlin, Germany. EM stefan.schwartz@charite.de OI Reinwald, Mark/0000-0002-6506-2136 FU Berliner Krebsgesellschaft FX M.V. has received a research grant from the Berliner Krebsgesellschaft. NR 33 TC 61 Z9 62 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 JUN 2 PY 2011 VL 117 IS 22 BP 5850 EP 5856 DI 10.1182/blood-2010-12-325886 PG 7 WC Hematology SC Hematology GA 772BA UT WOS:000291203200012 PM 21487110 ER PT J AU Silva, R Moir, S Kardava, L Debell, K Simhadri, VR Ferrando-Martinez, S Leal, M Pena, J Coligan, JE Borrego, F AF Silva, Rodolfo Moir, Susan Kardava, Lela Debell, Karen Simhadri, Venkateswara R. Ferrando-Martinez, Sara Leal, Manuel Pena, Jose Coligan, John E. Borrego, Francisco TI CD300a is expressed on human B cells, modulates BCR-mediated signaling, and its expression is down-regulated in HIV infection SO BLOOD LA English DT Article ID RECEPTOR IRP60 CD300A; INHIBITORY RECEPTOR; PERIPHERAL-BLOOD; NK CELLS; INDIVIDUALS; DISEASE; NEF; SUPERFAMILY; ACTIVATION; DYSREGULATION AB The immunomodulatory receptor CD300a is expressed on human B cells. Naive B cells express very low levels of this receptor, whereas memory B cells and plasmablasts/cells express variable levels of CD300a. Germinal center B cells are negative for CD300a expression. Stimulation of naive B cells via B-cell receptor (BCR) and Toll-like receptor 9, along with T-cell help, failed to up-regulate CD300a cell surface expression despite the increased expression of the memory marker CD27 and the down-regulation of CD305. However, Toll-like receptor 9 stimulation alone significantly increased CD300a expression on memory B cells, whereas interleukin-4 and transforming growth factor-beta 1 act as negative regulators of CD300a expression on memory B cells. Coligation of BCR and CD300a inhibits Ca(2+) mobilization and nuclear factor of activated T cell transcriptional activity evoked by BCR ligation alone. Suppression of CD300a expression in primary B cells with siRNA resulted in increased BCR-mediated proliferation, thereby con-firming the inhibitory capacity of CD300a. Finally, we show that CD300a expression levels are significantly down-regulated in the circulating B cells of HIV-infected patients. Altogether, these data demonstrate a novel mechanism for suppressing the activity of B cells and suggest a potential role for CD300a in the B-cell dysfunction observed in HIV-induced immunodeficiency. (Blood. 2011; 117(22): 5870-5880) C1 [Debell, Karen; Simhadri, Venkateswara R.; Borrego, Francisco] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, OBP,Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Silva, Rodolfo; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD USA. [Moir, Susan; Kardava, Lela] NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Ferrando-Martinez, Sara; Leal, Manuel] Virgen Rocio Univ Hosp, Infect Dis Serv, Lab Immunovirol, Biomed Inst Seville, Seville, Spain. [Pena, Jose] Hosp Reina Sofia, Serv Immunol, Cordoba, Spain. RP Borrego, F (reprint author), US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, OBP,Ctr Drug Evaluat & Res, Bldg 29B,Rm 3NN18,29 Lincoln Dr, Bethesda, MD 20892 USA. EM Francisco.Borrego@fda.hhs.gov RI Leal, Manuel/C-8458-2015; IBIS, INMUNOVIROLOGI/O-9246-2015 FU Food and Drug Administration; National Institute of Allergy and Infectious Diseases; Redes Tematicas de Investigacion en SIDA, Spain [ISCIII RETIC RD06/0006/0021]; Fondo de Investigaciones Sanitarias, Spain [PS09/00424] FX This work was supported by the Food and Drug Administration (intramural program), the National Institute of Allergy and Infectious Diseases (intramural program), the Redes Tematicas de Investigacion en SIDA (grant ISCIII RETIC RD06/0006/0021), Spain, and Fondo de Investigaciones Sanitarias (PS09/00424), Spain. NR 51 TC 22 Z9 23 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 2 PY 2011 VL 117 IS 22 BP 5870 EP 5880 DI 10.1182/blood-2010-09-310318 PG 11 WC Hematology SC Hematology GA 772BA UT WOS:000291203200015 PM 21482706 ER PT J AU Smith, NL Rice, KM Bovill, EG Cushman, M Bis, JC McKnight, B Lumley, T Glazer, NL Vlieg, AV Tang, WH Dehghan, A Strachan, DP O'Donnell, CJ Rotter, JI Heckbert, SR Psaty, BM Rosendaal, FR AF Smith, Nicholas L. Rice, Kenneth M. Bovill, Edwin G. Cushman, Mary Bis, Joshua C. McKnight, Barbara Lumley, Thomas Glazer, Nicole L. Vlieg, Astrid van Hylckama Tang, Weihong Dehghan, Abbas Strachan, David P. O'Donnell, Christopher J. Rotter, Jerome I. Heckbert, Susan R. Psaty, Bruce M. Rosendaal, Frits R. TI Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis SO BLOOD LA English DT Article ID GENOME-WIDE ASSOCIATION; DEEP-VEIN THROMBOSIS; POSTMENOPAUSAL WOMEN; AGING RESEARCH; FACTOR-VIII; DISEASE; DESIGN; HEART; OBJECTIVES; CONSORTIUM AB In a recent genome-wide association study, variants in 8 genes were associated with VWF level, a risk factor for venous thrombosis (VT). In an independent, population-based, case-control study of incident VT, we tested hypotheses that variants in these genes would be associated with risk. Cases were 656 women who experienced an incident VT, and controls comprised 710 women without a history of VT. DNA was obtained from whole blood. Logistic regression was used to test associations between incident VT and single nucleotide polymorphisms (SNPs) in 7 genes not previously shown to be associated with VT. Associations with P<.05 were candidates for replication in an independent case-control study of VT in both sexes. Two of the 7 SNPs tested yielded P<.05: rs1039084 (P=.005) in STXBP5, a novel candidate gene for VT, and rs1063856 (P=.04) in VWF, a gene whose protein level is associated with VT risk. Association results for the remaining 5 variants in SCARA5, STAB2, STX2, TC2N, and CLEC4M were not significant. Both STXBP5 and VWF findings were replicated successfully. Variation in genes associated with VWF levels in the genome-wide association study was found to be independently associated with incident VT. (Blood. 2011; 117(22): 6007-6011) C1 [Smith, Nicholas L.; Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Dept Vet Affairs, Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Smith, Nicholas L.; Heckbert, Susan R.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Rice, Kenneth M.; McKnight, Barbara; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Bovill, Edwin G.; Cushman, Mary] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT 05405 USA. [Bis, Joshua C.; Glazer, Nicole L.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Vlieg, Astrid van Hylckama; Rosendaal, Frits R.] Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands. [Tang, Weihong] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Dehghan, Abbas] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Strachan, David P.] St Georges Univ London, Div Populat Hlth Sci & Educ, London, England. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Rosendaal, Frits R.] Leiden Univ, Med Ctr, Dept Thrombosis & Haemostasis, Leiden, Netherlands. RP Smith, NL (reprint author), Cardiovasc Hlth Res Unit, 1730 Minor Ave,Ste 1360, Seattle, WA 98101 USA. EM nlsmith@u.washington.edu RI Rice, Kenneth/A-4150-2013; van Hylckama Vlieg, Astrid/A-3323-2017; OI Rice, Kenneth/0000-0001-5779-4495; Dehghan, Abbas/0000-0001-6403-016X FU National Heart, Lung, and Blood Institute (National Institutes of Health, Bethesda, MD) [HL43201, HL60739, HL68986, HL73410, HL74745, HL85251, HL95080]; Leducq Foundation (Paris, France); Netherlands Heart Foundation [NHS 98.113]; Dutch Cancer Foundation [RUL 99/1992]; Netherlands Organization for Scientific Research [912-03-033/2003]; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Leducq Foundation FX The Heart and Vascular Health Study is supported by National Heart, Lung, and Blood Institute (National Institutes of Health, Bethesda, MD) grants HL43201, HL60739, HL68986, HL73410, HL74745, HL85251, and HL95080, and by a grant from the Leducq Foundation (Paris, France) for the development of Transatlantic Networks of Excellence in Cardiovascular Research. The Multiple Environmental and Genetic Assessment (MEGA) study is funded by the Netherlands Heart Foundation (NHS 98.113), the Dutch Cancer Foundation (RUL 99/1992), and the Netherlands Organization for Scientific Research (912-03-033/2003). DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. A. v. H. V. is a recipient of a Leducq Transatlantic Fellowship from the Leducq Foundation. The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. N.L.S. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 25 TC 40 Z9 41 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 2 PY 2011 VL 117 IS 22 BP 6007 EP 6011 DI 10.1182/blood-2010-10-315473 PG 5 WC Hematology SC Hematology GA 772BA UT WOS:000291203200028 PM 21163921 ER PT J AU Chan, AWY Downing, PE AF Chan, Annie W. -Y. Downing, Paul E. TI Faces and eyes in human lateral prefrontal cortex SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE faces; eyes; prefrontal cortex; FFA; fMRI ID HUMAN EXTRASTRIATE CORTEX; TEMPORAL CORTEX; FUNCTIONAL MRI; HUMAN AMYGDALA; BODY PARTS; OCCIPITOTEMPORAL CORTEX; INFEROTEMPORAL CORTEX; RESPONSE PROPERTIES; FACIAL EXPRESSIONS; VISUAL INFORMATION AB Much of the work on face-selective neural activity has focused on posterior, ventral areas of the human and non-human primate brain. However, electrophysiological and fMRI studies have identified face responses in the prefrontal cortex. Here we used fMRI to characterize these responses in the human prefrontal cortex compared with face selectivity in posterior ventral region. We examined a region at the junction of the right inferior frontal sulcus and the precentral sulcus (right inferior frontal junction or rIFJ) that responds more to faces than to several other object categories. We find that the rIFJ and the right fusiform face area (rFFA) are broadly similar in their responses to whole faces, headless bodies, tools, and scenes. Strikingly, however, while the rFFA preferentially responds to the whole face, the rIFJ response to faces appears to be driven primarily by the eyes. This dissociation provides clues to the functional role of the rIFJ face response. We speculate on this role with reference to emotion perception, gaze perception, and to behavioral relevance more generally. C1 [Chan, Annie W. -Y.; Downing, Paul E.] Bangor Univ, Wales Inst Cognit Neurosci, Sch Psychol, Bangor, Gwynedd, Wales. RP Chan, AWY (reprint author), NIMH, Unit Learning & Plast, Lab Brain & Cognit, NIH, 9000 Rockville Pike,Bldg 10,3N228, Bethesda, MD 20892 USA. EM chanannie@mail.nih.gov OI Downing, Paul/0000-0002-5046-2858 FU Economic and Social Research Council (UK) FX This work was supported by The Economic and Social Research Council (UK) PhD studentship to Annie W.-Y. Chan. The authors would like to thank Dr. Chris Baker, Assaf Harel, and Cibu Thomas for their helpful comments and discussions on the manuscript. NR 84 TC 9 Z9 9 U1 1 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD JUN 2 PY 2011 VL 5 DI 10.3389/fnhum.2011.00051 PG 10 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 773YZ UT WOS:000291349500001 ER PT J AU Stopfer, M AF Stopfer, Mark TI MALARIA Mosquitoes bamboozled SO NATURE LA English DT Editorial Material ID AVOIDANCE-BEHAVIOR; DROSOPHILA C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Stopfer, M (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov NR 7 TC 5 Z9 5 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 2 PY 2011 VL 474 IS 7349 BP 40 EP 41 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 771KV UT WOS:000291156700028 PM 21637247 ER PT J AU Schwartzentruber, DJ Lawson, DH Richards, JM Conry, RM Miller, DM Treisman, J Gailani, F Riley, L Conlon, K Pockaj, B Kendra, KL White, RL Gonzalez, R Kuzel, TM Curti, B Leming, PD Whitman, ED Balkissoon, J Reintgen, DS Kaufman, H Marincola, FM Merino, MJ Rosenberg, SA Choyke, P Vena, D Hwu, P AF Schwartzentruber, Douglas J. Lawson, David H. Richards, Jon M. Conry, Robert M. Miller, Donald M. Treisman, Jonathan Gailani, Fawaz Riley, Lee Conlon, Kevin Pockaj, Barbara Kendra, Kari L. White, Richard L. Gonzalez, Rene Kuzel, Timothy M. Curti, Brendan Leming, Phillip D. Whitman, Eric D. Balkissoon, Jai Reintgen, Douglas S. Kaufman, Howard Marincola, Francesco M. Merino, Maria J. Rosenberg, Steven A. Choyke, Peter Vena, Don Hwu, Patrick TI gp100 Peptide Vaccine and Interleukin-2 in Patients with Advanced Melanoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID METASTATIC MELANOMA; CANCER-IMMUNOTHERAPY; DOSE INTERLEUKIN-2; T-CELLS; BLOCKADE AB Background Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. Methods We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA(star)A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100: 209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. Results The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). Conclusions In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.) C1 [Schwartzentruber, Douglas J.] Indiana Univ, Hlth Goshen Ctr Canc Care, Goshen, IN 46526 USA. [Lawson, David H.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Conry, Robert M.] Univ Alabama Birmingham, Hlth Serv Fdn, Ctr Comprehens Canc, Birmingham, AL USA. [Miller, Donald M.] Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. [Treisman, Jonathan] St Lukes Med Ctr, Milwaukee, WI USA. [Gailani, Fawaz] Kaiser Permanente Med Ctr, Riverside, CA USA. [Balkissoon, Jai] Summit Med Ctr, Oakland, CA USA. [Riley, Lee] St Lukes Hosp, Bethlehem, PA USA. [Merino, Maria J.] Dept Surg Pathol, New Haven, CT 06520 USA. [Rosenberg, Steven A.] Surg Branch, Bethesda, MD USA. [Conlon, Kevin] Canc Therapy Evaluat Program, Bethesda, MD USA. [Choyke, Peter] NCI, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. [Vena, Don] EMMES Corp, Rockville, MD USA. [Pockaj, Barbara] Mayo Clin, Phoenix, AZ USA. [Kendra, Kari L.] Ohio State Univ, Columbus, OH 43210 USA. [White, Richard L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Gonzalez, Rene] Univ Colorado, Denver, CO 80202 USA. [Kuzel, Timothy M.] Northwestern Univ, Chicago, IL 60611 USA. [Kaufman, Howard] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Curti, Brendan] Earle A Chiles Res Inst, Portland, OR USA. [Leming, Phillip D.] Christ Hosp, Cincinnati, OH 45219 USA. [Whitman, Eric D.] Atlantic Melanoma Ctr, Morristown, NJ USA. [Reintgen, Douglas S.] Univ S Florida, Tampa, FL USA. [Hwu, Patrick] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Schwartzentruber, DJ (reprint author), Indiana Univ, Hlth Goshen Ctr Canc Care, 200 High Pk Ave, Goshen, IN 46526 USA. EM dschwart@iuhealth.org FU National Cancer Institute; Indiana University Health Goshen, Goshen Hospital and Health Care Foundation, Chiron; Novartis FX Supported by the National Cancer Institute, Indiana University Health Goshen, Goshen Hospital and Health Care Foundation, Chiron, and Novartis.; We thank Juliann Wu, M. S., of EMMES, Rockville, MD, for data management and statistics; Paul Duray, M. D., for review of pathology slides; Lien Ngo, M. S., Surgery Branch, National Cancer Institute (NCI), Bethesda, MD, for performing in vitro studies; personnel at the NCI Cancer Therapy Evaluation Program and Division of Cancer Treatment and Diagnosis for guidance and support for this project; and Jana Risemas for assistance with the preparation of the manuscript. NR 16 TC 360 Z9 372 U1 6 U2 42 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 2 PY 2011 VL 364 IS 22 BP 2119 EP 2127 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 772AB UT WOS:000291200700010 PM 21631324 ER PT J AU Tse, T Ide, NC Zarin, DA AF Tse, Tony Ide, Nicholas C. Zarin, Deborah A. TI The ClinicalTrials.gov Results Database REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Tse, Tony; Ide, Nicholas C.; Zarin, Deborah A.] Natl Lib Med, Bethesda, MD 20894 USA. RP Tse, T (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. EM dzarin@mail.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 2 PY 2011 VL 364 IS 22 BP 2170 EP 2170 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 772AB UT WOS:000291200700034 ER PT J AU Li, R Ackerman, WE Summerfield, TL Yu, LB Gulati, P Zhang, J Huang, K Romero, R Kniss, DA AF Li, Ruth Ackerman, William E. Summerfield, Taryn L. Yu, Lianbo Gulati, Parul Zhang, Jie Huang, Kun Romero, Roberto Kniss, Douglas A. TI Inflammatory Gene Regulatory Networks in Amnion Cells Following Cytokine Stimulation: Translational Systems Approach to Modeling Human Parturition SO PLOS ONE LA English DT Article ID NF-KAPPA-B; FACTOR-BINDING SITES; NECROSIS-FACTOR-ALPHA; TOLL-LIKE RECEPTORS; INDEPENDENT COMPONENT ANALYSIS; SINGULAR-VALUE DECOMPOSITION; AP-2 TRANSCRIPTION FACTORS; PROMOTER IN-VIVO; EXPRESSION DATA; PRETERM LABOR AB A majority of the studies examining the molecular regulation of human labor have been conducted using single gene approaches. While the technology to produce multi-dimensional datasets is readily available, the means for facile analysis of such data are limited. The objective of this study was to develop a systems approach to infer regulatory mechanisms governing global gene expression in cytokine-challenged cells in vitro, and to apply these methods to predict gene regulatory networks (GRNs) in intrauterine tissues during term parturition. To this end, microarray analysis was applied to human amnion mesenchymal cells (AMCs) stimulated with interleukin-1 beta, and differentially expressed transcripts were subjected to hierarchical clustering, temporal expression profiling, and motif enrichment analysis, from which a GRN was constructed. These methods were then applied to fetal membrane specimens collected in the absence or presence of spontaneous term labor. Analysis of cytokine-responsive genes in AMCs revealed a sterile immune response signature, with promoters enriched in response elements for several inflammation-associated transcription factors. In comparison to the fetal membrane dataset, there were 34 genes commonly upregulated, many of which were part of an acute inflammation gene expression signature. Binding motifs for nuclear factor-kappa B were prominent in the gene interaction and regulatory networks for both datasets; however, we found little evidence to support the utilization of pathogen-associated molecular pattern (PAMP) signaling. The tissue specimens were also enriched for transcripts governed by hypoxia-inducible factor. The approach presented here provides an uncomplicated means to infer global relationships among gene clusters involved in cellular responses to labor-associated signals. C1 [Li, Ruth; Ackerman, William E.; Summerfield, Taryn L.; Kniss, Douglas A.] Ohio State Univ, Div Maternal Fetal Med, Columbus, OH 43210 USA. [Li, Ruth; Ackerman, William E.; Summerfield, Taryn L.; Kniss, Douglas A.] Ohio State Univ, Lab Perinatal Res, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Kniss, Douglas A.] Ohio State Univ, Dept Biomed Engn, Columbus, OH 43210 USA. [Yu, Lianbo; Gulati, Parul] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Zhang, Jie; Huang, Kun] Ohio State Univ, Dept Biomed Informat, Columbus, OH 43210 USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Intramural Div, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. [Romero, Roberto] Hutzel Womens Hosp, Detroit, MI USA. RP Li, R (reprint author), Ohio State Univ, Div Maternal Fetal Med, Columbus, OH 43210 USA. EM kniss.1@osu.edu RI Ackerman, William/E-2612-2011; Huang, Kun/E-3272-2011; Gulati, Parul/K-7375-2013 OI Gulati, Parul/0000-0001-9341-9844 FU National Institute of Child Health and Human Development [WSU07043, N01-HD-2-3342]; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS; NIH [K08 HD049628]; Ohio State University Perinatal Research and Development FX This work was supported in part by subcontract WSU07043 under National Institute of Child Health and Human Development Contract N01-HD-2-3342 and Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. Additional support was provided by NIH K08 HD049628 (WEA) and The Ohio State University Perinatal Research and Development Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 157 TC 9 Z9 9 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 2 PY 2011 VL 6 IS 6 AR e20560 DI 10.1371/journal.pone.0020560 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773ME UT WOS:000291310600016 PM 21655103 ER PT J AU Jimeno-Yepes, AJ McInnes, BT Aronson, AR AF Jimeno-Yepes, Antonio J. McInnes, Bridget T. Aronson, Alan R. TI Exploiting MeSH indexing in MEDLINE to generate a data set for word sense disambiguation SO BMC BIOINFORMATICS LA English DT Article ID CORPUS; TERMS; UMLS AB Background: Evaluation of Word Sense Disambiguation (WSD) methods in the biomedical domain is difficult because the available resources are either too small or too focused on specific types of entities (e. g. diseases or genes). We present a method that can be used to automatically develop a WSD test collection using the Unified Medical Language System (UMLS) Metathesaurus and the manual MeSH indexing of MEDLINE. We demonstrate the use of this method by developing such a data set, called MSH WSD. Methods: In our method, the Metathesaurus is first screened to identify ambiguous terms whose possible senses consist of two or more MeSH headings. We then use each ambiguous term and its corresponding MeSH heading to extract MEDLINE citations where the term and only one of the MeSH headings co-occur. The term found in the MEDLINE citation is automatically assigned the UMLS CUI linked to the MeSH heading. Each instance has been assigned a UMLS Concept Unique Identifier (CUI). We compare the characteristics of the MSH WSD data set to the previously existing NLM WSD data set. Results: The resulting MSH WSD data set consists of 106 ambiguous abbreviations, 88 ambiguous terms and 9 which are a combination of both, for a total of 203 ambiguous entities. For each ambiguous term/abbreviation, the data set contains a maximum of 100 instances per sense obtained from MEDLINE. We evaluated the reliability of the MSH WSD data set using existing knowledge-based methods and compared their performance to that of the results previously obtained by these algorithms on the pre-existing data set, NLM WSD. We show that the knowledge-based methods achieve different results but keep their relative performance except for the Journal Descriptor Indexing (JDI) method, whose performance is below the other methods. Conclusions: The MSH WSD data set allows the evaluation of WSD algorithms in the biomedical domain. Compared to previously existing data sets, MSH WSD contains a larger number of biomedical terms/abbreviations and covers the largest set of UMLS Semantic Types. Furthermore, the MSH WSD data set has been generated automatically reusing already existing annotations and, therefore, can be regenerated from subsequent UMLS versions. C1 [Jimeno-Yepes, Antonio J.; Aronson, Alan R.] Natl Lib Med, Bethesda, MD 20894 USA. [McInnes, Bridget T.] Univ Minnesota Twin Cities, Dept Pharmacol, Minneapolis, MN 55155 USA. RP Jimeno-Yepes, AJ (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM antonio.jimeno@gmail.com OI Jimeno Yepes, Antonio Jose/0000-0002-6581-094X FU NIH, National Library of Medicine; National Library of Medicine FX This work was supported in part by the Intramural Research Program of the NIH, National Library of Medicine and by an appointment of A. Jimeno-Yepes to the NLM Research Participation Program sponsored by the National Library of Medicine and administered by the Oak Ridge Institute for Science and Education. NR 30 TC 14 Z9 14 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUN 2 PY 2011 VL 12 AR 223 DI 10.1186/1471-2105-12-223 PG 14 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 782SD UT WOS:000292030200001 PM 21635749 ER PT J AU Omeir, RL Teferedegne, B Foseh, GS Beren, JJ Snoy, PJ Brinster, LR Cook, JL Peden, K Lewis, AM AF Omeir, Romelda L. Teferedegne, Belete Foseh, Gideon S. Beren, Joel J. Snoy, Philip J. Brinster, Lauren R. Cook, James L. Peden, Keith Lewis, Andrew M., Jr. TI Heterogeneity of the Tumorigenic Phenotype Expressed by Madin-Darby Canine Kidney Cells SO COMPARATIVE MEDICINE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITIONS; MDCK CELLS; MODEL SYSTEM; TUMOR-CELLS; LINE MDCK; IN-VITRO; TRANSFORMATION; GROWTH; NUDE; TISSUE AB The mechanisms by which cells spontaneously immortalized in tissue culture develop the capacity to form tumors in vivo likely embody fundamental processes in neoplastic development. The evolution of Madin-Darby canine kidney (MDCK) cells from presumptively normal kidney cells to immortalized cells that become tumorigenic represents an example of neoplastic development in vitro. Studies of the mechanisms by which spontaneously immortalized cells develop the capacity to form tumors would benefit from quantitative in vivo assays. Most mechanistic correlations are evaluated by using single-dose tumor-induction experiments, which indicate only whether cells are or are not tumorigenic. Here we used quantitative tumorigenicity assays to measure dose- and time-dependent tumor development in nude mice of 3 lots of unmodified MDCK cells. The results revealed lot-to-lot variations in the tumorigenicity of MDCK cells, which were reflected by their tumor-inducing efficiency (threshold cell dose represented by mean tumor-producing dose; log(10) 50% endpoints of 5.2 for vial 1 and 4.4 for vial 2, and a tumor-producing dose of 5.8 for vial 3) and mean tumor latency (vial 1, 6.6 wk; vial 2, 2.9 wk; and vial 3, 3.8 wk). These studies provide a reference for further characterization of the MDCK cell neoplastic phenotype and may be useful in delineating aspects of neoplastic development in vitro that determine tumor-forming capacity. Such data also are useful when considering MDCK cells as a reagent for vaccine manufacture. C1 [Omeir, Romelda L.; Teferedegne, Belete; Foseh, Gideon S.; Peden, Keith; Lewis, Andrew M., Jr.] US FDA, Div Viral Prod, Off Vaccines Res & Review, Bethesda, MD 20014 USA. [Beren, Joel J.; Snoy, Philip J.] US FDA, Div Vet Serv, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Brinster, Lauren R.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Cook, James L.] Univ Illinois, Dept Med, Sect Infect Dis Immunol & Int Med, Chicago, IL USA. RP Lewis, AM (reprint author), US FDA, Div Viral Prod, Off Vaccines Res & Review, Bethesda, MD 20014 USA. EM andrew.lewis@fda.hhs.gov FU Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases; University of Illinois at Chicago FX This research was supported in part by a contract from the Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases through an interagency agreement with CBER/FDA and by the support of the James A and Marion C Grant Fund at the University of Illinois at Chicago. NR 40 TC 13 Z9 13 U1 0 U2 3 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD JUN PY 2011 VL 61 IS 3 BP 243 EP 250 PG 8 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 915QQ UT WOS:000302042900008 PM 21819694 ER PT J AU Chan, CC Liu, MM Tsai, JC AF Chan, Chi-Chao Liu, Melissa M. Tsai, James C. TI The First Western-Style Hospital in China SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID CANTON AB Peter Parker (1804-1888), a Yale University-trained missionary and physician, founded the first Western-style hospital in China, the Ophthalmic Hospital in Canton (now known as Guangzhou), on November 4, 1835. During its first 3 months, Parker treated 1061 patients, of whom 1020 (96.1%) had ocular illnesses. Since then, the Ophthalmic Hospital in Canton has become a comprehensive institution that is affiliated with Sun Yat-sen University and is one of the largest hospitals in China. In 1965, the Department of Ophthalmology, which originally employed only 2 ophthalmologists, expanded to become an ophthalmic hospital. In 1983, it joined the Eye Research Institute and the Office of Prevention of Blindness to form the Zhongshan Ophthalmic Center. The center currently employs nearly 800 staff members and provides care to more than 500 000 patients annually. The first Western-style hospital in China has survived and thrived; it is now one of the most prestigious ophthalmic institutes in the world. Arch Ophthalmol. 2011; 129(6): 791-797 C1 [Chan, Chi-Chao; Liu, Melissa M.] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Liu, Melissa M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Tsai, James C.] Yale Univ, Sch Med, Dept Ophthalmol & Visual Sci, New Haven, CT 06510 USA. 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 FU National Eye Institute; Research to Prevent Blindness, Inc. FX Funding support was provided to Dr Chan and Ms Liu from the National Eye Institute Intramural Research Program and to Dr Tsai from the Departmental Challenge Grant from Research to Prevent Blindness, Inc. NR 23 TC 2 Z9 2 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JUN PY 2011 VL 129 IS 6 BP 791 EP 797 PG 7 WC Ophthalmology SC Ophthalmology GA 776UJ UT WOS:000291563500018 PM 21670348 ER PT J AU Anthony, K AF Anthony, Kira TI MOLECULAR PROFILING A double agent SO NATURE REVIEWS CANCER LA English DT News Item ID NKX2-1 C1 NCI, Nat Pathway Interact Database, Bethesda, MD 20892 USA. RP Anthony, K (reprint author), NCI, Nat Pathway Interact Database, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 1 U2 2 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 JUN PY 2011 VL 11 IS 6 BP 390 EP 390 PG 1 WC Oncology SC Oncology GA 768CJ UT WOS:000290908800010 PM 21606938 ER PT J AU Anzinger, JJ Chang, J Xu, Q Bohnacker, T Wymann, MP Kruth, HS AF Anzinger, J. J. Chang, J. Xu, Q. Bohnacker, T. Wymann, M. P. Kruth, H. S. TI MURINE BONE MARROW-DERIVED MACROPHAGES DIFFERENTIATED WITH GM-CSF BECOME FOAM CELLS BY PI 3-KINASE GAMMA-DEPENDENT FLUID-PHASE PINOCYTOSIS OF NATIVE LDL SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 79th Congress of the European-Atherosclerosis-Society (EAS) CY JUN 26-29, 2011 CL Gothenburg, SWEDEN SP European Atherosclerosis Soc (EAS) C1 [Anzinger, J. J.; Chang, J.; Xu, Q.; Kruth, H. S.] NHLBI, Expt Atherosclerosis Sect, NIH, Bethesda, MD 20892 USA. [Bohnacker, T.; Wymann, M. P.] Univ Basel, Inst Biochem & Genet, Dept Biomed, Basel, Switzerland. RI Wymann, Matthias/C-3227-2008 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD JUN PY 2011 VL 12 IS 1 MA 130 BP 30 EP 30 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 890QG UT WOS:000300159000131 ER PT J AU Abe, K Saadat, S Fennessy, J Dandamudi, S Kitlinska, J Tilan, J Lu, C Hellerstein, MK Zukowska, Z AF Abe, K. Saadat, S. Fennessy, J. Dandamudi, S. Kitlinska, J. Tilan, J. Lu, C. Hellerstein, M. K. Zukowska, Z. TI SYMPATHETIC OUTFLOW TO BONE MARROW MEGAKARYOCYTES STIMULATES NEOINTIMA FORMATION VIA PLATELET-DERIVED NEUROPEPTIDE Y SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 79th Congress of the European-Atherosclerosis-Society (EAS) CY JUN 26-29, 2011 CL Gothenburg, SWEDEN SP European Atherosclerosis Soc (EAS) C1 [Abe, K.; Saadat, S.; Fennessy, J.; Dandamudi, S.; Kitlinska, J.; Tilan, J.; Lu, C.] Georgetown Univ, Washington, DC USA. [Abe, K.] NIH, Bethesda, MD 20892 USA. [Hellerstein, M. K.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Zukowska, Z.] Univ Minnesota, Dept Integrat Biol & Physiol, Minneapolis, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD JUN PY 2011 VL 12 IS 1 MA 569 BP 120 EP 121 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 890QG UT WOS:000300159000565 ER PT J AU Zarate, CA AF Zarate, C. A. TI New insight into the neurobiology of bipolar disorder and the development of rapid-acting antidepressants and biomarkers of response SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA C1 [Zarate, C. A.] NIMH, Expt Therapeut & Pathophysiol Branch, Div Intramural Res, Bethesda, MD 20892 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 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 18 EP 18 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400019 ER PT J AU Volkow, N AF Volkow, N. TI Co-occurring bipolar and substance abuse disorders: what do we know? SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA C1 [Volkow, N.] NIDA, NIH, Bethesda, MD 20892 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 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 20 EP 20 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400024 ER PT J AU Vandeleur, C Rothen, S Gholam-Rezaee, M Castelao, E Vidal, S Favre, S Ferrero, F Halfon, O Fumeaux, P Merikangas, KR Aubry, JM Preisig, M AF Vandeleur, C. Rothen, S. Gholam-Rezaee, M. Castelao, E. Vidal, S. Favre, S. Ferrero, F. Halfon, O. Fumeaux, P. Merikangas, K. R. Aubry, J. M. Preisig, M. TI Mental disorders in offspring of parents with bipolar and major depressive disorders SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE bipolar disorder; major depressive disorder; high-risk study; familial transmission C1 [Vandeleur, C.; Rothen, S.; Vidal, S.; Favre, S.; Ferrero, F.; Aubry, J. M.] Univ Hosp Geneva, Dept Mental Hlth & Psychiat, Geneva, Switzerland. [Vandeleur, C.; Rothen, S.; Gholam-Rezaee, M.; Castelao, E.; Vidal, S.; Halfon, O.; Fumeaux, P.; Preisig, M.] Univ Lausanne, CH-1015 Lausanne, Switzerland. [Merikangas, K. R.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. RI Rothen, Stephane/E-8325-2014 OI Rothen, Stephane/0000-0003-3891-277X 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 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 22 EP 23 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400030 ER PT J AU Frankel, E Drevets, W Luckenbaugh, D Speer, A Nugent, A Zarate, C Furey, M AF Frankel, E. Drevets, W. Luckenbaugh, D. Speer, A. Nugent, A. Zarate, C. Furey, M. TI Scopolamine as a fast-acting antidepressant agent in bipolar depression: a randomized placebo-controlled clinical trial SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE depression; bipolar; scopolamine C1 [Frankel, E.; Drevets, W.; Luckenbaugh, D.; Speer, A.; Nugent, A.; Zarate, C.; Furey, M.] NIMH, Bethesda, MD 20892 USA. RI Furey, Maura/H-5273-2013 NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 45 EP 46 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400094 ER PT J AU Friedman, ES Calabrese, JR Ketter, TA Bowden, CL Thase, ME Leon, AC Sylvia, LG Ostacher, MJ Iosifescu, DV Reilly-Harrington, NA Severe, J Nierenberg, AA AF Friedman, E. S. Calabrese, J. R. Ketter, T. A. Bowden, C. L. Thase, M. E. Leon, A. C. Sylvia, L. G. Ostacher, M. J. Iosifescu, D. V. Reilly-Harrington, N. A. Severe, J. Nierenberg, A. A. TI Using comparative effectiveness design to improve the generalizability of bipolar treatment trials data: contrasting LiTMUS baseline data with pre-existing placebo controlled trials SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE comparative effectiveness; bipolar; baseline characteristics; generalizability; external validity C1 [Friedman, E. S.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Calabrese, J. R.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Ketter, T. A.; Ostacher, M. J.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Bowden, C. L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Thase, M. E.] Univ Penn, Philadelphia, PA 19104 USA. [Leon, A. C.] Weill Cornell Med Coll, New York, NY USA. [Sylvia, L. G.; Reilly-Harrington, N. A.; Nierenberg, A. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Iosifescu, D. V.] Mt Sinai Sch Med, New York, NY USA. [Severe, J.] NIMH, 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 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 46 EP 47 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400097 ER PT J AU Mallinger, AG Ibrahim, L Thase, ME Luckenbaugh, DA Kupfer, DJ Frank, E AF Mallinger, A. G. Ibrahim, L. Thase, M. E. Luckenbaugh, D. A. Kupfer, D. J. Frank, E. TI Serum lithium level/dose ratio: a predictor of affective episode recurrence with potential clinical utility SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE lithium; treatment outcome; bipolar disorder; medication adherence C1 [Mallinger, A. G.; Ibrahim, L.; Luckenbaugh, D. A.] NIMH, Expt Therapeut & Pathophysiol Branch, DIRP, NIH, Bethesda, MD 20892 USA. [Mallinger, A. G.; Thase, M. E.; Kupfer, D. J.; Frank, E.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Thase, M. E.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 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 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 69 EP 69 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400162 ER PT J AU Szczepanik, J Martin-Soelch, C Zarate, C Furey, M Drevets, W AF Szczepanik, J. Martin-Soelch, C. Zarate, C. Furey, M. Drevets, W. TI Presence of monetary incentive decreases response accuracy on a spatial working memory task in bipolar and unipolar depressed subjects SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE bipolar; unipolar; reward C1 [Szczepanik, J.; Martin-Soelch, C.; Zarate, C.; Furey, M.; Drevets, W.] NIMH, Bethesday, MD USA. RI Furey, Maura/H-5273-2013 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 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 97 EP 97 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400243 ER PT J AU Janicak, PG AF Janicak, Philip G. TI IN THIS ISSUE: Cases of Schizophrenia SO PSYCHIATRIC ANNALS LA English DT Editorial Material C1 [Janicak, Philip G.] Rush Univ, Chicago, IL 60612 USA. [Janicak, Philip G.] Rush Psychiat Clin Res, Chicago, IL USA. [Janicak, Philip G.] Amer Psychiat Assoc, Washington, DC 20005 USA. [Janicak, Philip G.] Univ Illinois, Med Ctr, NIH, Gen Clin Res Ctr, Chicago, IL 60680 USA. RP Janicak, PG (reprint author), Rush Univ, Chicago, IL 60612 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD JUN PY 2011 VL 41 IS 6 BP 300 EP 301 DI 10.3928/00485713-20110119-02 PG 2 WC Psychiatry SC Psychiatry GA 885AL UT WOS:000299749900002 ER PT J AU Wang, PM Kachel, DL Cesta, MF Martin, WJ AF Wang, Ping M. Kachel, Diane L. Cesta, Mark F. Martin, William J., II TI Direct Leukocyte Migration across Pulmonary Arterioles and Venules into the Perivascular Interstitium of Murine Lungs during Bleomycin Injury and Repair SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; NEURAL CREST CELLS; PHENOTYPIC HETEROGENEITY; ENDOTRACHEAL BLEOMYCIN; INFLAMMATORY RESPONSE; NEUTROPHIL MIGRATION; ENDOTHELIAL-CELLS; ANIMAL-MODELS; FIBROSIS; MICE AB During acute lung injury and repair, leukocytes are thought to enter the lung primarily across alveolar capillaries and postcapillary venules. We hypothesized that leukocytes also migrate across pulmonary arterioles and venules, which serve as alternative sites for leukocyte influx into the lung during acute lung injury and repair. Lung sections from C57BL/6J mice up to 14 days after intratracheal bleomycin (3.33 U/kg) or saline instillation were assessed by light, fluorescence, confocal, and transmission electron microscopy for evidence of inflammatory cell sequestration and transmigration at these sites. After bleomycin treatment, large numbers of leukocytes (including neutrophils, eosinophils, and monocytes) were present in the vascular lumina and in perivascular interstitia of pulmonary arterioles and venules, as well as within the vascular walls. Leukocytes were observed within well-defined pathways in arteriolar walls and much less structured pathways in venular walls, apparently in the process of transmigration. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were expressed at sites of leukocyte interaction with the luminal surface, especially in arterioles. Leukocytes appeared to exit from the vessels near collagen fibers into the perivascular interstitium. Results indicate that leukocytes can directly migrate across arteriolar and venular walls into the perivascular interstitium, which may represent under-recognized pathway for leukocyte influx into the lung during injury and repair. (Am J Pathol 2011, 178:2560-2572; DOI: 10.1016/j.ajpath.2011.02.047) C1 [Wang, Ping M.; Martin, William J., II] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Cesta, Mark F.] NIEHS, Cellular Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Kachel, Diane L.] Univ Minnesota, Dept Med, Div Pulm Allergy Crit Care & Sleep Med, Ctr Lung Sci & Hlth, Minneapolis, MN 55455 USA. RP Martin, WJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 31 Ctr Dr,Bldg 31,Rm 2A31, Bethesda, MD 20892 USA. EM wjmartin@mail.nih.gov FU NIH, National Institute of Environmental Health Sciences FX Supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 80 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 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2011 VL 178 IS 6 BP 2560 EP 2572 DI 10.1016/j.ajpath.2011.02.047 PG 13 WC Pathology SC Pathology GA 865JJ UT WOS:000298306900013 PM 21641381 ER PT J AU Okada, Y Reinach, PS Shirai, K Kitano, A Kao, WWY Flanders, KC Miyajima, M Liu, HS Zhang, JH Saika, S AF Okada, Yuka Reinach, Peter S. Shirai, Kumi Kitano, Ai Kao, Winston W. -Y. Flanders, Kathleen C. Miyajima, Masayasu Liu, Hongshan Zhang, Jianhua Saika, Shizuya TI TRPV1 Involvement in Inflammatory Tissue Fibrosis in Mice SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID RECEPTOR POTENTIAL VANILLOID-1; EPITHELIAL BASEMENT-MEMBRANE; CORNEAL ALKALI BURNS; CAPSAICIN RECEPTOR; IN-VITRO; CHANNELS; RAT; EXPRESSION; MOUSE; NOCICEPTORS AB We examined whether absence or blocking of transient receptor potential vanilloid subtype 1 (TRPV1) affects the level of inflammation and fibrosis/scarring during healing of injured tissue using an alkali burn model of cornea in mice. A cornea burn was produced with 1 N NaOH instilled into one eye of TRPV1 -/- (KO) (n = 88) or TRPV1+1+ (n = 94) mice. Examinations of the corneal surface and eye globe size suggested that the loss of TRPV1 suppressed inflammation and fibrosis/scarring after alkali burn, and this was confirmed by histology, IHC, and gene expression analysis. The loss of TRPV1 inhibited inflammatory cell invasion and myofibroblast generation in association with reduction of expression of proinflammatory and profibrogenic components. Experiments of bone marrow transplantation between either genotype of mice showed that KO corneal tissue resident cells, but not KO bone marrow derived cells, are responsible for KO-type wound healing with reduced inflammation and fibrosis. The absence of TRPV1 attenuated expression of transforming growth factor beta 1 (TGF beta 1) and other proinflammatory gene expression in cultured ocular fibroblasts, but did not affect TGF beta 1 expression in macrophages. Loss of TRPV1 inhibited myofibroblast transdifferentiation in cultured fibroblasts. Systemic TRPV1 antagonists reproduced the KO type of healing. In conclusion, absence or blocking of TRPV1 healing of alkali-burned mouse cornea. TRPV1 is a potential drug target for improving the outcome of inflammatory/fibrogenic wound healing. (Am J Pathol 2011, 178:2654-2664; DOI: 10.1016/j.ajpath.2011.02.043) C1 [Okada, Yuka; Shirai, Kumi; Kitano, Ai; Saika, Shizuya] Wakayama Med Univ, Dept Ophthalmol, Wakayama 6410012, Japan. [Miyajima, Masayasu] Wakayama Med Univ, Lab Anim Ctr, Wakayama 6410012, Japan. [Reinach, Peter S.] SUNY Coll Optometry, Dept Biol Sci, New York, NY 10010 USA. [Kao, Winston W. -Y.; Liu, Hongshan; Zhang, Jianhua] Univ Cincinnati, Sch Med, Dept Ophthalmol, Cincinnati, OH USA. [Flanders, Kathleen C.] NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Okada, Y (reprint author), Wakayama Med Univ, Dept Ophthalmol, 811-1 Kimiidera, Wakayama 6410012, Japan. EM yokada@wakayama-med.ac.jp FU Ministry of Education, Science, Sports and Culture of Japen [C21592241, C19592036]; Mitsui Life Social Welfare Foundation; Mochida Memorial Foundation; Takeda Science Foundation; Uehara Foundation [EY04795]; NIH [EY011845, EY013755]; Research to Prevent Blindness; Ohio Lions Eye Research Foundation FX Supported by grants from the Ministry of Education, Science, Sports and Culture of Japen (C21592241 to Y.O.; C19592036 to S.S.); the Mitsui Life Social Welfare Foundation, Mochida Memorial Foundation, Takeda Science Foundation, and Uehara Foundation (S.S.); EY04795 (P.S.R.); NIH grants EY011845 and EY013755, and the Research to Prevent Blindness and Ohio Lions Eye Research Foundation (W.W.Y.K.). NR 42 TC 37 Z9 37 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2011 VL 178 IS 6 BP 2654 EP 2664 DI 10.1016/j.ajpath.2011.02.043 PG 11 WC Pathology SC Pathology GA 865JJ UT WOS:000298306900021 PM 21641388 ER PT J AU Vasilevsky, S Liu, Q Koontz, SM Kastenmayer, R Shea, K Jackson, SH AF Vasilevsky, Sam Liu, Qi Koontz, Sherry M. Kastenmayer, Robin Shea, Katherine Jackson, Sharon H. TI Role of p47phox in Antigen-Presenting Cell-Mediated Regulation of Humoral Immunity in Mice SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; LISTERIA-MONOCYTOGENES INFECTION; STREPTOCOCCUS-PNEUMONIAE ELICIT; REDUCED OXIDATIVE BURST; DENDRITIC CELLS; IN-VIVO; ARTHRITIS; RESPONSES; MUTATION; GENE AB Microbial-induced inflammation is important for eliciting humoral immunity. Genetic defects of NADPH oxidase 2-based proteins interrupt phagocyte superoxide generation and are the basis for the human immnunodeficiency chronic granulomatous disease (CGD). Hyperinflammation is also a significant clinical manifestation of CGD. Herein, we evaluated humoral immunity in the phagocyte oxidase p47(Phox)-deficient model of CGD and found that UV-inactivated Streptococcus pneumoniae and Listeria monocytogenes (Lm) elicited higher specific antibody (Ab) titers in p47(phox-/-) mice than wild-type (WT) mice. Both organisms elicited robust and distinct antigen-presenting cell maturation phenotypes, including IL-12 hypersecretion, and higher major histocompatibility complex II and costimulatory protein expression in Lm-stimulated p47(phox-/-) dendritic cells (DCs) relative to WT DCs. Furthermore, p47(phox-/-) DCs pulsed with Lm and adoptively transferred into naive WT mice elicited Ab titers, whereas Lm-pulsed WT DCs did not elicit these titers. The observed robust p47(Phox-/-) mouse humoral response was recapitulated with live Lm and sustained in vivo in p47(Phox-/-) mice. Notably, anti-serum samples from p47(phox-/-) mice that survived secondary Lm infection were protective in WT and p47(Phox-/-) mice that were re-challenged with secondary lethal Lm infection. These findings demonstrate a novel benefit of NADPH oxidase 2 deficiency (ie, dependent inflammation in antigen-presenting cell-mediated humoral immunity) and that anti-Lm Ab can be protective in an immunodeficient CGD host. (Am J Pathol 2011, 178: 2774-2784. DOI: 10.1016/j.ajpath.2011.02.038) C1 [Jackson, Sharon H.] NIAID, Host Def Lab, NIH, CRC,Mol Trafficking Unit, Bethesda, MD 20892 USA. [Kastenmayer, Robin; Shea, Katherine] NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. RP Jackson, SH (reprint author), NIAID, Host Def Lab, NIH, CRC,Mol Trafficking Unit, Bldg 5 W Labs,10 Ctr Dr,MSC 1456,Room 5-3942, Bethesda, MD 20892 USA. EM sjackson@niaid.nih.gov FU Division of Intramural Research of the National Institutes of Health/National Institute of Allergy and Infectious Diseases; National Institutes of Health/National Center on Minority Health and Health Disparities FX Supported by the Division of Intramural Research of the National Institutes of Health/National Institute of Allergy and Infectious Diseases and partially supported by the National Institutes of Health/National Center on Minority Health and Health Disparities. NR 43 TC 8 Z9 8 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2011 VL 178 IS 6 BP 2774 EP 2782 DI 10.1016/j.ajpath.2011.02.038 PG 9 WC Pathology SC Pathology GA 865JJ UT WOS:000298306900032 PM 21641399 ER PT J AU Wen, J Nikitakis, NG Chaisuparat, R Greenwell-Wild, T Gliozzi, M Jin, WW Adli, A Moutsopoulos, N Wu, TX Warburton, G Wahl, SM AF Wen, Jie Nikitakis, Nikolaos G. Chaisuparat, Risa Greenwell-Wild, Teresa Gliozzi, Maria Jin, Wenwen Adli, Azita Moutsopoulos, Niki Wu, Tanxia Warburton, Gary Wahl, Sharon M. TI Secretory Leukocyte Protease Inhibitor (SLPI) Expression and Tumor Invasion in Oral Squamous Cell Carcinoma SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID LYMPH-NODE METASTASIS; ANNEXIN-II; PLASMINOGEN-ACTIVATOR; IN-VITRO; CANCER CELLS; WOUND REPAIR; KAPPA-B; RECEPTOR; PROGRESSION; SUPPRESSES AB Differential expression of secretory leukocyte protease inhibitor (SLPI) impacts on tumor progression. SLPI directly inhibits elastase and other serine proteases, and regulates matrix metalloproteinases, plasminogen activation, and plasmin downstream targets to influence invasion. We examined tissues from human oral squamous cell carcinoma (OSCC) for SLPI expression in parallel with proteases associated with tumor progression and evaluated their relationships using tumor cell lines. Significantly decreased SLPI was detected in OSCC compared to normal oral epithelium. Furthermore, an inverse correlation between SLPI and histological parameters associated with tumor progression, including stage of invasion, pattern of invasion, invasive cell grade, and composite histological tumor score was evident. Conversely, elevated plasmin and elastase were positively correlated with histological parameters of tumor invasion. In addition to its known inhibition of elastase, we identify SLPI as a novel inhibitor of plasminogen activation through its interaction with annexin A2 with concomitant reduced plasmin generation by macrophages and OSCC cell lines. In an in vitro assay measuring invasive activity, SLPI blocked protease-dependent tumor cell migration. Our data suggest that SIPI may possess antitumorigenic activity by virtue of its ability to interfere with multiple requisite proteolytic steps underlying tumor cell invasion and may provide insight into potential stratification of oral cancer according to risk of occult metastasis, guiding treatment strategies. (Am J Pathol 2011, 178:2866-287 DOI: 10.1016/j.ajpath.2011.02.017) C1 [Wen, Jie; Greenwell-Wild, Teresa; Gliozzi, Maria; Jin, Wenwen; Adli, Azita; Moutsopoulos, Niki; Wu, Tanxia; Warburton, Gary; Wahl, Sharon M.] NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Nikitakis, Nikolaos G.; Chaisuparat, Risa] Univ Maryland, Dept Diagnost Sci & Pathol, Baltimore, MD 21201 USA. RP Wahl, SM (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Rm 320,30 Convent Dr,MSC4352, Bethesda, MD 20892 USA. EM smwahl@dir.nidcr.nih.gov FU National Institutes of Health, National Institute of Dental and Craniofacial Research FX Supportedin part by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. NR 62 TC 22 Z9 23 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2011 VL 178 IS 6 BP 2866 EP 2878 DI 10.1016/j.ajpath.2011.02.017 PG 13 WC Pathology SC Pathology GA 865JJ UT WOS:000298306900041 PM 21641406 ER PT J AU Boyd, SD AF Boyd, Sarita D. TI Management of HIV infection in treatment-naive patients: A review of the most current recommendations SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Review DE Antiretroviral agents; Atazanavir; Combined therapy; Darunavir; Department of Health and Human Services; Dosage; Efavirenz; Emtricitabine; HIV infections; Mechanism of action; Protocols; Quality of life; Raltegravir; Ritonavir; Tenofovir; Toxicity ID ACTIVE ANTIRETROVIRAL THERAPY; REVERSE-TRANSCRIPTASE INHIBITORS; ONCE-DAILY DARUNAVIR/RITONAVIR; HIV-1-INFECTED PATIENTS; COLLABORATIVE ANALYSIS; MYOCARDIAL-INFARCTION; COMBINATION THERAPY; HETEROSEXUAL TRANSMISSION; RESISTANCE MUTATIONS; PROTEASE INHIBITORS AB Purpose. The most current guidelines issued by the Department of Health and Human Services (DHHS) on the management of human immunodeficiency virus (HIV) infection in treatment-naive patients are reviewed. Summary. Treatment guidelines are updated frequently because of the emergence of data demonstrating the risks and benefits of antiretroviral therapy. The DHHS guidelines strongly recommend initiating therapy in patients with certain conditions regardless of CD4 cell count and in patients with CD4 cell counts of <350 cells/mm(3). Although supporting data are less definitive, treatment is also recommended for patients with CD4 cell counts of 350-500 cells/mm(3). Treatment for patients with CD4 cell counts of >500 cells/mm3 is controversial. Although cumulative observational data and biological evidence support treatment it higher CD4 cell counts, randomized controlled trial data to support this are not available, and the risk of antiretroviral toxicities, resistance, non-adherence, and cost should be considered in individual patients. The preferred regimens have been consolidated to four options, including a dual-nucleoside reverse transcriptase inhibitor backbone (tenofovir plus emtricitabine) with a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir plus ritonavir or darunavir plus ritonavir), or an integrase strand-transfer inhibitor (raltegravir). Regimens are classified as alternative or acceptable when they have potential safety or efficacy concerns, have higher pill burdens, or require more-frequent administration compared with preferred regimens. Conclusion. The DHHS 2011 guidelines advocate earlier antiretroviral therapy initiation than recommended in recent years, and preferred regimens have been refined to maximize efficacy, safety, and quality of life for treatment-naive HIV-infected patients. C1 [Boyd, Sarita D.] US FDA, Off Safety & Epidemiol, Silver Spring, MD 20993 USA. [Boyd, Sarita D.] NIAID, SAIC Frederick, Div Clin Res, NIH, Frederick, MD USA. RP Boyd, SD (reprint author), US FDA, Off Safety & Epidemiol, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM sarita.boyd@fda.hhs.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. NR 76 TC 11 Z9 13 U1 0 U2 4 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD JUN 1 PY 2011 VL 68 IS 11 BP 991 EP 1001 DI 10.2146/ajhp100156 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 858CK UT WOS:000297773300008 PM 21593227 ER PT J AU Minig, L AF Minig, Lucas TI The combination of intravenous and intraperitoneal chemotherapy improves survival for women ovarian cancer SO SALUD I CIENCIA LA Spanish DT Article DE epithelial ovarian cancer; chemotherapy; treatment; intraperitoneal chemotherapy ID GYNECOLOGIC-ONCOLOGY-GROUP; PRIMARY PERITONEAL CANCER; EPITHELIAL OVARIAN; PLUS PACLITAXEL; PHASE-II; CISPLATIN; CYCLOPHOSPHAMIDE; CARBOPLATIN; TRIAL; METAANALYSIS AB There is compelling evidence from seven RCTs that a combination of intravenous (IV) and intraperitoneal (IP) chemotherapy given after optimal cytoreductive surgery significantly improves survival for women with FIGO stage III epithelial ovarian cancer. On the basis of this data, the US-NCI issued a Clinical Announcement in January 2006 recommending that women and their physicians consider such combined IV/IP chemotherapy where appropriate. Despite ongoing educational efforts, IP/IV regimens have not become the standard of care in many hospitals. Ongoing clinical research seeks to reduce the toxicity associated with IP chemotherapy while retaining efficacy and integrating new biological approaches to treatment. C1 [Minig, Lucas] Hosp Univ Madrid Sanchinaro, Madrid, Spain. RP Minig, L (reprint author), NCI, Bethesda, MD 20892 USA. EM tt6m@nih.gov NR 17 TC 0 Z9 0 U1 0 U2 0 PU SOC IBEROAMERICANA INFORMACION CIENTIFICA-S I I C PI BUENOS AIRES PA AVE BELGRANO 430-C1092AAR, BUENOS AIRES, 00000, ARGENTINA SN 1667-8982 J9 SALUD CIENC JI Salud Cienc. PD JUN PY 2011 VL 18 IS 4 BP 323 EP 325 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 838CG UT WOS:000296263700003 ER PT J AU Castellini, MA Buguliskis, JS Casta, LJ Butz, CE Clark, AB Kunkel, TA Taraschi, TF AF Castellini, Meryl A. Buguliskis, Jeffrey S. Casta, Louis J. Butz, Charles E. Clark, Alan B. Kunkel, Thomas A. Taraschi, Theodore F. TI Malaria drug resistance is associated with defective DNA mismatch repair SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Malaria; Drug resistance; DNA repair; Plasmodium falciparum; Chloroquine ID PLASMODIUM-FALCIPARUM; CHLOROQUINE-RESISTANCE; ESCHERICHIA-COLI; POLYMORPHISM; FREQUENCIES; STRAINS; PFCRT AB Malarial parasites exhibit striking genetic plasticity, a hallmark of which is an ever-increasing rate of resistance to new drugs, especially in Southeast Asia where multi-drug resistance (MDR) threatens the last line of antimalarial drugs, the artesunate compounds. Previous studies quantified the accelerated resistance to multiple drugs (ARMD) phenomenon, but the underpinning mechanism(s) remains unknown. We utilize a forward genetic assay to investigate a new hypothesis that defective DNA mismatch repair (MMR) contributes to the development of MDR by Plasmodium falciparum parasites. We report that two ARMD parasites, W2 and Dd2, have defective MMR, as do the chloroquine-resistant parasites T9-94, 7C12, and 7G8. By contrast, the chloroquine-sensitive parasites HB3, D6 and 3D7 were MMR proficient. Interestingly, W2 was unable to repair substrates with a strand break located 3' to the mismatch, which is attributable to a large observed decrease in PfMutL alpha content. These data imply that antimalarial drug resistance can result from defective MMR. (C) 2011 Elsevier B.V. All rights reserved. C1 [Taraschi, Theodore F.] Thomas Jefferson Univ, Jefferson Med Coll, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Taraschi, TF (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dept Pathol Anat & Cell Biol, 1020 Locust St, Philadelphia, PA 19107 USA. EM Theodore.Taraschi@jefferson.edu FU NIH [AI 072723, T32ES007282]; Department of the Army [W911NF-09-1-0475]; Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES065089] FX This work was supported in part by NIH grant AI 072723 and Department of the Army Grant W911NF-09-1-0475 to TFT and Project Z01 ES065089 to TAK from the Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences. Meryl Castellini was supported as a pre-doctoral fellow by NIH training grant T32ES007282. We thank Paul Modrich for the generous gift of the human MutL alpha and helpful discussions, Michael Ferdig for helpful discussions and the generous gift of 7C12 parasite strain, Xin-zhuan Su and Jianbing Mu for sequencing the MLH1 genes. NR 19 TC 21 Z9 22 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD JUN PY 2011 VL 177 IS 2 BP 143 EP 147 DI 10.1016/j.molbiopara.2011.02.004 PG 5 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 843KM UT WOS:000296670700008 PM 21315772 ER PT J AU Tanaka, TQ Williamson, KC AF Tanaka, Takeshi Q. Williamson, Kim C. TI A malaria gametocytocidal assay using oxidoreduction indicator, alamarBlue SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE AlamarBlue; Drug screening; Gametocyte; Plasmodium falciparum ID PLASMODIUM-FALCIPARUM GAMETOCYTES; ARTEMISININ COMBINATION THERAPIES; FLOW-CYTOMETRY; RESISTANCE; MEFLOQUINE; AFRICA AB Efforts to move from malaria control to eradication will require new approaches to block malaria transmission, such as the development of anti-malarial drugs with gametocytocidal activity. Here fluorescent oxidoreduction indicator alamarBlue is used to develop a screen for gametocyte viability. The fluorescent signal increases linearly with gametocyte number (R(2) = 0.99) and determination of the IC(50) of epoxomicin demonstrated the assay was reproducible and sensitive (IC(50) 2.16 +/- 0.57 nM, Z'-factor 0.81 +/- 0.01). Six anti-malarials were also tested and at 10 mu M only primaquine and dihydroartemisinin (DHA) had gametocytocidal activity. This new assay provides an important tool to efficiently screen compounds for gametocytocidal activity. Published by Elsevier B.V. C1 [Tanaka, Takeshi Q.; Williamson, Kim C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. [Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60660 USA. RP Williamson, KC (reprint author), 12735 Twinbrook Pkwy,TBIII Rm 3E28C, Rockville, MD 20892 USA. EM williamsonk2@mail.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Dr. S. Desai for use of the fluorescent plate reader and Dr. B. Morahan for critical reading of the manuscript. NR 20 TC 49 Z9 49 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD JUN PY 2011 VL 177 IS 2 BP 160 EP 163 DI 10.1016/j.molbiopara.2011.02.005 PG 4 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 843KM UT WOS:000296670700012 PM 21316401 ER PT J AU Liu, ZH Chuang, DM Smith, CB AF Liu, Zhong-Hua Chuang, De-Maw Smith, Carolyn Beebe TI Lithium ameliorates phenotypic deficits in a mouse model of fragile X syndrome SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Behaviour; dendritic spines; fragile X syndrome; lithium; medial prefrontal cortex ID MEDIAL FRONTAL-CORTEX; FMR1 KNOCKOUT MICE; SYNAPTIC PLASTICITY; MENTAL-RETARDATION; MUTANT MOUSE; RAT; BEHAVIORS; MEMORY; STRESS; BLOOD AB As our understanding of the underlying defects in fragile X syndrome (FXS) increases so does the potential for development of treatments aimed at modulating the defects and ameliorating the constellation of symptoms seen in patients. Symptoms of FXS include cognitive disability, hyperactivity, autistic behaviour, seizures and learning deficits. Lithium is a drug used clinically to treat bipolar disorder, and it has been used to treat mood dysregulation in individuals with FXS. We examined whether dietary lithium would alter behavioural and morphological abnormalities in fmr1 knockout (KO) mice. We studied wildtype (WT) and KO mice untreated (control chow) or treated with lithium (0.3% lithium-carbonate-containing chow) commenced at weaning and maintained throughout the experiment. At age 8-12 wk, mice were subjected to the following behavioural tests : open field, social interaction, elevated plus maze, elevated zero maze and passive avoidance. At 13 wk, brains were prepared for Golgi staining and analysis of dendritic spine morphology in medial prefrontal cortex. We found that compared to untreated WT, untreated KO mice were hyperactive and had reduced anxiety, impaired social interactions, and deficits on a learning test. Dendritic spines in medial prefrontal cortex were longer and increased in number. Lithium treatment ameliorated the hyperactivity and reversed impaired social interaction and deficits on the learning test. Lithium treatment also partially normalized general anxiety levels and dendritic spine morphology. Our findings and those from other laboratories on the efficacy of lithium treatment in animal models support further studies in patients with FXS. C1 [Smith, Carolyn Beebe] NIMH, Sect Neuroadaptat & Prot Metab, NIH, Bethesda, MD 20892 USA. [Chuang, De-Maw] NIMH, Mol Neurobiol Sect, Bethesda, MD 20892 USA. RP Smith, CB (reprint author), NIMH, Sect Neuroadaptat & Prot Metab, NIH, 10 Ctr Dr,Room 2D54,MSC 1298, Bethesda, MD 20892 USA. EM beebe@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health FX We thank Zengyan Xia for overseeing the breeding colony and determining genotypes. We also thank Mei Qin for helpful discussions and Guangping Liu for assistance with Western blotting. The research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. NR 48 TC 51 Z9 54 U1 0 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2011 VL 14 IS 5 BP 618 EP 630 DI 10.1017/S1461145710000520 PG 13 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 757SW UT WOS:000290109000005 PM 20497624 ER PT J AU Szmuilowicz, ED Manson, JE Rossouw, JE Howard, BV Margolis, KL Greep, NC Brzyski, RG Stefanick, ML O'Sullivan, MJ Wu, CY Allison, M Grobbee, DE Johnson, KC Ockene, JK Rodriguez, BL Sarto, GE Vitolins, MZ Seely, EW AF Szmuilowicz, Emily D. Manson, Joann E. Rossouw, Jacques E. Howard, Barbara V. Margolis, Karen L. Greep, Nancy C. Brzyski, Robert G. Stefanick, Marcia L. O'Sullivan, Mary Jo Wu, Chunyuan Allison, Matthew Grobbee, Diederick E. Johnson, Karen C. Ockene, Judith K. Rodriguez, Beatriz L. Sarto, Gloria E. Vitolins, Mara Z. Seely, Ellen W. TI Vasomotor symptoms and cardiovascular events in postmenopausal women SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Vasomotor symptoms; Hot flashes; Cardiovascular disease; Women's health ID ESTROGEN PLUS PROGESTIN; CORONARY-HEART-DISEASE; HOT FLASHES; HORMONE-THERAPY; BLOOD-PRESSURE; HEALTH; MENOPAUSE; FLUSHES; RISK; MORTALITY AB Objective: Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Women's Health Initiative Observational Study (WHI-OS). Methods: We compared the risk of incident CVD events and all-cause mortality between four groups of women (total N = 60,027): (1) no VMS at menopause onset and no VMS at WHI-OS enrollment (no VMS [referent group]), (2) VMS at menopause onset but not at WHI-OS enrollment (early VMS), (3) VMS at both menopause onset and WHI-OS enrollment (persistent VMS [early and late]), and (4) VMS at WHI-OS enrollment but not at menopause onset (late VMS). Results: For women with early VMS (n = 24,753), compared with no VMS (n = 18,799), hazard ratios (95% CIs) in fully adjusted models were as follows: major coronary heart disease (CHD), 0.94 (0.84-1.06); stroke, 0.83 (0.72-0.96); total CVD, 0.89 (0.81-0.97); and all-cause mortality, 0.92 (0.85-0.99). For women with persistent VMS (n = 15,084), there was no significant association with clinical events. For women with late VMS (n = 1,391), compared with no VMS, hazard ratios (95% CIs) were as follows: major CHD, 1.32 (1.01-1.71); stroke, 1.14 (0.82-1.59); total CVD, 1.23 (1.00-1.52); and all-cause mortality, 1.29 (1.08-1.54). Conclusions: Early VMS were not associated with increased CVD risk. Rather, early VMS were associated with decreased risk of stroke, total CVD events, and all-cause mortality. Late VMS were associated with increased CHD risk and all-cause mortality. The predictive value of VMS for clinical CVD events may vary with the onset of VMS at different stages of menopause. Further research examining the mechanisms underlying these associations is needed. Future studies will also be necessary to investigate whether VMS that develop for the first time in the later postmenopausal years represent a pathophysiologic process distinct from the classic perimenopausal VMS. C1 [Szmuilowicz, Emily D.] Northwestern Univ, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Manson, Joann E.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Manson, Joann E.; Seely, Ellen W.] Harvard Univ, Sch Med, Boston, MA USA. [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20892 USA. [Howard, Barbara V.] MedStar Res Inst, Washington, DC USA. [Howard, Barbara V.] Georgetown Univ, Sch Med, Washington, DC USA. [Margolis, Karen L.] HealthPartners Res Fdn, Minneapolis, MN USA. [Greep, Nancy C.] John Wayne Canc Inst, Santa Monica, CA USA. [Brzyski, Robert G.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. [Stefanick, Marcia L.] Stanford Univ, Dept Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [O'Sullivan, Mary Jo] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Wu, Chunyuan] Fred Hutchinson Canc Res Ctr, Womens Hlth Initiat Clin Coordinating Ctr, Seattle, WA 98104 USA. [Allison, Matthew] Univ Calif San Diego, San Diego, CA 92103 USA. [Grobbee, Diederick E.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Johnson, Karen C.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Ockene, Judith K.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Rodriguez, Beatriz L.] Univ Hawaii, Dept Geriatr Med, Honolulu, HI 96822 USA. [Rodriguez, Beatriz L.] Univ Hawaii, Dept Pediat, Honolulu, HI 96822 USA. [Rodriguez, Beatriz L.] Univ Hawaii, Dept Med, Honolulu, HI 96822 USA. [Sarto, Gloria E.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Vitolins, Mara Z.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Seely, Ellen W.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. RP Szmuilowicz, ED (reprint author), Northwestern Univ, Div Endocrinol Metab & Mol Med, 211 E Chicago Ave,1050, Chicago, IL 60611 USA. EM edszmuilowicz@post.harvard.edu RI Grobbee, Diederick/C-7651-2014; OI Grobbee, Diederick/0000-0003-4472-4468; Allison, Matthew/0000-0003-0777-8272 FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; Sanofi-Aventis; Bayer Health Care; Merck/Schering-Plough FX The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221.; Dr. Szmuilowicz reported that she was previously a subinvestigator in a clinical trial of a diabetes treatment (glucagon-like peptide 1 agonist) sponsored by Sanofi-Aventis, and she received no financial compensation. Dr. Seely reported that she received a Bayer Health Care investigatorYinitiated grant. Dr. Howard reported that she is a consultant for Merck/Schering-Plough, that she received research support from the donation of drugs from Merck/Schering-Plough, and that she lectures for Merck/Schering-Plough. None of the other authors reported financial disclosures. NR 25 TC 48 Z9 48 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD JUN PY 2011 VL 18 IS 6 BP 603 EP 610 DI 10.1097/gme.0b013e3182014849 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 769HV UT WOS:000291004400005 PM 21358352 ER PT J AU Rezvani, AH Robinson, E Eisenberg, L Levin, ED Bonaventure, P Motley, T Lovenberg, TW Heilig, M Thorsell, A Cippitelli, A AF Rezvani, A. H. Robinson, E. Eisenberg, L. Levin, E. D. Bonaventure, P. Motley, T. Lovenberg, T. W. Heilig, M. Thorsell, A. Cippitelli, A. TI EFFECTS OF A NOVEL, SELECTIVE BRAIN NPY Y2 RECPTOR ANATONIST JNJ-31020028, ON ALCOHOL CONSUMPTION, RELAPSE AND ANXIETY IN RATS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 Duke Univ, Med Ctr, Durham, NC 27710 USA. NIAAA, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 68A EP 68A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300230 ER PT J AU Aguayo, L Castro, P Lovinger, D Homanics, GE AF Aguayo, L. Castro, P. Lovinger, D. Homanics, G. E. TI ALTERED ETHANOL RESPONSES IN KNOCK-IN MICE WITH GLYCINE RECEPTORS THAT ARE INSENSTIVE TO GB Gamma MODULATION SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 NIAAA, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA 15261 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 72A EP 72A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300248 ER PT J AU Puentes, YM Villafuerte, S Gleiberman, L Weder, A Burmeister, M AF Puentes, Y. M. Villafuerte, S. Gleiberman, L. Weder, A. Burmeister, M. TI A PERSONALITY RISK PROFILE FOR ALCOHOLISM:DRD1 ASSOCIATED WITH AGREEABLENESS AND GABRA4 & HTR2A WITH LOW CONSCIENTIOUSNESS AND HIGH EXCITEMENT SEEKING SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Puentes, Y. M.] Univ Michigan, NIH, Postbaccaleaureate Res Educ Program, Ann Arbor, MI 48109 USA. [Villafuerte, S.; Burmeister, M.] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Gleiberman, L.; Weder, A.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. RI Burmeister, Margit/A-3157-2013 OI Burmeister, Margit/0000-0002-1914-2434 NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 132A EP 132A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300487 ER PT J AU Vatsalya, V Momenan, R Hommer, D Ramchandani, VA AF Vatsalya, V. Momenan, R. Hommer, D. Ramchandani, V. A. TI ASSOCIATION BETWEEN CHANGES IN HEART RATE AND SUBJECTIVE RESPONSES DURING ACUTE INTRAVENOUS ALCOHOL INFUSIONS IN SOCIAL DRINKERS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Vatsalya, V.; Momenan, R.; Hommer, D.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 222A EP 222A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301342 ER PT J AU Grant, KA Helms, C Cuzon, V Alverez, V Lovinger, D AF Grant, K. A. Helms, C. Cuzon, V. Alverez, V. Lovinger, D. TI REGULATION OF CHRONIC, HEAVY, ETHANOL SELF-ADMINISTRATION IN MONKEYS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 263A EP 263A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301502 ER PT J AU Gao, B AF Gao, B. TI TH17 CELLS AND THEIR ASSOCIATED CYTOKINES IN T CELL HEPATITIS AND ALCOHOLIC LIVER INJURY SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Gao, B.] NIAAA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 271A EP 271A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301535 ER PT J AU Rajesh, M Horvath, B Mukhopadhyay, P Park, O Ki, SH Gao, B Pacher, P AF Rajesh, M. Horvath, B. Mukhopadhyay, P. Park, O. Ki, S. H. Gao, B. Pacher, P. TI ROLE OF POLY (ADP-RIBOSE) POLYMERASE 1 (PARP-1) IN LIVER INJURY, INFLAMMATION, AND FIBROSIS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Rajesh, M.; Horvath, B.; Mukhopadhyay, P.; Park, O.; Ki, S. H.; Gao, B.; Pacher, P.] NIAAA, NIH, Bethesda, MD USA. RI Horvath, Bela/A-7368-2009 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 273A EP 273A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301543 ER PT J AU Tam, J Cinar, R Chorvat, RJ McElroy, JF Kunos, G AF Tam, J. Cinar, R. Chorvat, R. J. McElroy, J. F. Kunos, G. TI SELECTIVE BLOCKADE OF PERIPHERAL CB1 RECEPTORS IS EFFECTIVE IN THE TREATMENT OF OBESITY AND BOTH NONALCOHOLIC AND ALCOHOLIC FATTY LIVER SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Tam, J.; Cinar, R.; Kunos, G.] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Chorvat, R. J.; McElroy, J. F.] Jenrin Discovery Inc, W Chester, PA 19382 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 303A EP 303A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301664 ER PT J AU Bevilacqua, L Doly, S Kaprio, J Yuan, Q Tikkanen, R Paunio, T Zhou, Z Wedenoja, J Maroteaux, L Diaz, S Belmer, A Hodgkinson, C Dell'Osso, L Suvisaari, J Coccaro, E Rose, R Virkkunen, M Goldman, D AF Bevilacqua, L. Doly, S. Kaprio, J. Yuan, Q. Tikkanen, R. Paunio, T. Zhou, Z. Wedenoja, J. Maroteaux, L. Diaz, S. Belmer, A. Hodgkinson, C. Dell'Osso, L. Suvisaari, J. Coccaro, E. Rose, R. Virkkunen, M. Goldman, D. TI 2B OR NOT 2B: A COMMON, POPULATION-SPECIFIC HTR2B STOP CODON LEADING TO IMPULSIVITY AND ALCOHOLISM SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Bevilacqua, L.; Doly, S.; Kaprio, J.; Yuan, Q.; Tikkanen, R.; Paunio, T.; Zhou, Z.; Wedenoja, J.; Maroteaux, L.; Diaz, S.; Belmer, A.; Hodgkinson, C.; Dell'Osso, L.; Suvisaari, J.; Coccaro, E.; Rose, R.; Virkkunen, M.; Goldman, D.] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 306A EP 306A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301674 ER PT J AU Enoch, MA Zhou, Z Mash, DC Yuan, Q Goldman, D AF Enoch, M. -A. Zhou, Z. Mash, D. C. Yuan, Q. Goldman, D. TI THE EFFECTS OF CHRONIC ALCOHOL AND COCAINE EXPOSURE ON EXPRESSION OF GABAERGIC GENES IN THE HUMAN HIPPOCAMPUS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Enoch, M. -A.; Zhou, Z.; Mash, D. C.; Yuan, Q.; Goldman, D.] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 313A EP 313A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301702 ER PT J AU Hingson, R AF Hingson, R. TI MAGNITUDE OF AND TRENDS IN ALCOHOL-RELATED MORTALITY AND MORBIDITY AMONG US COLLEGE STUDENTS AGES 18 TO 24, 1998-2007 SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Hingson, R.] NIAAA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 315A EP 315A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301711 ER PT J AU Kim, SK Riley, L Abrol, R Jacobson, KA Goddard, WA AF Kim, Soo-Kyung Riley, Lindsay Abrol, Ravinder Jacobson, Kenneth A. Goddard, William A., III TI Predicted structures of agonist and antagonist bound complexes of adenosine A(3) receptor SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE docking; GPCR; agonists; antagonist; membrane protein predicted structure; adenosine receptor ID PROTEIN-COUPLED RECEPTOR; ANGSTROM CRYSTAL-STRUCTURE; 3D STRUCTURE; BINDING-SITE; BETA-2-ADRENERGIC RECEPTOR; EXPERIMENTAL VALIDATION; MOLECULAR-DYNAMICS; NUCLEOSIDES; IDENTIFICATION; RECOGNITION AB We used the GEnSeMBLE Monte Carlo method to predict ensemble of the 20 best packings (helix rotations and tilts) based on the neutral total energy (E) from a vast number (10 trillion) of potential packings for each of the four subtypes of the adenosine G protein-coupled receptors (GPCRs), which are involved in many cytoprotective functions. We then used the DarwinDock Monte Carlo methods to predict the binding pose for the human A(3) adenosine receptor (hAA(3)R) for subtype selective agonists and antagonists. We found that all four A(3) agonists stabilize the 15th lowest conformation of apo-hAA(3)R while also binding strongly to the 1st and 3rd. In contrast the four A(3) antagonists stabilize the 2nd or 3rd lowest conformation. These results show that different ligands can stabilize different GPCR conformations, which will likely affect function, complicating the design of functionally unique ligands. Interestingly all agonists lead to a trans chi(1) angle for W6.48 that experiments on other GPCRs associate with G-protein activation while all 20 apo-AA(3)R conformations have a W6.48 gauche+ chi(1) angle associated experimentally with inactive GPCRs for other systems. Thus docking calculations have identified critical ligand-GPCR structures involved with activation. We found that the predicted binding site for selective agonist Cl-IB-MECA to the predicted structure of hAA(3)R shows favorable interactions to three subtype variable residues, I253(6.58), V169(EL2), and Q167(EL2), while the predicted structure for hAA(2A)R shows weakened to the corresponding amino acids: T256(6.58), E169(EL2), and L167(EL2), explaining the observed subtype selectivity. Proteins 2011; 79:1878-1897. (C) 2011 Wiley-Liss, Inc. C1 [Kim, Soo-Kyung; Abrol, Ravinder; Goddard, William A., III] CALTECH, Mat & Proc Simulat Ctr MC139 74, Div Chem & Chem Engn, Pasadena, CA 91125 USA. [Riley, Lindsay] Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA 90095 USA. [Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RP Goddard, WA (reprint author), CALTECH, Mat & Proc Simulat Ctr MC139 74, Div Chem & Chem Engn, 1200 E Calif Blvd, Pasadena, CA 91125 USA. EM wag@wag.caltech.edu RI Abrol, Ravinder/B-4980-2010; Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Gifts to the Materials and Process Simulation Center (MSC) (California Institute of Technology) FX Grant sponsor: Gifts to the Materials and Process Simulation Center (MSC) (California Institute of Technology). NR 48 TC 15 Z9 15 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD JUN PY 2011 VL 79 IS 6 BP 1878 EP 1897 DI 10.1002/prot.23012 PG 20 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 762NF UT WOS:000290485500017 PM 21488099 ER PT J AU Spitz, MR Caporaso, NE Freedman, AN AF Spitz, Margaret R. Caporaso, Neil E. Freedman, Andrew N. TI Epidemiology-Found in Translation SO CANCER DISCOVERY LA English DT Editorial Material ID BREAST-CANCER; POSTMENOPAUSAL WOMEN; RALOXIFENE; RISK; TAMOXIFEN; DISEASE; TRIAL AB We highlight the value of carefully designed observational epidemiologic analyses in translating basic science discoveries to clinical application and in providing the impetus for exploring underlying mechanisms for observed associations. Coupling epidemiologic data with an in vitro screen of commonly used therapeutic agents may identify novel applications for further clinical testing. Cancer Discovery; 1(1); 21-2. (C) 2011 AACR. C1 [Spitz, Margaret R.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Spitz, Margaret R.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Caporaso, Neil E.] NCI, NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Freedman, Andrew N.] NCI, NIH, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Spitz, MR (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Dept Epidemiol, Box 1340,1155 Pressler, Houston, TX 77030 USA. EM mspitz@mdanderson.org NR 14 TC 2 Z9 2 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD JUN PY 2011 VL 1 IS 1 BP 21 EP 22 DI 10.1158/2159-8274.CD-11-0042 PG 2 WC Oncology SC Oncology GA 832CY UT WOS:000295780300016 PM 22586315 ER PT J AU Zhang, SJ Midthune, D Guenther, PM Krebs-Smith, SM Kipnis, V Dodd, KW Buckman, DW Tooze, JA Freedman, L Carroll, RJ AF Zhang, Saijuan Midthune, Douglas Guenther, Patricia M. Krebs-Smith, Susan M. Kipnis, Victor Dodd, Kevin W. Buckman, Dennis W. Tooze, Janet A. Freedman, Laurence Carroll, Raymond J. TI A NEW MULTIVARIATE MEASUREMENT ERROR MODEL WITH ZERO-INFLATED DIETARY DATA, AND ITS APPLICATION TO DIETARY ASSESSMENT SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Bayesian methods; dietary assessment; Latent variables; measurement error; mixed models; nutritional epidemiology; nutritional surveillance; zero-inflated data ID HEALTHY EATING INDEX-2005; EPISODICALLY CONSUMED FOODS; REGRESSION CALIBRATION; DENSITY-ESTIMATION; DECONVOLUTION; EPIDEMIOLOGY; PERFORMANCE; VARIABLES; CANCER; SIMEX AB In the United States the preferred method of obtaining dietary intake data is the 24-hour dietary recall, yet the measure of most interest is usual or long-term average daily intake, which is impossible to measure. Thus, usual dietary intake is assessed with considerable measurement error. Also, diet represents numerous foods, nutrients and other components, each of which have distinctive attributes. Sometimes, it is useful to examine intake of these components separately, but increasingly nutritionists are interested in exploring them collectively to capture overall dietary patterns. Consumption of these components varies widely: some are consumed daily by almost everyone on every day, while others are episodically consumed so that 24-hour recall data are zero-inflated. In addition, they are often correlated with each other. Finally, it is often preferable to analyze the amount of a dietary component relative to the amount of energy (calories) in a diet because dietary recommendations often vary with energy level. The quest to understand overall dietary patterns of usual intake has to this point reached a standstill. There are no statistical methods or models available to model such complex multivariate data with its measurement error and zero inflation. This paper proposes the first such model, and it proposes the first workable solution to fit such a model. After describing the model, we use survey-weighted MCMC computations to fit the model, with uncertainty estimation coming from balanced repeated replication. The methodology is illustrated through an application to estimating the population distribution of the Healthy Eating Index-2005 (HEI-2005), a multi-component dietary quality index involving ratios of interrelated dietary components to energy, among children aged 2-8 in the United States. We pose a number of interesting questions about the HEI-2005 and provide answers that were not previously within the realm of possibility, and we indicate ways that our approach can be used to answer other questions of importance to nutritional science and public health. C1 [Guenther, Patricia M.] USDA, Ctr Nutr Policy & Promot, Alexandria, VA 22302 USA. [Buckman, Dennis W.] Informat Management Serv Inc, Silver Spring, MD 20904 USA. [Freedman, Laurence] Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, IL-52161 Tel Hashomer, Israel. [Midthune, Douglas; Kipnis, Victor; Dodd, Kevin W.] NCI, Canc Prevent Div, Biometry Res Grp, Bethesda, MD 20892 USA. [Krebs-Smith, Susan M.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. [Tooze, Janet A.] Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. RP Zhang, SJ (reprint author), Merck & Co Inc, 126 E Lincoln Ave,POB 2000,RY34-A316, Rahway, NJ 07065 USA. EM saijuan.zhang@merck.com; midthund@mail.nih.gov; Patricia.Guenther@cnpp.usda.gov; krebssms@mail.nih.gov; kipnisv@mail.nih.gov; doddk@mail.nih.gov; BuckmanD@imsweb.com; jtooze@wfubmc.edu; lsf@actcom.co.il; carroll@stat.tamu.edu FU National Science Foundation [0922866]; National Cancer Institute [CA57030] FX Supported by National Science Foundation Instrumentation Grant number 0922866.; Supported by a Grant from the National Cancer Institute (CA57030). NR 39 TC 20 Z9 20 U1 2 U2 15 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD JUN PY 2011 VL 5 IS 2B BP 1456 EP 1487 DI 10.1214/10-AOAS446 PG 32 WC Statistics & Probability SC Mathematics GA 827UJ UT WOS:000295453900015 PM 21804910 ER PT J AU Friedenreich, CM Neilson, HK Woolcott, CG McTiernan, A Wang, QG Ballard-Barbash, R Jones, CA Stanczyk, FZ Brant, RF Yasui, Y Irwin, ML Campbell, KL McNeely, ML Karvinen, KH Courneya, KS AF Friedenreich, Christine M. Neilson, Heather K. Woolcott, Christy G. McTiernan, Anne Wang, Qinggang Ballard-Barbash, Rachel Jones, Charlotte A. Stanczyk, Frank Z. Brant, Rollin F. Yasui, Yutaka Irwin, Melinda L. Campbell, Kristin L. McNeely, Margaret L. Karvinen, Kristina H. Courneya, Kerry S. TI Changes in insulin resistance indicators, IGFs, and adipokines in a year-long trial of aerobic exercise in postmenopausal women SO ENDOCRINE-RELATED CANCER LA English DT Article ID BREAST-CANCER RISK; RANDOMIZED CLINICAL-TRIAL; BETA-CELL FUNCTION; GROWTH-FACTOR-I; PHYSICAL-ACTIVITY; BODY-FAT; CIRCULATING LEVELS; MODEL ASSESSMENT; GLUCOSE CLAMP; PLASMA LEPTIN AB Physical activity is a known modifiable lifestyle means for reducing postmenopausal breast cancer risk, but the biologic mechanisms are not well understood. Metabolic factors may be involved. In this study, we aimed to determine the effects of exercise on insulin resistance (IR) indicators, IGF1, and adipokines in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-armed randomized controlled trial in postmenopausal, inactive, cancer-free women. A year-long aerobic exercise intervention of 225 min/week (n=160) was compared with a control group asked to maintain usual activity levels (n=160). Baseline, 6- and 12-month serum levels of insulin, glucose, IGF1, IGF-binding protein 3 (IGFBP3), adiponectin, and leptin were assayed, and after data collection, homeostasis model assessment of IR (HOMA-IR) scores were calculated. Intention-to-treat analyses were performed using linear mixed models. The treatment effect ratio (TER) of exercisers to controls was calculated. Data were available on 308 (96.3%) women at 6 months and 310 (96.9%) women at 12 months. Across the study period, statistically significant reductions in insulin (TER=0.87, 95% confidence interval (95% CI) = 0.81-0.93), HOMA-IR (TER=0.86, 95% CI=0.80-0.93), and leptin (TER=0.82,95% CI=0.78-0.87), and an increase in the adiponectin/leptin ratio (TER=1.21, 95% CI=1.13-1.28) were observed in the exercise group compared with the control group. No significant differences were observed for glucose, IGF1, IGFBP3, adiponectin or the IGF1/IGFBP3 ratio. Previously inactive postmenopausal women who engaged in a moderate-to-vigorous intensity exercise program experienced changes in insulin, HOMA-IR, leptin, and adiponectin/leptin that might decrease the risk for postmenopausal breast cancer. C1 [Friedenreich, Christine M.; Neilson, Heather K.; Wang, Qinggang] Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB T2N 4N2, Canada. [Friedenreich, Christine M.] Univ Calgary, Dept Oncol, Fac Med, Calgary, AB T2N 4N2, Canada. [Friedenreich, Christine M.] Univ Calgary, Dept Community Hlth Sci, Fac Med, Calgary, AB T2N 4N2, Canada. [Woolcott, Christy G.] Dalhousie Univ, Dept Obstet & Gynaecol, Perinatal Epidemiol Res Unit, Halifax, NS B3K 6R8, Canada. [Woolcott, Christy G.] Dalhousie Univ, Dept Pediat, Perinatal Epidemiol Res Unit, Halifax, NS B3K 6R8, Canada. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Prevent Ctr, Seattle, WA 98109 USA. [Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Jones, Charlotte A.] Univ Calgary, Dept Med, Fac Med, Calgary, AB T2N 4N2, Canada. [Stanczyk, Frank Z.] Univ So Calif, Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Brant, Rollin F.] Univ British Columbia, Dept Stat, Vancouver, BC V6T 1Z2, Canada. [Yasui, Yutaka] Univ Alberta, Dept Publ Hlth Sci, Edmonton, AB T6G 2T4, Canada. [Irwin, Melinda L.] Yale Univ, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Campbell, Kristin L.] Univ British Columbia, Dept Phys Therapy, Vancouver, BC V6T 1Z3, Canada. [McNeely, Margaret L.] Univ Alberta, Dept Phys Therapy, Edmonton, AB T6G 2G4, Canada. [McNeely, Margaret L.] Univ Alberta, Dept Oncol, Edmonton, AB T6G 2G4, Canada. [Karvinen, Kristina H.] E Carolina Univ, Dept Exercise & Sport Sci, Greenville, NC 27858 USA. [Courneya, Kerry S.] Univ Alberta, Fac Phys Educ & Recreat, Edmonton, AB T6G 2H9, Canada. RP Friedenreich, CM (reprint author), Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB T2N 4N2, Canada. EM christine.friedenreich@albertahealthservices.ca RI Yasui, Yutaka/E-2564-2015; OI Yasui, Yutaka/0000-0002-7717-8638; Brant, Rollin/0000-0002-8026-2451 FU Canadian Breast Cancer Research Alliance [017468]; Alberta Cancer Foundation [22170]; Canadian Institutes of Health Research; Alberta Heritage Foundation for Medical Research; Canada Research Chairs Program FX This study was funded by the Canadian Breast Cancer Research Alliance (#017468) and the Alberta Cancer Foundation (#22170). Dr C M F was funded by career awards from Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research. Dr Courneya is supported by the Canada Research Chairs Program. The funders were not involved in any aspects of the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. NR 76 TC 45 Z9 45 U1 0 U2 8 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUN PY 2011 VL 18 IS 3 BP 357 EP 369 DI 10.1530/ERC-10-0303 PG 13 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 821SY UT WOS:000294995900010 PM 21482635 ER PT J AU Chong, WH Molinolo, AA Chen, CC Collins, MT AF Chong, William H. Molinolo, Alfredo A. Chen, Clara C. Collins, Michael T. TI Tumor-induced osteomalacia SO ENDOCRINE-RELATED CANCER LA English DT Review ID PHOSPHATURIC MESENCHYMAL TUMOR; FIBROBLAST GROWTH FACTOR-23; ONCOGENIC HYPOPHOSPHATEMIC OSTEOMALACIA; OF-THE-LITERATURE; CONNECTIVE-TISSUE VARIANT; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; RENAL TUBULAR REABSORPTION; X-LINKED HYPOPHOSPHATEMIA; VITAMIN-D METABOLISM; FIBROUS DYSPLASIA AB Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures, and muscle weakness. The cause is high blood levels of the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very small and difficult to locate. FGF23 acts primarily at the renal tubule and impairs phosphate reabsorption and 1 alpha-hydroxylation of 25-hydroxyvitamin D, leading to hypophosphatemia and low levels of 1,25-dihydroxy vitamin D. A step-wise approach utilizing functional imaging (F-18 fluorodeoxyglucose positron emission tomography and octreotide scintigraphy) followed by anatomical imaging (computed tomography and/or magnetic resonance imaging), and, if needed, selective venous sampling with measurement of FGF23 is usually successful in locating the tumors. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful; however, the medical regimen can be cumbersome and associated with complications. This review summarizes the current understanding of the pathophysiology of the disease and provides guidance in evaluating and treating these patients. Novel imaging modalities and medical treatments, which hold promise for the future, are also reviewed. C1 [Chong, William H.; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. [Molinolo, Alfredo A.] Natl Inst Dent & Craniofacial Res, Oral Pharyngeal Canc Branch, Bethesda, MD 20892 USA. [Chen, Clara C.] NIH, Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Collins, MT (reprint author), Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. EM mc247k@nih.gov FU Division of Intramural Research, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA FX This work was supported by the funding from the Division of Intramural Research, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA. NR 224 TC 93 Z9 100 U1 1 U2 8 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUN PY 2011 VL 18 IS 3 BP R53 EP R77 DI 10.1530/ERC-11-0006 PG 25 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 821SY UT WOS:000294995900003 PM 21490240 ER PT J AU Liao, CZ Sitzmann, M Pugliese, A Nicklaus, MC AF Liao, Chenzhong Sitzmann, Markus Pugliese, Angelo Nicklaus, Marc C. TI Software and resources for computational medicinal chemistry SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID MOLECULAR DOCKING PROGRAMS; PROTEIN-LIGAND DOCKING; HIV-1 INTEGRASE INHIBITORS; VIRTUAL SCREENING APPROACH; AIDED DRUG DISCOVERY; BINDING FREE-ENERGY; RECEPTOR LIGANDS; PHARMACOPHORE MODEL; QUANTUM-MECHANICS; SCORING FUNCTIONS AB Computer-aided drug design plays a vital role in drug discovery and development and has become an indispensable tool in the pharmaceutical industry. Computational medicinal chemists can take advantage of all kinds of software and resources in the computer-aided drug design field for the purposes of discovering and optimizing biologically active compounds. This article reviews software and other resources related to computer-aided drug design approaches, putting particular emphasis on structure-based drug design, ligand-based drug design, chemical databases and chemoinformatics tools. C1 [Liao, Chenzhong; Sitzmann, Markus; Pugliese, Angelo; Nicklaus, Marc C.] NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. RP Liao, CZ (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. EM czliao@helix.nih.gov RI Nicklaus, Marc/N-4183-2014; OI Nicklaus, Marc/0000-0002-4775-7030 FU Intramural NIH HHS [ZIA BC011336-01, ZIC BC010517-08, ZIC BC010639-07] NR 185 TC 37 Z9 38 U1 1 U2 50 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 JUN PY 2011 VL 3 IS 8 BP 1057 EP 1085 DI 10.4155/FMC.11.63 PG 29 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 814MP UT WOS:000294459700017 PM 21707404 ER PT J AU Vovk, A Cox, RW Suput, D Stare, J Saad, ZS AF Vovk, Andrej Cox, Robert W. Suput, Dusan Stare, Janez Saad, Ziad. S. TI Use of signatures to create probability maps of brain tissues in health and disease - a new diagnostic tool? SO ZDRAVNISKI VESTNIK-SLOVENIAN MEDICAL JOURNAL LA English DT Article DE atlas guided segmentation; brain probability maps; tissue similarity; statistic signatures; brain pathology ID SEGMENTATION; MRI; IMAGES; SCHIZOPHRENIA AB Segmentation of brain MRI into white matter, gray matter, cerebrospinal fluid, skull, and other categories is an integral part of MRI analysis. To date, most widely used segmentation approaches require the use of population-based spatial segmentation priors, mostly to improve robustness to shading artifacts and noise. Prior generation requires a set of segmented volumes from a population similar to the one to be studied, and an alignment approach for aligning brains from multiple subjects. Aim: In this paper we present a method for generating segmentation priors that is insensitive to noise and field bias and does not require registration to a template space. Methods: Our approach relies on using signatures, a set of local descriptive statistics, computed over multiple spatial scales. In the training process, signatures of each tissue are clustered into representative sub-classes. Representative signatures are the median of signatures in each subclass. In a new dataset, voxel signatures are compared to the set of representative signatures and tissue classification priors are generated using Bayes' rule and total probability. Results: These signature-based probability maps can replace spatially-based population priors in segmentation. We also show that signature similarity can be used interactively to delineate brain lesions, such as tumours, thereby facilitating diagnostic procedures. Conclusions: Voxel signatures consisting of spatial texture information across multiple scales, can be used either as simple similarity measure to select tissue of the same type or to create tissue prior probability maps that can be used in brain segmentation and in other clinically relevant procedures. C1 [Vovk, Andrej; Suput, Dusan] Univ Ljubljana, Fac Med, Inst Pathophysiol, Ljubljana, Slovenia. [Cox, Robert W.; Saad, Ziad. S.] NIMH, US Dept HHS, NIH, Bethesda, MD 20891 USA. [Stare, Janez] Univ Ljubljana, Fac Med, Inst Biostat Med Informatiko, Ljubljana, Slovenia. RP Suput, D (reprint author), Univ Ljubljana, Fac Med, Inst Pathophysiol, Zaloska 4, Ljubljana, Slovenia. EM dusan.suput@mf.uni-lj.si FU NIH; [ARRS P30019] FX Parts of this research were supported by the NIMH and NINDS Intramural Research Programs of the NIH, and by the Slovenian research grant ARRS P30019. Andrej Vovk and Ziad Saad have contributed equally to the development of statistical approach used in this study. NR 22 TC 1 Z9 1 U1 1 U2 1 PU SLOVENE MEDICAL SOC PI LJUBLJANA PA ZDRAVNISKI VESTNIK, DALMATINOVA 10, P P 26, LJUBLJANA, 1001, SLOVENIA SN 1318-0347 J9 ZDR VESTN JI Zdr. Vestn. PD JUN PY 2011 VL 80 IS 6 BP 476 EP 482 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 785QP UT WOS:000292244100008 ER PT J AU Bainbridge, KE Hoffman, HJ AF Bainbridge, K. E. Hoffman, H. J. TI HEAVY METALS AND AUDIOMETRIC PURE-TONE THRES HOLDS IN ADOLESCENTS: NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES), 2005-2008. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 3rd North American Congress of Epidemiology CY JUN 21-24, 2011 CL Montreal, CANADA C1 [Bainbridge, K. E.; Hoffman, H. J.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2011 VL 173 SU 11 BP S177 EP S177 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810GU UT WOS:000294114600691 ER PT J AU Barone-Adesi, F Chapman, R He, X Hu, W Vermeulen, RCH Rothman, N Lan, Q AF Barone-Adesi, F. Chapman, R. He, X. Hu, W. Vermeulen, R. C. H. Rothman, N. Lan, Q. TI USE OF DIFFERENT COAL TYPES AND RISK OF LUNG CANCER IN XUANWEI, CHINA SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 3rd North American Congress of Epidemiology CY JUN 21-24, 2011 CL Montreal, CANADA C1 [Barone-Adesi, F.; Chapman, R.; He, X.; Hu, W.; Vermeulen, R. C. H.; Rothman, N.; Lan, Q.] NCI, Bethesda, MD 20892 USA. RI Hu, Wei/M-3524-2013 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2011 VL 173 SU 11 BP S90 EP S90 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810GU UT WOS:000294114600353 ER PT J AU Cook, MB Kamangar, F Taylor, PR Virtamo, J Albanes, D Petty, G Wood, RJ Cross, AJ Dawsey, SM AF Cook, M. B. Kamangar, F. Taylor, P. R. Virtamo, J. Albanes, D. Petty, G. Wood, R. J. Cross, A. J. Dawsey, S. M. TI IRON IN RELATION TO GASTRIC CANCER IN THE ATBC CANCER PREVENTION STUDY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 3rd North American Congress of Epidemiology CY JUN 21-24, 2011 CL Montreal, CANADA C1 [Cook, M. B.; Kamangar, F.; Taylor, P. R.; Virtamo, J.; Albanes, D.; Petty, G.; Wood, R. J.; Cross, A. J.; Dawsey, S. M.] NCI, Bethesda, MD USA. RI Albanes, Demetrius/B-9749-2015 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2011 VL 173 SU 11 BP S6 EP S6 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810GU UT WOS:000294114600022 ER PT J AU Fei, C DeRoo, LA Sandler, DP Weinberg, CR AF Fei, C. DeRoo, L. A. Sandler, D. P. Weinberg, C. R. TI INFERTILITY DRUGS AND YOUNG-ONSET BREAST CANCER: RESULTS FROM THE TWO SISTER STUDY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 3rd North American Congress of Epidemiology CY JUN 21-24, 2011 CL Montreal, CANADA C1 [Fei, C.; DeRoo, L. A.; Sandler, D. P.; Weinberg, C. R.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2011 VL 173 SU 11 BP S236 EP S236 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810GU UT WOS:000294114601218 ER PT J AU Hoffman, HJ Reed, GW Tambs, K Kvestad, E Krog, N Engdahl, B AF Hoffman, H. J. Reed, G. W. Tambs, K. Kvestad, E. Krog, N. Engdahl, B. TI FAMILIAL RISK FOR NOISE-INDUCED HEARING LOSS (NIHL) AND PRESBYCUSIS: THE NORD-TRONDELAG HEARING LOSS STUDY, 1996-1998 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 3rd North American Congress of Epidemiology CY JUN 21-24, 2011 CL Montreal, CANADA C1 [Hoffman, H. J.; Reed, G. W.; Tambs, K.; Kvestad, E.; Krog, N.; Engdahl, B.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2011 VL 173 SU 11 BP S17 EP S17 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810GU UT WOS:000294114600065 ER PT J AU Hofmann, JN Baccarelli, A Schwartz, K Davis, FG Ruterbusch, JJ Hoxha, M McCarthy, BJ Savage, SA Wacholder, S Rothman, N Graubard, BI Colt, JS Chow, WH Purdue, MP AF Hofmann, J. N. Baccarelli, A. Schwartz, K. Davis, F. G. Ruterbusch, J. J. Hoxha, M. McCarthy, B. J. Savage, S. A. Wacholder, S. Rothman, N. Graubard, B. I. Colt, J. S. Chow, W. H. Purdue, M. P. TI RISK OF RENAL CELL CARCINOMA IN RELATION TO BLOOD LEUKOCYTE TELOMERE LENGTH IN A POPULATION-BASED CASE-CONTROL STUDY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 3rd North American Congress of Epidemiology CY JUN 21-24, 2011 CL Montreal, CANADA C1 [Hofmann, J. N.; Baccarelli, A.; Schwartz, K.; Davis, F. G.; Ruterbusch, J. J.; Hoxha, M.; McCarthy, B. J.; Savage, S. A.; Wacholder, S.; Rothman, N.; Graubard, B. I.; Colt, J. S.; Chow, W. H.; Purdue, M. P.] NCI, Bethesda, MD 20892 USA. RI Purdue, Mark/C-9228-2016; Savage, Sharon/B-9747-2015 OI Purdue, Mark/0000-0003-1177-3108; Savage, Sharon/0000-0001-6006-0740 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2011 VL 173 SU 11 BP S3 EP S3 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810GU UT WOS:000294114600012 ER PT J AU Klebanoff, M AF Klebanoff, M. CA Eunice Kennedy Shriver Natl Inst Human Dev Maternal Fetal Med Units TI TREATMENT OF GESTATIONAL DIABETES (GDM), WEIGHT GAIN AND PERINATAL OUTCOME - MARGINAL STRUCTURAL MODEL (MSM) ANALYSIS SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 3rd North American Congress of Epidemiology CY JUN 21-24, 2011 CL Montreal, CANADA C1 [Klebanoff, M.; Eunice Kennedy Shriver Natl Inst; Human Dev Maternal Fetal Med Units] NICHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2011 VL 173 SU 11 BP S41 EP S41 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810GU UT WOS:000294114600161 ER PT J AU Lam, TK Freedman, ND Fan, JH Qiao, YL Dawsey, SM Taylor, PR Abnet, CC AF Lam, T. K. Freedman, N. D. Fan, J-H Qiao, Y-L Dawsey, S. M. Taylor, P. R. Abnet, C. C. TI PRE-DIAGNOSTIC PLASMA VITAMIN C AND RISK OF ESOPHAGEAL AND GASTRIC CANCERS IN THE GENERAL POPULATION NUTRITION INTERVENTION TRIAL COHORT SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 3rd North American Congress of Epidemiology CY JUN 21-24, 2011 CL Montreal, CANADA C1 [Lam, T. K.; Freedman, N. D.; Fan, J-H; Qiao, Y-L; Dawsey, S. M.; Taylor, P. R.; Abnet, C. C.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RI Qiao, You-Lin/B-4139-2012; Freedman, Neal/B-9741-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Freedman, Neal/0000-0003-0074-1098 NR 0 TC 0 Z9 0 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2011 VL 173 SU 11 BP S6 EP S6 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810GU UT WOS:000294114600021 ER PT J AU Roosen-Runge, M Grewal, J Zhang, J Lazaga, A Souza, J Widmer, M Merialdi, M AF Roosen-Runge, M. Grewal, J. Zhang, J. Lazaga, A. Souza, J. Widmer, M. Merialdi, M. TI SEVERE ANEMIA, SICKLE CELL DISEASE, AND THALASSEMIA AS RISK FACTORS FOR PREECLAMPSIA IN DEVELOPING COUNTRIES SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 3rd North American Congress of Epidemiology CY JUN 21-24, 2011 CL Montreal, CANADA C1 [Roosen-Runge, M.; Grewal, J.; Zhang, J.; Lazaga, A.; Souza, J.; Widmer, M.; Merialdi, M.] NICHD, Epidemiol Branch, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2011 VL 173 SU 11 BP S321 EP S321 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810GU UT WOS:000294114601543 ER PT J AU Schonfeld, SJ Brenner, AV Neta, G Sturgis, EM Pfeiffer, RM Hutchinson, AA Xu, L Wheeler, W Guenel, P Rajaraman, P de Vathaire, F Ron, E Tucker, MA Chanock, SJ Sigurdson, AJ AF Schonfeld, S. J. Brenner, A. V. Neta, G. Sturgis, E. M. Pfeiffer, R. M. Hutchinson, A. A. Xu, L. Wheeler, W. Guenel, P. Rajaraman, P. de Vathaire, F. Ron, E. Tucker, M. A. Chanock, S. J. Sigurdson, A. J. TI COMMON GENETIC VARIANTS IN SEX HORMONE PATHWAY GENES AND PAPILLARY THYROID CANCER RISK SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 3rd North American Congress of Epidemiology CY JUN 21-24, 2011 CL Montreal, CANADA C1 [Schonfeld, S. J.; Brenner, A. V.; Neta, G.; Sturgis, E. M.; Pfeiffer, R. M.; Hutchinson, A. A.; Xu, L.; Wheeler, W.; Guenel, P.; Rajaraman, P.; de Vathaire, F.; Ron, E.; Tucker, M. A.; Chanock, S. J.; Sigurdson, A. J.] NCI, DCEG, NIH, Bethesda, MD 20892 USA. RI Pfeiffer, Ruth /F-4748-2011; Tucker, Margaret/B-4297-2015 NR 0 TC 0 Z9 0 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2011 VL 173 SU 11 BP S165 EP S165 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810GU UT WOS:000294114600642 ER PT J AU Whitworth, KW Haug, LS Baird, DD Becher, G Hoppin, JA Skjaerven, R Thomsen, C Eggesbo, M Travlos, G Wilson, R Longnecker, MP AF Whitworth, K. W. Haug, L. S. Baird, D. D. Becher, G. Hoppin, J. A. Skjaerven, R. Thomsen, C. Eggesbo, M. Travlos, G. Wilson, R. Longnecker, M. P. TI PLASMA CONCENTRATIONS OF PERFLUORINATED COMPOUNDS AND SUBFECUNDITY IN THE NORWEGIAN MOTHER AND CHILD COHORT STUDY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 3rd North American Congress of Epidemiology CY JUN 21-24, 2011 CL Montreal, CANADA C1 [Whitworth, K. W.; Haug, L. S.; Baird, D. D.; Becher, G.; Hoppin, J. A.; Skjaerven, R.; Thomsen, C.; Eggesbo, M.; Travlos, G.; Wilson, R.; Longnecker, M. P.] NIEHS, NIH, DHHS, Durham, NC 27703 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2011 VL 173 SU 11 BP S10 EP S10 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810GU UT WOS:000294114600040 ER PT J AU Llewellyn, DJ Lang, IA Langa, KM Muniz-Terrera, G Phillips, CL Cherubini, A Ferrucci, L Melzer, D AF Llewellyn, David J. Lang, Iain A. Langa, Kenneth M. Muniz-Terrera, Graciela Phillips, Caroline L. Cherubini, Antonio Ferrucci, Luigi Melzer, David TI Vitamin D and Risk of Cognitive Decline in Elderly Persons EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB The findings of a report published in 2007 suggested that over 40% of older, community-living adults in the United States and Europe were vitamin D deficient. There is clinical evidence for a relationship between low serum 25-hydroxyvitamin D (25[OH] D) levels and cognitive dysfunction with aging. Although data in several small clinical studies showing such an association were equivocal, 3 of 4 large population-based cross-sectional studies reported a relationship between levels of serum 25(OH) D and cognitive dysfunction in the elderly. No prior prospective population-based studies have investigated the possible association between vitamin D status and incident dementia or cognitive decline. This prospective population-based study was designed to determine whether low serum levels of 25(OH) D were associated with an increased risk of substantial cognitive decline in an elderly population. Data were obtained from a sample of elderly individuals enrolled in the InCHIANTI study, a large, prospective cohort study conducted in Italy to identify risk factors for late-life disability. The study participants were 858 adults aged 65 years or older who had completed 1 or more follow-up cognitive assessment between 1998 and 2006, with follow-up every 3 years. Cognitive decline was assessed using 2 tests of cognitive function: the Mini-Mental State Examination (MMSE) and the Trail-Making Tests A and B; both were administered at baseline, with follow-up at 3 and 6 years. Substantial cognitive decline was defined with MMSE as a decrease in score of 3 or more points, and with Trails A and Trails B as scoring in the worst 10% of cognitive decline or having the testing discontinued. In multivariate logistic regression fully adjusted models, the relative risk (RR) of substantial cognitive decline on the MMSE among participants who were severely 25(OH) D deficient was 60% greater compared with those who were 25(OH) D sufficient (RR, 1.60; 95% confidence interval [CI], 1.19-2.00; P (value for linear trend) <0.02). In fully adjusted random-effects models, the MMSE score declined by an additional 0.3 points per year more among severely 25(OH) D deficient participants compared with those who were 25(OH) D sufficient. With the Trails B, severely vitamin D deficient participants were 31% more likely of having a substantial decline in cognitive performance scores compared to those with sufficient levels of vitamin D; the RR was 1.31, with a 95% CI of 1.03-1.51 (P (value for linear trend) < 0.04). No significant association was found between 25(OH) D levels and cognitive performance on Trails A. These findings are the first to show in a prospective study that low levels of vitamin D are associated with increased risk of substantial cognitive decline in an elderly population. The data suggest that tests of cognitive function may be useful in future prospective trials of vitamin D supplementation in the elderly. C1 [Llewellyn, David J.] Univ Exeter, Peninsula Med Sch, Publ Hlth & Epidemiol Grp, Exeter, Devon, England. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Vet Affairs Ctr Practice Management & Outcomes Re, Ann Arbor, MI USA. Med Res Council Biostat Unit, Cambridge, England. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Perugia Univ Hosp, Inst Gerontol & Geriatr, Perugia, Italy. Univ Perugia, Sch Med, I-06100 Perugia, Italy. RP Llewellyn, DJ (reprint author), Univ Exeter, Peninsula Med Sch, Publ Hlth & Epidemiol Grp, Exeter, Devon, England. RI Lang, Iain/B-8255-2008 NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD JUN PY 2011 VL 66 IS 6 BP 354 EP 355 DI 10.1097/OGX.0b013e31822c1957 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 809KP UT WOS:000294054100014 ER PT J AU Mann-Wrobel, MC Carreno, JT Dickinson, D AF Mann-Wrobel, Monica C. Carreno, Jaymee T. Dickinson, Dwight TI Meta-analysis of neuropsychological functioning in euthymic bipolar disorder: an update and investigation of moderator variables SO BIPOLAR DISORDERS LA English DT Article DE bipolar disorder; cognition; euthymia; meta-analysis; neuropsychology ID 1ST-DEGREE RELATIVES; CLINICAL STATE; RATING-SCALE; IMPAIRMENT; DEFICITS; MEMORY; SCHIZOPHRENIA; MANIA AB Objectives: Cognitive impairment is frequently observed among individuals with bipolar disorder during acute and euthymic phases of the illness. The purpose of this study was to provide an updated meta-analysis on the neuropsychological functioning of euthymic bipolar disorder individuals and to explore study design, demographic, and clinical variables that could moderate observed effects. Methods: Searches were conducted on Medline and PsychInfo databases and 28 studies were selected that met inclusion criteria. A total of 28 cognitive variables were examined in the meta-analysis. The effects of four continuous (age, percent female, education, and illness duration) and two dichotomous (clinical course and diagnostic rigor) moderator variables were explored. Results: Compared to controls, euthymic bipolar disorder individuals demonstrated impaired neuropsychological functioning across almost all domains, with medium-large effect sizes. Notably, vocabulary and word reading did not differ from controls. Sex did not impact neuropsychological functioning, and neuropsychological impairment decreased as education increased. Contrary to expectations, age and illness duration were negatively correlated with cognitive impairment. Diagnostic rigor of euthymia did not appear to impact effect sizes; however, clinical course received some tentative support as a moderator variable. Conclusions: Current results suggest that generalized, rather than specific, cognitive impairment characterizes euthymic bipolar disorder. Age, illness duration, education, and clinical course may moderate these broad cognitive effects. Against this general impairment backdrop, there may be a relative preservation of crystallized verbal ability. C1 [Mann-Wrobel, Monica C.] VA Maryland Hlth Care Syst VISN 6, Durham Med Ctr, MIRECC, VA Capitol Network VISN 6, Durham, NC 27705 USA. [Carreno, Jaymee T.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Dickinson, Dwight] NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Dickinson, Dwight] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Mann-Wrobel, MC (reprint author), VA Maryland Hlth Care Syst VISN 6, Durham Med Ctr, MIRECC, VA Capitol Network VISN 6, 508 Fulton St, Durham, NC 27705 USA. EM monica.mann-wrobel@va.gov NR 28 TC 111 Z9 112 U1 3 U2 17 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 IS 4 BP 334 EP 342 DI 10.1111/j.1399-5618.2011.00935.x PG 9 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 807QK UT WOS:000293914600002 PM 21843273 ER PT J AU Jolly, SE Eilat-Adar, S Wang, H Mete, M Fabsitz, RR Devereux, RB Ebbesson, SOE Umans, JG Howard, BV AF Jolly, Stacey E. Eilat-Adar, Sigal Wang, Hong Mete, Mihriye Fabsitz, Richard R. Devereux, Richard B. Ebbesson, Sven O. E. Umans, Jason G. Howard, Barbara V. TI Sex-specific associations of nutrition with hypertension and systolic blood pressure in Alaska Natives findings from the GOCADAN study SO INTERNATIONAL JOURNAL OF CIRCUMPOLAR HEALTH LA English DT Article DE nutrition; Alaska Native; sex; systolic blood pressure; epidemiology ID CARDIOVASCULAR-DISEASE; GENDER-DIFFERENCES; AMERICAN-INDIANS; DIETARY SALT; ADULTS; ATHEROSCLEROSIS; METAANALYSIS; ACID; AGE AB Objectives. To examine sex-specific associations of nutritional factors with prevalent hypertension (HTN) and systolic blood pressure (SBP) in Alaska Natives. Diet is known to affect SBP, a major risk factor for cardiovascular disease. Study design. Cross-sectional analysis of participants without diabetes in the Genetics of Coronary Artery Disease in Alaska Natives study. Methods. Macronutrients such as fat, carbohydrate and protein and micronutrients such as sodium were investigated. HTN was defined as SBP >= 140 mmHg, diastolic blood pressure >= 90 mmHg and/or taking anti-HTN medication. Analyses were stratified by sex and covariates included age, body mass index (BMI), energy intake, smoking and physical activity. Results. Mean age was 42 years for men (n=456) and women (n=602). Men with HTN (n=106) compared to men without HEN consumed a higher proportion of calories from total (p=0.01), saturated (p<0.01) and trans fatty acid (p=0.03) fats. Women with HTN (n=99) compared to women without HTN consumed more total (p=0.03) and monounsaturated (p=0.04) fat, higher protein (p=0.02) and lower total (p<0.01) and simple (p<0.01) carbohydrates. After covariate adjustment, men not on anti-HTN medications (n=407) had significantly higher average SBP with increasing quartiles of trans fatty acid intake (p for linear trend=0.01) and sodium intake (p for linear trend=0.02). For women not on anti-HTN medications (n=528), after covariate adjustment, average SBP decreased with increasing quartiles of omega 3 fatty acid intake (p for linear trend <0.01). Conclusions. Prospective evaluation of the sex-specific associations of nutritional factors with HTN and SBP on outcomes is needed along with novel interventions to lower the risk of cardiovascular disease. (Int J Circumpolar Health 2011; 70(3):254-265) C1 [Jolly, Stacey E.] Cleveland Clin, Inst Med, Cleveland, OH 44106 USA. [Eilat-Adar, Sigal] Zinman Coll Phys Educ & Sports, Wingate Inst, Netanya, Israel. [Eilat-Adar, Sigal; Wang, Hong; Mete, Mihriye; Umans, Jason G.; Howard, Barbara V.] MedStar Hlth Res Inst, Hyattsville, MD USA. [Fabsitz, Richard R.] NHLBI, Bethesda, MD 20892 USA. [Devereux, Richard B.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Ebbesson, Sven O. E.] Norton Sound Hlth Corp, Nome, AK USA. [Umans, Jason G.; Howard, Barbara V.] Georgetown Howard Univ, Ctr Clin & Translat Sci, Washington, DC USA. RP Jolly, SE (reprint author), Cleveland Clin, Inst Med, 9500 Euclid Ave,G10, Cleveland, OH 44106 USA. EM jollys@ccf.org FU NHLBI [U01HL064244-09S1]; National Institutes of Health, Bethesda, MD [U01HL064244, U01HL082490, U01HL082458, M01RR000047, UL1RR031975] FX Dr. Jolly was supported by an NHLBI diversity supplement, U01HL064244-09S1. The GOCADAN study and these analyses were supported by U01HL064244, U01HL082490, U01HL082458 and M01RR000047, and UL1RR031975 from the National Institutes of Health, Bethesda, MD. None of the above authors listed have any financial conflict of interests to disclose. NR 41 TC 4 Z9 4 U1 0 U2 3 PU INT ASSOC CIRCUMPOLAR HEALTH PUBL PI OULU PA AAPISTIE1, OULU, FIN-90220, FINLAND SN 1239-9736 J9 INT J CIRCUMPOL HEAL JI Int. J. Circumpolar Health PD JUN PY 2011 VL 70 IS 3 BP 254 EP 265 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 808QX UT WOS:000293994600006 PM 21631966 ER PT J AU Ionides, EL Bhadra, A Atchade, Y King, A AF Ionides, Edward L. Bhadra, Anindya Atchade, Yves King, Aaron TI ITERATED FILTERING SO ANNALS OF STATISTICS LA English DT Article DE Dynamic systems; sequential Monte Carlo; filtering; importance sampling; state space model; partially observed Markov process ID MONTE-CARLO METHODS; LATENT VARIABLE MODELS; TIME-SERIES ANALYSIS; STATE-SPACE MODELS; STOCHASTIC-APPROXIMATION; PARTICLE FILTERS; DISEASE DYNAMICS; INFERENCE; MEASLES; POPULATIONS AB Inference for partially observed Markov process models has been a long-standing methodological challenge with many scientific and engineering applications. Iterated filtering algorithms maximize the likelihood function for partially observed Markov process models by solving a recursive sequence of filtering problems. We present new theoretical results pertaining to the convergence of iterated filtering algorithms implemented via sequential Monte Carlo filters. This theory complements the growing body of empirical evidence that iterated filtering algorithms provide an effective inference strategy for scientific models of nonlinear dynamic systems. The first step in our theory involves studying a new recursive approach for maximizing the likelihood function of a latent variable model, when this likelihood is evaluated via importance sampling. This leads to the consideration of an iterated importance sampling algorithm which serves as a simple special case of iterated filtering, and may have applicability in its own right. C1 [Ionides, Edward L.; Bhadra, Anindya; Atchade, Yves] Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA. [Ionides, Edward L.; King, Aaron] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [King, Aaron] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. RP Ionides, EL (reprint author), Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA. EM ionides@umich.edu; tatar@umich.edu; yvesa@umich.edu; kingaa@umich.edu RI King, Aaron/B-8092-2012; OI King, Aaron/0000-0001-6159-3207; Atchade, Yves/0000-0002-0487-6136 FU NSF [DMS-08-05533, EF-04-30120, DEB-0553768]; Graham Environmental Sustainability Institute; Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; University of California, Santa Barbara; State of California FX Supported by NSF Grants DMS-08-05533 and EF-04-30120, the Graham Environmental Sustainability Institute, the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health.; This work was conducted as part of the Inference for Mechanistic Models Working Group supported by the National Center for Ecological Analysis and Synthesis, a Center funded by NSF Grant DEB-0553768, the University of California, Santa Barbara and the State of California. NR 48 TC 33 Z9 33 U1 1 U2 18 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 0090-5364 J9 ANN STAT JI Ann. Stat. PD JUN PY 2011 VL 39 IS 3 BP 1776 EP 1802 DI 10.1214/11-AOS886 PG 27 WC Statistics & Probability SC Mathematics GA 805HC UT WOS:000293716500016 ER PT J AU Hosgood, HD Wei, H Sapkota, A Choudhury, I Bruce, N Smith, KR Rothman, N Lan, Q AF Hosgood, H. Dean, III Wei, Hu Sapkota, Amir Choudhury, Imran Bruce, Nigel Smith, Kirk R. Rothman, Nathaniel Lan, Qing TI Household coal use and lung cancer: systematic review and meta-analysis of case-control studies, with an emphasis on geographic variation SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Review DE China; Taiwan; India; indoor air pollution; solid fuels; cooking; heating ID INDOOR AIR-POLLUTION; RISK-FACTORS; XUAN-WEI; NORTHEAST CHINA; SOLID FUELS; WOMEN; COMBUSTION; MORTALITY; EMISSIONS; EXPOSURE AB Background Emissions from household coal combustion associated with cooking and heating are an important public health issue, particularly in China where hundreds of millions of people are exposed. Although coal emissions are a known human carcinogen, there is still uncertainty about the level of risk for lung and other cancers. Methods We performed a meta-analysis on 25 case-control studies (10 142 cases and 13 416 controls) to summarize the association between household coal use and lung cancer risk, and to explore the effect modification of this association by geographical location. Results Using random-effects models, household coal use was found to be associated with lung cancer risk among all studies throughout the world [odds ratio (OR) = 2.15; 95% confidence interval (CI) = 1.61-2.89, N-studies = 25], and particularly among those studies carried out in mainland China and Taiwan (OR = 2.27; 95% CI = 1.65-3.12, N-studies = 20). Stratification by regions of mainland China and Taiwan found a variation in effects across the regions, with south/southeastern (OR = 3.27; 95% CI = 1.27-8.42, N-studies = 3) and southwestern China (OR = 2.98; 95% CI = 1.18-7.53, N-studies = 3) experiencing the highest risk. The elevated risk associated with coal use throughout Asia was also observed when stratifying studies by gender, smoking status, sample size, design (population vs hospital case-control) and publication language. No significant publication bias was found (p(Begg's) = 0.15). Conclusions Our results provide evidence that although the carcinogenic effect of coal use varies by location, coals from many locations exhibit elevated lung cancer risks. C1 [Hosgood, H. Dean, III] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. [Wei, Hu] China Natl Environm Monitoring Ctr, Beijing, Peoples R China. [Sapkota, Amir] Univ Maryland Coll Pk, Maryland Inst Appl Environm Hlth, Sch Publ Hlth, College Pk, MD USA. [Choudhury, Imran; Bruce, Nigel] Univ Liverpool, Div Publ Hlth, Liverpool L69 3BX, Merseyside, England. [Smith, Kirk R.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. RP Hosgood, HD (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, 6120 Execut Blvd,EPS 8120,MCS 7240, Bethesda, MD 20892 USA. EM hosgoodd@mail.nih.gov RI Sapkota, Amir/A-5968-2011; Hu, Wei/M-3524-2013 FU National Cancer Institute, National Institutes of Health; Bill and Melinda Gates Foundation FX Intramural programme of the National Cancer Institute, National Institutes of Health (partial); Bill and Melinda Gates Foundation [to the Global Burden of Diseases, Injuries, and Risk Factors Study (K.R.S.)]. NR 52 TC 36 Z9 36 U1 2 U2 19 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2011 VL 40 IS 3 BP 719 EP 728 DI 10.1093/ije/dyq259 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 803YF UT WOS:000293618300022 PM 21278196 ER PT J AU Cook, MB Chia, VM Berndt, SI Graubard, BI Chanock, SJ Rubertone, MV Erickson, RL Hayes, RB McGlynn, KA AF Cook, Michael B. Chia, Victoria M. Berndt, Sonja I. Graubard, Barry I. Chanock, Stephen J. Rubertone, Mark V. Erickson, Ralph L. Hayes, Richard B. McGlynn, Katherine A. TI Genetic contributions to the association between adult height and testicular germ cell tumors SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Body height; case-control studies; epidemiology; polymorphism; single nucleotide; testicular neoplasms ID PROTEIN-COUPLED RECEPTORS; BODY-SIZE; PERINATAL VARIABLES; CANCER-EXPERIENCES; EUROPEAN COUNTRIES; RISK; BIRTH; SUSCEPTIBILITY; TRENDS; MEN AB Background Previously, we have shown that increasing adult height is associated with increased risk of testicular germ-cell tumor (TGCT). Recently, a number of single nucleotide polymorphisms (SNPs) have been found to be related to height. We examined whether these SNPs were associated with TGCT and whether they explained the relationship between height and TGCT. Methods We genotyped 15 height-related SNPs in the US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) case-control study. DNA was extracted from buccal cell samples and Taqman assays were used to type the selected SNPs. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs). Results There were 561 cases and 676 controls for analysis. Two SNPs were found to be associated with risk of TGCT, rs6060373 (CC vs TT, OR = 1.51, 95% CI: 1.06-2.15) and rs143384 (CC vs TT, OR = 1.53, 95% CI: 1.09-2.15). rs6060373 is an intronic polymorphism of ubiquinol-cytochrome c reductase complex chaperone (UQCC), and rs143384 is a 5'UTR polymorphism of growth differentiation factor 5 (GDF5). No individual SNP attenuated the association between height and TGCT. Adjustment for all SNPs previously associated with adult height reduced the associations between adult height and TGCT by similar to 8.5%, although the P-value indicated only weak evidence that this difference was important (P = 0.26). Conclusions This novel analysis provides tentative evidence that SNPs which are associated with adult height may also share an association with risk of TGCT. C1 [Cook, Michael B.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20852 USA. [Rubertone, Mark V.] USA, Ctr Hlth Promot & Prevent Med, Silver Spring, MD USA. [Erickson, Ralph L.] Walter Reed Army Inst Res, Silver Spring, MD USA. RP Cook, MB (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS Suite 550,Room 5012, Bethesda, MD 20852 USA. EM cookmich@mail.nih.gov RI Cook, Michael/A-5641-2009; OI Cook, Michael/0000-0002-0533-7302; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX Intramural Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 42 TC 6 Z9 6 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2011 VL 40 IS 3 BP 731 EP 739 DI 10.1093/ije/dyq260 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 803YF UT WOS:000293618300024 PM 21233139 ER PT J AU Tangrea, MA Mukherjee, S Gao, B Markey, SP Du, Q Armani, M Kreitman, MS Rosenberg, AM Wallis, BS Eberie, FC Duncan, FC Hanson, JC Chuaqui, RF Rodriguez-Canales, J Emmert-Buck, MR AF Tangrea, Michael A. Mukherjee, Sumana Gao, Bing Markey, Sanford P. Du, Qiang Armani, Michael Kreitman, Matthew S. Rosenberg, Alex M. Wallis, Benjamin S. Eberie, Franziska C. Duncan, Francesca C. Hanson, Jeffrey C. Chuaqui, Rodrigo F. Rodriguez-Canales, Jaime Emmert-Buck, Michael R. TI Effect of Immunohistochemistry on Molecular Analysis of Tissue Samples: Implications for Microdissection Technologies SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE immunostaining; immunohistochemistry; proteomics; DNA; RNA; tissue microdissection; expression microdissection; immuno-LCM ID LASER CAPTURE MICRODISSECTION; PARAFFIN-EMBEDDED TISSUES; ENZYME-LABELED ANTIBODIES; POLYMERASE CHAIN-REACTION; RNA EXPRESSION ANALYSIS; MESSENGER-RNA; GENE-EXPRESSION; PROMOTER METHYLATION; PROSTATE-CANCER; IN-SITU AB Laser-based tissue microdissection is an important tool for the molecular evaluation of histological sections. The technology has continued to advance since its initial commercialization in the 1990s, with improvements in many aspects of the process. More recent developments are tailored toward an automated, operator-independent mode that relies on antibodies as targeting probes, such as immuno-laser capture microdissection or expression microdissection (xMD). Central to the utility of expression-based dissection techniques is the effect of the staining process on the biomolecules in histological sections. To investigate this issue, the authors analyzed DNA, RNA, and protein in immunostained, microdissected samples. DNA was the most robust molecule, exhibiting no significant change in quality after immunostaining but a variable 50% to 75% decrease in the total yield. In contrast, RNA in frozen and ethanol-fixed, paraffin-embedded samples was susceptible to hydrolysis and digestion by endogenous RNases during the initial steps of staining. Proteins from immunostained tissues were successfully analyzed by one-dimensional electrophoresis and mass spectrometry but were less amenable to solution phase assays. Overall, the results suggest investigators can use immunoguided microdissection methods for important analytic techniques; however, continued improvements in staining protocols and molecular extraction methods are key to further advancing the capability of these methods. (J Histochem Cytochem 59:591-600, 2011) C1 [Tangrea, Michael A.; Mukherjee, Sumana; Du, Qiang; Rosenberg, Alex M.; Wallis, Benjamin S.; Duncan, Francesca C.; Chuaqui, Rodrigo F.; Emmert-Buck, Michael R.] NCI, Pathogenet Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Gao, Bing; Markey, Sanford P.] NIMH, Lab Neurotoxicol, NIH, Bethesda, MD 20892 USA. [Eberie, Franziska C.] NCI, Hematopathol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Emmert-Buck, MR (reprint author), NCI, Pathogenet Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM mbuck@helix.nih.gov OI Rodriguez-Canales, Jaime/0000-0002-0885-2377 FU NIH, National Cancer Institute, Center for Cancer Research FX The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: This research was supported in part by the intramural program of the NIH, National Cancer Institute, Center for Cancer Research. NR 49 TC 13 Z9 13 U1 0 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD JUN PY 2011 VL 59 IS 6 BP 591 EP 600 DI 10.1369/0022155411404704 PG 10 WC Cell Biology SC Cell Biology GA 805CL UT WOS:000293703900003 PM 21430260 ER PT J AU Reid, AE Kim, SW Seiner, B Fowler, FW Hooker, J Ferrieri, R Babst, B Fowler, JS AF Reid, Alicia E. Kim, Sung Won Seiner, Brienne Fowler, Frank W. Hooker, Jacob Ferrieri, Richard Babst, Benjamin Fowler, Joanna S. TI Radiosynthesis of C-11 labeled auxin (3-indolyl[1-C-11]acetic acid) and its derivatives from gramine SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE auxins; plant imaging; cyanide; gramine ID BOX PROTEIN TIR1; CARBON; BIOSYNTHESIS; JASMONATE; RECEPTOR; INDOLES AB 3-Indolylacetic acid (IAA) is the major auxin in higher plants and plays a key role in plant growth and development. We report the rapid radiolabeling of the important plant hormone using carbon-11 (half life: 20.4 min) enabling in vivo imaging of its distribution and movement in whole plants. 3-Indolyl[1-C-11]acetic acid was synthesized in 2-steps: (1) reaction of gramine with [C-11]cyanide to give 3-indolyl[1-C-11]acetonitrile in >99% radiochemical purity; (2) hydrolysis of the intermediate in aqueous sodium hydroxide solution to give 3-indolyl[1-C-11] acetic acid in >98% radiochemical purity after HPLC purification. The overall nondecay corrected radiochemical yield was 28%, synthesis time was 68 min and specific activity was (0.7 mCi/nmol). Hydrolysis proceeded through the formation of 3-indolyl[1-C-11]acetamide and by varying the temperature of this step, either C-11 labeled acid or amide were obtained. This procedure provides unexpectedly high C-11 incorporation in a short time and using a simple and selective hydrolysis without the need of an indole-nitrogen protecting group or a typical leaving group. Since 3-indolylacetonitrile and 3-indolylacetamide are also intermediates in the biosynthesis of IAA, and also function as auxins, this versatile reaction makes all three of these labeled compounds available for imaging studies in whole plants in vivo. C1 [Reid, Alicia E.] CUNY Medgar Evers Coll, Dept Chem, Brooklyn, NY 11225 USA. [Kim, Sung Won] NIAAA, Bethesda, MD 20892 USA. [Seiner, Brienne] Univ Missouri, Dept Chem, Columbia, MO 65211 USA. [Fowler, Frank W.] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA. [Hooker, Jacob] Martinos Ctr, Dept Radiol, Boston, MA 02129 USA. [Hooker, Jacob; Ferrieri, Richard; Babst, Benjamin; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. RP Reid, AE (reprint author), CUNY Medgar Evers Coll, Dept Chem, Brooklyn, NY 11225 USA. EM alreid@mec.cuny.edu OI Hooker, Jacob/0000-0002-9394-7708 FU U. S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-98CH10886]; National Science Foundation; National Institute on Alcoholism and Alcohol Abuse; National Institutes of Health [T32 EB004822]; Goldhaber Distinguished Fellowship FX This work was supported in part by the U. S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-98CH10886, in part by the National Science Foundation Faculty and Student Teachers Grant (to A. R.) and in part by the National Institute on Alcoholism and Alcohol Abuse (S. W. K.). We also acknowledge support from National Institutes of Health training grant for Brienne Seiner (T32 EB004822) and a Goldhaber Distinguished Fellowship for Ben Babst. We thank Michael Schueller for cyclotron operations and David Alexoff for help with precursor preparation. NR 24 TC 8 Z9 8 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD JUN PY 2011 VL 54 IS 8 BP 433 EP 437 DI 10.1002/jlcr.1894 PG 5 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 805OP UT WOS:000293738800006 ER PT J AU Landgren, O Korde, N AF Landgren, Ola Korde, Neha TI Multiple Myeloma Precursor Disease: Current Clinical and Epidemiological Insights and Future Opportunities THE KYLE/BUADI/RAJKUMAR ARTICLE REVIEWED SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID INDEPENDENT RISK-FACTOR; LIGHT-CHAIN RATIO; MONOCLONAL GAMMOPATHY; UNDETERMINED SIGNIFICANCE; PLASMA-CELLS; PROGRESSION; CLASSIFICATION; MANAGEMENT; PROGNOSIS; CRITERIA C1 [Landgren, Ola; Korde, Neha] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Korde, Neha] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NR 16 TC 7 Z9 7 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUN PY 2011 VL 25 IS 7 BP 589 EP 590 PG 2 WC Oncology SC Oncology GA 800EZ UT WOS:000293343900003 PM 21888256 ER PT J AU Terse, PS Johnson, JD Hawk, MA Ritchie, GD Ryan, MJ Vasconcelos, DY Contos, DA Perrine, SP Peggins, JO Tomaszewski, JE AF Terse, Pramod S. Johnson, Jerry D. Hawk, Michael A. Ritchie, Glenn D. Ryan, Michael J. Vasconcelos, Daphne Y. Contos, Denise A. Perrine, Susan P. Peggins, James O. Tomaszewski, Joseph E. TI Short-term Toxicity Study of ST-20 (NSC-741804) by Oral Gavage in Sprague-Dawley Rats SO TOXICOLOGIC PATHOLOGY LA English DT Article DE ST-20; thalassemia; neurotoxicity; toxicologic pathology ID BETA-THALASSEMIA MAJOR; FATTY-ACID DERIVATIVES; FETAL-HEMOGLOBIN; ERYTHROID PRECURSORS; SUBCHRONIC TOXICITY; BUTYRATE THERAPY; ERYTHROPOIESIS; APOPTOSIS; INDUCTION; EXPRESSION AB ST-20 (sodium 2,2-dimethylbutyrate) is a potential therapeutic agent for treatment of beta-thalassemia and sickle cell disease. A subchronic oral toxicity study was conducted in Sprague-Dawley rats (10/sex/dose) at gavage dosages of 0 (vehicle control), 200, 600, or 1,000 mg/kg, once daily for up to 15 days followed by a 14-day recovery. Ataxia (females), rough coat/thin appearance (males), and decreased body weights were observed at 1,000 mg/kg. Functional observational battery (FOB) deficits were observed more frequently in females and included decreased body tone, rectal temperature, emotional reactivity, neuromotor-neuromuscular activity (as exhibited by a deficit in visual/tactile placing accuracy, ataxia, hind limb dragging, and decreased grip strength), and rearing. ST-20 caused a decrease in WBC/RBC counts and RBC parameters; increase in reticulocytes and red cell inclusion bodies; decrease in total protein, globulin, and glucose; and increase in AG ratio. Micronucleated polychromatic erythrocytes of the bone marrow increased significantly in males at 1,000 mg/kg. Mean liver and kidney weights increased, and hepatocellular hypertrophy was observed in males at 1,000 mg/kg. Toxicologic findings were fully recovered during the 14-day recovery period. In conclusion, the no-observed adverse effect level for FOB and general toxicity was 200 mg/kg following gavage administration of ST-20 for up to 15 consecutive days. C1 [Terse, Pramod S.; Peggins, James O.; Tomaszewski, Joseph E.] NCI, Bethesda, MD 20892 USA. [Johnson, Jerry D.; Hawk, Michael A.; Ritchie, Glenn D.; Ryan, Michael J.; Vasconcelos, Daphne Y.; Contos, Denise A.] Battelle Mem Inst, Columbus, OH USA. [Perrine, Susan P.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Terse, PS (reprint author), NCI, Div Canc Treatment & Diag, Dev Therapeut Program, 6130 Execut Blvd,EPN Rm 8154,MSC 7451, Rockville, MD 20852 USA. EM tersep@mail.nih.gov FU NCI [N01-CM-42200]; NIH [R01 DK-52962, R42 HL-62715]; NHLBI; NIDDK FX The authors declared no potential conflicts of interest with respect to the authorship and/or publication of this article. The authors declared the following source of funding: Supported by NCI contract N01-CM-42200; NIH grants R01 DK-52962, R42 HL-62715, and NHLBI; and NIDDK under NIH-RAID Pilot Program. NR 33 TC 2 Z9 2 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2011 VL 39 IS 4 BP 614 EP 622 DI 10.1177/0192623311406933 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA 800RC UT WOS:000293381100005 PM 21558467 ER PT J AU Hoenerhoff, MJ Pandiri, AR Lahousse, SA Hong, HH Ton, TV Masinde, T Auerbach, SS Gerrish, K Bushel, PR Shockley, KR Peddada, SD Sills, RC AF Hoenerhoff, Mark J. Pandiri, Arun R. Lahousse, Stephanie A. Hong, Hu-Hua Tai-Vu Ton Masinde, Tiwanda Auerbach, Scott S. Gerrish, Kevin Bushel, Pierre R. Shockley, Keith R. Peddada, Shyamal D. Sills, Robert C. TI Global Gene Profiling of Spontaneous Hepatocellular Carcinoma in B6C3F1 Mice: Similarities in the Molecular Landscape with Human Liver Cancer SO TOXICOLOGIC PATHOLOGY LA English DT Article DE hepatocellular carcinoma; B6C3F1 mouse; microarray; gene expression analysis; comparative genomics ID NF-KAPPA-B; MAMMARY EPITHELIAL-CELLS; C-JUN; E-CADHERIN; SIGNALING PATHWAY; BREAST-CANCER; MOUSE-LIVER; INTRAHEPATIC METASTASIS; PROGNOSTIC-SIGNIFICANCE; TRANSCRIPTION FACTOR AB Hepatocellular carcinoma (HCC) is an important cause of morbidity and mortality worldwide. Although the risk factors of human HCC are well known, the molecular pathogenesis of this disease is complex, and in general, treatment options remain poor. The use of rodent models to study human cancer has been extensively pursued, both through genetically engineered rodents and rodent models used in carcinogenicity and toxicology studies. In particular, the B6C3F1 mouse used in the National Toxicology Program (NTP) two-year bioassay has been used to evaluate the carcinogenic effects of environmental and occupational chemicals, and other compounds. The high incidence of spontaneous HCC in the B6C3F1 mouse has challenged its use as a model for chemically induced HCC in terms of relevance to the human disease. Using global gene expression profiling, we identify the dysregulation of several mediators similarly altered in human HCC, including re-expression of fetal oncogenes, upregulation of protooncogenes, downregulation of tumor suppressor genes, and abnormal expression of cell cycle mediators, growth factors, apoptosis regulators, and angiogenesis and extracellular matrix remodeling factors. Although major differences in etiology and pathogenesis remain between human and mouse HCC, there are important similarities in global gene expression and molecular pathways dysregulated in mouse and human HCC. These data provide further support for the use of this model in hazard identification of compounds with potential human carcinogenicity risk, and may help in better understanding the mechanisms of tumorigenesis resulting from chemical exposure in the NTP two-year carcinogenicity bioassay. C1 [Hoenerhoff, Mark J.; Pandiri, Arun R.; Lahousse, Stephanie A.; Hong, Hu-Hua; Tai-Vu Ton; Masinde, Tiwanda; Sills, Robert C.] NIEHS, Cellular & Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Auerbach, Scott S.] NIEHS, Biomol Screening Branch, NIH, Res Triangle Pk, NC 27709 USA. [Gerrish, Kevin] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Bushel, Pierre R.; Shockley, Keith R.; Peddada, Shyamal D.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Hoenerhoff, MJ (reprint author), B350 Rall Bldg,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM hoenerhm@niehs.nih.gov RI Peddada, Shyamal/D-1278-2012 FU NIH, National Institute of Environmental Health Sciences FX We would like to thank Grace Kissling of the Biostatistics Branch, NIEHS, for assistance with statistical analysis; Laura Wharey for microarray analysis; and the NIEHS histology and immunohistochemistry departments for their assistance. This research [in part] was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 134 TC 20 Z9 20 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2011 VL 39 IS 4 BP 678 EP 699 DI 10.1177/0192623311407213 PG 22 WC Pathology; Toxicology SC Pathology; Toxicology GA 800RC UT WOS:000293381100010 PM 21571946 ER PT J AU Damiano, DL Norman, T Stanley, CJ Park, HS AF Damiano, Diane L. Norman, Tracy Stanley, Christopher J. Park, Hyung-Soon TI Comparison of elliptical training, stationary cycling, treadmill walking and overground walking SO GAIT & POSTURE LA English DT Article DE Gait; Rehabilitation; Locomotor; Variability; Coordination ID JOINT KINEMATICS; CEREBRAL-PALSY; SPINAL-CORD; GAIT; CHILDREN AB The extent to which therapeutic, exercise or robotic devices can maximize gait function is a major unresolved issue in neurorehabilitation. Several factors may influence gait outcomes such as similarity of the task to overground walking, degree of coordination within and across limbs, and cycle-to-cycle variability in each device. Our objective was to compare lower extremity kinematics, coordination and variability during four locomotor tasks: overground walking, treadmill walking, elliptical training and stationary cycling in 10 non-disabled adults (6 male; mean age 22.7 +/- 2.9 yrs, range 20-29). All first performed four overground walking trials at self-selected speed with mean temporal-spatial data used to pace the other conditions. Joint positions, excursions, and the Gait Deviation Index (GDI) were compared across conditions to evaluate kinematic similarity. Time-series data were correlated within and across limbs to evaluate intralimb and interlimb coordination, respectively. Variability in cadence was quantified to assess how constrained the locomotor rhythm was compared to overground walking. Treadmill walking most closely resembled overground with GDI values nearly overlapping, reinforcing its appropriateness for gait training. Cycling showed the largest GDI difference from overground, with elliptical closer but still a significant distance from all three. Cycling showed greater hip reciprocation Cycling and elliptical showed stronger intralimb synergism at the hip and knee than the other two. Based on kinematics, results suggest that elliptical training may have greater transfer to overground walking than cycling and cycling may be more useful for enhancing reciprocal coordination. Further evaluation of these devices in neurological gait disorders is needed. Published by Elsevier B.V. C1 [Damiano, Diane L.; Norman, Tracy; Stanley, Christopher J.; Park, Hyung-Soon] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Damiano, DL (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bldg 10,Room 1-1469, Bethesda, MD 20892 USA. EM damianod@cc.nih.gov RI Park, Hyung-Soon/B-3334-2010; Damiano, Diane/B-3338-2010 OI Park, Hyung-Soon/0000-0003-4274-7420; Damiano, Diane/0000-0002-2770-5356 FU NIH Clinical Center FX This work was funded by the intramural research program at the NIH Clinical Center. NR 18 TC 11 Z9 11 U1 0 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0966-6362 J9 GAIT POSTURE JI Gait Posture PD JUN PY 2011 VL 34 IS 2 BP 260 EP 264 DI 10.1016/j.gaitpost.2011.05.010 PG 5 WC Neurosciences; Orthopedics; Sport Sciences SC Neurosciences & Neurology; Orthopedics; Sport Sciences GA 801HS UT WOS:000293429800022 PM 21683599 ER PT J AU Hwang, SY Putney, JW AF Hwang, Sung-Yong Putney, James W., Jr. TI Orai1-Mediated Calcium Entry Regulates Differentiation and Function of Osteoclast Cells: Implications in Drug Development for Bone Diseases such as Osteoporosis and Rheumatoid Arthritis SO IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL LA English DT Meeting Abstract C1 [Hwang, Sung-Yong; Putney, James W., Jr.] NIEHS, Lab Signal Transduct, DHHS, NIH, Res Triangle Pk, NC 27709 USA. EM hwangs3@niehs.nih.gov; putney@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-2690 J9 IN VITRO CELL DEV-AN JI In Vitro Cell. Dev. Biol.-Anim. PD JUN PY 2011 VL 47 SU 1 BP S32 EP S32 PG 1 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 799IZ UT WOS:000293281700075 ER PT J AU Davis, J Piatigorsky, J AF Davis, Janine Piatigorsky, Joram TI Overexpression of Pax6 in Mouse Cornea Directly Alters Corneal Epithelial Cells: Changes in Immune Function, Vascularization, and Differentiation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ANIRIDIA-RELATED KERATOPATHY; GENE-EXPRESSION; EYE DEVELOPMENT; ANTERIOR SEGMENT; SQUAMOUS METAPLASIA; OXIDATIVE STRESS; STEM-CELLS; LENS; ABNORMALITIES; MICE AB PURPOSE. To assess whether Pax6 functions directly in the cornea, a corneal-preferred promoter was used to overexpress Pax6 specifically in the cornea. METHODS. Transgenic mice harboring a construct containing mouse Pax6 coding sequences fused downstream of the aldehyde dehydrogenase 3a1 (Aldh3a1) promoter were generated (Pax6 Tg). Pax6 expression was analyzed by Western blot and immunohistochemistry. Eye sections were stained with hematoxylin and eosin, Schiff reagent, and fluorescein, to assess morphologic changes, the presence of goblet cells, and barrier integrity, respectively. Gene expression changes in mildly affected Pax6 Tg corneas were compared to age-matched, wildtype (WT) corneas by microarray analysis and quantitative PCR. Promoter regulation of several differentially expressed genes was examined by monitoring luciferase activity of reporter constructs after cotransfection with Pax6 in COS7 cells. RESULTS. Corneal overexpression of Pax6 produces an abnormal cornea with altered epithelial cell morphology, neovascularization, immune cell invasion, and a compromised barrier; the lens appeared normal. Major changes in expression of genes involved in immune function, vascularization, and epithelial differentiation occurred in corneas from Pax6 Tg versus WT mice. The keratin (K) profile was dramatically altered in the Pax6 Tg corneas, as were several components of the Wnt signaling pathway. In severely affected Pax6 Tg corneas, K12 was reduced, and Pax6 was redistributed into the cytoplasm. Promoters from the chitinase 3-like 3, Wnt inhibitory factor 1, and fms-related tyrosine kinase 1/soluble VEGF receptor genes were upregulated five-, seven-, and threefold, respectively, by Pax6 in transfected COS7 cells. CONCLUSIONS. Pax6 functions directly to maintain normal, corneal epithelial cells. (Invest Ophthalmol Vis Sci. 2011;52:4158-4168) DOI:10.1167/iovs.10-6726 C1 [Davis, Janine; Piatigorsky, Joram] NEI, Lab Mol & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Davis, J (reprint author), NEI, NIH, 5625 Fishers Lane,Room 1S-02, Rockville, MD 20852 USA. EM davisj@nei.nih.gov NR 71 TC 14 Z9 15 U1 0 U2 3 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 JUN PY 2011 VL 52 IS 7 BP 4158 EP 4168 DI 10.1167/iovs.10-6726 PG 11 WC Ophthalmology SC Ophthalmology GA 800BP UT WOS:000293332500031 PM 21447684 ER PT J AU Olsen, TW Feng, X Wabner, K Csaky, K Pambuccian, S Cameron, JD AF Olsen, Timothy W. Feng, Xiao Wabner, Kathy Csaky, Karl Pambuccian, Stefan Cameron, J. Douglas TI Pharmacokinetics of Pars Plana Intravitreal Injections versus Microcannula Suprachoroidal Injections of Bevacizumab in a Porcine Model SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID MACULAR DEGENERATION; INTRAOCULAR INFLAMMATION; AVASTIN THERAPY; AGE; PERMEABILITY; RANIBIZUMAB; ALBUMIN; SCLERA; SPACE AB PURPOSE. To compare the pharmacokinetics and tissue response between intravitreal and microcannulation injections into the suprachoroidal space using bevacizumab. METHODS. Sixty-two pigs were studied. Either a pars plana intravitreal bevacizumab or a viscoelastic-enhanced microcannula suprachoroidal injection was performed with either 1.25 mg (group 1) or 3 mg (group 2). In group 1, six animals were euthanatized at 0.5, 7, 30, 60, 90, and 120 days after injection (n = 36). In group 2, six animals were euthanatized at 0.5, 7, 14, and 32 days (n = 24). Eyes were enucleated, dissected, and snap-frozen, or they were fixed for histology. Analysis of drug tissue levels was performed at two separate laboratories using masked specimens. RESULTS. Both laboratories were confirmatory. Intravitreal bevacizumab pharmacokinetics demonstrated a gradual decline in tissue levels over 30 to 60 days in both groups 1 and 2. In addition, suprachoroidal bevacizumab tissue levels declined rapidly and were not measurable at or beyond 7 days. Vitreitis and granulomatous vasculitis were noted in 7 of 30 intravitreal injection eyes. Immunohistology suggested a distinctive drug distribution. CONCLUSIONS. Direct intravitreal injection of bevacizumab has a more sustained pharmacologic profile than does a similar dose delivered to the suprachoroidal space. Intravitreal injections distributed more to the inner retina, whereas suprachoroidal delivery occurred primarily at the choroid, retinal pigment epithelium, and photoreceptor outer segments. Sustained release formulation of larger biological molecules should be considered to optimize suprachoroidal delivery. Inflammation from injections is granulomatous, seen only with intravitreal injections, and may result from either an altered immune response or a dose-related effect. (Invest Ophthalmol Vis Sci. 2011;52:4749-4756) DOI:10.1167/iovs.10-6291 C1 [Olsen, Timothy W.] Emory Univ, Dept Ophthalmol, Emory Eye Ctr, Atlanta, GA 30322 USA. [Olsen, Timothy W.; Feng, Xiao; Wabner, Kathy; Pambuccian, Stefan] Univ Minnesota, Dept Ophthalmol, Minneapolis, MN 55455 USA. [Csaky, Karl] NEI, Bethesda, MD 20892 USA. [Cameron, J. Douglas] Mayo Clin, Rochester, MN USA. RP Olsen, TW (reprint author), Emory Univ, Dept Ophthalmol, Emory Eye Ctr, 1365B Clifton Rd NE, Atlanta, GA 30322 USA. EM tolsen@emory.edu FU iScience Interventional Inc. (University of Minnesota); Research to Prevent Blindness; University of Minnesota FX Supported in part by an industry-sponsored grant from iScience Interventional Inc. (approved through the Sponsored Projects Administration at the University of Minnesota) and an unrestricted grant from Research to Prevent Blindness to the Departments of Ophthalmology at Emory University and at the University of Minnesota. NR 20 TC 35 Z9 35 U1 0 U2 7 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 JUN PY 2011 VL 52 IS 7 BP 4749 EP 4756 DI 10.1167/iovs.10-6291 PG 8 WC Ophthalmology SC Ophthalmology GA 800BP UT WOS:000293332500109 PM 21447680 ER PT J AU Lobanenkov, V Loukinov, D Pugacheva, E AF Lobanenkov, Victor Loukinov, Dmitry Pugacheva, Elena TI Conference Scene Environmental epigenomics and disease susceptibility SO EPIGENOMICS LA English DT Article AB The main objective of this conference was to provide solid evidence that environmental exposures during early development can affect faithful reproduction of individual parental epigenomes without changing DNA sequence in the offspring. No doubt, this important goal has been successfully achieved owing to the high quality of presented epidemiological and experimental studies and engaging discussions of many yet to be published results. Compelling data suggested a strong causal link between prenatal vulnerability of future parental epigenomes to damaging environmental factors aggravated by abnormal socio-cultural conditions (including, for instance, malnutrition and chronic stress) and the alarming risk of developing heritable complex medical conditions later in life, such as asthma, autism, cancer, cardiovascular disease, diabetes, obesity, schizophrenia and a whole range of rare neuromuscular pathologies. It was concluded that modern epigenetic research promises to markedly improve our ability to diagnose, prevent and treat these and other pathological conditions of humans. However, the complex heritability pattern of 'epigenetic syndromes' also introduces unique legal and ethical issues that were discussed at the end of this outstanding meeting. C1 [Lobanenkov, Victor; Loukinov, Dmitry; Pugacheva, Elena] NIAID, Mol Pathol Sect, Immunopathol Lab, Rockville, MD 20852 USA. RP Lobanenkov, V (reprint author), NIAID, Mol Pathol Sect, Immunopathol Lab, Twinbrook 1,Room 1417,MSC-8152,5640 Fishers Lane, Rockville, MD 20852 USA. EM vlobanenkov@niaid.nih.gov OI Lobanenkov, Victor/0000-0001-6665-3635 NR 0 TC 4 Z9 6 U1 3 U2 9 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1750-1911 J9 EPIGENOMICS-UK JI Epigenomics PD JUN PY 2011 VL 3 IS 3 BP 261 EP 266 DI 10.2217/EPI.11.25 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 798XV UT WOS:000293246400007 PM 22122336 ER PT J AU Strand, BH Cooper, R Hardy, R Kuh, D Guralnik, J AF Strand, Bjorn Heine Cooper, Rachel Hardy, Rebecca Kuh, Diana Guralnik, Jack TI Lifelong socioeconomic position and physical performance in midlife: results from the British 1946 birth cohort SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Physical performance; Ageing; Childhood; Lifetime socioeconomic position; Life course ID GRIP STRENGTH; OLD-AGE; SOCIAL INEQUALITIES; WHITEHALL-II; CHILDHOOD; HEALTH; CIRCUMSTANCES; DISABILITY; WOMEN; MEN AB Socioeconomic position (SEP) across life is found to be related to adult physical performance, but the underlying pathways are not well characterized. Using a British birth cohort (N = 2956), the associations of SEP from childhood into midlife with objective physical performance measures in midlife were examined, adjusting for possible confounders or mediators, including indicators of muscle development and central nervous system function. Childhood and adulthood SEP were positively related to standing balance and chair rise performance, but not to grip strength after basic adjustments. When both father's occupation and mother's education were included in the same model, having a mother with low education was associated with 0.6 standard deviations (SD) (95% confidence interval (CI: 0.3, 0.8)) poorer standing balance time compared with having a mother with the highest educational level, and having a father in the lowest occupational group was associated with a 0.3 SD (95% CI: 0.1, 0.6) lower chair rise score compared with having a father in the highest occupational group. These associations were maintained, albeit attenuated, after adjustment. In contrast, the associations of own education and adult occupation with physical performance were generally not maintained after adjustment. SEP across life impacts on midlife physical performance, and thereby the ageing process. C1 [Strand, Bjorn Heine; Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Strand, Bjorn Heine; Cooper, Rachel; Hardy, Rebecca; Kuh, Diana] MRC Unit Lifelong Hlth & Ageing, MRC Natl Survey Hlth & Dev, London WC1B 5JU, England. RP Strand, BH (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C309, Bethesda, MD 20892 USA. EM heine@fhi.no OI Strand, Bjorn/0000-0003-4385-8886; Cooper, Rachel/0000-0003-3370-5720 FU MRC Unit for Lifelong Health and Ageing in UK; National Institute on Aging, NIH in USA; Research Council of Norway FX The manuscript is funded by MRC Unit for Lifelong Health and Ageing in UK and supported in part by the Intramural Research Program, National Institute on Aging, NIH in USA, and the Research Council of Norway. The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. NR 29 TC 29 Z9 29 U1 3 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0393-2990 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD JUN PY 2011 VL 26 IS 6 BP 475 EP 483 DI 10.1007/s10654-011-9562-9 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 797XX UT WOS:000293164500007 PM 21416275 ER PT J AU Marcus, PM Bergstralh, EJ Kramer, BS Fontana, R AF Marcus, Pamela M. Bergstralh, Eric J. Kramer, Barnett S. Fontana, Robert TI The Mayo Lung Project lung cancer mortality findings are unlikely to be biased by a volunteer effect SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 [Marcus, Pamela M.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Bergstralh, Eric J.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Kramer, Barnett S.] NCI, Rockville, MD 20852 USA. RP Marcus, PM (reprint author), NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. EM marcusp@mail.nih.gov; bergstra@mayo.edu; kramerb@mail.nih.gov; robfontana@aol.com NR 4 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0393-2990 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD JUN PY 2011 VL 26 IS 6 BP 503 EP 504 DI 10.1007/s10654-011-9580-7 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 797XX UT WOS:000293164500010 PM 21503749 ER PT J AU Madan, RA Aragon-Ching, JB Gulley, JL Dahut, WL AF Madan, Ravi A. Aragon-Ching, Jeanny B. Gulley, James L. Dahut, William L. TI From clinical trials to clinical practice: therapeutic cancer vaccines for the treatment of prostate cancer SO EXPERT REVIEW OF VACCINES LA English DT Article DE castration-resistant; metastatic; prostate cancer; therapeutic cancer vaccine; treatment ID REGULATORY T-CELLS; IMMUNOLOGICAL SELF-TOLERANCE; ANDROGEN-DEPRIVATION THERAPY; ABIRATERONE ACETATE; COMBINATION THERAPY; DENDRITIC CELLS; SIPULEUCEL-T; METASTATIC MELANOMA; ANTITUMOR-ACTIVITY; IMMUNE-RESPONSES AB Therapeutic options for patients with metastatic castration-resistant prostate cancer are increasing, spurring an urgent need to better understand which treatments are best for individual patients. The recent approval of a first-in-class agent, sipuleucel-T, has intensified this need. This therapeutic cancer vaccine has demonstrated a survival advantage in two Phase Ill trials, but does not alter progression in the short term. Therefore, a new therapeutic approach for patients with metastatic castration-resistant prostate cancer is taking shape, based on broader understanding of available therapies. This new clinical approach seeks to maximize patient benefit from treatment, minimize associated toxicities, and may have far-reaching implications for other therapeutic cancer vaccines currently in clinical development. C1 [Madan, Ravi A.; Gulley, James L.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20912 USA. [Madan, Ravi A.; Aragon-Ching, Jeanny B.; Gulley, James L.; Dahut, William L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20912 USA. RP Gulley, JL (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20912 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016; OI Gulley, James/0000-0002-6569-2912; Aragon-Ching, Jeanny/0000-0002-6714-141X FU NIH, National Cancer Institute, Center for Cancer Research; Medivation FX The authors acknowledge the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research for their support of this study. Jeanny B Aragon-Ching has served on the Speakers' Bureau of Sanofi-Aventis, served on the Advisory Board for Centocor Orthobiotech and has served as an investigator on a research study sponsored by Medivation. 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 83 TC 12 Z9 12 U1 1 U2 2 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD JUN PY 2011 VL 10 IS 6 SI SI BP 743 EP 753 DI 10.1586/ERV.11.70 PG 11 WC Immunology SC Immunology GA 797HT UT WOS:000293115800012 PM 21692697 ER PT J AU Gulley, JL Madan, RA Schlom, J AF Gulley, J. L. Madan, R. A. Schlom, J. TI Impact of tumour volume on the potential efficacy of therapeutic vaccines SO CURRENT ONCOLOGY LA English DT Article DE Cancer vaccine; immunotherapy; overall survival; Prostvac; TroVax; Stimuvax ID REFRACTORY PROSTATE-CANCER; COLONY-STIMULATING FACTOR; BLP25 LIPOSOME VACCINE; RANDOMIZED PHASE-II; CELL LUNG-CANCER; SIPULEUCEL-T; METASTATIC CARCINOMA; SURVIVAL ANALYSIS; IMMUNOTHERAPY; TRIAL AB With the recent approval by the U.S. Food and Drug Administration of the first therapeutic vaccine for cancer, the long-awaited goal of harnessing a patient's immune system to attack cancer through this modality is finally realized. However, as researchers in the field of cancer immunotherapy continue to perform randomized definitive studies, much remains to be learned about potential surrogate endpoints and appropriate patient populations for therapeutic vaccines. The present review addresses available data from clinical trials of immunotherapeutic agents relevant to the selection of appropriate patient populations. We believe that the weight of evidence supports the use of immunotherapy earlier in the disease course and in patients with less aggressive disease, and that the relevant findings have important implications for the design of clinical trials with therapeutic vaccines. C1 [Gulley, J. L.; Madan, R. A.; Schlom, J.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,8B09 MSC 1750, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU National Cancer Institute, Center for Cancer Research, National Institutes of Health FX Grant support was provided by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. The authors thank Bonnie L. Casey for her editorial assistance in the preparation of this manuscript. NR 32 TC 34 Z9 36 U1 0 U2 2 PU MULTIMED INC PI TORONTO PA 66 MARTIN ST, TORONTO, ON L9T 2R2, CANADA SN 1198-0052 J9 CURR ONCOL JI Curr. Oncol. PD JUN PY 2011 VL 18 IS 3 BP E150 EP E157 PG 8 WC Oncology SC Oncology GA 793DG UT WOS:000292800000013 PM 21655153 ER PT J AU Blonder, J Issaq, HJ Veenstra, TD AF Blonder, Josip Issaq, Haleem J. Veenstra, Timothy D. TI Proteomic biomarker discovery: It's more than just mass spectrometry SO ELECTROPHORESIS LA English DT Review DE Biomarker; Discovery; LC; MS; Validation ID RENAL-CELL CARCINOMA; INTERSTITIAL CYSTITIS; VALIDATION; TISSUES AB The previous decade witnessed an enormous number of studies with the singular goal of identifying protein biomarkers for diseases such as cancer. A large majority of these studies have focused on comparative studies of serum or plasma obtained from disease-affected and control patients. In these studies, proteins identified in the samples using MS were compared with the hope that differences between samples would reveal useful biomarkers. Unfortunately, finding clinically relevant biomarkers has often been elusive and frustrating. As with most research efforts, both successes and failures, much has been learned about what strategies work and which do not. Part of the problem can be attributed to underestimating the effort required to discover novel biomarkers and depending too heavily on MS analysis of peripheral blood samples. Fortunately, the future for biomarker discovery still appears bright. MS technology continues to increase in sensitivity, throughput, and accuracy while novel types of samples and clever experimental designs coupled with innovative bioinformatics will make this vision of routine biomarker discovery a reality. To achieve ultimate success is going to require concomitant application of a number of different technologies, all providing the information necessary for discovering and validating clinically useful biomarkers. C1 [Blonder, Josip; Issaq, Haleem J.; Veenstra, Timothy D.] SAIC Frederick Inc, Lab Prote & Analyt Technol, Adv Technol Program, NCI, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), SAIC Frederick Inc, Lab Prote & Analyt Technol, Adv Technol Program, NCI, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. NR 17 TC 22 Z9 22 U1 2 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2011 VL 32 IS 13 SI SI BP 1541 EP 1548 DI 10.1002/elps.201000585 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 795JR UT WOS:000292971000002 PM 21557261 ER PT J AU Guzman, NA Phillips, TM AF Guzman, Norberto A. Phillips, Terry M. TI Immunoaffinity capillary electrophoresis: A new versatile tool for determining protein biomarkers in inflammatory processes SO ELECTROPHORESIS LA English DT Review DE Immunoaffinity capillary electrophoresis; Microscale metabolic studies; Organ-on-a-chip; Protein biomarkers; Single cell capture device ID TANDEM MASS-SPECTROMETRY; INDUCED FLUORESCENCE DETECTION; ACUTE MYOCARDIAL-INFARCTION; SOLID-PHASE EXTRACTION; ANALYTE PRECONCENTRATION; POLYREACTIVE ANTIBODIES; MULTIPLEX TECHNOLOGIES; MOLECULAR RECOGNITION; CONCENTRATION LIMITS; CLINICAL PROTEOMICS AB Many diseases caused by inflammatory processes can progress to a chronic state causing deterioration in the quality of life and a poor prognosis for long-term survival. To address inflammatory diseases effectively, early detection and novel therapeutics are required. However, this can be challenging, in part because of the lack of early predictive biomarkers and the limited availability of adequate technologies capable of the identification/characterization of key predictive biomarkers present in biological materials, especially those found at picomolar concentrations and below. This review highlights the need for state-of-the art methodologies, with high-sensitivity and high-throughput capabilities, for determination of multiple biomarkers. Although many new biomarkers have been discovered recently, existing technology has failed to successfully bring this advancement to the patient's bedside. We present an overview of the various advances available today to extend the discovery of predictive biomarkers of inflammatory diseases; in particular, we review the technology of immunoaffinity capillary electrophoresis (IACE), which combines the use of antibodies as highly selective capture agents with the high resolving power of capillary electrophoresis. This two-dimensional hybrid technology permits the quantification and characterization of several protein biomarkers simultaneously, including subtle structural changes such as variants, isoforms, peptide fragments, and post-translational modifications. Furthermore, the results are rapid, sensitive, can be performed at a relatively low cost, without the introduction of false positive or false negative data. The IACE instrumentation can have relevance to medical, pharmaceutical, environmental, military, cultural heritage (authenticity of art work), forensic science, industrial and research fields, and in particular as a point-of-care biomarker analyzer in translational medicine. C1 [Guzman, Norberto A.] Princeton Biochem Inc, Lab Bioanal Toxicoprote & Immunochem, Princeton, NJ 08543 USA. [Phillips, Terry M.] Natl Inst Biomed Imaging & Bioengn, Ultramicro Immunodiagnost Sect, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. RP Guzman, NA (reprint author), Princeton Biochem Inc, Lab Bioanal Toxicoprote & Immunochem, POB 7102, Princeton, NJ 08543 USA. EM guzman@affinityce.com NR 140 TC 30 Z9 32 U1 1 U2 36 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2011 VL 32 IS 13 SI SI BP 1565 EP 1578 DI 10.1002/elps.201000700 PG 14 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 795JR UT WOS:000292971000004 PM 21647923 ER PT J AU Su, Q Zhu, BP Lee, JH Bi, ZX Shung, K Zhou, QF Takeuchi, S Park, BH Jia, QX Wang, HY AF Su, Qing Zhu, Benpeng Lee, Joon Hwan Bi, Zhenxing Shung, Kirk Zhou, Qifa Takeuchi, Shinichi Park, Bae Ho Jia, Quanxi Wang, Haiyan TI Self-separated PZT thick films with bulk-like piezoelectric and electromechanical properties SO JOURNAL OF MATERIALS RESEARCH LA English DT Article ID ULTRASONIC TRANSDUCER; OPTIMIZATION; MEMBRANE AB Self-separated Pb(Zr(0.52)Ti(0.48))O(3) (PZT) films were processed by a hydrothermal deposition and a rapid thermal separation method, followed by a sol-gel filling and sintering process. The films possess excellent piezoelectric and electromechanical properties close to those of bulk material. The maximum remnant polarization is over 30 mu C/cm(2) and the electromechanical coupling factor (k(t)) reaches as high as 0.52. The unique microstructure characteristics of the PZT films, such as their highly dense structure, columnar grains, well-connected grain boundaries, and well-dispersed nanopores, could all contribute to the enhanced piezoelectric and electromechanical properties. C1 [Zhu, Benpeng; Shung, Kirk; Zhou, Qifa] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Zhu, Benpeng; Shung, Kirk; Zhou, Qifa] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Su, Qing; Lee, Joon Hwan; Wang, Haiyan] Texas A&M Univ, Mat Sci & Engn Program, College Stn, TX 77843 USA. [Bi, Zhenxing; Wang, Haiyan] Texas A&M Univ, Dept Elect & Comp Engn, College Stn, TX 77843 USA. [Takeuchi, Shinichi] Toin Univ Yokohama, Med Engn Course, Grad Sch Engn, Yokohama, Kanagawa 2258501, Japan. [Park, Bae Ho] Konkuk Univ, Div Quantum Phases & Devices, Dept Phys, Seoul 143701, South Korea. [Jia, Quanxi] Los Alamos Natl Lab, Ctr Integrated Nanotechnol, Los Alamos, NM 87545 USA. RP Zhou, QF (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu; qxjia@lanl.gov; wangh@ece.tamu.edu RI Park, Bae Ho/D-4840-2011; Jia, Q. X./C-5194-2008; Su, Qing/N-2518-2014; Wang, Haiyan/P-3550-2014; OI Wang, Haiyan/0000-0002-7397-1209; Su, Qing/0000-0003-2477-0002 FU National Science Foundation [NSF-1007969, NSF-0846504]; National Institutes of Health [P41-EB2182]; Ministry Of Education, Science and Technology [R31-2008-000-10057-0] FX The research effort at Texas A&M University was supported by National Science Foundation (NSF-1007969 and NSF-0846504). The effort at Los Alamos National Laboratory was performed, in part, at the Center for Integrated Nanotechnologies, a U.S. Department of Energy, Office of Basic Energy Sciences user facility. The effort at University of Southern California was partially supported by National Institutes of Health P41-EB2182. BHP was partially supported by the World Class University program through the National Research Foundation funded by Ministry Of Education, Science and Technology (Grant No. R31-2008-000-10057-0). NR 16 TC 2 Z9 2 U1 0 U2 10 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0884-2914 J9 J MATER RES JI J. Mater. Res. PD JUN PY 2011 VL 26 IS 11 BP 1431 EP 1435 DI 10.1557/jmr.2011.115 PG 5 WC Materials Science, Multidisciplinary SC Materials Science GA 793OJ UT WOS:000292832700010 PM 21852893 ER PT J AU Khurana, S Verma, N Yewdell, JW Hilbert, AK Castellino, F Lattanzi, M Del Giudice, G Rappuoli, R Golding, H AF Khurana, Surender Verma, Nitin Yewdell, Jonathan W. Hilbert, Anne Katrin Castellino, Flora Lattanzi, Maria Del Giudice, Giuseppe Rappuoli, Rino Golding, Hana TI MF59 Adjuvant Enhances Diversity and Affinity of Antibody-Mediated Immune Response to Pandemic Influenza Vaccines SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID SYNCYTIAL VIRUS-DISEASE; A H1N1 VACCINE; H5N1 VACCINE; MF59-ADJUVANTED VACCINE; CELL RESPONSE; OFF-RATE; IMMUNOGENICITY; MATURATION; SAFETY; NEUTRALIZATION AB Oil-in-water adjuvants have been shown to improve immune responses against pandemic influenza vaccines as well as reduce the effective vaccine dose, increasing the number of doses available to meet global vaccine demand. Here, we use genome fragment phage display libraries and surface plasmon resonance to elucidate the effects of MF59 on the quantity, diversity, specificity, and affinity maturation of human antibody responses to the swine-origin H1N1 vaccine in different age groups. In adults and children, MF59 selectively enhanced antibody responses to the hemagglutinin 1 (HA1) globular head relative to the more conserved HA2 domain in terms of increased antibody titers as well as a more diverse antibody epitope repertoire. Antibody affinity, as inferred by greatly diminished (>= 10-fold) off-rate constants, was significantly increased in toddlers and children who received the MF59-adjuvanted vaccine. Moreover, MF59 also improved antibody affinity maturation after each sequential vaccination against avian H5N1 in adults. For both pandemic influenza vaccines, there was a close correlation between serum antibody affinity and virus-neutralizing capacity. Thus, MF59 quantitatively and qualitatively enhances functional antibody responses to HA-based vaccines by improving both epitope breadth and binding affinity, demonstrating the added value of such adjuvants for influenza vaccines. C1 [Khurana, Surender; Verma, Nitin; Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Hilbert, Anne Katrin] Novartis Vaccines & Diagnost GmbH, D-35041 Marburg, Germany. [Castellino, Flora; Lattanzi, Maria; Del Giudice, Giuseppe; Rappuoli, Rino] Novartis Vaccines & Diagnost Res Ctr, I-53100 Siena, Italy. RP Golding, H (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM hana.golding@fda.hhs.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 FU Division of Microbiology and Infectious Diseases, NIH [IAA 224-10-1006] FX This study was partly supported by IAA 224-10-1006 from the Division of Microbiology and Infectious Diseases, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 80 Z9 85 U1 1 U2 11 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUN 1 PY 2011 VL 3 IS 85 AR 85ra48 DI 10.1126/scitranslmed.3002336 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 795NE UT WOS:000292980100004 PM 21632986 ER PT J AU Hudson, D Kovalchuk, I Koturbash, I Kolb, B Martin, OA Kovalchuk, O AF Hudson, Darryl Kovalchuk, Igor Koturbash, Igor Kolb, Bryan Martin, Olga A. Kovalchuk, Olga TI Induction and persistence of radiation-induced DNA damage is more pronounced in young animals than in old animals SO AGING-US LA English DT Article DE radiation; DNA damage and repair; aging ID DOUBLE-STRAND BREAKS; DOSE-RESPONSE RELATIONSHIP; HISTONE H2AX PHOSPHORYLATION; GEV/NUCLEON FE-56 IONS; IONIZING-RADIATION; GAMMA-RAYS; CHERNOBYL ACCIDENT; CHILDHOOD-CANCER; IN-VIVO; COMPUTED-TOMOGRAPHY AB Younger individuals are more prone to develop cancer upon ionizing radiation (IR) exposure. Radiation-induced tumors are associated with inefficient repair of IR-induced DNA damage and genome instability. Phosphorylation of histone H2AX (gamma-H2AX) is the initial event in repair of IR-induced DNA damage on the chromatin flanking the DNA strand breaks. This step is crucially important for the repair of DNA strand breaks and for the maintenance of genome stability. We studied the molecular underpinnings of the age-related IR effects using an animal model. By assaying for IR-induced gamma-H2AX foci we analyzed the induction and repair of the DNA strand breaks in spleen, thymus, liver, lung, kidney, cerebellum, hippocampus, frontal cortex and olfactory bulb of 7, 14, 24, 30 and 45 days old male and female mice as a function of age. We demonstrate that tissues of younger animals are much more susceptible to IR-induced DNA damage. Younger animals exhibited higher levels of gamma-H2AX formation which partially correlated with cellular proliferation and expression of DNA repair proteins. Induction and persistence of gamma-H2AX foci was the highest in lymphoid organs (thymus and spleen) of 7 and 14 day old mice. The lowest focal induction was seen in lung and brain of young animals. The mechanisms of cell and tissue-specificity of in vivo IR responses need to be further dissected. This study provides a roadmap for the future analyses of DNA damage and repair induction in young individuals. C1 [Hudson, Darryl; Kovalchuk, Igor; Koturbash, Igor; Kovalchuk, Olga] Univ Lethbridge, Dept Biol Sci, Lethbridge, AB T1K 3M4, Canada. [Kolb, Bryan] Univ Lethbridge, Dept Neurosci, Lethbridge, AB T1K 3M4, Canada. [Martin, Olga A.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kovalchuk, O (reprint author), Univ Lethbridge, Dept Biol Sci, Lethbridge, AB T1K 3M4, Canada. EM olga.kovalchuk@uleth.ca FU Canadian Institutes for Health Research; Natural Sciences and Engineering Research Council of Canada; National Cancer Institute, NIH FX Work was supported by the Canadian Institutes for Health Research and the Natural Sciences and Engineering Research Council of Canada Operating grants to Olga Kovalchuk and by the Intramural Research Program of the National Cancer Institute, NIH. We are thankful to Sam Stevenson, Rocio Rodriguez-Juarez, Kristy Kutanzi and Jonathan Loree for technical assistance, to Diane Harms for careful proofreading of this manuscript and to William Bonners for useful discussion and invaluable suggestions. NR 75 TC 20 Z9 20 U1 1 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD JUN PY 2011 VL 3 IS 6 BP 609 EP 620 PG 12 WC Cell Biology SC Cell Biology GA 789IB UT WOS:000292507800006 PM 21685513 ER PT J AU Zhang, ZW Albert, PS AF Zhang, Zhiwei Albert, Paul S. TI Binary Regression Analysis with Pooled Exposure Measurements: A Regression Calibration Approach SO BIOMETRICS LA English DT Article DE Bias correction; Logistic regression; Measurement error; Missing covariates; Pooling; Probit regression ID ERRORS-IN-VARIABLES; ROC CURVE ANALYSIS; POLYCHLORINATED-BIPHENYLS; LONGITUDINAL DATA; BIOMARKERS; BIOSPECIMENS; SUBJECT; MODELS; ASSESSMENTS; DESIGN AB It has become increasingly common in epidemiological studies to pool specimens across subjects to achieve accurate quantitation of biomarkers and certain environmental chemicals. In this article, we consider the problem of fitting a binary regression model when an important exposure is subject to pooling. We take a regression calibration approach and derive several methods, including plug-in methods that use a pooled measurement and other covariate information to predict the exposure level of an individual subject, and normality-based methods that make further adjustments by assuming normality of calibration errors. Within each class we propose two ways to perform the calibration (covariate augmentation and imputation). These methods are shown in simulation experiments to effectively reduce the bias associated with the naive method that simply substitutes a pooled measurement for all individual measurements in the pool. In particular, the normality-based imputation method performs reasonably well in a variety of settings, even under skewed distributions of calibration errors. The methods are illustrated using data from the Collaborative Perinatal Project. C1 [Zhang, Zhiwei; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Zhang, ZW (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. EM zhiwei.zhang@nih.gov; albertp@mail.nih.gov FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors thank Drs Enrique Schisterman and Mary Hediger for helpful discussions, Drs Matthew Longnecker, Zhen Chen, and Mark Klebanoff for providing the CPP data, and the associate editor and an anonymous referee for insightful comments that improved the article. NR 23 TC 11 Z9 11 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 JUN PY 2011 VL 67 IS 2 BP 636 EP 645 DI 10.1111/j.1541-0420.2010.01464.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 789GS UT WOS:000292504000032 PM 20662830 ER PT J AU Branco, MC Sigano, DM Schneider, JP AF Branco, Monica C. Sigano, Dina M. Schneider, Joel P. TI Materials from peptide assembly: towards the treatment of cancer and transmittable disease SO CURRENT OPINION IN CHEMICAL BIOLOGY LA English DT Review ID VIRUS-LIKE PARTICLES; CELL-DEATH; FUTURE PERSPECTIVES; BIOMATERIALS; DESIGN; NANOSTRUCTURES; THERAPEUTICS; INDUCTION; PROTEINS; DELIVERY AB As the prevalence of cancer and transmittable disease persists, the development of new and more advanced therapies remains a priority in medical research. An emerging platform for the treatment of these illnesses is the use of materials formed via peptide assembly where the bulk material itself acts as the therapeutic. Higher ordered peptide structures with defined chemistry are capable of cellular targeting, recognition, and internalization. Recent design efforts are being made to exploit the nanoscale definition of the materials formed by assembling peptides to target cancer and microbial cells and to function as vaccines. This review focuses on assembled peptide materials that actively participate in the biological processes important to cancer and transmittable diseases to exert an anticipated functional outcome. C1 [Branco, Monica C.; Sigano, Dina M.; Schneider, Joel P.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. RP Schneider, JP (reprint author), NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. EM Joel.Schneider@nih.gov RI Sigano, Dina/M-6144-2014; Schneider, Joel/N-2610-2014 OI Sigano, Dina/0000-0001-7489-9555; FU Intramural NIH HHS [ZIA BC011313-02, ZIA BC011314-02] NR 57 TC 30 Z9 31 U1 4 U2 49 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1367-5931 J9 CURR OPIN CHEM BIOL JI Curr. Opin. Chem. Biol. PD JUN PY 2011 VL 15 IS 3 BP 427 EP 434 DI 10.1016/j.cbpa.2011.03.021 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 788HB UT WOS:000292434900013 PM 21507707 ER PT J AU Mann, ZF Kelley, MW AF Mann, Zoe F. Kelley, Matthew W. TI Development of tonotopy in the auditory periphery SO HEARING RESEARCH LA English DT Review ID COCHLEAR HAIR-CELLS; ACTIVATED POTASSIUM CHANNELS; CALCIUM-BINDING PROTEINS; MESSENGER-RNA EXPRESSION; BASILAR-MEMBRANE MOTION; SPIRAL GANGLION NEURONS; TECTORIAL MEMBRANE; INNER-EAR; POSTNATAL-DEVELOPMENT; ACTIN-FILAMENTS AB Acoustic frequency analysis plays an essential role in sound perception, communication and behavior. The auditory systems of most vertebrates that perceive sounds in air are organized based on the separation of complex sounds into component frequencies. This process begins at the level of the auditory sensory epithelium where specific frequencies are distributed along the tonotopic axis of the mammalian cochlea or the avian/reptilian basilar papilla (BP). Mechanical and electrical mechanisms mediate this process, but the relative contribution of each mechanism differs between species. Developmentally, structural and physiological specializations related to the formation of a tonotopic axis form gradually over an extended period of time. While some aspects of tonotopy are evident at early stages of auditory development, mature frequency discrimination is typically not achieved until after the onset of hearing. Despite the importance of tonotopic organization, the factors that specify unique positional identities along the cochlea or basilar papilla are unknown. However, recent studies of developing systems, including the inner ear provide some clues regarding the signalling pathways that may be instructive for the formation of a tonotopic axis. Published by Elsevier B.V. C1 [Mann, Zoe F.; Kelley, Matthew W.] NIDCD, Lab Cochlear Dev, NIH, Bethesda, MD 20892 USA. RP Mann, ZF (reprint author), NIDCD, Lab Cochlear Dev, NIH, 35 Convent Dr,Room 2A-104, Bethesda, MD 20892 USA. EM mannz@nidcd.nih.gov NR 148 TC 29 Z9 29 U1 4 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD JUN PY 2011 VL 276 IS 1-2 SI SI BP 2 EP 15 DI 10.1016/j.heares.2011.01.011 PG 14 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 788IP UT WOS:000292438900002 PM 21276841 ER PT J AU Mirza, NM Klein, CJ Palmer, MG Mccarter, R He, JP Ebbeling, CB Ludwig, DS Yanovski, JA AF Mirza, Nazrat M. Klein, Catherine J. Palmer, Matilde G. Mccarter, Robert He, Jianping Ebbeling, Cara B. Ludwig, David S. Yanovski, Jack A. TI Effects of high and low glycemic load meals on energy intake, satiety and hunger in obese Hispanic-American youth SO INTERNATIONAL JOURNAL OF PEDIATRIC OBESITY LA English DT Article DE Obese; Hispanic youth; glycemic load; food intake; hunger; satiety; fullness ID IMPAIRED FASTING GLUCOSE; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; INDEX; US; ADOLESCENTS; PREVALENCE; CHILDREN; ADULTS; SECRETION AB Some short-term pediatric studies have suggested beneficial effects of low glycemic load (LGL) meals on feelings of hunger and on energy intake. However, the effects of LGL diets have not been systematically studied in obese Hispanic children, who stand to benefit from successful interventions. Objective. To examine the effects of LGL and high-GL (HGL) meals on appetitive responses and ad libitum energy intake of obese Hispanic youth. Methods. A total of 88 obese Hispanic youth aged 7-15 years were enrolled in a community-based obesity intervention program and randomly assigned to consume meals designed as either LGL (n = 45) or HGL (n = 43). After 12 weeks, participants were admitted for a 24-hour metabolic study. Following the morning test meal, subjects serially reported hunger, fullness, and satiety using a visual analog scale. Blood insulin and glucose were measured. After 5 hours, participants were fed another test meal and given a snack platter from which to eat ad libitum. All test food was weighed and the energy, macronutrients, and glycemic load (GL) of consumed foods were calculated. Results. The HGL group had significantly higher insulin (p = 0.0005) and glucose (p = 0.0001) responses to the breakfast meal compared with the LGL group. There were no significant between-group differences in energy consumed from the snack platter (1303 vs. 1368 kcal, p = 0.5), or in the subjective feelings of hunger (p = 0.3), fullness (p = 0.5) or satiety (p = 0.3) between the two groups. Conclusions. Our study provides no evidence that, for obese Hispanic youth, changing the GL of the diet affects short-term hunger, fullness, satiety, or energy intake. C1 [Mirza, Nazrat M.; Klein, Catherine J.; Palmer, Matilde G.; Mccarter, Robert; He, Jianping] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Ebbeling, Cara B.; Ludwig, David S.] Childrens Hosp, Boston, MA 02115 USA. [Mirza, Nazrat M.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dept Hlth & Human Serv, Unit Growth & Obes,Program Dev Endocrinol & Genet, Bethesda, MD USA. RP Mirza, NM (reprint author), Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. EM nmirza@cnmc.org RI Klein, Catherine/F-3940-2011; OI Yanovski, Jack/0000-0001-8542-1637 FU NIH [K23-RR022227]; National Center for Research Resources (NCRR, Bethesda, MD) [MO1-RR-020359]; Consumer Health Foundation; Jessie Ball DuPont Foundation; United Way of the National Capital Area; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Center on Minority Health and Health Disparities of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases [K24DK082730] FX This research was supported by NIH Grants K23-RR022227 (to N.M.M), MO1-RR-020359 awarded by the National Center for Research Resources (NCRR, Bethesda, MD) to support the General Clinical Research Center (GCRC) at Children's National Medical Center, and the following foundations and organizations: Consumer Health Foundation; The Jessie Ball DuPont Foundation; and United Way of the National Capital Area. Dr. Yanovski is a Commissioned Officer in the United States Public Health Service and is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center on Minority Health and Health Disparities of the National Institutes of Health. Dr Ludwig is supported in part by career award K24DK082730 from the National Institute of Diabetes and Digestive and Kidney Diseases. The National Institute of Diabetes and Digestive and Kidney Diseases had no role in the preparation, review, or approval of the manuscript. NR 28 TC 8 Z9 8 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1747-7166 J9 INT J PEDIATR OBES JI Int. J. Pediatr. Obes. PD JUN PY 2011 VL 6 IS 2-2 BP E523 EP E531 DI 10.3109/17477166.2010.544740 PG 9 WC Pediatrics SC Pediatrics GA 791YA UT WOS:000292704500064 PM 21309658 ER PT J AU Noss, PA AF Noss, Philip A. TI Gbaya-French Dictionary SO JOURNAL OF AFRICAN LANGUAGES AND LINGUISTICS LA English DT Book Review C1 [Noss, Philip A.] Nida Inst Bibl Scholarship, New York, NY 10023 USA. RP Noss, PA (reprint author), Nida Inst Bibl Scholarship, New York, NY 10023 USA. EM PNoss@americanbible.org NR 14 TC 0 Z9 0 U1 0 U2 0 PU MOUTON DE GRUYTER PI BERLIN PA GENTHINER STRASSE 13, 10785 BERLIN, GERMANY SN 0167-6164 J9 J AFR LANG LINGUIST JI J. Afr. Lang. Linguist. PD JUN PY 2011 VL 32 IS 1 BP 159 EP 163 PG 5 WC Linguistics; Language & Linguistics SC Linguistics GA 791SM UT WOS:000292685200009 ER PT J AU Scott, AP Laing, NG Mastaglia, F Needham, M Walter, MC Dalakas, MC Allcock, RJN AF Scott, Adrian P. Laing, Nigel G. Mastaglia, Frank Needham, Merrilee Walter, Maggie C. Dalakas, Marinos C. Allcock, Richard J. N. TI Recombination mapping of the susceptibility region for sporadic inclusion body myositis within the major histocompatibility complex SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Sporadic inclusion body myositis; Recombination mapping; Major histocompatibility complex ID HLA CLASS-I; INFLAMMATORY MYOPATHIES; MHC HAPLOTYPES; GENES; EXPRESSION; MOLECULE; BTNL2; ASSOCIATIONS; SARCOIDOSIS; INHIBITION AB Susceptibility to sporadic inclusion body myositis (sIBM) in Caucasians has been consistently associated with alleles of the major histocompatibility complex (MHC) 8.1 ancestral haplotype (AH) (defined by HLA-B*0801 and HLA-DRB1*0301). In this study recombination mapping was utilised to further refine the known 8.1AH susceptibility region near HLA-DRB1*0301. Caucasian sIBM patients carrying part of the 8.1AH were genotyped for a selection of 8.1AH-haplotypic polymorphisms. A common 8.1AH-specific susceptibility region was defined, spanning 172 kb and encompassing three genes - HLA-DRB3, HLA-DRA and BTNL2. It is thus likely that 8.1AH-derived susceptibility to sIBM originates from at least one of these genes. (C) 2011 Published by Elsevier B.V. C1 [Scott, Adrian P.; Allcock, Richard J. N.] Univ Western Australia, Sch Pathol & Lab Med, Perth, WA 6009, Australia. [Scott, Adrian P.; Laing, Nigel G.] Univ Western Australia, Med Res Ctr, Perth, WA 6009, Australia. [Scott, Adrian P.; Laing, Nigel G.] Univ Western Australia, Western Australian Inst Med Res, Perth, WA 6009, Australia. [Mastaglia, Frank; Needham, Merrilee] Univ Western Australia, Ctr Neuromuscular & Neurol Disorders, Perth, WA 6009, Australia. [Mastaglia, Frank; Needham, Merrilee] Univ Western Australia, Australian Neuromuscular Res Inst, Perth, WA 6009, Australia. [Walter, Maggie C.] Univ Munich, Dept Neurol, Friedrich Baur Inst, D-80539 Munich, Germany. [Dalakas, Marinos C.] NIH, Bethesda, MD 20892 USA. RP Scott, AP (reprint author), Univ Western Australia, Sch Pathol & Lab Med, M504,35 Stirling Highway, Crawley, WA 6009, Australia. EM ascott@cyllene.uwa.edu.au FU Australian National Health and Medical Research Council (NHMRC) [403941, 392500] FX We thank Dr A Corbett from Concord Hospital in Sydney and Dr T Day and Dr L Kiers from the Royal Melbourne Hospital in Melbourne who referred cases of sIBM for the study. This study was supported by the Australian National Health and Medical Research Council (NH&MRC) Fellowship Grants 403941 and 392500. NR 54 TC 12 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUN PY 2011 VL 235 IS 1-2 BP 77 EP 83 DI 10.1016/j.jneuroim.2011.02.011 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 791KV UT WOS:000292665000010 PM 21543121 ER PT J AU Taylor, TR Makambi, K Sween, J Roltsch, M Adams-Campbell, LL AF Taylor, Teletia R. Makambi, Kepher Sween, Jennifer Roltsch, Mark Adams-Campbell, Lucile L. TI The Effect of a Supervised Exercise Trial on Exercise Adherence Among African American Men: A Pilot Study SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE exercise; adherence; African Americans; men's health ID RANDOMIZED CONTROLLED-TRIALS; PHYSICAL-ACTIVITY; CANCER SURVIVORS; HEALTH AB Objective: The objective of this pilot study was to determine the effect of a supervised short-term exercise trial on exercise adherence in a sample of African American males. Methods: We observed exercise adherence rates among a group of African American men in response to an exercise intervention. Exercise adherence was determined by dividing the total number of actual sessions attended by the total number of possible sessions (12 sessions). A participant was classified as an adherer if they completed 9 out of 12 exercise sessions (75%). Results: Seventy-one percent of the study participants (12/17) completed at least 75% of the study sessions and therefore adhered to the study protocol. Among the adherers, 7 out of 12 (58%) had adherence rates of 100%. Five participants withdrew from the exercise group due to lack of time and lack of interest. Conclusion: Exercise adherence rates among African-American men in this study were favorable cluing this supervised exercise intervention and were comparable to adherence rates observed in other supervised exercise. interventions. Recommendations based on this pilot study are provided to reduce participant withdrawal and to inform future large-scale studies. C1 [Taylor, Teletia R.] Howard Univ, Ctr Canc, Washington, DC 20060 USA. [Makambi, Kepher; Sween, Jennifer; Adams-Campbell, Lucile L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Roltsch, Mark] NHLBI, NIH, Off Res Training & Career Dev, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Taylor, TR (reprint author), Howard Univ, Ctr Canc, 2041 Georgia Ave NW, Washington, DC 20060 USA. EM t_r_taylor@howard.edu FU Department of Defense [W81XWH-05-1-0366] FX This research was supported by Department of Defense grant W81XWH-05-1-0366, awarded to Dr Taylor. NR 16 TC 1 Z9 1 U1 0 U2 1 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD JUN PY 2011 VL 103 IS 6 BP 488 EP 491 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 792CB UT WOS:000292717000003 PM 21830631 ER PT J AU Kreps, GL Villagran, MM Zhao, XQ McHorney, CA Ledford, C Weathers, M Keefe, B AF Kreps, Gary L. Villagran, Melinda M. Zhao, Xiaoquan McHorney, Colleen A. Ledford, Christy Weathers, Melinda Keefe, Brian TI Development and validation of motivational messages to improve prescription medication adherence for patients with chronic health problems SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Medication adherence; Communication interventions; Motivational messages; Chronic diseases ID USER PERSPECTIVE; DRUG-THERAPY; NONADHERENCE; DISEASE; COMMUNICATION; PHARMACY; OUTCOMES; INTERVENTIONS; PREVENTION; PHYSICIANS AB Objective: Poor adherence with prescription medications is a serious problem in health care, especially true for patients with chronic diseases. Previous strategies to promote adherence have generally not resulted in long-term improvements. This research program is designed to improve on past intervention strategies by developing evidence-based and theoretically grounded communication interventions to promote increased adherence. Methods: Phase 1 of this research program used qualitative methods to examine the uncertainties and concerns that influence medication adherence, identify messages for addressing these concerns, and develop refined motivational messages for promoting medication adherence. Phase 2 of this research program experimentally assessed chronic disease patients' evaluations of the refined motivational messages. Results: Phase 1 qualitative research indicated that patient concerns about their need for the prescribed medication (commitment) was the primary adherence issue, followed by concerns about side effects and the safety of prescription medications, and concerns about the medication costs. These three key issues were translated into draft motivational messages which were evaluated, validated, and refined. Phase 2 experimental research showed that exposure to motivational messages increased consumers' intention to adhere with medication recommendations. Conclusion: Follow-up intervention research is warranted to test the use of these motivational messages to promote medication adherence. Practice implications: Pharmacies and pharmacists have the potential to perform a central role in providing consumers with the relevant information they need to make responsible decisions that lead to increased adherence with prescription medication recommendations. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Kreps, Gary L.; Villagran, Melinda M.; Zhao, Xiaoquan; Ledford, Christy; Weathers, Melinda] George Mason Univ, Dept Commun, Fairfax, VA 22030 USA. [Keefe, Brian] NCI, Bethesda, MD 20892 USA. RP Kreps, GL (reprint author), George Mason Univ, Dept Commun, 4400 Univ Dr,MS 3D6, Fairfax, VA 22030 USA. EM gkreps@gmu.edu OI Villagran, Melinda/0000-0002-1116-9683 FU Merck and Co., Inc. FX This research program was funded through a grant from Merck and Co., Inc. There was active collaboration between the Center for Health and Risk Communication at George Mason University and the US Outcomes Research Division at Merck and Co., Inc. on the design, data collection, analysis, interpretation of data, preparation of the research report, and the decision to submit this research for publication. NR 41 TC 13 Z9 14 U1 4 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD JUN PY 2011 VL 83 IS 3 SI SI BP 375 EP 381 DI 10.1016/j.pec.2011.04.029 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 790JV UT WOS:000292585200013 PM 21602010 ER PT J AU Seliger, B Dressler, SP Massa, C Recktenwald, CV Altenberend, F Bukur, J Marincola, FM Wang, E Stevanovic, S Lichtenfels, R AF Seliger, Barbara Dressler, Sven P. Massa, Chiara Recktenwald, Christian V. Altenberend, Florian Bukur, Juergen Marincola, Francesco M. Wang, Ena Stevanovic, Stefan Lichtenfels, Rudolf TI Identification and characterization of human leukocyte antigen class I ligands in renal cell carcinoma cells SO PROTEOMICS LA English DT Article DE Biomarkers; Cell biology; HLA antigens; Peptide ligands; Renal cell carcinoma; T-cell response ID MASS-SPECTROMETRY; CANDIDATE BIOMARKERS; TUMOR-ANTIGENS; KIDNEY CANCER; MHC LIGANDS; ENDOPLASMIC-RETICULUM; PRESENTED PEPTIDES; HLA; IMMUNOTHERAPY; GENERATION AB The presentation of tumor antigen-derived peptides by human leukocyte antigen (HLA) class I surface antigens on tumor cells is a key prerequisite to trigger effective T-cell responses in cancer patients. Multiple complementary strategies like cDNA and serological expression cloning, reverse immunology and different 'ome'-based methods have been employed to identify potential T-cell targets. This report focuses on a ligandomic profiling approach leading to the identification of 49 naturally processed HLA class I peptide ligands presented on the cell surface of renal cell carcinoma (RCC) cells. The source proteins of the defined HLA ligands are classified according to their biological function and subcellular localization. Previously established cDNA microarray data of paired tissue specimen of RCC and renal epithelium assessed the transcriptional regulation for 28 source proteins. In addition, HLA-A2-restricted, peptide-specific T cells directed against a HLA ligand derived from sulfiredoxin-1 (SRXN1) were generated, which were able to recognize and lyse ligand-presenting target cells in a HLA class I-restricted manner. Furthermore, tumor-infiltrating T cells isolated from a RCC patient were also able to kill SRXN1 expressing tumor cells. Thus, this experimental strategy might be suited to define potential candidate biomarkers and novel targets for T-cell-based immunotherapies of this disease. C1 [Seliger, Barbara; Dressler, Sven P.; Massa, Chiara; Recktenwald, Christian V.; Bukur, Juergen; Lichtenfels, Rudolf] Univ Halle Wittenberg, Inst Med Immunol, D-06112 Halle, Germany. [Altenberend, Florian; Stevanovic, Stefan] Univ Tubingen, Inst Cell Biol, Dept Immunol, Tubingen, Germany. [Marincola, Francesco M.; Wang, Ena] NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Seliger, B (reprint author), Univ Halle Wittenberg, Inst Med Immunol, Magdeburger Str 2, D-06112 Halle, Germany. EM barbara.seliger@medizin.uni-halle.de FU BMBF, Bonn [031U101H]; Mildred Scheel Foundation [10-1712-Se5]; Wilhelm Sander Foundation [2007.001.1] FX Part of the work in this report was supported by the BMBF, Bonn, project grant 031U101H (B.S.), the Mildred Scheel Foundation, grant 10-1712-Se5 (B.S.) and the Wilhelm Sander Foundation, grant 2007.001.1 (C.M.). In addition, the authors thank Professor. Dr. Paolo Fornara (Clinic for Urology and Kidney Transplantation Center, University Hospital Halle) for providing us with clinical samples following standard ethical procedures according to the institutional policy, Dr. Dagmar Riemann for asservating tumor and control tissue specimen along with TIL, Barbara Malenica for her excellent technical assistance and Sylvi Magdeburg and Nicole Ott for secretarial help in preparing the manuscript. NR 72 TC 11 Z9 11 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1615-9853 J9 PROTEOMICS JI Proteomics PD JUN PY 2011 VL 11 IS 12 BP 2528 EP 2541 DI 10.1002/pmic.201000486 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 793OH UT WOS:000292832500013 PM 21595034 ER PT J AU Falk-Krzesinski, HJ Contractor, N Fiore, SM Hall, KL Kane, C Keyton, J Klein, JT Spring, B Stokols, D Trochim, W AF Falk-Krzesinski, Holly J. Contractor, Noshir Fiore, Stephen M. Hall, Kara L. Kane, Cathleen Keyton, Joann Klein, Julie Thompson Spring, Bonnie Stokols, Daniel Trochim, William TI Mapping a research agenda for the science of team science SO RESEARCH EVALUATION LA English DT Article ID TRANSDISCIPLINARY RESEARCH; SYSTEMS THINKING; SOCIAL-SCIENCES; COLLABORATION; HEALTH; INTERDISCIPLINARITY; ENVIRONMENT; READINESS; BEHAVIOR; OUTCOMES AB An increase in cross-disciplinary, collaborative team science initiatives over the last few decades has spurred interest by multiple stakeholder groups in empirical research on scientific teams, giving rise to an emergent field referred to as the science of team science (SciTS). This study employed a collaborative team science concept-mapping evaluation methodology to develop a comprehensive research agenda for the SciTS field. Its integrative mixed-methods approach combined group process with statistical analysis to derive a conceptual framework that identifies research areas of team science and their relative importance to the emerging SciTS field. The findings from this concept-mapping project constitute a lever for moving SciTS forward at theoretical, empirical, and translational levels. C1 [Falk-Krzesinski, Holly J.] Northwestern Univ, Res Team Support & Dev, Clin & Translat Sci NUCATS Inst, Chicago, IL 60611 USA. [Contractor, Noshir] Northwestern Univ, Dept Ind Engn & Management Sci, Evanston, IL 60208 USA. [Fiore, Stephen M.] Univ Cent Florida, Dept Philosophy, Orlando, FL 32826 USA. [Fiore, Stephen M.] Univ Cent Florida, Inst Simulat, Orlando, FL 32826 USA. [Hall, Kara L.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Kane, Cathleen] Weill Cornell Med Coll, Clin & Translat Sci Ctr, Ithaca, NY 14853 USA. [Keyton, Joann] N Carolina State Univ, Dept Commun, Raleigh, NC 27695 USA. [Klein, Julie Thompson] Wayne State Univ, Dept English, Detroit, MI 48202 USA. [Klein, Julie Thompson] Wayne State Univ, Off Teaching & Learning, Detroit, MI 48202 USA. [Spring, Bonnie] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Stokols, Daniel] Univ Calif Irvine, Dept Planning Policy & Design, Irvine, CA 92697 USA. [Stokols, Daniel] Univ Calif Irvine, Dept Psychol & Social Behav, Irvine, CA 92697 USA. [Trochim, William] Cornell Univ, Dept Policy Anal & Management, Ithaca, NY 14853 USA. RP Falk-Krzesinski, HJ (reprint author), Northwestern Univ, Res Team Support & Dev, Clin & Translat Sci NUCATS Inst, Chicago, IL 60611 USA. EM h-falk@northwestern.edu RI Contractor, Noshir/B-7456-2009; Falk-Krzesinski, Holly/E-8870-2011; OI Falk-Krzesinski, Holly/0000-0001-8112-2445; Fiore, Stephen/0000-0003-3529-1322 FU NCATS NIH HHS [R13 TR000046]; NCRR NIH HHS [R13 RR032238, U24 RR029822, UL1 RR024996, UL1 RR025741] NR 88 TC 28 Z9 28 U1 3 U2 44 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0958-2029 EI 1471-5449 J9 RES EVALUAT JI Res. Evaluat. PD JUN PY 2011 VL 20 IS 2 BP 145 EP 158 DI 10.3152/095820211X12941371876580 PG 14 WC Information Science & Library Science SC Information Science & Library Science GA 789SS UT WOS:000292537200005 PM 23223093 ER PT J AU Kong, HDH AF Kong, Heidi H. TI Skin microbiome: genomics-based insights into the diversity and role of skin microbes SO TRENDS IN MOLECULAR MEDICINE LA English DT Review ID CUTANEOUS BACTERIAL; NASAL COLONIZATION; MOLECULAR ANALYSIS; WOUND MICROBIOTA; GUT MICROBIOME; BODY HABITATS; LEG ULCERS; INFECTIONS; DEFENSE; PROJECT AB Recent advances in DNA sequencing methodology have facilitated studies of human skin microbes that circumvent difficulties in isolating and characterizing fastidious microbes. Sequence-based approaches have identified a greater diversity of cutaneous bacteria than studies using traditional cultivation techniques. However, improved sequencing technologies and analytical methods are needed to study all skin microbes, including bacteria, archaea, fungi, viruses and mites, and how they interact with each other and their human hosts. This review discusses current skin microbiome research, with a primary focus on bacteria, and the challenges facing investigators striving to understand how skin microorganisms contribute to health and disease. C1 NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kong, HDH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Rm 12N238, Bethesda, MD 20892 USA. EM konghe@mail.nih.gov OI Kong, Heidi/0000-0003-4424-064X FU NCI; NIH [AR057504] FX The author thanks Julia A. Segre for her close collaboration; Elizabeth A Grice and Mark C. Udey for discussions; and Maria L. Turner for guidance and support. The author has no conflict of interest. This work was supported by the NCI Intramural Research Program and NIH Common Fund AR057504. NR 60 TC 64 Z9 65 U1 8 U2 79 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 JUN PY 2011 VL 17 IS 6 BP 320 EP 328 DI 10.1016/j.molmed.2011.01.013 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 791PB UT WOS:000292676000004 PM 21376666 ER PT J AU Larremore, DB Shew, WL Ott, E Restrepo, JG AF Larremore, Daniel B. Shew, Woodrow L. Ott, Edward Restrepo, Juan G. TI Effects of network topology, transmission delays, and refractoriness on the response of coupled excitable systems to a stochastic stimulus SO CHAOS LA English DT Article ID NEURONAL AVALANCHES; CORTICAL NETWORKS; NEURAL-NETWORKS; CRITICALITY; RANGE AB We study the effects of network topology on the response of networks of coupled discrete excitable systems to an external stochastic stimulus. We extend recent results that characterize the response in terms of spectral properties of the adjacency matrix by allowing distributions in the transmission delays and in the number of refractory states and by developing a nonperturbative approximation to the steady state network response. We confirm our theoretical results with numerical simulations. We find that the steady state response amplitude is inversely proportional to the duration of refractoriness, which reduces the maximum attainable dynamic range. We also find that transmission delays alter the time required to reach steady state. Importantly, neither delays nor refractoriness impact the general prediction that criticality and maximum dynamic range occur when the largest eigenvalue of the adjacency matrix is unity. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3600760] C1 [Larremore, Daniel B.; Restrepo, Juan G.] Univ Colorado, Dept Appl Math, Boulder, CO 80309 USA. [Shew, Woodrow L.] Natl Inst Mental Hlth, NIH, Bethesda, MD 20892 USA. [Ott, Edward] Univ Maryland, Inst Res Elect & Appl Phys, College Pk, MD 20742 USA. RP Larremore, DB (reprint author), Univ Colorado, Dept Appl Math, Boulder, CO 80309 USA. EM daniel.larremore@colorado.edu RI O, E/F-1630-2015; OI Shew, Woodrow/0000-0003-0679-1766 FU NSF [DMS-0602284, DMS-0908221]; National Institute of Mental Health; ONR [N00014-07-1-0734] FX We thank Dietmar Plenz for useful discussions. The work of Daniel B. Larremore was supported by the NSF's Mentoring Through Critical Transition Points (MCTP) Grant No. DMS-0602284. The work of Woodrow L. Shew was supported by the Intramural Research Program of the National Institute of Mental Health. The work of Edward Ott was supported by ONR Grant No. N00014-07-1-0734. The work of Juan G. Restrepo was supported by NSF Grant No. DMS-0908221. NR 32 TC 19 Z9 19 U1 0 U2 10 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 1054-1500 J9 CHAOS JI Chaos PD JUN PY 2011 VL 21 IS 2 AR 025117 DI 10.1063/1.3600760 PG 10 WC Mathematics, Applied; Physics, Mathematical SC Mathematics; Physics GA 786TH UT WOS:000292330300053 PM 21721795 ER PT J AU Rasetti, R Weinberger, DR AF Rasetti, Roberta Weinberger, Daniel R. TI Intermediate phenotypes in psychiatric disorders SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID CATECHOL-O-METHYLTRANSFERASE; ANTERIOR CINGULATE CORTEX; VERBAL FLUENCY TASK; GENETIC-VARIATION; HEALTHY-INDIVIDUALS; SCHIZOPHRENIA-RISK; CORTICAL FUNCTION; BRAIN ACTIVATION; VAL(158)MET GENOTYPE; NEUREGULIN 1 AB The small effect size of most individual risk factors for psychiatric disorders likely reflects biological heterogeneity and diagnostic imprecision, which has encouraged genetic studies of intermediate biological phenotypes that are closer to the molecular effects of risk genes than are the clinical symptoms. Neuroimaging-based intermediate phenotypes have emerged as particularly promising because they map risk associated gene effects onto physiological processes in brain that are altered in patients and in their healthy relatives. Recent evidence using this approach has elucidated discrete, dissociable biological mechanisms of risk genes at the level of neural circuitries, and their related cognitive functions. This approach may greatly contribute to our understanding of the genetics and pathophysiology of psychiatric disorders. C1 [Rasetti, Roberta; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. EM weinberd@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. We thank Venkata S. Mattay for helpful discussion. NR 72 TC 66 Z9 68 U1 0 U2 13 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD JUN PY 2011 VL 21 IS 3 BP 340 EP 348 DI 10.1016/j.gde.2011.02.003 PG 9 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 789AX UT WOS:000292486800015 PM 21376566 ER PT J AU Parker, SCJ Tullius, TD AF Parker, Stephen C. J. Tullius, Thomas D. TI DNA shape, genetic codes, and evolution SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID CODING REGION; HUMAN GENOME; NUCLEOSOME ORGANIZATION; FUNCTIONAL ELEMENTS; SEQUENCE; RECOGNITION; BINDING; YEAST; IDENTIFICATION; SUBSTITUTION AB Although the three-letter genetic code that maps nucleotide sequence to protein sequence is well known, there must exist other codes that are embedded in the human genome. Recent work points to sequence-dependent variation in DNA shape as one mechanism by which regulatory and other information could be encoded in DNA. Recent advances include the discovery of shape-dependent recognition of DNA that depends on minor groove width and electrostatics, the existence of overlapping codes in protein-coding regions of the genome, and evolutionary selection for compensatory changes in nucleotide composition that facilitate nucleosome occupancy. It is becoming clear that DNA shape is important to biological function, and therefore will be subject to evolutionary constraint. C1 [Tullius, Thomas D.] Boston Univ, Dept Chem, Boston, MA 02215 USA. [Tullius, Thomas D.] Boston Univ, Program Bioinformat, Boston, MA 02215 USA. [Parker, Stephen C. J.] NHGRI, Genome Informat Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Tullius, TD (reprint author), Boston Univ, Dept Chem, 590 Commonwealth Ave, Boston, MA 02215 USA. EM tullius@bu.edu RI Tullius, Thomas/A-9685-2008 OI Tullius, Thomas/0000-0003-4425-796X FU National Human Genome Research Institute of the National Institutes of Health [R01 HG003541] FX We thank Adam Woolfe for help in identifying papers reporting exonic enhancers, and Jason A Greenbaum for permission to use Figure 2. This work was supported by a grant to TDT from the National Human Genome Research Institute of the National Institutes of Health (R01 HG003541). SCJP was supported by the Intramural Research Program of the NHGRI, NIH. NR 54 TC 22 Z9 23 U1 2 U2 12 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD JUN PY 2011 VL 21 IS 3 BP 342 EP 347 DI 10.1016/j.sbi.2011.03.002 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 787HW UT WOS:000292368200007 PM 21439813 ER PT J AU Olson, WK Zhurkin, VB AF Olson, Wilma K. Zhurkin, Victor B. TI Working the kinks out of nucleosomal DNA SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; RING-CLOSURE PROBABILITIES; NUCLEIC-ACID STRUCTURES; CORE PARTICLE; B-DNA; ANGSTROM RESOLUTION; COMPUTATIONAL ANALYSIS; CRYSTAL-STRUCTURE; FORCE-FIELD; SEQUENCE AB Condensation of DNA in the nucleosome takes advantage of its double-helical architecture. The DNA deforms at sites where the base pairs face the histone octamer. The largest so-called kink-and-slide deformations occur in the vicinity of arginines that penetrate the minor groove. Nucleosome structures formed from the 601 positioning sequence differ subtly from those incorporating an AT-rich human a-satellite DNA. Restraints imposed by the histone arginines on the displacement of base pairs can modulate the sequence-dependent deformability of DNA and potentially contribute to the unique features of the different nucleosomes. Steric barriers mimicking constraints found in the nucleosome induce the simulated large-scale rearrangement of canonical B DNA to kink-and-slide states. The pathway to these states shows nonharmonic behavior consistent with bending profiles inferred from AFM measurements. C1 [Zhurkin, Victor B.] NCI, NIH, Bethesda, MD 20892 USA. [Olson, Wilma K.] Rutgers State Univ, Wright Rieman Labs, Piscataway, NJ 08854 USA. RP Zhurkin, VB (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM zhurkin@nih.gov FU U.S.P.H.S. [GM34809] FX We are grateful to Dr. Song Tan for sharing unpublished data and Drs. Andrew V. Colasanti and Difei Wang for assistance with data collections and figures. Support of this work through U.S.P.H.S. grant GM34809 is gratefully acknowledged. NR 51 TC 31 Z9 31 U1 5 U2 13 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD JUN PY 2011 VL 21 IS 3 BP 348 EP 357 DI 10.1016/j.sbi.2011.03.006 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 787HW UT WOS:000292368200008 PM 21482100 ER PT J AU Ren, XF Hurley, JH AF Ren, Xuefeng Hurley, James H. TI Structural basis for endosomal recruitment of ESCRT-I by ESCRT-0 in yeast SO EMBO JOURNAL LA English DT Article DE crystal structure; Cps1; protein structure; vacuole; yeast genetics ID MULTIVESICULAR BODY BIOGENESIS; UBIQUITINATED PROTEINS; MEMBRANE-PROTEINS; SORTING COMPLEX; LATE DOMAIN; MACHINERY; TSG101; VACUOLAR; RECOGNITION; REQUIRES AB The ESCRT-0 and ESCRT-I complexes coordinate the clustering of ubiquitinated cargo with intralumenal budding of the endosomal membrane, two essential steps in vacuolar/lysosomal protein sorting from yeast to humans. The 1.85-angstrom crystal structure of interacting regions of the yeast ESCRT-0 and ESCRT-I complexes reveals that PSDP motifs of the Vps27 ESCRT-0 subunit bind to a novel electropositive N-terminal site on the UEV domain of the ESCRT-I subunit Vps23 centred on Trp16. This novel site is completely different from the C-terminal part of the human UEV domain that binds to P(S/T)AP motifs of human ESCRT-0 and HIV-1 Gag. Disruption of the novel PSDP-binding site eliminates the interaction in vitro and blocks enrichment of Vps23 in endosome-related class E compartments in yeast cells. However, this site is non-essential for sorting of the ESCRT cargo Cps1. Taken together, these results show how a conserved motif/domain pair can evolve to use strikingly different binding modes in different organisms. The EMBO Journal (2011) 30, 2130-2139. doi:10.1038/emboj.2011.122; Published online 19 April 2011 C1 [Ren, Xuefeng; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDK, Mol Biol Lab, NIH, Bldg 50,Room 4517,50 S Dr, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; NIH, NIDDK; Office of the Director, NIH; Intramural AIDS Research Fellowship FX We thank Markus Babst and Will Prinz for strains, and Rob Piper for discussions. Data were collected at Southeast Regional Collaborative Access Team 22-ID 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. This research was supported by the Intramural Program of the NIH, NIDDK (JHH), the Intramural AIDS Targeted Anti-viral Program of the Office of the Director, NIH (JHH), and an Intramural AIDS Research Fellowship (XF). NR 43 TC 11 Z9 11 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 1 PY 2011 VL 30 IS 11 BP 2130 EP 2139 DI 10.1038/emboj.2011.122 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 788DD UT WOS:000292424700006 PM 21505419 ER PT J AU Loring, DW Lowenstein, DH Barbaro, NM Fureman, BE Odenkirchen, J Jacobs, MP Austin, JK Dlugos, DJ French, JA Gaillard, WD Hermann, BP Hesdorffer, DC Roper, SN Van Cott, AC Grinnon, S Stout, A AF Loring, David W. Lowenstein, Daniel H. Barbaro, Nicholas M. Fureman, Brandy E. Odenkirchen, Joanne Jacobs, Margaret P. Austin, Joan K. Dlugos, Dennis J. French, Jacqueline A. Gaillard, William Davis Hermann, Bruce P. Hesdorffer, Dale C. Roper, Steven N. Van Cott, Anne C. Grinnon, Stacie Stout, Alexandra TI Common data elements in epilepsy research: Development and implementation of the NINDS epilepsy CDE project SO EPILEPSIA LA English DT Article DE Research; Epilepsy; National Institute of Neurological Disorders and Stroke ID HARMONIZATION; STATEMENT; TRIALS AB The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start-up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward "harmonization'' of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS. C1 [Loring, David W.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Loring, David W.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Lowenstein, Daniel H.; Barbaro, Nicholas M.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Barbaro, Nicholas M.] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA USA. [Fureman, Brandy E.; Odenkirchen, Joanne; Jacobs, Margaret P.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Austin, Joan K.] Indiana Univ Purdue Univ, Sch Nursing, Indianapolis, IN 46202 USA. [Dlugos, Dennis J.] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA. [Dlugos, Dennis J.] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [French, Jacqueline A.] NYU, Dept Neurol, New York, NY 10016 USA. [Gaillard, William Davis] George Washington Univ, Childrens Natl Med Ctr, Ctr Neurosci, Washington, DC USA. [Hermann, Bruce P.] Univ Wisconsin, Dept Neurol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Hesdorffer, Dale C.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Roper, Steven N.] Univ Florida, Dept Neurosurg, Gainesville, FL USA. [Van Cott, Anne C.] VA Pittsburgh Healthcare Syst, Div Neurol, Pittsburgh, PA USA. [Van Cott, Anne C.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Grinnon, Stacie; Stout, Alexandra] KAI Res Inc, Rockville, MD USA. RP Loring, DW (reprint author), Emory Univ, Dept Neurol, 101 Woodruff Circle,Suite 6000, Atlanta, GA 30322 USA. EM dloring@emory.edu RI shengkun, yu/B-8440-2012; French, Jacqueline/G-6795-2013 OI French, Jacqueline/0000-0003-2242-8027 FU NINDS NIH HHS [N01NS72372] NR 8 TC 42 Z9 42 U1 2 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD JUN PY 2011 VL 52 IS 6 BP 1186 EP 1191 DI 10.1111/j.1528-1167.2011.03018.x PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 788QY UT WOS:000292460700022 PM 21426327 ER PT J AU Burbelo, PD Ching, KH Bren, KE Iadarola, MJ AF Burbelo, Peter D. Ching, Kathryn H. Bren, Kathleen E. Iadarola, Michael J. TI Searching for biomarkers: humoral response profiling with luciferase immunoprecipitation systems SO EXPERT REVIEW OF PROTEOMICS LA English DT Review DE antibody profiling; autoantibodies; autoimmune; biomarker; chronic disease; infectious disease; luciferase immunoprecipitation systems ID ANTI-CYTOKINE AUTOANTIBODIES; SEROLOGICAL DETECTION; 4-ANTIGEN MIXTURE; SJOGRENS-SYNDROME; INTERFERON-ALPHA; INFECTION; DISEASE; ASSAY; HUMAN-HERPESVIRUS-8; INTERLEUKIN-12 AB B-cell-mediated humoral responses are triggered in many human diseases, including autoimmune diseases, cancer, and neurologic and infectious diseases. However, the full exploitation of the information contained within a patient's antibody repertoire for diagnosis, monitoring and even disease prediction has been limited due to the poor diagnostic performance of many immunoassay formats. We have developed luciferase immunoprecipitation systems (LIPS) that harnesses light-emitting proteins to generate high-definition antibody profiles that are optimal for both diagnostics and biomarker discovery. Here, we describe the results and implications from a range of LIPS-antibody profiling studies performed in our laboratory. These include highly sensitive diagnostics for domestic and global pathogens, insights into infection-related diseases, discovery of new biomarkers for human diseases, subcategorization of symptoms and identification of pathogenic autoantibodies against self-proteins. These investigations highlight the types of humoral response profiles associated with different diseases, provide new information related to disease pathogenesis and offer a framework for incorporating LIPS antibody profiling into global health initiatives and disease monitoring. C1 [Burbelo, Peter D.; Ching, Kathryn H.; Bren, Kathleen E.; Iadarola, Michael 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 burbelop@nidcr.nih.gov FU National Institute of Dental and Craniofacial Research, NIH FX The laboratory that the authors work in is supported by the intramural research program of the National Institute of Dental and Craniofacial Research, NIH. Two of the authors (Peter D Burbelo and Michael J Iadarola) have patent applications submitted using luciferase immunoprecipitation system. 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 34 TC 15 Z9 16 U1 1 U2 7 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1478-9450 J9 EXPERT REV PROTEOMIC JI Expert Rev. Proteomics PD JUN PY 2011 VL 8 IS 3 BP 309 EP 316 DI 10.1586/EPR.11.23 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 788DC UT WOS:000292424600008 PM 21679112 ER PT J AU Eaton, WA AF Eaton, W. A. TI Single-molecule FRET and transition paths in protein folding SO FEBS JOURNAL LA English DT Meeting Abstract CT 36th FEBS Congress of the Biochemistry for Tomorrows Medicine CY JUN 25-30, 2011 CL Torino, ITALY SP Federat Soc Biochem & Mol Biol C1 [Eaton, W. A.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD USA. NR 2 TC 0 Z9 0 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2011 VL 278 SU 1 SI SI BP 13 EP 13 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786UJ UT WOS:000292333100039 ER PT J AU Rodriguez-Boulan, E Carvajal, JM Mattera, R Deborde, S Perez-Bay, A Schreiner, R Salvarezza, S Thuenauer, R Bonifacino, J Gravotta, D AF Rodriguez-Boulan, E. Carvajal, J. M. Mattera, R. Deborde, S. Perez-Bay, A. Schreiner, R. Salvarezza, S. Thuenauer, R. Bonifacino, J. Gravotta, D. TI Clathrin adaptors and polarized trafficking in epithelia SO FEBS JOURNAL LA English DT Meeting Abstract CT 36th FEBS Congress of the Biochemistry for Tomorrows Medicine CY JUN 25-30, 2011 CL Torino, ITALY SP Federat Soc Biochem & Mol Biol C1 [Rodriguez-Boulan, E.; Carvajal, J. M.; Deborde, S.; Perez-Bay, A.; Schreiner, R.; Salvarezza, S.; Thuenauer, R.; Gravotta, D.] Weill Cornell Med Coll, Margaret Dyson Vis Res Inst, New York, NY USA. [Mattera, R.; Bonifacino, J.] NIH, Cell Biol & Metab Program, 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 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2011 VL 278 SU 1 SI SI BP 19 EP 20 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786UJ UT WOS:000292333100059 ER PT J AU de Cabo, R Ellis, J Sinclair, D Minor, RK AF de Cabo, R. Ellis, J. Sinclair, D. Minor, R. K. TI Sirtuin activating compounds, resveratrol and SRT1720, extend healthspan and lifespan of C57BL6 male mice SO FEBS JOURNAL LA English DT Meeting Abstract CT 36th FEBS Congress of the Biochemistry for Tomorrows Medicine CY JUN 25-30, 2011 CL Torino, ITALY SP Federat Soc Biochem & Mol Biol C1 [de Cabo, R.; Minor, R. K.] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Ellis, J.] Sirtris Pharmaceut Inc, Cambridge, MA USA. [Sinclair, D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Sinclair, D.] Harvard Univ, Sch Med, Glenn Labs Aging Res, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2011 VL 278 SU 1 SI SI BP 44 EP 44 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786UJ UT WOS:000292333100124 ER PT J AU Barry, CE AF Barry, C. E. TI The biochemistry of activation of nitroimidazole antibiotics in Mycobacterium tuberculosis SO FEBS JOURNAL LA English DT Meeting Abstract CT 36th FEBS Congress of the Biochemistry for Tomorrows Medicine CY JUN 25-30, 2011 CL Torino, ITALY SP Federat Soc Biochem & Mol Biol C1 [Barry, C. E.] NIAID, NIH, Bethesda, MD 20892 USA. RI Barry, III, Clifton/H-3839-2012 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 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2011 VL 278 SU 1 SI SI BP 61 EP 61 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786UJ UT WOS:000292333100169 ER PT J AU Awada, R Gres, S Saulnier-Blache, JS Harry, J d'Hellencourt, CL AF Awada, R. Gres, S. Saulnier-Blache, J. S. Harry, J. d'Hellencourt, C. L. TI Anti-inflammatory effects of autotaxin on microglial cells SO FEBS JOURNAL LA English DT Meeting Abstract CT 36th FEBS Congress of the Biochemistry for Tomorrows Medicine CY JUN 25-30, 2011 CL Torino, ITALY SP Federat Soc Biochem & Mol Biol C1 [Awada, R.; d'Hellencourt, C. L.] Univ La Reunion, FST, CYROI, GEICO, St Denis, France. [Gres, S.; Saulnier-Blache, J. S.] I2MC, INSERM U1048, Toulouse, France. [Harry, J.] NIEHS, Neurotoxicol Grp, LTP, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2011 VL 278 SU 1 SI SI BP 266 EP 266 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786UJ UT WOS:000292333102068 ER PT J AU Caterino, M Chandler, RJ Venditti, CP Ruoppolo, M AF Caterino, M. Chandler, R. J. Venditti, C. P. Ruoppolo, M. TI Proteomic analysis in the characterization of pathogenic mechanisms of methylmalonic acidemia (MMA) SO FEBS JOURNAL LA English DT Meeting Abstract CT 36th FEBS Congress of the Biochemistry for Tomorrows Medicine CY JUN 25-30, 2011 CL Torino, ITALY SP Federat Soc Biochem & Mol Biol C1 [Caterino, M.] Fdn SDN Napoli, Ist Ric Diagnost & Nucl, Naples, Italy. [Caterino, M.; Ruoppolo, M.] Univ Naples Federico 2, Dipartimento Biochim & Biotecnol Med, Naples, Italy. [Chandler, R. J.; Venditti, C. P.] NHGRI, NIH, Bethesda, MD 20892 USA. [Ruoppolo, M.] Scarl, CEINGE Biotecnol Avanzate, Naples, Italy. 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 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2011 VL 278 SU 1 SI SI BP 407 EP 408 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786UJ UT WOS:000292333102491 ER PT J AU Green, JG Avenevoli, S Finkelman, M Gruber, MJ Kessler, RC Merikangas, KR Sampson, NA Zaslavsky, AM AF Green, Jennifer Greif Avenevoli, Shelli Finkelman, Matthew Gruber, Michael J. Kessler, Ronald C. Merikangas, Kathleen R. Sampson, Nancy A. Zaslavsky, Alan M. TI Validation of the diagnoses of panic disorder and phobic disorders in the US National Comorbidity Survey Replication Adolescent (NCS-A) supplement SO INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH LA English DT Article DE panic disorder; specific phobia; social phobia; agoraphobia; WHO Composite International Diagnostic Interview (CIDI); US National Comorbidity Survey Replication Adolescent (NCS-A) supplement ID SOCIAL PHOBIA; K-SADS; SUBTYPES; AGREEMENT; VERSION; CONCORDANCE; SCHEDULE; CHILDREN; DESIGN; CIDI AB Validity of the adolescent version of the World Health Organization Composite International Diagnostic Interview (CIDI) Version 3.0, a fully-structured research diagnostic interview designed to be used by trained lay interviewers, is assessed in comparison to independent clinical diagnoses based on the Schedule for Affective Disorders and Schizophrenia for School-age Children (K-SADS). This assessment is carried out in the clinical reappraisal sub-sample (n = 347) of the US National Comorbidity Survey Adolescent (NCS-A) supplement, a large (n = 10,148) community epidemiological survey of the prevalence and correlates of adolescent mental disorders in the United States. The diagnoses considered are panic disorder and phobic disorders (social phobia, specific phobia, agoraphobia). CIDI diagnoses are found to have good concordance with K-SADS diagnoses [area under the receiver operating characteristic curve (AUC) = 0.81-0.94], although the CIDI diagnoses are consistency somewhat higher than the K-SADS diagnoses. Data are also presented on criterion-level concordance in an effort to pinpoint CIDI question series that might be improved in future modifications of the instrument. Finally, data are presented on the factor structure of the fears associated with social phobia, the only disorder in this series where substantial controversy exists about disorder subtypes. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Gruber, Michael J.; Kessler, Ronald C.; Sampson, Nancy A.; Zaslavsky, Alan M.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Green, Jennifer Greif] Boston Univ, Sch Educ, Boston, MA 02215 USA. [Avenevoli, Shelli] NIMH, Div Dev Translat Res, Bethesda, MD 20892 USA. [Finkelman, Matthew] Tufts Univ, Sch Dent Med, Dept Gen Dent, Boston, MA 02111 USA. [Merikangas, Kathleen R.] NIMH, Genet Epidemiol Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM kessler@hcp.med.harvard.edu FU National Institute of Mental Health (NIMH) [U01-MH60220, R01-MH66627, R01-MH070884, R13-MH066849, R01-MH069864, R01-MH077883]; Robert Wood Johnson Foundation (RWJF) [044780]; John W. Alden Trust; NIDA [R01-DA016558]; Fogarty International Center of the National Institutes of Health (FIRCA) [R03-TW006481]; John D. and Catherine T. MacArthur Foundation; Pfizer Foundation; Pan American Health Organization; Astra Zeneca; BristolMyersSquibb; Eli Lilly and Company; GlaxoSmithKline; Ortho-McNeil; Pfizer; Sanofi-Aventis; Wyeth FX The National Comorbidity Survey Replication Adolescent Supplement (NCS-A) is supported by the National Institute of Mental Health (NIMH; U01-MH60220 and R01-MH66627) with supplemental support from the National Institute on Drug Abuse (NIDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; Grant 044780), and the John W. Alden Trust. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or US Government. A complete list of NCS-A publications can be found at http://www.hcp.med.harvard.edu/ncs. Send correspondence to ncs@hcp.med.harvard.edu. The NCS-A is carried out in conjunction with the World Health Organization World Mental Health (WMH) Survey Initiative. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centers for assistance with instrumentation, fieldwork, and consultation on data analysis. The WMH Data Coordination Centers have received support from NIMH (R01-MH070884, R13-MH066849, R01-MH069864, R01-MH077883), NIDA (R01-DA016558), the Fogarty International Center of the National Institutes of Health (FIRCA R03-TW006481), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, and the Pan American Health Organization. The WMH Data Coordination Centers have also received unrestricted educational grants from Astra Zeneca, BristolMyersSquibb, Eli Lilly and Company, GlaxoSmithKline, Ortho-McNeil, Pfizer, Sanofi-Aventis, and Wyeth. A complete list of WMH publications can be found at http://www.hcp.med.harvard.edu/wmh/. NR 24 TC 6 Z9 6 U1 3 U2 6 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 JUN PY 2011 VL 20 IS 2 BP 105 EP 115 DI 10.1002/mpr.336 PG 11 WC Psychiatry SC Psychiatry GA 788RW UT WOS:000292463100007 PM 21495110 ER PT J AU Kagulire, SC Opendi, P Stamper, PD Nakavuma, JL Mills, LA Makumbi, F Gray, RH Shott, JP Serwadda, D Reynolds, SJ AF Kagulire, S. C. Opendi, P. Stamper, P. D. Nakavuma, J. L. Mills, L. A. Makumbi, F. Gray, R. H. Shott, J. P. Serwadda, D. Reynolds, S. J. TI Field evaluation of five rapid diagnostic tests for screening of HIV-1 infections in rural Rakai, Uganda SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE HIV; rapid diagnostic testing; Uganda; point of care tests; resource-poor settings AB The performance characteristics of HIV rapid diagnostic tests (RDTs) vary by test and by population. We assessed five commercial RDTs in Uganda where all but one RDT (Determine; Abbott Laboratories, Germany) performed close to manufacturer's expectations. Determine had low specificity (85.2%, positive predictive value 67.3%) due to false-positive results with weak-positive bands. Properly trained staff, good quality control programmes and validation of RDTs with laboratories having confirmatory testing capacity may be warranted to assure accuracy in each setting. C1 [Shott, J. P.; Reynolds, S. J.] NIAID, NIH, Bethesda, MD 20892 USA. [Shott, J. P.] NCI, Clin Monitoring Res Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Makumbi, F.; Serwadda, D.] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Nakavuma, J. L.] Makerere Univ, Fac Vet Med, Kampala, Uganda. [Stamper, P. D.; Gray, R. H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Stamper, P. D.; Mills, L. A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Kagulire, S. C.; Opendi, P.; Mills, L. A.; Makumbi, F.] Rakai Hlth Sci Program, Kalisizo, Uganda. RP Reynolds, SJ (reprint author), US Embassy Kampala, POB 7007, Kampala, Uganda. EM sjr@jhmi.edu FU National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; Calypte Biomedical Corporation and Intercross Agencies, Kenya FX The authors gratefully acknowledge the Rakai Health Science Program field clinical staff; and the Rakai Cohort participants for providing samples used for the evaluation. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract HHSN261200800001E. This research was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. This research was supported in part by Calypte Biomedical Corporation and Intercross Agencies, Kenya. NR 8 TC 13 Z9 13 U1 0 U2 2 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0956-4624 J9 INT J STD AIDS JI Int. J. STD AIDS PD JUN PY 2011 VL 22 IS 6 BP 308 EP 309 DI 10.1258/ijsa.2009.009352 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 789DK UT WOS:000292493300004 PM 21680664 ER PT J AU Spacek, LA Lutwama, F Shihab, HM Summerton, J Kamya, MR Ronald, A Laeyendecker, O Quinn, TC Mayanja-Kizza, H AF Spacek, L. A. Lutwama, F. Shihab, H. M. Summerton, J. Kamya, M. R. Ronald, A. Laeyendecker, O. Quinn, T. C. Mayanja-Kizza, H. TI Diagnostic accuracy of ultrasensitive heat-denatured HIV-1 p24 antigen in non-B subtypes in Kampala, Uganda SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE HIV; viral load; ultrasensitive HIV-1 p24 assay; monitoring ART; resource-limited setting; Uganda; Africa; sensitivity; specificity; diagnosis; non-B subtypes ID RNA VIRAL LOAD; ANTIRETROVIRAL THERAPY; SIGNAL-AMPLIFICATION; BOOSTED ELISA; WEST-AFRICA; TYPE-1 RNA; ASSAY; INFECTION; PLASMA; ADULTS AB We evaluated the accuracy of heat-denatured, amplification-boosted ultrasensitive p24 assay (Up24) compared with reverse transcriptase polymerase chain reaction (RT-PCR). We tested 394 samples from Ugandans infected with HIV-1 non-B subtypes. We compared Up24 levels (HIV-1 p24 Core Profile enzyme-linked immunosorbent assay (ELISA), NEN Life Science Products) to RNA viral loads (Amplicor HIV-1 Monitor 1.5, Roche) by linear regression, and calculated sensitivity, specificity, positive and negative predictive values. Median viral load was 4.9 log10 copies/mL (interquartile range [IQR], 2.6-5.5); 114 samples (29%) were undetectable (<400 copies/mL). Sensitivity of the Up24 assay to detect viral load >= 400 copies/mL was 69%, specificity was 67%, and positive and negative predictive values were 84% and 47%, respectively. Sensitivity of Up24 was 90%, 80%, 68%, 62% and 45% to detect viral loads of >500,000, 250,000-500,000, 100,000-250,000, 50,000-100,000 and 400-50,000 copies/mL, respectively. In conclusion, when compared with RT-PCR for patients infected with non-B subtypes, the Up24 demonstrated limited sensitivity especially at low viral loads. Moreover, the Up24 was positive in 33% of samples deemed undetectable by RT-PCR, which may limit the use of the Up24 to detect viral suppression. C1 [Spacek, L. A.; Shihab, H. M.; Summerton, J.; Laeyendecker, O.; Quinn, T. C.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Kamya, M. R.; Ronald, A.] Makerere Univ, Coll Hlth Sci, Sch Med, Kampala, Uganda. [Ronald, A.] Univ Manitoba, Winnipeg, MB, Canada. [Laeyendecker, O.; Quinn, T. C.] NIAID, Immunoregulat Lab, Div Intramural Res, Bethesda, MD 20892 USA. RP Spacek, LA (reprint author), Johns Hopkins Sch Med, 1830 E Monument St, Baltimore, MD 21287 USA. EM lspacek@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Mayanja-Kizza, Harriet/0000-0002-9297-6208; Ronald, Allan/0000-0002-5746-3490; Laeyendecker, Oliver/0000-0002-6429-4760 FU Academic Alliance for AIDS Care and Prevention in Africa; Infectious Diseases Institute; Bill and Melinda Gates Foundation; Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Institutes of Health [K-23 AI060384] FX Financial support for this project was provided by the Academic Alliance for AIDS Care and Prevention in Africa; the Infectious Diseases Institute; the Bill and Melinda Gates Foundation; the Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases; and from the National Institutes of Health, K-23 AI060384 research training award. NR 33 TC 2 Z9 2 U1 0 U2 1 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0956-4624 J9 INT J STD AIDS JI Int. J. STD AIDS PD JUN PY 2011 VL 22 IS 6 BP 310 EP 314 DI 10.1258/ijsa.2009.009363 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 789DK UT WOS:000292493300005 PM 21680665 ER PT J AU Neal, JD Tobian, AAR Laeyendecker, O Ngo, TD Redd, AD Reynolds, SJ Morrow, RA Manucci, JL Serwadda, D Gray, RH Quinn, TC AF Neal, J. D. Tobian, A. A. R. Laeyendecker, O. Ngo, T. D. Redd, A. D. Reynolds, S. J. Morrow, R. Ashley Manucci, J. L. Serwadda, D. Gray, R. H. Quinn, T. C. TI Performance of the Euroline Western blot assay in the detection of herpes simplex virus type 2 antibody in Uganda, China and the USA SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE herpes simplex virus type 2 (HSV-2); genital herpes; serologic diagnostic assays; enzyme-linked immunosorbent assays (ELISAs); Western blot; diagnosis; antibody; Euro line ID LINKED-IMMUNOSORBENT-ASSAY; COMMERCIAL SEX WORKERS; ENZYME IMMUNOASSAYS; YUNNAN PROVINCE; INFECTION; MEN; RAKAI; HSV-2 AB Herpes simplex virus type 2 (HSV-2) infection is one of the most common sexually transmitted infections (STIs) worldwide. While glycoprotein G-2 enzyme-linked immunosorbent assays are commonly used for the serological detection of HSV-2 antibodies, they have low specificity in developing countries. The Euro line Western blot (WB) is a commercially available assay that is easy to perform; however, little is known about its performance characteristics. This study evaluated Euro line WB for the detection of HSV-2 antibodies compared with University of Washington Western blot in three geographically different regions: Baltimore, MD, USA; Rakai, Uganda; and Kunming, China. Among the 135 American men attending a STI clinic in Baltimore, MD, 72% (n = 97) were HSV-2-positive by Euro line WB, showing a sensitivity of 97.8% and a specificity of 81.8%. Among the 273 commercial sex workers in Kunming, 62.3% were HSV-2-positive by Euro line WB (sensitivity 96.9%, specificity 89.1%). Among the 437 Ugandans in Rakai, 67.3% were HSV-2-positive by Euro line WB (sensitivity 98.7%, specificity 65.4%). The Euro line WB has a consistently high sensitivity, but specificity varied significantly among the different locations. C1 [Neal, J. D.; Laeyendecker, O.; Reynolds, S. J.; Manucci, J. L.; Quinn, T. C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Tobian, A. A. R.; Ngo, T. D.; Redd, A. D.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Laeyendecker, O.; Reynolds, S. J.; Quinn, T. C.] NIAID, NIH, Bethesda, MD 20892 USA. [Morrow, R. Ashley] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Serwadda, D.] Makerere Univ, Inst Publ Hlth, Kampala, Uganda. [Gray, R. H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth Sci, Baltimore, MD USA. RP Quinn, TC (reprint author), John Rangos Sr Bldg,Room 530,855 N Wolfe St, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); NIAID, National Institute on Drug Abuse, National Institute of Mental Health; Office of AIDS Research of the NIH, Department of Health and Human Services [U01-AI-068613]; MAID [P01AI030731-19] FX This study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). Additional support was received from the HIV Prevention Trials Network sponsored by the NIAID, National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research of the NIH, Department of Health and Human Services (U01-AI-068613). The UWWB testing was supported by MAID (P01AI030731-19). We wish to thank Charlotte Gaydos, Nancy E Maldeis and Shenghan Lai for supplying samples. NR 19 TC 2 Z9 2 U1 0 U2 0 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0956-4624 J9 INT J STD AIDS JI Int. J. STD AIDS PD JUN PY 2011 VL 22 IS 6 BP 342 EP 344 DI 10.1258/ijsa.2009.009327 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 789DK UT WOS:000292493300012 PM 21680672 ER PT J AU Freeman, AF Avila, EM Shaw, PA Davis, J Hsu, AP Welch, P Matta, JR Hadigan, C Pettigrew, RI Holland, SM Gharib, AM AF Freeman, Alexandra F. Avila, Elizabeth Mannino Shaw, Pamela A. Davis, Joie Hsu, Amy P. Welch, Pamela Matta, Jatin R. Hadigan, Colleen Pettigrew, Roderic I. Holland, Steven M. Gharib, Ahmed M. TI Coronary Artery Abnormalities in Hyper-IgE Syndrome SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Hyper-IgE syndrome; STAT3; coronary artery aneurysm; atherosclerosis; Job's syndrome; tortuosity ID MAGNETIC-RESONANCE ANGIOGRAPHY; KAWASAKI-DISEASE; MATRIX METALLOPROTEINASES; COMPUTED-TOMOGRAPHY; STAT3 ACTIVATION; MOYAMOYA-DISEASE; MARFANS-SYNDROME; ANEURYSMS; MMP-9; EXPRESSION AB Objective Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency caused by autosomal dominant STAT3 mutations resulting in recurrent infections and connective tissue abnormalities. Coronary artery abnormalities have been reported infrequently. We aimed to determine the frequency and characteristics of coronary artery abnormalities. Design STAT3-mutated HIES patients (n = 38), ranging in age from 8 to 57 years, underwent coronary artery imaging by computed tomography or magnetic resonance imaging. Images were evaluated for tortuosity, dilation, and aneurysm. Charts were reviewed for cardiac risk factors. To allow blinded image interpretation, an age- and gender-matched non-HIES group was also evaluated (n = 33). Results Coronary artery tortuosity or dilation occurred in 70% of HIES patients, with aneurysms present in 37%, incidences much higher than in the literature and in our non-HIES group, in which 21% had tortuosity or dilation and 3% had aneurysms. Hypertension was more common in the HIES group than in the general population and was associated with vessel abnormalities. Atherosclerosis was uncommon and mild. Conclusions Coronary artery aneurysms and tortuosity are common in HIES, despite a paucity of atherosclerosis, suggesting that STAT3 plays an integral role in human vascular remodeling and atherosclerosis. C1 [Freeman, Alexandra F.; Davis, Joie; Hsu, Amy P.; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Avila, Elizabeth Mannino] Duke Univ, Sch Med, Clin Res Training Program, NIH,Pfizer, Durham, NC USA. [Shaw, Pamela A.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Welch, Pamela] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Matta, Jatin R.; Pettigrew, Roderic I.; Gharib, Ahmed M.] NIDDK, NIH, Bethesda, MD USA. [Hadigan, Colleen] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Freeman, AF (reprint author), NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH Bldg 10,Room 11N234,10 Ctr Dr, Bethesda, MD 20892 USA. EM freemaal@mail.nih.gov RI Gharib, Ahmed/O-2629-2016 OI Gharib, Ahmed/0000-0002-2476-481X FU NIAID; NIDDK; NIH, Bethesda, MD; Clinical Research Training Program; NIH; Pfizer FX This research was supported by the Intramural Research Programs of the NIAID, NIDDK, and NIH, Bethesda, MD 20892. The views expressed in this article are those of the authors and do not reflect the official policy of the US government.; Elizabeth Mannino Avila was supported by the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer (via a grant to the Foundation for NIH from Pfizer). NR 47 TC 31 Z9 32 U1 1 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JUN PY 2011 VL 31 IS 3 BP 338 EP 345 DI 10.1007/s10875-011-9515-9 PG 8 WC Immunology SC Immunology GA 789YQ UT WOS:000292556000006 PM 21494893 ER PT J AU Ellison, CA Lissitsyn, YV Packiasamy, JA Leonard, WJ Gartner, JG AF Ellison, Cynthia A. Lissitsyn, Yuriy V. Packiasamy, Juliet A. Leonard, Warren J. Gartner, John G. TI Role of Thymic Stromal Lymphopoietin (TSLP) in Palifermin-Mediated Immune Modulation and Protection from Acute Murine Graft-Versus-Host Disease SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Graft-versus-host disease; keratinocyte growth factor; palifermin; thymic stromal lymphopoietin ID KERATINOCYTE GROWTH-FACTOR; BONE-MARROW-TRANSPLANTATION; EPITHELIAL-CELL GROWTH; NECROSIS-FACTOR-ALPHA; REGULATORY T-CELLS; AIRWAY INFLAMMATION; NITRIC-OXIDE; FACTOR KGF; IN-VIVO; MICE AB Using the C57BL/6 ->(C57BL/6 x DBA/2)F(1)-hybrid model of acute graft-versus-host disease (GVHD), we previously showed that treating the donor mice with palifermin provides protection from morbidity and a shift from Th1 to Th2 cytokine production. To determine whether thymic stromal lymphopoietin (TSLP) is involved in palifermin-mediated immune modulation, we used donors from the following groups: (1) untreated wild-type donors, (2) palifermin-treated wild-type donors, (3) untreated TSLPR(-/-) donors, and (4) palifermin-treated TSLPR(-/-) donors. Survival in the recipients was 0%, 100%, 31%, and 0%, for groups 1-4, respectively, indicating that TSLP responsiveness is required for palifermin-mediated protection from GVHD. We also found that the increases in Th2 cytokine levels that are induced by palifermin treatment are obviated in TSLPR(-/-) donors, and that protection from GVHD (group 2) is associated with a higher percentage of CD4(+)CD25(+)Foxp3(+) cells in the graft. Collectively, our findings show that when palifermin and TSLP act in concert, the predominant effect is protection in this model. C1 [Ellison, Cynthia A.; Lissitsyn, Yuriy V.; Packiasamy, Juliet A.; Gartner, John G.] Univ Manitoba, Dept Pathol, Fac Med, Brodie Ctr 401, Winnipeg, MB R3E 3P5, Canada. [Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Ellison, CA (reprint author), Univ Manitoba, Dept Pathol, Fac Med, Brodie Ctr 401, 727 McDermot Ave, Winnipeg, MB R3E 3P5, Canada. EM ellisonc@ms.umanitoba.ca FU Canadian Institute of Health Research [MOP 67065] FX We are grateful to Mr. Monroe Chan for sharing his expertise and assisting with the flow cytometry analyses. This project is supported by an operating grant to JGG, CAE and K.T. HayGlass from the Canadian Institute of Health Research (MOP 67065). NR 51 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JUN PY 2011 VL 31 IS 3 BP 406 EP 413 DI 10.1007/s10875-010-9491-5 PG 8 WC Immunology SC Immunology GA 789YQ UT WOS:000292556000012 PM 21161346 ER PT J AU Chatterjee, R Bhattacharya, P Gavrilova, O Glass, K Moitra, J Myakishev, M Pack, S Jou, W Feigenbaum, L Eckhaus, M Vinson, C AF Chatterjee, Raghunath Bhattacharya, Paramita Gavrilova, Oksana Glass, Kimberly Moitra, Jaideep Myakishev, Max Pack, Stephanie Jou, William Feigenbaum, Lionel Eckhaus, Michael Vinson, Charles TI Suppression of the C/EBP family of transcription factors in adipose tissue causes lipodystrophy SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article ID ACTIVATED-RECEPTOR-GAMMA; CONGENITAL GENERALIZED LIPODYSTROPHY; BINDING-PROTEIN-ALPHA; HOMOZYGOUS NONSENSE MUTATION; HIV-ASSOCIATED LIPODYSTROPHY; SEVERE INSULIN-RESISTANCE; GENE-EXPRESSION; PPAR-GAMMA; ADIPOCYTE DIFFERENTIATION; METABOLIC SYNDROME AB Adipose-specific inactivation of both AP-1 and CCAAT-enhancer-binding protein (C/EBP) families of B-ZIP transcription factors in transgenic mice causes severe lipoatrophy. To evaluate whether inactivation of only C/EBP members was critical for lipoatrophy, A-C/EBP, a dominant-negative protein that specifically inhibits the DNA binding of the C/EBP members, was expressed in adipose tissue. For the first 2 weeks after birth, aP2-A-C/EBP mice had no white adipose tissue (WAT), drastically reduced brown adipose tissue (BAT), and exhibited marked hepatic steatosis, hyperinsulinemia, and hyperlipidemia. However, WAT appeared during the third week, coinciding with significantly improved metabolic functioning. In adults, BAT remained reduced, causing cold intolerance. At 30 weeks, the aP2-A-C/EBP mice had only 35% reduced WAT, with clear morphological signs of lipodystrophy in subcutaneous fat. Circulating leptin and adiponectin levels were less than the wild-type levels, and these mice exhibited impaired triglyceride clearance. Insulin resistance, glucose intolerance, and reduced free fatty acid release in response to beta 3-adrenergic agonist suggest improper functioning of the residual WAT. Gene expression analysis of inguinal WAT identified reduced mRNA levels of several enzymes involved in fatty acid synthesis and glucose metabolism that are known C/EBP alpha transcriptional targets. There were increased levels for genes involved in inflammation and muscle differentiation. However, when dermal fibroblasts from aP2-A-C/EBP mice were differentiated into adipocytes in tissue culture, muscle markers were elevated more than the inflammatory markers. These results demonstrate that the C/EBP family is essential for adipose tissue development during the early postnatal period, the regulation of glucose and lipid homeostasis in adults, and the suppression of the muscle lineage. C1 [Chatterjee, Raghunath; Bhattacharya, Paramita; Moitra, Jaideep; Myakishev, Max; Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Gavrilova, Oksana; Pack, Stephanie; Jou, William] NIDDK, Mouse Metab Lab, Bethesda, MD 20892 USA. [Glass, Kimberly] Univ Maryland, Dept Phys, College Pk, MD 20783 USA. [Feigenbaum, Lionel] NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. [Eckhaus, Michael] NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 3128, Bethesda, MD 20892 USA. EM vinsonc@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH); NIDDK, NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), and NIDDK, NIH. 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 76 TC 13 Z9 14 U1 0 U2 4 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD JUN PY 2011 VL 46 IS 3 BP 175 EP 192 DI 10.1530/JME-10-0172 PG 18 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 789LB UT WOS:000292515900006 PM 21321096 ER PT J AU Zhu, XG Kim, DW Goodson, ML Privalsky, ML Cheng, SY AF Zhu, Xu-guang Kim, Dong Wook Goodson, Michael L. Privalsky, Martin L. Cheng, Sheue-Yann TI NCoR1 regulates thyroid hormone receptor isoform-dependent adipogenesis SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article ID TRANSCRIPTIONAL ACTIVITY; INTERACTING DOMAINS; LIGAND-BINDING; BETA-RECEPTOR; CO-REPRESSOR; ALPHA-GENE; RESISTANCE; COREPRESSOR; MICE; MUTATION AB We previously showed that two thyroid hormone receptor (TR) isoforms - TR alpha 1 and TR beta 1 - differentially regulate thyroid hormone (triiodothyroxine, T(3))-stimulated adipogenesis in vivo. This study aims to understand the role of the nuclear receptor corepressor, NCoR1, in TR isoform-dependent adipogenesis. We found that T(3)-stimulated adipogenesis of 3T3-L1 cells was accompanied by progressive loss of NCoR1 protein levels. In 3T3-L1 cells stably expressing a mutated TR alpha 1, PV (L1-alpha 1PV cells), the T(3)-stimulated adipogenesis was more strongly inhibited than that in 3T3-L1 cells stably expressing an identical mutation in TR beta 1 (L1-beta 1PV cells). The stronger inhibition of adipogenesis in L1-alpha 1PV cells was associated with a higher NCoR1 protein level. These results indicate that the degree of loss of NCoR1 correlates with the extent of adipogenesis. siRNA knockdown of NCoR1 promoted adipogenesis of control 3T3-L1 cells and reversed the inhibited adipogenesis of L1-alpha 1PV and L1-beta 1PV cells, indicating that NCoR1 plays an essential role in TR isoform-dependent adipogenesis. An ubiquitin ligase, mSiah2, that targets NCoR1 for proteasome degradation was upregulated on day 1 before the onset of progressive loss of NCoR1. NCoR1 was found to associate with mSiah2 and with TR, TR alpha 1PV, or TR beta 1PV, but a stronger interaction of NCoR1 with TR alpha 1PV than with TR beta 1PV was detected. Furthermore, TR alpha 1PV-NCoR1 complex was more avidly recruited than TR beta 1PV-NCoR1 to the promoter of the C/ebp alpha gene, leading to more inhibition in its expression. These results indicate that differential interaction of NCoR1 with TR isoforms accounted for the TR isoform-dependent regulation of adipogenesis and that aberrant interaction of NCoR1 with TR could underlie the pathogenesis of lipid disorders in hypothyroidism. C1 [Zhu, Xu-guang; Kim, Dong Wook; Cheng, Sheue-Yann] NCI, Mol Biol Lab, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Goodson, Michael L.; Privalsky, Martin L.] Univ Calif Davis, Coll Biol Sci, Dept Microbiol, Davis, CA 95616 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, NIH, Ctr Canc Res, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov OI Goodson, Michael/0000-0002-3464-490X FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 24 TC 8 Z9 9 U1 0 U2 0 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD JUN PY 2011 VL 46 IS 3 BP 233 EP 244 DI 10.1530/JME-10-0163 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 789LB UT WOS:000292515900011 PM 21389087 ER PT J AU Turtzo, LC Budde, M Gold, E Lewis, B Janes, L Watson, W Frank, J AF Turtzo, L. Christy Budde, Matthew Gold, Eric Lewis, Bobbi Janes, Lindsay Watson, William Frank, Joseph TI THE EVOLUTION OF TRAUMATIC BRAIN INJURY IN A RAT MODEL: IMPLICATIONS FOR MRI CELL TRACKING SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 29th Annual National Neurotrauma Symposium CY JUL 10-13, 2011 CL Hollywood Beach, FL C1 [Budde, Matthew; Lewis, Bobbi; Frank, Joseph] NIH, Bethesda, MD 20892 USA. [Turtzo, L. Christy; Gold, Eric; Janes, Lindsay; Watson, William] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN PY 2011 VL 28 IS 6 BP A60 EP A61 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 788PT UT WOS:000292457600196 ER PT J AU Villapol, S Yaszemski, A Sanchez-Lemus, E Saavedra, JM Symes, A AF Villapol, Sonia Yaszemski, Alexandra Sanchez-Lemus, Enrique Saavedra, Juan M. Symes, Aviva TI THE ANGIOTENSIN RECEPTOR BLOCKER, CANDESARTAN, IMPROVES RECOVERY AFTER TRAUMATIC BRAIN INJURY IN MICE SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 29th Annual National Neurotrauma Symposium CY JUL 10-13, 2011 CL Hollywood Beach, FL C1 [Villapol, Sonia; Yaszemski, Alexandra; Symes, Aviva] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Villapol, Sonia; Yaszemski, Alexandra; Symes, Aviva] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. [Sanchez-Lemus, Enrique; Saavedra, Juan M.] NIMH, Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN PY 2011 VL 28 IS 6 BP A74 EP A74 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 788PT UT WOS:000292457600237 ER PT J AU Rabinovich, JE Kitron, UD Obed, Y Yoshioka, M Gottdenker, N Chaves, LF AF Eduardo Rabinovich, Jorge Kitron, Uriel Dan Obed, Yamila Yoshioka, Miho Gottdenker, Nicole Fernando Chaves, Luis TI Ecological patterns of blood-feeding by kissing-bugs (Hemiptera: Reduviidae: Triatominae) SO MEMORIAS DO INSTITUTO OSWALDO CRUZ LA English DT Article DE foraging; null models; diet analysis; multivariate statistics; Chagas disease; niche breadth ID PANSTRONGYLUS-MEGISTUS HEMIPTERA; LABORATORY CONDITIONS HEMIPTERA; RHODNIUS-PALLESCENS HEMIPTERA; RUBROFASCIATA DE-GEER; NORTH-WEST ARGENTINA; NULL MODEL ANALYSIS; CHAGAS-DISEASE; TRYPANOSOMA-CRUZI; DEFECATION PATTERNS; NUTRITIONAL-STATUS AB Host use by vectors is important in understanding the transmission of zoonotic diseases, which can affect humans, wildlife and domestic animals. Here, a synthesis of host exploitation patterns by kissing-bugs, vectors of Chagas disease, is presented. For this synthesis, an extensive literature review restricted to feeding sources analysed by precipitin tests was conducted. Modern tools from community ecology and multivariate statistics were used to determine patterns of segregation in host use. Rather than innate preferences for host species, host use by kissing-bugs is influenced by the habitats they colonise. One of the major limitations of studies on kissing-bug foraging has been the exclusive focus on the dominant vector species. We propose that expanding foraging studies to consider the community of vectors will substantially increase the understanding of Chagas disease transmission ecology. Our results indicate that host accessibility is a major factor that shapes the blood-foraging patterns of kissing-bugs. Therefore, from an applied perspective, measures that are directed at disrupting the contact between humans and kissing-bugs, such as housing improvement, are among the most desirable strategies for Chagas disease control. C1 [Eduardo Rabinovich, Jorge; Obed, Yamila] Natl Univ La Plata, Ctr Estudios Parasitol & Vectores, RA-1900 Buenos Aires, DF, Argentina. [Kitron, Uriel Dan; Yoshioka, Miho; Fernando Chaves, Luis] Emory Univ, Atlanta, GA 30322 USA. [Kitron, Uriel Dan] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Gottdenker, Nicole] Univ Georgia, Coll Vet Med, Dept Pathol, Athens, GA 30602 USA. [Fernando Chaves, Luis] Univ Nacl, Escuela Med Vet, Programa Invest Enfermedades Trop, Heredia, Costa Rica. [Fernando Chaves, Luis] Cent Univ Venezuela, Fac Ciencias, Inst Ecol & Zool Trop, Lab Biol Teor, Caracas, Venezuela. RP Rabinovich, JE (reprint author), Natl Univ La Plata, Ctr Estudios Parasitol & Vectores, Calle 2 584, RA-1900 Buenos Aires, DF, Argentina. EM jorge.rabinovich@gmail.com RI Chaves, Luis Fernando/F-3448-2010 OI Chaves, Luis Fernando/0000-0002-5301-2764 NR 200 TC 29 Z9 31 U1 2 U2 27 PU FUNDACO OSWALDO CRUZ PI RIO DE JANEIRO, RJ PA AV BRASIL 4365, 21045-900 RIO DE JANEIRO, RJ, BRAZIL SN 0074-0276 EI 1678-8060 J9 MEM I OSWALDO CRUZ JI Mem. Inst. Oswaldo Cruz PD JUN PY 2011 VL 106 IS 4 BP 479 EP 494 PG 16 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 787UN UT WOS:000292402300016 PM 21739038 ER PT J AU Arking, DE Junttila, MJ Goyette, P Huertas-Vazquez, A Eijgelsheim, M Blom, MT Newton-Cheh, C Reinier, K Teodorescu, C Uy-Evanado, A Carter-Monroe, N Kaikkonen, KS Kortelainen, ML Boucher, G Lagace, C Moes, A Zhao, XQ Kolodgie, F Rivadeneira, F Hofman, A Witteman, JCM Uitterlinden, AG Marsman, RF Pazoki, R Bardai, A Koster, RW Dehghan, A Hwang, SJ Bhatnagar, P Post, W Hilton, G Prineas, RJ Li, M Kottgen, A Ehret, G Boerwinkle, E Coresh, J Kao, WHL Psaty, BM Tomaselli, GF Sotoodehnia, N Siscovick, DS Burke, GL Marban, E Spooner, PM Cupples, LA Jui, J Gunson, K Kesaniemi, YA Wilde, AAM Tardif, JC O'Donnell, CJ Bezzina, CR Virmani, R Stricker, BHC Tan, HL Albert, CM Chakravarti, A Rioux, JD Huikuri, HV Chugh, SS AF Arking, Dan E. Junttila, M. Juhani Goyette, Philippe Huertas-Vazquez, Adriana Eijgelsheim, Mark Blom, Marieke T. Newton-Cheh, Christopher Reinier, Kyndaron Teodorescu, Carmen Uy-Evanado, Audrey Carter-Monroe, Naima Kaikkonen, Kari S. Kortelainen, Marja-Leena Boucher, Gabrielle Lagace, Caroline Moes, Anna Zhao, XiaoQing Kolodgie, Frank Rivadeneira, Fernando Hofman, Albert Witteman, Jacqueline C. M. Uitterlinden, Andre G. Marsman, Roos F. Pazoki, Raha Bardai, Abdennasser Koster, Rudolph W. Dehghan, Abbas Hwang, Shih-Jen Bhatnagar, Pallav Post, Wendy Hilton, Gina Prineas, Ronald J. Li, Man Koettgen, Anna Ehret, Georg Boerwinkle, Eric Coresh, Josef Kao, W. H. Linda Psaty, Bruce M. Tomaselli, Gordon F. Sotoodehnia, Nona Siscovick, David S. Burke, Greg L. Marban, Eduardo Spooner, Peter M. Cupples, L. Adrienne Jui, Jonathan Gunson, Karen Kesaniemi, Y. Antero Wilde, Arthur A. M. Tardif, Jean-Claude O'Donnell, Christopher J. Bezzina, Connie R. Virmani, Renu Stricker, Bruno H. Ch. Tan, Hanno L. Albert, Christine M. Chakravarti, Aravinda Rioux, John D. Huikuri, Heikki V. Chugh, Sumeet S. TI Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals SO PLOS GENETICS LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; QT INTERVAL DURATION; RESTING HEART-RATE; COMMON VARIANTS; VENTRICULAR-FIBRILLATION; RISK-FACTOR; POPULATION; FAMILY; EPIDEMIOLOGY; BROMODOMAIN AB Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8610 210). The risk allele, while ancestral, has a frequency of similar to 1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006). C1 [Arking, Dan E.; Moes, Anna; Bhatnagar, Pallav; Hilton, Gina; Ehret, Georg; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21218 USA. [Junttila, M. Juhani; Kaikkonen, Kari S.; Kortelainen, Marja-Leena; Kesaniemi, Y. Antero; Huikuri, Heikki V.] Univ Oulu, Dept Internal Med, Inst Clin Med, SF-90220 Oulu, Finland. [Junttila, M. Juhani] Univ Miami, Miller Sch Med, Div Cardiol, Miami, FL 33136 USA. [Goyette, Philippe; Boucher, Gabrielle; Lagace, Caroline; Tardif, Jean-Claude; Rioux, John D.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Goyette, Philippe; Boucher, Gabrielle; Lagace, Caroline; Tardif, Jean-Claude; Rioux, John D.] Univ Montreal, Montreal, PQ, Canada. [Huertas-Vazquez, Adriana; Reinier, Kyndaron; Teodorescu, Carmen; Uy-Evanado, Audrey; Marban, Eduardo; Chugh, Sumeet S.] Cedars Sinai Med Ctr, Inst Heart, Los Angeles, CA 90048 USA. [Eijgelsheim, Mark; Rivadeneira, Fernando; Hofman, Albert; Witteman, Jacqueline C. M.; Uitterlinden, Andre G.; Dehghan, Abbas; Stricker, Bruno H. Ch.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Blom, Marieke T.; Marsman, Roos F.; Pazoki, Raha; Bardai, Abdennasser; Koster, Rudolph W.; Wilde, Arthur A. M.; Bezzina, Connie R.; Tan, Hanno L.] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, Dept Clin & Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Newton-Cheh, Christopher; Hwang, Shih-Jen; Cupples, L. Adrienne; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. [Carter-Monroe, Naima; Zhao, XiaoQing; Kolodgie, Frank; Virmani, Renu] CVPath Inst, Gaithersburg, MD USA. [Rivadeneira, Fernando; Uitterlinden, Andre G.; Stricker, Bruno H. Ch.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Rivadeneira, Fernando; Hofman, Albert; Witteman, Jacqueline C. M.; Uitterlinden, Andre G.; Stricker, Bruno H. Ch.] NGI, NCHA, Rotterdam, Netherlands. [Post, Wendy; Tomaselli, Gordon F.; Spooner, Peter M.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Prineas, Ronald J.; Burke, Greg L.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Li, Man; Koettgen, Anna; Coresh, Josef; Kao, W. H. Linda] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Ehret, Georg] Univ Hosp Geneva, Dept Med, Geneva, Switzerland. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Coresh, Josef] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Sotoodehnia, Nona] Univ Washington, Dept Med, Div Cardiol, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Jui, Jonathan] Oregon Hlth & Sci Univ, Dept Emergency Med, Portland, OR 97201 USA. [Gunson, Karen] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Kesaniemi, Y. Antero] Univ Oulu, Bioctr Oulu, Oulu, Finland. [O'Donnell, Christopher J.] NHLBI, Bethesda, MD 20892 USA. [Stricker, Bruno H. Ch.] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Stricker, Bruno H. Ch.] Inspectorate Hlth Care, The Hague, Netherlands. [Albert, Christine M.] Harvard Univ, Brigham & Womens Hosp, Sch Med,Cardiovasc Div, Ctr Arrhythmia Prevent,Div Prevent Med,Dept Med, Boston, MA 02115 USA. RP Arking, DE (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21218 USA. EM arking@jhmi.edu; Sumeet.Chugh@cshs.org RI EHRET, Georg/A-9532-2009; Kottgen, Anna/D-2920-2012; Bhatnagar, Pallav/A-1280-2013; Rioux, John/A-9599-2015; Rivadeneira, Fernando/O-5385-2015; OI EHRET, Georg/0000-0002-5730-0675; Rioux, John/0000-0001-7560-8326; Rivadeneira, Fernando/0000-0001-9435-9441; Pazoki, Raha/0000-0002-5142-2348; Cupples, L. Adrienne/0000-0003-0273-7965; Dehghan, Abbas/0000-0001-6403-016X FU Netherlands Heart Foundation [2001D019, 2003T302, 2007B202]; Leducq Foundation [05-CVD]; Interuniversity Cardiology Institute of the Netherlands [27]; NHLBI [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, N01-HC-80007, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, HL068070, HL-26490, HL-34595, HL-34594, HL-35464, HL-46959, HL-080467]; NHGRI [U01HG004402]; NIH [HHSN268200625226C]; Netherlands Organization for Scientific Research [Mozaiek 017.003.084, ZonMW Vici 918.86.616]; Dutch Medicines Evaluation Board MEB/CBG; Boston University School of Medicine [N01-HC-25195]; Affymetrix [N02-HL-6-4278]; Boston University School of Medicine; Boston Medical Center; Finnish academy of Science, Helsinki, Finland; Sigrid Juselius Foundation, Helsinki, Finland; Foundation Leducq, Paris, France; Montreal Heart Institute Foundation; NCI [CA-34944, CA 40360, CA55075, CA-87969, CA 97193]; Burroughs Wellcome Fund; NHLIB [R01 HL105170-01, R01 HL088416, R01 HL088416-03S1]; Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture, and Science; Ministry for Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Netherlands Organization of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; National Center for Research Resources (NCRR) [1UL1RR025005] FX AGNES is supported by the Netherlands Heart Foundation (2001D019, 2003T302, 2007B202), the Leducq Foundation (05-CVD), and the Interuniversity Cardiology Institute of the Netherlands (project 27). ARIC is supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018 through N01-HC-55022, R01HL087641, R01HL59367, and R01HL086694; NHGRI contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by UL1RR025005. ARREST is supported by the Netherlands Organization for Scientific Research (Mozaiek 017.003.084, ZonMW Vici 918.86.616) and the Dutch Medicines Evaluation Board MEB/CBG. CHS is supported by N01-HC-80007, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295 from the NHLBI, with additional contribution from the NINDS. FHS is supported by the NHLBI and Boston University School of Medicine (N01-HC-25195), its contract with Affymetrix for genotyping services (N02-HL-6-4278), based on analyses by FHS investigators participating in the SHARe project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment at Boston University School of Medicine and Boston Medical Center. FinGesture is supported the Finnish academy of Science, Helsinki, Finland; Sigrid Juselius Foundation, Helsinki, Finland; and Foundation Leducq, Paris, France. The genetic work was supported by the Montreal Heart Institute Foundation (www.fondationicm.org). The Harvard Cohorts are supported by HL068070, HL-26490, HL-34595, HL-34594, HL-35464, HL-46959, HL-080467 (from the NHLBI); by CA-34944, CA 40360, CA55075, CA-87969, CA 97193 (from the NCI); and by a Career Award for Medical Scientists from the Burroughs Wellcome Fund. Oregon-SUDS is funded by the NHLIB (R01 HL105170-01, R01 HL088416, R01 HL088416-03S1 NIH NHLBI). The RS is funded by Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare, and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The GWA study was funded by the Netherlands Organization of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. This publication was made possible by Grant Number 1UL1RR025005 from the National Center for Research Resources (NCRR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 57 Z9 59 U1 0 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 JUN PY 2011 VL 7 IS 6 AR e1002158 DI 10.1371/journal.pgen.1002158 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 787OJ UT WOS:000292386300066 PM 21738491 ER PT J AU Braun, R Buetow, K AF Braun, Rosemary Buetow, Kenneth TI Pathways of Distinction Analysis: A New Technique for Multi-SNP Analysis of GWAS Data SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MULTIFACTOR DIMENSIONALITY REDUCTION; GONADOTROPIN-RELEASING-HORMONE; SET ENRICHMENT ANALYSIS; GENE-GENE INTERACTIONS; FALSE DISCOVERY RATE; HEPATOCELLULAR-CARCINOMA; BREAST-CANCER; HUMAN-DISEASES; GNRH ANTAGONISTS AB Genome-wide association studies (GWAS) have become increasingly common due to advances in technology and have permitted the identification of differences in single nucleotide polymorphism (SNP) alleles that are associated with diseases. However, while typical GWAS analysis techniques treat markers individually, complex diseases (cancers, diabetes, and Alzheimers, amongst others) are unlikely to have a single causative gene. Thus, there is a pressing need for multi-SNP analysis methods that can reveal system-level differences in cases and controls. Here, we present a novel multi-SNP GWAS analysis method called Pathways of Distinction Analysis (PoDA). The method uses GWAS data and known pathway-gene and gene-SNP associations to identify pathways that permit, ideally, the distinction of cases from controls. The technique is based upon the hypothesis that if a pathway is related to disease risk, cases will appear more similar to other cases than to controls (or vice versa) for the SNPs associated with that pathway. By systematically applying the method to all pathways of potential interest, we can identify those for which the hypothesis holds true, i.e., pathways containing SNPs for which the samples exhibit greater within-class similarity than across classes. Importantly, PoDA improves on existing single-SNP and SNP-set enrichment analyses, in that it does not require the SNPs in a pathway to exhibit independent main effects. This permits PoDA to reveal pathways in which epistatic interactions drive risk. In this paper, we detail the PoDA method and apply it to two GWAS: one of breast cancer and the other of liver cancer. The results obtained strongly suggest that there exist pathway-wide genomic differences that contribute to disease susceptibility. PoDA thus provides an analytical tool that is complementary to existing techniques and has the power to enrich our understanding of disease genomics at the systems-level. C1 [Braun, Rosemary; Buetow, Kenneth] NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. [Buetow, Kenneth] NCI, Ctr Biomed Informat & Informat Technol, NIH, Bethesda, MD 20892 USA. RP Braun, R (reprint author), NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. EM braunr@mail.nih.gov OI Braun, Rosemary/0000-0001-9668-9866 FU National Cancer Institute, National Institutes of Health, Bethesda, Maryland FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. RB was supported by the Cancer Prevention Fellowship Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 32 Z9 35 U1 0 U2 11 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 JUN PY 2011 VL 7 IS 6 AR e1002101 DI 10.1371/journal.pgen.1002101 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 787OJ UT WOS:000292386300020 PM 21695280 ER PT J AU Dumitrescu, L Carty, CL Taylor, K Schumacher, FR Hindorff, LA Ambite, JL Anderson, G Best, LG Brown-Gentry, K Buzkova, P Carlson, CS Cochran, B Cole, SA Devereux, RB Duggan, D Eaton, CB Fornage, M Franceschini, N Haessler, J Howard, BV Johnson, KC Laston, S Kolonel, LN Lee, ET MacCluer, JW Manolio, TA Pendergrass, SA Quibrera, M Shohet, RV Wilkens, LR Haiman, CA Le Marchand, L Buyske, S Kooperberg, C North, KE Crawford, DC AF Dumitrescu, Logan Carty, Cara L. Taylor, Kira Schumacher, Fredrick R. Hindorff, Lucia A. Ambite, Jose L. Anderson, Garnet Best, Lyle G. Brown-Gentry, Kristin Buzkova, Petra Carlson, Christopher S. Cochran, Barbara Cole, Shelley A. Devereux, Richard B. Duggan, Dave Eaton, Charles B. Fornage, Myriam Franceschini, Nora Haessler, Jeff Howard, Barbara V. Johnson, Karen C. Laston, Sandra Kolonel, Laurence N. Lee, Elisa T. MacCluer, Jean W. Manolio, Teri A. Pendergrass, Sarah A. Quibrera, Miguel Shohet, Ralph V. Wilkens, Lynne R. Haiman, Christopher A. Le Marchand, Loic Buyske, Steven Kooperberg, Charles North, Kari E. Crawford, Dana C. TI Genetic Determinants of Lipid Traits in Diverse Populations from the Population Architecture using Genomics and Epidemiology (PAGE) Study SO PLOS GENETICS LA English DT Article ID DENSITY-LIPOPROTEIN-CHOLESTEROL; WIDE ASSOCIATION ANALYSIS; NUTRITION EXAMINATION SURVEY; CORONARY-ARTERY-DISEASE; AFRICAN-AMERICANS; CARDIOVASCULAR-DISEASE; BLOOD-LIPIDS; JAPANESE POPULATION; TRIGLYCERIDE LEVELS; ALCOHOL DEPENDENCE AB For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (similar to 20,000), African American (similar to 9,000), American Indian (similar to 6,000), Mexican American/Hispanic (similar to 2,500), Japanese/East Asian (similar to 690), and Pacific Islander/Native Hawaiian (similar to 175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDLC and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits. C1 [Dumitrescu, Logan; Brown-Gentry, Kristin; Pendergrass, Sarah A.; Crawford, Dana C.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37203 USA. [Carty, Cara L.; Anderson, Garnet; Carlson, Christopher S.; Haessler, Jeff; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Taylor, Kira; Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Schumacher, Fredrick R.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hindorff, Lucia A.; Manolio, Teri A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Ambite, Jose L.] Univ So Calif, Inst Informat Sci, Los Angeles, CA USA. [Best, Lyle G.] Missouri Breaks Ind Res, Timber Lake, SD USA. [Buzkova, Petra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Cochran, Barbara] Baylor Coll Med, Sponsored Programs, Houston, TX 77030 USA. [Cole, Shelley A.; Laston, Sandra; MacCluer, Jean W.] SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. [Devereux, Richard B.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Duggan, Dave] Translat Genom Res Inst, Phoenix, AZ USA. [Eaton, Charles B.] Brown Univ, Sch Med, Alpert Med Sch, Dept Family Med & Community Hlth, Providence, RI 02912 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr, Div Epidemiol, Sch Publ Hlth, Houston, TX USA. [Howard, Barbara V.] Medstar Res Inst, Washington, DC USA. [Johnson, Karen C.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Kolonel, Laurence N.; Wilkens, Lynne R.; Le Marchand, Loic] Univ Hawaii, John A Burns Sch Med, Program Epidemiol, Ctr Canc,Dept Med, Honolulu, HI 96822 USA. [Lee, Elisa T.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Quibrera, Miguel] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Shohet, Ralph V.] Univ Hawaii, John A Burns Sch Med, Dept Med, Cardiovasc Res Ctr, Honolulu, HI 96822 USA. [Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. RP Dumitrescu, L (reprint author), Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37203 USA. EM crawford@chgr.mc.vanderbilt.edu RI Crawford, Dana/C-1054-2012; Carty, Cara/B-8683-2013; OI Buyske, Steven/0000-0001-8539-5416 FU National Human Genome Research Institute (NHGRI) [U01HG004803, U01HG004798, U01HG004802, U01HG004790, U01HG004801]; Johns Hopkins University from NHLBI [N01 -HV-48195]; Centers for Disease Control and Prevention; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; National Heart, Lung, and Blood Institute (NHLBI) (NIH); U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; NHLBI [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, N01-HC-85079, N01-HC-85086]; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Disease [DK063491]; National Institutes of Mental Health; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-35129, N01-HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01HL080295, R01 HL087652, U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521] FX The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center). Genotyping services for select EAGLE NHANES III SNPs presented here were also provided by the Johns Hopkins University under federal contract number (N01 -HV-48195) from NHLBI. EAGLE study participants derive from the National Health and Nutrition Examination Surveys (NHANES), and these studies are supported by the Centers for Disease Control and Prevention. The MEC study is funded through the National Cancer Institute (R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758). The WHI program is funded by the National Heart, Lung, and Blood Institute (NHLBI) (NIH) and by U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Funding support for individual CALiCo studies is as follows: The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022. The Coronary Artery Risk Development in Young Adults (CARDIA) study is supported by the following NHLBI contracts: N01-HC-95095, N01-HC-48047, N01-HC-48048,N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, and N01-HC-45205. The Cardiovascular Health Study (CHS) is 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, grants U01HL080295 and R01 HL087652 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. CHS GWAS DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Strong Heart Study (SHS) is supported by NHLBI grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, and U01 HL65521. Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG004801-01). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. NHGRI collaborators (LAH and TAM) assisted in the study design, analysis, and preparation of the manuscript. NR 76 TC 74 Z9 75 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2011 VL 7 IS 6 AR e1002138 DI 10.1371/journal.pgen.1002138 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 787OJ UT WOS:000292386300052 PM 21738485 ER PT J AU Freedman, BI Langefeld, CD Lu, LY Divers, J Comeau, ME Kopp, JB Winkler, CA Nelson, GW Johnson, RC Palmer, ND Hicks, PJ Bostrom, MA Cooke, JN McDonough, CW Bowden, DW AF Freedman, Barry I. Langefeld, Carl D. Lu, Lingyi Divers, Jasmin Comeau, Mary E. Kopp, Jeffrey B. Winkler, Cheryl A. Nelson, George W. Johnson, Randall C. Palmer, Nicholette D. Hicks, Pamela J. Bostrom, Meredith A. Cooke, Jessica N. McDonough, Caitrin W. Bowden, Donald W. TI Differential Effects of MYH9 and APOL1 Risk Variants on FRMD3 Association with Diabetic ESRD in African Americans SO PLOS GENETICS LA English DT Article ID STAGE RENAL-DISEASE; 9 GENE MYH9; KIDNEY-DISEASE; FERM DOMAIN; SUSCEPTIBILITY GENES; FAMILY; POLYMORPHISMS; NEPHROPATHY; MEMBRANE; LINKAGE AB Single nucleotide polymorphisms (SNPs) in MYH9 and APOL1 on chromosome 22 (c22) are powerfully associated with nondiabetic end-stage renal disease (ESRD) in African Americans (AAs). Many AAs diagnosed with type 2 diabetic nephropathy (T2DN) have non-diabetic kidney disease, potentially masking detection of DN genes. Therefore, genome-wide association analyses were performed using the Affymetrix SNP Array 6.0 in 966 AA with T2DN and 1,032 non-diabetic, non-nephropathy (NDNN) controls, with and without adjustment for c22 nephropathy risk variants. No associations were seen between FRMD3 SNPs and T2DN before adjusting for c22 variants. However, logistic regression analysis revealed seven FRMD3 SNPs significantly interacting with MYH9-a finding replicated in 640 additional AA T2DN cases and 683 NDNN controls. Contrasting all 1,592 T2DN cases with all 1,671 NDNN controls, FRMD3 SNPs appeared to interact with the MYH9 E1 haplotype (e. g., rs942280 interaction p-value = 9.3E(-7) additive; odds ratio [OR] 0.67). FRMD3 alleles were associated with increased risk of T2DN only in subjects lacking two MYH9 E1 risk haplotypes (rs942280 OR = 1.28), not in MYH9 E1 risk allele homozygotes (rs942280 OR = 0.80; homogeneity p-value = 4.3E(-4)). Effects were weaker stratifying on APOL1. FRMD3 SNPS were associated with T2DN, not type 2 diabetes per se, comparing AAs with T2DN to those with diabetes lacking nephropathy. T2DN-associated FRMD3 SNPs were detectable in AAs only after accounting for MYH9, with differential effects for APOL1. These analyses reveal a role for FRMD3 in AA T2DN susceptibility and accounting for c22 nephropathy risk variants can assist in detecting DN susceptibility genes. C1 [Freedman, Barry I.] Wake Forest Sch Med, Dept Internal Med, Nephrol Sect, Winston Salem, NC 27106 USA. [Langefeld, Carl D.; Lu, Lingyi; Divers, Jasmin; Comeau, Mary E.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Langefeld, Carl D.; Lu, Lingyi; Divers, Jasmin; Comeau, Mary E.] Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. [Winkler, Cheryl A.] NIDDK, Basic Res Lab, SAIC Frederick, NIH, Bethesda, MD USA. [Nelson, George W.; Johnson, Randall C.] NIDDK, BSP CCR Genet Core, SAIC Frederick, NIH, Bethesda, MD USA. [Johnson, Randall C.] Conservatoire Natl Arts & Metiers, Chaire Bioinformat, Paris, France. [Palmer, Nicholette D.; Hicks, Pamela J.; Bostrom, Meredith A.; Bowden, Donald W.] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA. [Palmer, Nicholette D.; Hicks, Pamela J.; Bostrom, Meredith A.; Cooke, Jessica N.; McDonough, Caitrin W.; Bowden, Donald W.] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA. [Palmer, Nicholette D.; Hicks, Pamela J.; Bostrom, Meredith A.; Cooke, Jessica N.; McDonough, Caitrin W.; Bowden, Donald W.] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA. [Cooke, Jessica N.; McDonough, Caitrin W.] Wake Forest Sch Med, Program Mol Med & Translat Sci, Winston Salem, NC USA. [Bowden, Donald W.] Wake Forest Sch Med, Dept Internal Med, Endocrinol Sect, Winston Salem, NC USA. RP Freedman, BI (reprint author), Wake Forest Sch Med, Dept Internal Med, Nephrol Sect, Winston Salem, NC 27106 USA. EM bfreedma@wakehealth.edu; clangefe@wakehealth.edu; dbowden@wakehealth.edu RI Johnson, Randall/B-1517-2014; OI Johnson, Randall/0000-0001-7754-0847; Kopp, Jeffrey/0000-0001-9052-186X FU NIH [R01 DK066358, R01 DK053591, R01 HL56266, RO1 DK070941, RO1 DK084149]; General Clinical Research Center of the Wake Forest University School of Medicine [M01 RR07122]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NCI; NIDDK; Genes Environment and Health Initiative Award; NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by NIH grants R01 DK066358 (DWB), R01 DK053591 (DWB), R01 HL56266 (BIF), RO1 DK070941 (BIF), RO1 DK084149 (BIF), and in part by the General Clinical Research Center of the Wake Forest University School of Medicine grant M01 RR07122. 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 the Intramural Research Programs of the NCI and NIDDK. 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 United States Government. This research was supported in part by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research, and by a Genes Environment and Health Initiative Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 36 Z9 37 U1 2 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 JUN PY 2011 VL 7 IS 6 AR e1002150 DI 10.1371/journal.pgen.1002150 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 787OJ UT WOS:000292386300059 PM 21698141 ER PT J AU Garcia-Ortiz, MV Marsin, S Arana, ME Gasparutto, D Guerois, R Kunkel, TA Radicella, JP AF Garcia-Ortiz, Maria-Victoria Marsin, Stephanie Arana, Mercedes E. Gasparutto, Didier Guerois, Raphael Kunkel, Thomas A. Radicella, J. Pablo TI Unexpected Role for Helicobacter pylori DNA Polymerase I As a Source of Genetic Variability SO PLOS GENETICS LA English DT Article ID ESCHERICHIA-COLI; NUCLEOTIDE INCORPORATION; SEQUENCE CONTEXT; ENDONUCLEASE III; BYPASS; MUTAGENESIS; MECHANISM; FIDELITY; DAMAGE; VITRO AB Helicobacter pylori, a human pathogen infecting about half of the world population, is characterised by its large intraspecies variability. Its genome plasticity has been invoked as the basis for its high adaptation capacity. Consistent with its small genome, H. pylori possesses only two bona fide DNA polymerases, Pol I and the replicative Pol III, lacking homologues of translesion synthesis DNA polymerases. Bacterial DNA polymerases I are implicated both in normal DNA replication and in DNA repair. We report that H. pylori DNA Pol I 5'-3' exonuclease domain is essential for viability, probably through its involvement in DNA replication. We show here that, despite the fact that it also plays crucial roles in DNA repair, Pol I contributes to genomic instability. Indeed, strains defective in the DNA polymerase activity of the protein, although sensitive to genotoxic agents, display reduced mutation frequencies. Conversely, overexpression of Pol I leads to a hypermutator phenotype. Although the purified protein displays an intrinsic fidelity during replication of undamaged DNA, it lacks a proofreading activity, allowing it to efficiently elongate mismatched primers and perform mutagenic translesion synthesis. In agreement with this finding, we show that the spontaneous mutator phenotype of a strain deficient in the removal of oxidised pyrimidines from the genome is in part dependent on the presence of an active DNA Pol I. This study provides evidence for an unexpected role of DNA polymerase I in generating genomic plasticity. C1 [Garcia-Ortiz, Maria-Victoria; Marsin, Stephanie; Radicella, J. Pablo] CEA, Inst Radiobiol Cellulaire & Mol, UMR 217, CNRS, Fontenay Aux Roses, France. [Arana, Mercedes E.; Kunkel, Thomas A.] Natl Inst Hlth Sci, Mol Genet Lab, NIH, Res Triangle Pk, NC USA. [Arana, Mercedes E.; Kunkel, Thomas A.] Natl Inst Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC USA. [Gasparutto, Didier] CEA, Inst Nanosci & Cryogenie, Grenoble, France. [Guerois, Raphael] CEA, IBiTecS, Gif Sur Yvette, France. [Guerois, Raphael] CNRS, URA 2096, Gif Sur Yvette, France. RP Garcia-Ortiz, MV (reprint author), CEA, Inst Radiobiol Cellulaire & Mol, UMR 217, CNRS, Fontenay Aux Roses, France. EM pablo.radicella@cea.fr RI Garcia-Ortiz, M Victoria/L-1623-2014; OI Radicella, J. Pablo/0000-0002-8807-7226 FU Commissariat a l'Energie Atomique; Agence Nationale de la Recherche [ANR-09-BLAN-0271-01]; Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES065070] FX This work was supported in part by the Commissariat a l'Energie Atomique, a grant from Agence Nationale de la Recherche (ANR-09-BLAN-0271-01) to JPR and RG, and by Project Z01 ES065070 to TAK from the Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 13 Z9 13 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 JUN PY 2011 VL 7 IS 6 AR e1002152 DI 10.1371/journal.pgen.1002152 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 787OJ UT WOS:000292386300061 PM 21731507 ER PT J AU Nalls, MA Couper, DJ Tanaka, T van Rooij, FJA Chen, MH Smith, AV Toniolo, D Zakai, NA Yang, Q Greinacher, A Wood, AR Garcia, M Gasparini, P Liu, Y Lumley, T Folsom, AR Reiner, AP Gieger, C Lagou, V Felix, JF Volzke, H Gouskova, NA Biffi, A Doring, A Volker, U Chong, S Wiggins, KL Rendon, A Dehghan, A Moore, M Taylor, K Wilson, JG Lettre, G Hofman, A Bis, JC Pirastu, N Fox, CS Meisinger, C Sambrook, J Arepalli, S Nauck, M Prokisch, H Stephens, J Glazer, NL Cupples, LA Okada, Y Takahashi, A Kamatani, Y Matsuda, K Tsunoda, T Tanaka, T Kubo, M Nakamura, Y Yamamoto, K Kamatani, N Stumvoll, M Tonjes, A Prokopenko, I Illig, T Patel, KV Garner, SF Kuhnel, B Mangino, M Oostra, BA Thein, SL Coresh, J Wichmann, HE Menzel, S Lin, JP Pistis, G Uitterlinden, AG Spector, TD Teumer, A Eiriksdottir, G Gudnason, V Bandinelli, S Frayling, TM Chakravarti, A van Duijn, CM Melzer, D Ouwehand, WH Levy, D Boerwinkle, E Singleton, AB Hernandez, DG Longo, DL Soranzo, N Witteman, JCM Psaty, BM Ferrucci, L Harris, TB O'Donnell, CJ Ganesh, SK AF Nalls, Michael A. Couper, David J. Tanaka, Toshiko van Rooij, Frank J. A. Chen, Ming-Huei Smith, Albert V. Toniolo, Daniela Zakai, Neil A. Yang, Qiong Greinacher, Andreas Wood, Andrew R. Garcia, Melissa Gasparini, Paolo Liu, Yongmei Lumley, Thomas Folsom, Aaron R. Reiner, Alex P. Gieger, Christian Lagou, Vasiliki Felix, Janine F. Voelzke, Henry Gouskova, Natalia A. Biffi, Alessandro Doering, Angela Voelker, Uwe Chong, Sean Wiggins, Kerri L. Rendon, Augusto Dehghan, Abbas Moore, Matt Taylor, Kent Wilson, James G. Lettre, Guillaume Hofman, Albert Bis, Joshua C. Pirastu, Nicola Fox, Caroline S. Meisinger, Christa Sambrook, Jennifer Arepalli, Sampath Nauck, Matthias Prokisch, Holger Stephens, Jonathan Glazer, Nicole L. Cupples, L. Adrienne Okada, Yukinori Takahashi, Atsushi Kamatani, Yoichiro Matsuda, Koichi Tsunoda, Tatsuhiko Tanaka, Toshihiro Kubo, Michiaki Nakamura, Yusuke Yamamoto, Kazuhiko Kamatani, Naoyuki Stumvoll, Michael Toenjes, Anke Prokopenko, Inga Illig, Thomas Patel, Kushang V. Garner, Stephen F. Kuhnel, Brigitte Mangino, Massimo Oostra, Ben A. Thein, Swee Lay Coresh, Josef Wichmann, H. -Erich Menzel, Stephan Lin, JingPing Pistis, Giorgio Uitterlinden, Andre G. Spector, Tim D. Teumer, Alexander Eiriksdottir, Gudny Gudnason, Vilmundur Bandinelli, Stefania Frayling, Timothy M. Chakravarti, Aravinda van Duijn, Cornelia M. Melzer, David Ouwehand, Willem H. Levy, Daniel Boerwinkle, Eric Singleton, Andrew B. Hernandez, Dena G. Longo, Dan L. Soranzo, Nicole Witteman, Jacqueline C. M. Psaty, Bruce M. Ferrucci, Luigi Harris, Tamara B. O'Donnell, Christopher J. Ganesh, Santhi K. TI Multiple Loci Are Associated with White Blood Cell Phenotypes SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; PROSTATE-CANCER SUSCEPTIBILITY; COLONY-STIMULATING FACTOR; DIFFERENTIAL LEUKOCYTE COUNT; COLORECTAL-CANCER; MYOCARDIAL-INFARCTION; ATHEROSCLEROSIS RISK; CHARGE CONSORTIUM; GENETIC-VARIANTS AB White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count-3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression-and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds. C1 [Nalls, Michael A.; Chong, Sean; Moore, Matt; Arepalli, Sampath; Singleton, Andrew B.; Hernandez, Dena G.] NIA, Neurogenet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Couper, David J.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [van Rooij, Frank J. A.; Felix, Janine F.; Dehghan, Abbas; Hofman, Albert; Oostra, Ben A.; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Rooij, Frank J. A.; Felix, Janine F.; Dehghan, Abbas; Hofman, Albert; Oostra, Ben A.; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] NGI, NCHA, Leiden, Netherlands. [Chen, Ming-Huei; Fox, Caroline S.; Cupples, L. Adrienne; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Toniolo, Daniela; Pistis, Giorgio] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Toniolo, Daniela] CNR, Inst Mol Genet, I-27100 Pavia, Italy. [Zakai, Neil A.] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Zakai, Neil A.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Yang, Qiong; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Greinacher, Andreas] Ernst Moritz Arndt Univ Greifswald, Inst Immunol & Transfus Med, Greifswald, Germany. [Wood, Andrew R.; Frayling, Timothy M.; Melzer, David] Univ Exeter, Peninsula Coll Med & Dent, Exeter EX4 4QJ, Devon, England. [Garcia, Melissa; Patel, Kushang V.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Gasparini, Paolo; Pirastu, Nicola] Univ Trieste, IRCCS Burlo Garofolo, Trieste, Italy. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Reiner, Alex P.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Gieger, Christian; Kuhnel, Brigitte] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Lagou, Vasiliki; Prokopenko, Inga] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Lagou, Vasiliki; Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Felix, Janine F.] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-6900 Heidelberg, Germany. [Gouskova, Natalia A.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC 27515 USA. [Biffi, Alessandro] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. [Biffi, Alessandro] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Doering, Angela; Wichmann, H. -Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Doering, Angela; Meisinger, Christa] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Voelker, Uwe; Teumer, Alexander] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Wiggins, Kerri L.; Bis, Joshua C.; Glazer, Nicole L.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Wiggins, Kerri L.; Bis, Joshua C.; Glazer, Nicole L.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Rendon, Augusto; Sambrook, Jennifer; Stephens, Jonathan; Garner, Stephen F.; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Rendon, Augusto; Sambrook, Jennifer; Stephens, Jonathan; Garner, Stephen F.; Ouwehand, Willem H.] Natl Hlth Serv Blood & Transplant, Cambridge, England. [Taylor, Kent] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Lettre, Guillaume] Univ Montreal, Montreal, PQ, Canada. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Nauck, Matthias] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Prokisch, Holger] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Prokisch, Holger] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Okada, Yukinori; Takahashi, Atsushi; Kamatani, Naoyuki] RIKEN, Inst Phys & Chem Res, CGM, Lab Stat Anal, Yokohama, Kanagawa, Japan. [Kamatani, Yoichiro] CEPH, Paris, France. [Matsuda, Koichi; Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Mol Med Lab, Tokyo, Japan. [Tsunoda, Tatsuhiko] RIKEN, CGM, Lab Med Informat, Yokohama, Kanagawa, Japan. [Okada, Yukinori; Yamamoto, Kazuhiko] Univ Tokyo, Grad Sch Med, Dept Allergy & Rheumatol, Tokyo, Japan. [Tanaka, Toshihiro] RIKEN, CGM, Lab Cardiovasc Dis, Yokohama, Kanagawa, Japan. [Kubo, Michiaki] RIKEN, CGM, Lab Genotyping Dev, Yokohama, Kanagawa, Japan. [Stumvoll, Michael; Toenjes, Anke] Univ Leipzig, Dept Med, Leipzig, Germany. [Stumvoll, Michael] Univ Leipzig, LIFE Study Ctr, Leipzig, Germany. [Illig, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Unit Mol Epidemiol, Neuherberg, Germany. [Mangino, Massimo; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Coresh, Josef] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Wichmann, H. -Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H. -Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Lin, JingPing] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Bandinelli, Stefania] Geriatr Unit ASF, Florence, Italy. [Chakravarti, Aravinda] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Melzer, David] PCMD, European Ctr Environm & Human Hlth, Truro, England. [Ouwehand, Willem H.; Soranzo, Nicole] Wellcome Trust Sanger Inst, Hinxton, England. [Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Hernandez, Dena G.] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Hernandez, Dena G.] UCL, Inst Neurol, Reta Lila Labs, London, England. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. RP Nalls, MA (reprint author), NIA, Neurogenet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM nallsm@mail.nih.gov; sganesh@umich.edu RI Singleton, Andrew/C-3010-2009; Pirastu, Nicola/G-4358-2011; Lagou, Vasiliki/N-8451-2013; Prokisch, Holger/N-8964-2013; Meisinger, Christine/B-5358-2014; Yang, Qiong/G-5438-2014; Tsunoda, Tatsuhiko/K-2061-2014; Kamatani, Yoichiro/N-5513-2015; Smith, Albert/K-5150-2015; Kubo, Michiaki/N-7947-2015; Gudnason, Vilmundur/K-6885-2015; Prokopenko, Inga/H-3241-2014; Tanaka, Toshihiro/J-9310-2014; mangino, massimo/F-5134-2011; OI Smith, Albert/0000-0003-1942-5845; Gudnason, Vilmundur/0000-0001-5696-0084; Prokopenko, Inga/0000-0003-1624-7457; Tanaka, Toshihiro/0000-0001-6201-9784; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Melzer, David/0000-0002-0170-3838; Ouwehand, Willem/0000-0002-7744-1790; Dehghan, Abbas/0000-0001-6403-016X; mangino, massimo/0000-0002-2167-7470; Gouskova, Natalia/0000-0001-7488-5014; Felix, Janine/0000-0002-9801-5774; Meisinger, Christa/0000-0002-9026-6544; Rendon, Augusto/0000-0001-8994-0039; Pirastu, Nicola/0000-0002-5363-3886; Cupples, L. Adrienne/0000-0003-0273-7965 FU NIA/NIH [AG000932-02]; NIH [N01-AG-12100, HHSN268200625226C, UL1RR025005, HHSN268200782096C, R01 AG24233-01, R01HL087641, R01HL59367, R01HL86694, U01HG004402]; NIA [1R01AG032098-01A1]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute [R01HL087641, R01HL59367, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL086694]; National Human Genome Research Institute [U01HG004402]; NIH Roadmap for Medical Research; Boston University School of Medicine; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix for genotyping services [N02-HL-6-4278]; NIH, National Institute on Aging, NIA [N01AG62101, N01AG62103, N01AG62106]; Italian Ministry of Health [ICS 110.1RS97.71]; U.S. National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 9164 13, 263 MD 821336]; National Institute on Aging, National Institutes of Health, USA; National Heart, Lung and Blood Institute [HL085251, HL087652, R01 HL-071862]; Health Ministry project [RF-FSR-2007-647201]; Fondazione Compagnia di San Paolo; Fondazione Cassa di Risparmio di Alessandria; Helmholtz Zentrum Munchen; German Research Center for Environmental Health, Neuherberg, Germany; German Federal Ministry of Education and Research (BMBF); German National Genome Research Network (NGFN); Munich Center of Health Sciences (MC Health); LMUinnovativ; Netherlands Organization of Scientific Research NWO [175.010.2005.011, 911.03.012, 918-76-619]; Research Institute for Diseases in the Elderly (RIDE); Netherlands Genomics Initiative (NGI)/NWO [050 060 810]; Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Netherlands Heart Foundation; Ministry of Education, Culture, and Science; Ministry of Health, Welfare, and Sports; European Commission (DG XII); Municipality of Rotterdam; Wellcome Trust [076113/C/04/Z, 091746/Z/10/Z]; European Community [HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413, QLG2-CT-2002-01254]; Dept of Health via the National Institute for Health Research (NIHR); NIHR; Biotechnology and Biological Sciences Research Council (BBSRC) [G20234]; Juvenile Diabetes Research Foundation [WT061858]; National Institute of Health Research of England; German Center for Diabetes Research; Systems Biology of Metabotypes [SysMBo #0315494A]; German Research Council [KFO-152]; IZKF [B27]; German Diabetes Association; European Community; ENGAGE project [HEALTH-F4-2007-201413]; NIH, National Institute on Aging; National Center on Minority Health and Health Disparities [Z01-AG000513]; National Heart, Lung, and Blood Institute (NHLBI) [U01 HL72518, R01 HL087698-01]; NIH/National Institute of Nursing Research [R01 NR08153]; NIH/National Center for Research Resources [M01-RR000052]; Johns Hopkins General Clinical Research Center; National Heart, Lung, and Blood Institute, National Institutes of Health, U. S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; Ministry of Education, Culture, Sports, Science, and Technology, Japan FX This research was made possible by NIA/NIH contract AG000932-02 (2009) Characterization of Normal Genomic Variability. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD [http://biowulf.nih.gov]. The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, and grants R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The National Heart, Lung, and Blood Institute's Framingham Heart Study is a joint project of the National Institutes of Health and Boston University School of Medicine and was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195) and its contract with Affymetrix for genotyping services (contract No. N02-HL-6-4278). Analyses reflect the efforts and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The Health ABC Study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, 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. The InChianti Study was supported as a "targeted project" (ICS 110.1RS97.71) by the Italian Ministry of Health, by the U.S. National Institute on Aging (Contracts N01-AG-916413, N01-AG-821336, 263 MD 9164 13, and 263 MD 821336), and in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health, USA. David Melzer's participation was supported in part by NIH grant R01 AG24233-01. The Heart and Vascular Health (HVH) Study was funded by grants HL085251 and HL087652 from the National Heart, Lung and Blood Institute. The INGI cohorts and their investigators would like to acknowledge the regions of Friuli Venezia Giulia region and Fondo Trieste, and funding from Health Ministry project RF-FSR-2007-647201, Fondazione Compagnia di San Paolo and Fondazione Cassa di Risparmio di Alessandria. The 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 wor was financed by the German National Genome Research Network (NGFN). This research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The GWAS database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research NWO (nr. 175.010.2005.011, 911.03.012) and the Research Institute for Diseases in the Elderly (RIDE). This study was supported by the Netherlands Genomics Initiative (NGI)/NWO project number 050 060 810 (Netherlands Consortium for Healthy Ageing). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands organization for scientific research (NWO); the Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Heart Foundation; the Ministry of Education, Culture, and Science; the Ministry of Health, Welfare, and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Janine F. Felix and Abbas Dehghan are supported by the Netherlands Organization for Scientific Research (NWO, VICI no. 918-76-619). The Twins UK study was funded by the Wellcome Trust, European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F2-2008-201865-GEFOS and (FP7/2007 2013), ENGAGE project grant agreement HEALTH-F4-2007-201413, and the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from the Dept 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. Tim D. Spector is an NIHR senior Investigator. The project also received support from a Biotechnology and Biological Sciences Research Council (BBSRC) project grant (G20234). Additional support includes the Wellcome Trust grant 076113/C/04/Z, the Juvenile Diabetes Research Foundation grant WT061858, and by the National Institute of Health Research of England. Nicole Soranzo is supported by Wellcome Trust (Core Grant Number 091746/Z/10/Z). The participation of Alex P. Reiner is supported by National Heart, Lung, and Blood Institute grant R01 HL-071862. Holger Prokisch's participation was supported by the German Federal Ministry of Education and Research (BMBF) funded German Center for Diabetes Research (DZD e. V.) and Systems Biology of Metabotypes (SysMBo #0315494A). Financial support was received from the German Research Council (KFO-152), IZKF (B27), and the German Diabetes Association. Inga Prokopenko and Vasiliki Lagou were partial funded through the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413. Acknowledgments from COGENT collaborators: COGENT and CARe: The authors acknowledge the essential role of the Continental Origins and Genetic Epidemiology Network (COGENT) Consortium in development and support of this manuscript. COGENT members participating in support of this manuscript include the WHI, ARIC, CARDIA, JHS, HANDLS, Health ABC, and GeneSTAR. CARe: 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 following parent studies contributed study data, ancillary study data, and DNA samples through the Broad Institute (N01-HC-65226) to create this genotype/phenotype data base fr wide dissemination to the biomedical research community: Atherosclerosis 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-55017), University of North Carolina (N01-HC-55018). Other NIH support contributing to the GWAS in ARIC are: R01HL087641, R01HL59367, R01HL86694, U01HG004402, and HHSN268200625226C. 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-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California, Irvine (N01-HC-45134, N01-HC-95100). Jackson Heart Study (JHS): Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), Tougaloo College (N01-HC-95172). Healthy Aging in Neighborhoods of Diversity across the Life Span Study (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, Maryland (http://biowulf.nih.gov). GeneSTAR: This research was supported by the National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI (U01 HL72518) and STAMPEED (R01 HL087698-01) consortia. Additional support was provided by grants from the NIH/National Institute of Nursing Research (R01 NR08153), and the NIH/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U. S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. RIKEN collaborators: We would like to thank all the staff of the Laboratory for Statistical Analysis at RIKEN for their technical assistance. This study was supported by Ministry of Education, Culture, Sports, Science, and Technology, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 84 TC 48 Z9 48 U1 0 U2 10 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 JUN PY 2011 VL 7 IS 6 AR e1002113 DI 10.1371/journal.pgen.1002113 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 787OJ UT WOS:000292386300030 PM 21738480 ER PT J AU Okada, Y Hirota, T Kamatani, Y Takahashi, A Ohmiya, H Kumasaka, N Higasa, K Yamaguchi-Kabata, Y Hosono, N Nalls, MA Chen, MH van Rooij, FJA Smith, AV Tanaka, T Couper, DJ Zakai, NA Ferrucci, L Longo, DL Hernandez, DG Witteman, JCM Harris, TB O'Donnell, CJ Ganesh, SK Matsuda, K Tsunoda, T Tanaka, T Kubo, M Nakamura, Y Tamari, M Yamamoto, K Kamatani, N AF Okada, Yukinori Hirota, Tomomitsu Kamatani, Yoichiro Takahashi, Atsushi Ohmiya, Hiroko Kumasaka, Natsuhiko Higasa, Koichiro Yamaguchi-Kabata, Yumi Hosono, Naoya Nalls, Michael A. Chen, Ming Huei van Rooij, Frank J. A. Smith, Albert V. Tanaka, Toshiko Couper, David J. Zakai, Neil A. Ferrucci, Luigi Longo, Dan L. Hernandez, Dena G. Witteman, Jacqueline C. M. Harris, Tamara B. O'Donnell, Christopher J. Ganesh, Santhi K. Matsuda, Koichi Tsunoda, Tatsuhiko Tanaka, Toshihiro Kubo, Michiaki Nakamura, Yusuke Tamari, Mayumi Yamamoto, Kazuhiko Kamatani, Naoyuki TI Identification of Nine Novel Loci Associated with White Blood Cell Subtypes in a Japanese Population SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CHARGE CONSORTIUM; BASOPHILS; VARIANTS; DISEASE; HEIGHT; ADULT; TRANSCRIPTION; PROTEIN; TMPRSS6 AB White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P < 5.0x10(-8), of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITGA4, MLZE, STXBP6 loci, and the MHC region for the monocyte count; the SLC45A3-NUCKS1, GATA2, NAALAD2, ERG loci for the basophil count). We further evaluated associations in the identified loci using 15,600 subjects from Caucasian populations. These WBC subtype-related loci demonstrated a variety of patterns of pleiotropic associations within the WBC subtypes, or with total WBC count, platelet count, or red blood cell-related traits (n = 30,454), which suggests unique and common functional roles of these loci in the processes of hematopoiesis. This study should contribute to the understanding of the genetic backgrounds of the WBC subtypes and hematological traits. C1 [Okada, Yukinori; Takahashi, Atsushi; Ohmiya, Hiroko; Kumasaka, Natsuhiko; Higasa, Koichiro; Yamaguchi-Kabata, Yumi; Kamatani, Naoyuki] RIKEN, Inst Phys & Chem Res, CGM, Lab Stat Anal, Yokohama, Kanagawa, Japan. [Okada, Yukinori; Yamamoto, Kazuhiko] Univ Tokyo, Grad Sch Med, Dept Allergy & Rheumatol, Tokyo, Japan. [Hirota, Tomomitsu; Tamari, Mayumi] Inst Phys & Chem Res, Ctr Genom Med, Lab Resp Dis, Yokohama, Kanagawa, Japan. [Kamatani, Yoichiro] CEPH, Paris, France. [Hosono, Naoya; Kubo, Michiaki] Inst Phys & Chem Res, Ctr Genom Med, Lab Genotyping Dev, Yokohama, Kanagawa, Japan. [Nalls, Michael A.; Hernandez, Dena G.] NIA, Neurogenet Lab, NIH, Baltimore, MD 21224 USA. [Chen, Ming Huei; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Chen, Ming Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [van Rooij, Frank J. A.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Rooij, Frank J. A.; Witteman, Jacqueline C. M.] Netherlands Genom Initiat, Netherlands Consortium Hlth Aging NGINCHA, Leiden, Netherlands. [Smith, Albert V.] Iceland Heart Assoc, Kopavogur, Iceland. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Longitudinal Studies Sect, NIH, Baltimore, MD 21224 USA. [Couper, David J.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Zakai, Neil A.] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Baltimore, MD USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Matsuda, Koichi; Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Mol Med Lab, Tokyo, Japan. [Tsunoda, Tatsuhiko] Inst Phys & Chem Res, Ctr Genom Med, Lab Med Informat, Yokohama, Kanagawa, Japan. [Tanaka, Toshihiro] Inst Phys & Chem Res, Ctr Genom Med, Lab Cardiovasc Dis, Yokohama, Kanagawa, Japan. RP Okada, Y (reprint author), RIKEN, Inst Phys & Chem Res, CGM, Lab Stat Anal, Yokohama, Kanagawa, Japan. EM yokada@src.riken.jp RI Tsunoda, Tatsuhiko/K-2061-2014; Tanaka, Toshihiro/J-9310-2014; Kamatani, Yoichiro/N-5513-2015; Smith, Albert/K-5150-2015; Kubo, Michiaki/N-7947-2015; Tamari, Mayumi/N-5378-2015 OI Tanaka, Toshihiro/0000-0001-6201-9784; Smith, Albert/0000-0003-1942-5845; FU Ministry of Education, Culture, Sports, Science, and Technology, Japan FX This study was supported by Ministry of Education, Culture, Sports, Science, and Technology, Japan. Full descriptions of funding source for the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium are provided in Text S1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 38 Z9 38 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 JUN PY 2011 VL 7 IS 6 AR e1002067 DI 10.1371/journal.pgen.1002067 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 787OJ UT WOS:000292386300006 PM 21738478 ER PT J AU Plagnol, V Nalls, MA Bras, JM Hernandez, DG Sharma, M Sheerin, UM Saad, M Simon-Sanchez, J Schulte, C Lesage, S Sveinbjornsdottir, S Amouyel, P Arepalli, S Band, G Barker, RA Bellinguez, C Ben-Shlomo, Y Berendse, HW Berg, D Bhatia, K de Bie, RMA Biffi, A Bloem, B Bochdanovits, Z Bonin, M Brockmann, K Brooks, J Burn, DJ Charlesworth, G Chen, HL Chinnery, PF Chong, S Clarke, CE Cookson, MR Cooper, JM Corvol, JC Counsell, C Damier, P Dartigues, JF Deloukas, P Deuschl, G Dexter, DT van Dijk, KD Dillman, A Durif, F Durr, A Edkins, S Evans, JR Foltynie, T Freeman, C Gao, JJ Gardner, M Gibbs, JR Goate, A Gray, E Guerreiro, R Gustafsson, O Harris, C Hellenthal, G van Hilten, JJ Hofman, A Hollenbeck, A Holton, J Hu, M Huang, XM Huber, H Hudson, G Hunt, SE Huttenlocher, J Illig, T Jonsson, PV Langford, C Lees, A Lichtner, P Limousin, P Lopez, G Lorenz, D McNeill, A Moorby, C Moore, M Morris, H Morrison, KE Mudanohwo, E O'Sullivan, SS Pearson, J Pearson, R Perlmutter, JS Petursson, H Pirinen, M Pollak, P Post, B Potter, S Ravina, B Revesz, T Riess, O Rivadeneira, F Rizzu, P Ryten, M Sawcer, S Schapira, A Scheffer, H Shaw, K Shoulson, I Sidransky, E de Silva, R Smith, C Spencer, CCA Stefansson, H Steinberg, S Stockton, JD Strange, A Su, Z Talbot, K Tanner, CM Tashakkori-Ghanbaria, A Tison, F Trabzuni, D Traynor, BJ Uitterlinden, AG Vandrovcova, J Velseboer, D Vidailhet, M Vukcevic, D Walker, R van de Warrenburg, B Weale, ME Wickremaratchi, M Williams, N Williams-Gray, CH Winder-Rhodes, S Stefansson, K Martinez, M Donnelly, P Singleton, AB Hardy, J Heutink, P Brice, A Gasser, T Wood, NW AF Plagnol, Vincent Nalls, Michael A. Bras, Jose M. Hernandez, Dena G. Sharma, Manu Sheerin, Una-Marie Saad, Mohamad Simon-Sanchez, Javier Schulte, Claudia Lesage, Suzanne Sveinbjornsdottir, Sigurlaug Amouyel, Philippe Arepalli, Sampath Band, Gavin Barker, Roger A. Bellinguez, Celine Ben-Shlomo, Yoav Berendse, Henk W. Berg, Daniela Bhatia, Kailash de Bie, Rob M. A. Biffi, Alessandro Bloem, Bas Bochdanovits, Zoltan Bonin, Michael Brockmann, Kathrin Brooks, Janet Burn, David J. Charlesworth, Gavin Chen, Honglei Chinnery, Patrick F. Chong, Sean Clarke, Carl E. Cookson, Mark R. Cooper, J. Mark Corvol, Jean Christophe Counsell, Carl Damier, Philippe Dartigues, Jean-Francois Deloukas, Panos Deuschl, Guenther Dexter, David T. van Dijk, Karin D. Dillman, Allissa Durif, Frank Duerr, Alexandra Edkins, Sarah Evans, Jonathan R. Foltynie, Thomas Freeman, Colin Gao, Jianjun Gardner, Michelle Gibbs, J. Raphael Goate, Alison Gray, Emma Guerreiro, Rita Gustafsson, Omar Harris, Clare Hellenthal, Garrett van Hilten, Jacobus J. Hofman, Albert Hollenbeck, Albert Holton, Janice Hu, Michele Huang, Xuemei Huber, Heiko Hudson, Gavin Hunt, Sarah E. Huttenlocher, Johanna Illig, Thomas Jonsson, Palmi V. Langford, Cordelia Lees, Andrew Lichtner, Peter Limousin, Patricia Lopez, Grisel Lorenz, Delia McNeill, Alisdair Moorby, Catriona Moore, Matthew Morris, Huw Morrison, Karen E. Mudanohwo, Ese O'Sullivan, Sean S. Pearson, Justin Pearson, Richard Perlmutter, Joel S. Petursson, Hjoervar Pirinen, Matti Pollak, Pierre Post, Bart Potter, Simon Ravina, Bernard Revesz, Tamas Riess, Olaf Rivadeneira, Fernando Rizzu, Patrizia Ryten, Mina Sawcer, Stephen Schapira, Anthony Scheffer, Hans Shaw, Karen Shoulson, Ira Sidransky, Ellen de Silva, Rohan Smith, Colin Spencer, Chris C. A. Stefansson, Hreinn Steinberg, Stacy Stockton, Joanna D. Strange, Amy Su, Zhan Talbot, Kevin Tanner, Carlie M. Tashakkori-Ghanbaria, Avazeh Tison, Francois Trabzuni, Daniah Traynor, Bryan J. Uitterlinden, Andre G. Vandrovcova, Jana Velseboer, Daan Vidailhet, Marie Vukcevic, Damjan Walker, Robert van de Warrenburg, Bart Weale, Michael E. Wickremaratchi, Mirdhu Williams, Nigel Williams-Gray, Caroline H. Winder-Rhodes, Sophie Stefansson, Kari Martinez, Maria Donnelly, Peter Singleton, Andrew B. Hardy, John Heutink, Peter Brice, Alexis Gasser, Thomas Wood, Nicholas W. CA WTCCC2 TI A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; FIBROBLAST-GROWTH-FACTOR; ALPHA-SYNUCLEIN; GENE; MUTATIONS; RISK; POPULATION; HAPLOTYPES; VARIANTS; SEQUENCE AB A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5x10(-10), PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci. C1 [Plagnol, Vincent; Arepalli, Sampath; Brooks, Janet; Wood, Nicholas W.] UCL, UCL Genet Inst, London, England. [Nalls, Michael A.; Hernandez, Dena G.; Chong, Sean; Cookson, Mark R.; Dillman, Allissa; Gibbs, J. Raphael; Moore, Matthew; Traynor, Bryan J.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Bras, Jose M.; Hernandez, Dena G.; Sheerin, Una-Marie; Charlesworth, Gavin; Gardner, Michelle; Gibbs, J. Raphael; Guerreiro, Rita; Ryten, Mina; de Silva, Rohan; Trabzuni, Daniah; Vandrovcova, Jana; Hardy, John; Wood, Nicholas W.] UCL, Dept Mol Neurosci, Inst Neurol, London, England. [Sharma, Manu; Saad, Mohamad; Martinez, Maria] Ctr Physiopathol Toulouse Purpan, INSERM, UMR 1043, Toulouse, France. [Saad, Mohamad; Martinez, Maria] Univ Toulouse 3, Toulouse, France. [Simon-Sanchez, Javier; Bochdanovits, Zoltan; Rizzu, Patrizia; Heutink, Peter] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands. [Schulte, Claudia; Berg, Daniela; Brockmann, Kathrin; Huber, Heiko; Gasser, Thomas] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany. [Schulte, Claudia; Berg, Daniela; Brockmann, Kathrin; Duerr, Alexandra; Huber, Heiko; Gasser, Thomas] German Ctr Neurodegenerat Dis, Deutsch Zentrum Neurodegenerat Erkrangungen, Tubingen, Germany. [Lesage, Suzanne; Corvol, Jean Christophe; Duerr, Alexandra; Vidailhet, Marie; Brice, Alexis] INSERM, UMR S975, Paris, France. [Lesage, Suzanne; Corvol, Jean Christophe; Duerr, Alexandra; Vidailhet, Marie; Brice, Alexis] Univ Paris 06, Ctr Rech, Inst Cerveau & Moelleepiniere, UMR S975, Paris, France. [Lesage, Suzanne; Corvol, Jean Christophe; Vidailhet, Marie; Brice, Alexis] CNRS, UMR 7225, Paris, France. [Sveinbjornsdottir, Sigurlaug] Landspitali Univ Hosp, Dept Neurol, Reykjavik, Iceland. [Sveinbjornsdottir, Sigurlaug] Broomfield Hosp, Mid Essex Hosp, Dept Neurol, Chelmsford, Essex, England. [Sveinbjornsdottir, Sigurlaug] Univ London, Queen Mary Coll, London, England. [Amouyel, Philippe; Huttenlocher, Johanna] INSERM, U744, F-59045 Lille, France. [Amouyel, Philippe] Univ Lille Nord, Inst Pasteur Lille, Lille, France. [Band, Gavin; Bellinguez, Celine; Freeman, Colin; Hellenthal, Garrett; Pearson, Richard; Pirinen, Matti; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter] Wellcome Trust Ctr Human Genet, Oxford, England. [Barker, Roger A.; Williams-Gray, Caroline H.] Univ Cambridge, Addenbrookes Hosp, Dept Neurol, Cambridge CB2 2QQ, England. [Ben-Shlomo, Yoav] Univ Bristol, Dept Social Med, Bristol, Avon, England. [Berendse, Henk W.; van Dijk, Karin D.] Vrije Univ Amsterdam Med Ctr, Dept Neurol, Amsterdam, Netherlands. [Berendse, Henk W.; van Dijk, Karin D.] Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Amsterdam, Netherlands. [Bhatia, Kailash] UCL, Inst Neurol, Dept Motor Neurosci, London, England. [de Bie, Rob M. A.; Velseboer, Daan] Univ Amsterdam, Acad Med Ctr, Dept Neurol, NL-1105 AZ Amsterdam, Netherlands. [Biffi, Alessandro] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Biffi, Alessandro] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Biffi, Alessandro] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Bloem, Bas; Post, Bart; van de Warrenburg, Bart] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6525 ED Nijmegen, Netherlands. [Bonin, Michael; Petursson, Hjoervar; Riess, Olaf] Univ Tubingen, Dept Med Genet, Inst Human Genet, Tubingen, Germany. [Burn, David J.] Newcastle Univ, Clin Ageing Res Unit, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Chen, Honglei; Gao, Jianjun] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. [Chinnery, Patrick F.; Hudson, Gavin] Newcastle Univ, Dept Neurol, Sch Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Clarke, Carl E.; Moorby, Catriona; Morrison, Karen E.; Stockton, Joanna D.] Univ Birmingham, Sch Clin & Expt Med, Birmingham, W Midlands, England. [Clarke, Carl E.] W Birmingham Hosp NHS Trust, Birmingham, W Midlands, England. [Cooper, J. Mark; McNeill, Alisdair; Schapira, Anthony] UCL, Inst Neurol, Dept Clin Neurosci, London, England. [Corvol, Jean Christophe] Hop La Pitie Salpetriere, INSERM, CIC 9503, Paris, France. [Counsell, Carl; Harris, Clare] Univ Aberdeen, Div Appl Hlth Sci, Populat Hlth Sect, Aberdeen, Scotland. [Damier, Philippe] CHU Nantes, CIC0004, Serv Neurol, F-44035 Nantes 01, France. [Dartigues, Jean-Francois] Univ Victor Segalen, INSERM, U897, Bordeaux, France. [Deloukas, Panos; Edkins, Sarah; Gray, Emma; Hunt, Sarah E.; Potter, Simon; Tashakkori-Ghanbaria, Avazeh] Wellcome Trust Sanger Inst, Cambridge, England. [Deuschl, Guenther; Lorenz, Delia] Univ Kiel, Neurol Klin, Univ Klinikum Schleswig Holstein, D-2300 Kiel, Germany. [Dexter, David T.] Univ London Imperial Coll Sci Technol & Med, Parkinsons Dis Res Grp, Fac Med, London, England. [Durif, Frank] Hop Gabriel Montpied, Serv Neurol, Clermont Ferrand, France. [Duerr, Alexandra; Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, Paris, France. [Evans, Jonathan R.; Langford, Cordelia] Univ Cambridge, Cambridge Ctr Brain Repair, Cambridge, England. [Goate, Alison; Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Psychiat, Dept Neurol, St Louis, MO 63110 USA. [Gustafsson, Omar; Petursson, Hjoervar; Stefansson, Hreinn; Steinberg, Stacy; Stefansson, Kari] 14 DeCODE Genet, Reykjavik, Iceland. [van Hilten, Jacobus J.] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. [Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Hollenbeck, Albert] Amer Assoc Retired Persons, Washington, DC USA. [Holton, Janice; Lees, Andrew; O'Sullivan, Sean S.; Revesz, Tamas; Shaw, Karen] UCL, Inst Neurol, Queen Sq Brain Bank Neurol Disorders, London, England. [Hu, Michele] John Radcliffe Hosp, Dept Clin Neurol, Oxford OX3 9DU, England. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Kinesiol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Bioengn, Hershey, PA 17033 USA. [Illig, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Jonsson, Palmi V.] Landspitali Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Lichtner, Peter] German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Limousin, Patricia] UCL, Inst Neurol, Sobell Dept, Unit Funct Neurosurg, London, England. [Lopez, Grisel; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Morris, Huw; Pearson, Justin; Williams, Nigel] Cardiff Univ, Sch Med, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Morrison, Karen E.] Univ Hosp Birmingham NHS Fdn Trust, Queen Elizabeth Hosp, Dept Neurosci, Birmingham, W Midlands, England. [Mudanohwo, Ese] UCL, Natl Hosp Neurol & Neurosurg, Inst Neurol, Neurogenet Unit, London, England. [Pollak, Pierre] CHU Grenoble, Serv Neurol, F-38043 Grenoble, France. [Ravina, Bernard] Biogen Idec Inc, Translat Neurol, Cambridge, MA USA. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Sawcer, Stephen] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England. [Scheffer, Hans] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Shoulson, Ira] Univ Rochester, Dept Neurol, Rochester, NY USA. [Smith, Colin; Walker, Robert] Univ Edinburgh, Dept Pathol, Edinburgh, Midlothian, Scotland. [Spencer, Chris C. A.; Talbot, Kevin] Univ Oxford, John Radcliffe Hosp, Dept Clin Neurol, Oxford OX3 9DU, England. [Tanner, Carlie M.] Parkinsons Inst & Clin Ctr, Dept Clin Res, Sunnyvale, CA USA. [Tison, Francois] Hop Haut Leveque, Serv Neurol, Pessac, France. [Weale, Michael E.] Kings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England. [Wickremaratchi, Mirdhu] Cardiff Univ, Dept Neurol, Cardiff, S Glam, Wales. [Winder-Rhodes, Sophie] Univ Cambridge, Dept Psychiat, Cambridge, England. [Winder-Rhodes, Sophie] Univ Cambridge, MRC, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England. RP Plagnol, V (reprint author), UCL, UCL Genet Inst, London, England. EM n.wood@ion.ucl.ac.uk RI Singleton, Andrew/C-3010-2009; turton, miranda/F-4682-2011; Holton, Janice/F-6831-2011; Talbot, Kevin /F-7361-2011; Plagnol, Vincent/A-5667-2011; O'Sullivan, Sean/C-9333-2012; Morris, Huw/B-8527-2008; Scheffer, Hans/E-4644-2012; Bloem, Bastiaan/E-3812-2010; Guerreiro, Rita/A-1327-2011; Traynor, Bryan/G-5690-2010; Deloukas, Panos/B-2922-2013; Hardy, John/C-2451-2009; Weale, Michael/F-2587-2010; Hudson, Gavin/E-7117-2017; Bras, Jose/A-1428-2011; Charlesworth, Gavin/B-5895-2011; Cooper, J Mark/D-5826-2013; Deuschl, Gunther/A-7986-2010; Wood, Nicholas/C-2505-2009; Bloem, B.R./H-8013-2014; Trabzuni, Daniah/C-4034-2012; Rivadeneira, Fernando/O-5385-2015; van de Warrenburg, Bart/D-1935-2010; de Silva, Rohan/C-1734-2008; Martinez, Maria/B-3111-2013; corvol, jean-christophe/I-6387-2012; Revesz, Tamas/A-8732-2010 OI Holton, Janice/0000-0002-3882-5249; O'Sullivan, Sean/0000-0002-0583-7956; Morris, Huw/0000-0002-5473-3774; Scheffer, Hans/0000-0002-2986-0915; Deloukas, Panos/0000-0001-9251-070X; Weale, Michael/0000-0003-4593-1186; Walker, Robert/0000-0001-7383-7846; Bras, Jose/0000-0001-8186-0333; Hunt, Sarah/0000-0002-8350-1235; Plagnol, Vincent/0000-0002-5597-9215; Stefansson, Hreinn/0000-0002-9331-6666; Bhatia, Kailash/0000-0001-8185-286X; Chen, Honglei/0000-0003-3446-7779; Cooper, J Mark/0000-0002-3007-3054; Wood, Nicholas/0000-0002-9500-3348; Trabzuni, Daniah/0000-0003-4826-9570; Rivadeneira, Fernando/0000-0001-9435-9441; de Silva, Rohan/0000-0002-5052-5775; Martinez, Maria/0000-0003-2180-4537; corvol, jean-christophe/0000-0001-7325-0199; Revesz, Tamas/0000-0003-2501-0259 FU Wellcome Trust/MRC [WT089698]; Department of Health NIHR Biomedical Research Centre; Parkinson's UK [8047, J-0804]; Medical Research Council [G0700943]; Wellcome Trust [085475/B/08/Z, 085475/Z/08/Z]; Wolfson-Royal Society; UK Medical Research Council [G0901254]; Reta Lila Weston Trust for Medical Research; Landspitali University Hospital; Icelandic Research Council; European Community [PIAP-GA-2008-230596 MarkMD]; National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services [Z01 AG000949-02, Z01-ES101986]; US Department of Defense [W81XWH-09-2-0128]; National Institutes of Health [NS057105, RR024992]; American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; ForschungszentrumfurUmwelt und Gesundheit (GSF); German Federal Ministry of Education, Science, Research, and Technology; State of Bavaria; German National Genome Network (NGFNplus) [01GS08134]; German Federal Ministry of Education and Research (BMBF) NGFN [01GR0468]; Helmholtz Association [HA-215]; French National Agency of Research [ANR-08-MNP-012]; National Research Funding Agency [ANR-08-NEUR-004-01] FX This work was supported in part by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC), whose members are from the UCL/Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee. Additionally, part of the study was undertaken at UCLH/UCL using funding through a Department of Health NIHR Biomedical Research Centre. This work was also supported by Parkinson's UK (Grants 8047 and J-0804) and the Medical Research Council (G0700943). Genotyping of UK replication cases on Immunochip was part of the Wellcome Trust Case Control Consortium 2 project which is funded by the Wellcome Trust (085475/B/08/Z and 085475/Z/08/Z). P Damier is partly supported by a Wolfson-Royal Society Merit award. The UK gene expression work was supported in part by the UK Medical Research Council (G0901254) to researchers based in the UCL Institute of Neurology and King's College London. J Holton receives support from the Reta Lila Weston Trust for Medical Research. This work was also supported by the Landspitali University Hospital Research Fund (S Sveinbjornsdottir), the Icelandic Research Council (S Sveinbjornsdottir), the European Community Framework Programme 7, People programme, IAPP on novel genetic and phenotypic markers of Parkinson's disease, and Essential Tremor (MarkMD), contract no PIAP-GA-2008-230596 MarkMD (H Petursson, J Holton). This US work was supported in part by the Intramural Research Programs of the National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services; project numbers Z01 AG000949-02 and Z01-ES101986. In addition this study was supported by the US Department of Defense, award number W81XWH-09-2-0128. Funding to support collection of a portion of the samples was obtained from the National Institutes of Health (grants NS057105 and RR024992), the American Parkinson Disease Association (APDA), Barnes Jewish Hospital Foundation, and the Greater St. Louis Chapter of the APDA. The KORA research platform (KORA: Cooperative Research in the Region of Augsburg; http://www.gsf.de/KORA) was initiated and financed by the ForschungszentrumfurUmwelt und Gesundheit (GSF), which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. The study was additionally funded by the German National Genome Network (NGFNplus #01GS08134; German Ministry for Education and Research) and by the German Federal Ministry of Education and Research (BMBF) NGFN (01GR0468) and in the frame of ERA-Net NEURON (01GW0908). This work was also supported by the Helmholtz Alliance Mental Health in an Ageing Society (HelMA, HA-215) funded by the Initiative and Networking Fund of the Helmholtz Association. The French GWA scan work was supported by the French National Agency of Research (http://www.agence-nationale-recherche.fr, ANR-08-MNP-012) and by the National Research Funding Agency (ANR-08-NEUR-004-01) in ERANET NEURON framework (http://www.neuron-eranet.eu). We also want to thank the Hersenstichting Nederland (http://www.hersenstichting.nl), the Neuroscience Campus Amsterdam and the section of Medical genomics, the Prinses Beatrix Fonds(http://www.prinsesbeatrixfonds. nl) for sponsoring this work.; The funders had no role in study design, data collection and analysis, decision to publish, or preparation f the manuscript. NR 35 TC 21 Z9 21 U1 0 U2 23 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 JUN PY 2011 VL 7 IS 6 AR e1002142 DI 10.1371/journal.pgen.1002142 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 787OJ UT WOS:000292386300055 ER PT J AU Reiner, AP Lettre, G Nalls, MA Ganesh, SK Mathias, R Austin, MA Dean, E Arepalli, S Britton, A Chen, Z Couper, D Curb, JD Eaton, CB Fornage, M Grant, SFA Harris, TB Hernandez, D Kamatini, N Keating, BJ Kubo, M LaCroix, A Lange, LA Liu, SM Lohman, K Meng, Y Mohler, ER Musani, S Nakamura, Y O'Donnell, CJ Okada, Y Palmer, CD Papanicolaou, GJ Patel, KV Singleton, AB Takahashi, A Tang, H Taylor, HA Taylor, K Thomson, C Yanek, LR Yang, LY Ziv, E Zonderman, AB Folsom, AR Evans, MK Liu, YM Becker, DM Snively, BM Wilson, JG AF Reiner, Alexander P. Lettre, Guillaume Nalls, Michael A. Ganesh, Santhi K. Mathias, Rasika Austin, Melissa A. Dean, Eric Arepalli, Sampath Britton, Angela Chen, Zhao Couper, David Curb, J. David Eaton, Charles B. Fornage, Myriam Grant, Struan F. A. Harris, Tamara B. Hernandez, Dena Kamatini, Naoyuki Keating, Brendan J. Kubo, Michiaki LaCroix, Andrea Lange, Leslie A. Liu, Simin Lohman, Kurt Meng, Yan Mohler, Emile R., III Musani, Solomon Nakamura, Yusuke O'Donnell, Christopher J. Okada, Yukinori Palmer, Cameron D. Papanicolaou, George J. Patel, Kushang V. Singleton, Andrew B. Takahashi, Atsushi Tang, Hua Taylor, Herman A., Jr. Taylor, Kent Thomson, Cynthia Yanek, Lisa R. Yang, Lingyao Ziv, Elad Zonderman, Alan B. Folsom, Aaron R. Evans, Michele K. Liu, Yongmei Becker, Diane M. Snively, Beverly M. Wilson, James G. TI Genome-Wide Association Study of White Blood Cell Count in 16,388 African Americans: the Continental Origins and Genetic Epidemiology Network (COGENT) SO PLOS GENETICS LA English DT Article ID DUFFY ANTIGEN RECEPTOR; NEUTROPHIL COUNT; CHEMOKINES DARC; G-CSF; PLASMODIUM-VIVAX; CXC CHEMOKINES; LUNG INJURY; POPULATION; METAANALYSIS; VARIANTS AB Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived "null" variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5 x 10(-8)). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS. C1 [Reiner, Alexander P.; LaCroix, Andrea] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Reiner, Alexander P.; Austin, Melissa A.; LaCroix, Andrea] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Lettre, Guillaume] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Nalls, Michael A.; Arepalli, Sampath; Britton, Angela; Hernandez, Dena; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Mathias, Rasika; Yanek, Lisa R.; Becker, Diane M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Austin, Melissa A.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Austin, Melissa A.] Univ Washington, Sch Publ Hlth, Inst Publ Hlth Genet, Seattle, WA 98195 USA. [Dean, Eric; Ziv, Elad] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Chen, Zhao] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Div Epidemiol & Biostat, Tucson, AZ USA. [Couper, David] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Curb, J. David] Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. [Eaton, Charles B.] Brown Univ, Alpert Med Sch, Ctr Primary Care & Prevent, Providence, RI 02912 USA. [Fornage, Myriam] Univ Texas Houston, Houston Inst Mol Med, Houston, TX USA. [Grant, Struan F. A.; Keating, Brendan J.] Childrens Hosp Philadelphia Res Inst, Div Human Genet, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Harris, Tamara B.; Patel, Kushang V.] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. [Kamatini, Naoyuki; Okada, Yukinori; Takahashi, Atsushi] RIKEN, Inst Phys & Chem Res, CGM, Lab Stat Anal, Yokohama, Kanagawa, Japan. [Kubo, Michiaki] RIKEN, CGM, Lab Genotyping Dev, Yokohama, Kanagawa, Japan. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Liu, Simin] Univ Calif Los Angeles, Dept Epidemiol, Los Angeles, CA USA. [Liu, Simin] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Lohman, Kurt; Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Ctr Human Genom,Div Publ Hlth Sci, Winston Salem, NC USA. [Meng, Yan; Palmer, Cameron D.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Mohler, Emile R., III] Univ Penn, Sch Med, Dept Med, Cardiovasc Div,Vasc Med Sect, Philadelphia, PA 19104 USA. [Musani, Solomon] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Mol Med Lab, Tokyo, Japan. [O'Donnell, Christopher J.; Papanicolaou, George J.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Tang, Hua] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Taylor, Herman A., Jr.] Jackson State Univ, Tougaloo Coll, Jackson, MS USA. [Taylor, Herman A., Jr.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Taylor, Kent] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Thomson, Cynthia] Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. [Yang, Lingyao; Snively, Beverly M.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Evans, Michele K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. RP Reiner, AP (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. EM apreiner@u.washington.edu; jgwilson2@umc.edu RI Singleton, Andrew/C-3010-2009; Liu, Simin/I-3689-2014; Ziv, Elad/L-5396-2014; Kubo, Michiaki/N-7947-2015; OI Liu, Simin/0000-0003-2098-3844; Zonderman, Alan B/0000-0002-6523-4778 FU NIH [R01HL087641, R01HL59367, R01HL86694, U01HG004402, HHSN268200625226C, R01 HL71862-06, ARRA N000949304]; NIH, National Institute on Aging; National Heart, Lung, and Blood Institute (NHLBI) [U01 HL72518, R01 HL087698-01]; NIH/National Institute of Nursing Research [R01 NR08153]; NIH/National Center for Research Resources [M01-RR000052]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; U.S. Public Health Service [RR03655]; National Center for Research Resources; [N01-HC-55015]; [N01-HC-55016]; [N01-HC-55021]; [N01-HC-55019]; [N01-HC-55020]; [N01-HC-55017]; [N01-HC-55018] FX The following parent studies contributed study data, ancillary study data, and DNA samples through the Broad Institute (N01-HC-65226) to create this genotype/phenotype data base for wide dissemination to the biomedical research community. Atherosclerosis Risk in Communities (ARIC): University of North Carolina at Chapel Hill (funded by 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-55017), University of North Carolina (N01-HC-55018). Other NIH support contributing to the GWAS in ARIC are: R01HL087641, R01HL59367, R01HL86694, U01HG004402, and HHSN268200625226C. 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-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC- 05187), University of California, Irvine (N01-HC-45134, N01-HC-95100). Jackson Heart Study (JHS): Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), Tougaloo College (N01-HC-95172). Healthy Aging in Neighborhoods of Diversity across the Life Span Study (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). Health ABC: 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. GeneSTAR Acknowledgement: This research was supported by the National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI (U01 HL72518) and STAMPEED (R01 HL087698-01) consortia. Additional support was provided by grants from the NIH/National Institute of Nursing Research (R01 NR08153) and the NIH/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Additional support for this work was provided by NIH R01 HL71862-06 and ARRA N000949304 (to APR). Some of the results of this paper were obtained by using the program package S. A. G. E., which is supported by a U.S. Public Health Service Resource Grant (RR03655) from the National Center for Research Resources.; The funders had no role in study design, data collection and analysis, decision to publish, orpreparation of the manuscript. NR 59 TC 56 Z9 56 U1 0 U2 8 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 JUN PY 2011 VL 7 IS 6 AR e1002108 DI 10.1371/journal.pgen.1002108 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 787OJ UT WOS:000292386300027 PM 21738479 ER PT J AU Smith, EN Koller, DL Panganiban, C Szelinger, S Zhang, P Badner, JA Barrett, TB Berrettini, WH Bloss, CS Byerley, W Coryell, W Edenberg, HJ Foroud, T Gershon, ES Greenwood, TA Guo, Y Hipolito, M Keating, BJ Lawson, WB Liu, C Mahon, PB McInnis, MG McMahon, FJ McKinney, R Murray, SS Nievergelt, CM Nurnberger, JI Nwulia, EA Potash, JB Rice, J Schulze, TG Scheftner, WA Shilling, PD Zandi, PP Zollner, S Craig, DW Schork, NJ Kelsoe, JR AF Smith, Erin N. Koller, Daniel L. Panganiban, Corrie Szelinger, Szabolcs Zhang, Peng Badner, Judith A. Barrett, Thomas B. Berrettini, Wade H. Bloss, Cinnamon S. Byerley, William Coryell, William Edenberg, Howard J. Foroud, Tatiana Gershon, Elliot S. Greenwood, Tiffany A. Guo, Yiran Hipolito, Maria Keating, Brendan J. Lawson, William B. Liu, Chunyu Mahon, Pamela B. McInnis, Melvin G. McMahon, Francis J. McKinney, Rebecca Murray, Sarah S. Nievergelt, Caroline M. Nurnberger, John I., Jr. Nwulia, Evaristus A. Potash, James B. Rice, John Schulze, Thomas G. Scheftner, William A. Shilling, Paul D. Zandi, Peter P. Zoellner, Sebastian Craig, David W. Schork, Nicholas J. Kelsoe, John R. TI Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes SO PLOS GENETICS LA English DT Article ID 7 COMMON DISEASES; POWER ANALYSIS; RISK; METAANALYSIS; INDIVIDUALS; ANK3 AB Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5 x 10(-7)). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (+/- 10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies. C1 [Smith, Erin N.; Bloss, Cinnamon S.; Murray, Sarah S.; Schork, Nicholas J.] Scripps Genom Med & Scripps Translat Sci Inst, La Jolla, CA USA. [Smith, Erin N.] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. [Smith, Erin N.] Univ Calif San Diego, Sch Med, Radys Childrens Hosp, La Jolla, CA 92093 USA. [Smith, Erin N.; Bloss, Cinnamon S.; Murray, Sarah S.] Scripps Hlth, La Jolla, CA USA. [Koller, Daniel L.; Edenberg, Howard J.; Foroud, Tatiana] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN USA. [Panganiban, Corrie; Szelinger, Szabolcs; Craig, David W.] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA. [Zhang, Peng; McInnis, Melvin G.; Zoellner, Sebastian] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Badner, Judith A.; Gershon, Elliot S.; Liu, Chunyu] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Barrett, Thomas B.] Portland VA Med Ctr, Dept Psychiat, Portland, OR USA. [Berrettini, Wade H.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Byerley, William] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Coryell, William] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Edenberg, Howard J.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN USA. [Greenwood, Tiffany A.; McKinney, Rebecca; Nievergelt, Caroline M.; Shilling, Paul D.; Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Guo, Yiran] Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Genon, Philadelphia, PA 19104 USA. [Guo, Yiran] Beijing Genom Inst Shenzhen, Shenzhen, Peoples R China. [Hipolito, Maria; Lawson, William B.; Nwulia, Evaristus A.] Howard Univ, Dept Psychiat, Washington, DC 20059 USA. [Keating, Brendan J.] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Keating, Brendan J.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Mahon, Pamela B.; Potash, James B.; Zandi, Peter P.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. [McMahon, Francis J.; Schulze, Thomas G.] NIMH, Mood & Anxiety Sect, Human Genet Branch, Intramural Res Program,NIH,US Dept Hlth & Human S, Bethesda, MD 20892 USA. [Nurnberger, John I., Jr.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN USA. [Rice, John] Washington Univ, Div Biostat, St Louis, MO USA. [Schulze, Thomas G.] Univ Gottingen, Dept Psychiat & Psychotherapy, Gottingen, Germany. [Scheftner, William A.] Rush Univ, Dept Psychiat, Chicago, IL 60612 USA. [Schork, Nicholas J.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Kelsoe, John R.] VA San Diego Healthcare Syst, Dept Psychiat, La Jolla, CA USA. RP Smith, EN (reprint author), Scripps Genom Med & Scripps Translat Sci Inst, La Jolla, CA USA. EM dcraig@tgen.org; nschork@scripps.edu; jkelsoe@ucsd.edu RI Guo, Yiran/H-4120-2011; Liu, Chunyu/G-7561-2012; Smith, Erin/E-5933-2011; McInnis, Melvin/F-6963-2012; Greenwood, Tiffany/F-6356-2012; Schulze, Thomas/H-2157-2013; Zhang, Peng/N-2920-2014; OI McMahon, Francis/0000-0002-9469-305X; Guo, Yiran/0000-0002-6549-8589; Liu, Chunyu/0000-0002-5986-4415; Edenberg, Howard/0000-0003-0344-9690; McInnis, Melvin/0000-0002-0375-6247; Greenwood, Tiffany/0000-0002-6080-6503; Zhang, Peng/0000-0003-1182-1392; Nievergelt, Caroline/0000-0001-5766-8923; Nurnberger, John/0000-0002-7674-1767; Lawson, William/0000-0002-9324-7090 FU NIMH; NHGRI [MH078151, MH081804, MH059567]; Genetic Association Information Network (GAIN); Tzedakah Foundation; NIH [R01 MH59553]; Philip and Marcia Cohen; Scripps Translational Sciences Institute; NIH/NCRR [UL1 RR025774]; Scripps Genomic Medicine FX This work was supported by grants from the NIMH and NHGRI to JRK (MH078151, MH081804, MH059567 supplement) and by the Genetic Association Information Network (GAIN). This work was additionally funded in part by the NIMH Intramural Research Program (FJM and TGS). WHB was supported by a grant from the Tzedakah Foundation, a grant from NIH (R01 MH59553), and a grant from Philip and Marcia Cohen. ENS, CSB, SSM, and NJS are supported in part by the Scripps Translational Sciences Institute Clinical Translational Science Award [NIH/NCRR Grant Number UL1 RR025774] and Scripps Genomic Medicine. DWC and CP would like to acknowledge the Stardust foundation. Follow-up genotyping was performed in the laboratory of HJE at Indiana University School of Medicine. Data and biomaterials were collected in four projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1991-1998, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, U01 MH46282, John Nurnberger, M. D., Ph. D., Marvin Miller, M. D., and Elizabeth Bowman, M. D.; Washington University, St. Louis, MO, U01 MH46280, Theodore Reich, M. D., Allison Goate, Ph. D., and John Rice, Ph. D.; Johns Hopkins University, Baltimore, MD U01 MH46274, J. Raymond DePaulo, Jr., M. D., Sylvia Simpson, M. D., MPH, and Colin Stine, Ph. D.; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD, Elliot Gershon, M. D., Diane Kazuba, B. A., and Elizabeth Maxwell, M. S. W. Data and biomaterials were collected as part of ten projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1999-2007, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, R01 MH59545, John Nurnberger, M. D., Ph. D., Marvin J. Miller, M. D., Elizabeth S. Bowman, M. D., N. Leela Rau, M. D., P. Ryan Moe, M. D., Nalini Samavedy, M. D., Rif El-Mallakh, M. D. (at University of Louisville), Husseini Manji, M. D. (at Wayne State University), Debra A. Glitz, M. D. (at Wayne State University), Eric T. Meyer, M. S., Carrie Smiley, R. N., Tatiana Foroud, Ph. D., Leah Flury, M. S., Danielle M. Dick, Ph. D., Howard J. Edenberg, Ph. D.; Washington University, St. Louis, MO, R01 MH059534, John Rice, Ph. D, Theodore Reich, M. D., Allison Goate, Ph. D., Laura Bierut, M. D.; Johns Hopkins University, Baltimore, MD, R01 MH59533, Melvin McInnis M. D., J. Raymond DePaulo, Jr., M. D., Dean F. MacKinnon, M. D., Francis M. Mondimore, M. D., James B. Potash, M. D., Peter P. Zandi, Ph. D, Dimitrios Avramopoulos, and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553, Wade Berrettini M. D., Ph. D.; University of California at Irvine, CA, R01 MH60068, William Byerley M. D., and Mark Vawter M. D.; University of Iowa, IA, R01 MH059548, William Coryell M. D., and Raymond Crowe M. D.; University of Chicago, IL, R01 MH59535, Elliot Gershon, M. D., Judith Badner Ph. D., Francis McMahon M. D., Chunyu Liu Ph. D., Alan Sanders M. D., Maria Caserta, Stephen Dinwiddie M. D., Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567, John Kelsoe, M. D., Rebecca McKinney, B. A.; Rush University, IL, R01 MH059556, William Scheftner M. D., Howard M. Kravitz, D. O., M. P. H., Diana Marta, B. S., Annette Vaughn-Brown, MSN, RN, and Laurie Bederow, MA; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, Francis J. McMahon, M. D., Layla Kassem, PsyD, Sevilla Detera-Wadleigh, Ph. D, Lisa Austin, Ph. D, Dennis L. Murphy, M. D.; Data nd biomaterials from the NIMH GI (Genetics Initiative) MGS2 (Molecular Genetics of Schizophrenia) control sample were collected by NorthShore University HealthSystem, Evanston, IL, R01 MH59571, Pablo V. Gejman, M. D. (Collaboration Coordinator; PI) as part of a collaborative R01 application comprised of ten sites. From 2003-2006, the Principal Investigators and Co-Investigators were: NorthShore University HealthSystem, Evanston, IL, R01 MH59571, Pablo V. Gejman, M. D. (Collaboration Coordinator; PI), Alan R. Sanders, M. D.; Emory University School of Medicine, Atlanta, GA, R01 MH59587, Farooq Amin, M. D. (PI); University of California, San Francisco, CA, R01 MH60870, William F. Byerley, M. D. (PI); University of Iowa, Iowa, IA, R01 MH59566, Donald W. Black, M. D. (PI), Raymond R. Crowe, M. D.; Washington University, St. Louis, MO, R01 MH60879, C. Robert Cloninger, M. D. (PI); University of Colorado, Denver, CO, R01 MH59565, Robert Freedman, M. D. (PI), Ann Olincy, M. D.; Stanford University, Palo Alto, CA, R01 MH61675, Douglas F. Levinson, M. D. (PI); Louisiana State University, New Orleans, LA, R01 MH67257, Nancy G. Buccola, APRN, BC, MSN (PI); University of Queensland, Brisbane, Queensland, Australia, R01 MH59588, Bryan J. Mowry, M. D. (PI); Mt. Sinai School of Medicine, New York, NY, R01 MH59586, Jeremy M. Silverman, Ph. D. (PI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 36 Z9 37 U1 1 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 JUN PY 2011 VL 7 IS 6 AR e1002134 DI 10.1371/journal.pgen.1002134 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 787OJ UT WOS:000292386300049 PM 21738484 ER PT J AU McFarland, MJ Wright, BRE Weakliem, DL AF McFarland, Michael J. Wright, Bradley R. E. Weakliem, David L. TI Educational Attainment and Religiosity: Exploring Variations by Religious Tradition SO SOCIOLOGY OF RELIGION LA English DT Article DE education; attendance; prayer; beliefs; biblical literalism; denominations ID SOCIOECONOMIC-STATUS; NETWORK THEORY; PARTICIPATION; FUNDAMENTALISM; PREDICTORS; COMMUNITY; CHURCH AB This study examines the relationship between educational attainment and various dimensions of religiosity. On the basis of a network closure argument, we hypothesize that the relationship between education and religiosity varies by religious tradition. Analyzing data from the 1972-2006 General Social Survey, we found that educational attainment predicted increased attendance at religious services, decreased levels of prayer, increased inclination to view the Bible as a book of fables, and decreased inclination to view the Bible as the literal word of God. These relationships, however, significantly interacted with religious tradition. Increased education largely resulted in greater religiosity among evangelical Protestants, black Protestants, and Catholics but not among mainline Protestants and the nonaffiliated. Overall, this study shows that education does not uniformly decrease religiosity and highlights the importance of considering religious tradition in future research. C1 [McFarland, Michael J.] Univ Texas Austin, Dept Sociol, NICHD, Austin, TX 78705 USA. [Wright, Bradley R. E.] Univ Connecticut, Dept Sociol, Storrs, CT 06269 USA. RP McFarland, MJ (reprint author), Univ Texas Austin, Dept Sociol, NICHD, Austin, TX 78705 USA. EM mmcfarland@prc.utexas.edu NR 46 TC 16 Z9 16 U1 5 U2 34 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1069-4404 J9 SOCIOL RELIG JI Sociol. Relig. PD SUM PY 2011 VL 72 IS 2 BP 166 EP 188 DI 10.1093/socrel/srq065 PG 23 WC Sociology; Religion SC Sociology; Religion GA 788PX UT WOS:000292458000003 ER PT J AU Norton, JA Harris, EJ Chen, YJ Visser, BC Poultsides, GA Kunz, PC Fisher, GA Jensen, RT AF Norton, Jeffrey A. Harris, Edmund J. Chen, Yijun Visser, Brendan C. Poultsides, George A. Kunz, Pamela C. Fisher, George A. Jensen, Robert T. TI Pancreatic Endocrine Tumors With Major Vascular Abutment, Involvement, or Encasement and Indication for Resection SO ARCHIVES OF SURGERY LA English DT Article ID ZOLLINGER-ELLISON-SYNDROME; ISLET-CELL-CARCINOMA; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS; BLEEDING GASTRIC VARICES; SPLENIC VEIN OCCLUSION; PORTAL-VEIN; PROGNOSTIC-FACTORS; LONG-TERM; LIVER METASTASES AB Background: Surgery for pancreatic endocrine tumors (PETs) with blood vessel involvement is controversial. Hypothesis: Resection of PETs with major blood vessel involvement can be beneficial. Design: The combined databases of the National Institutes of Health and Stanford University hospitals were queried. Main Outcome Measures: Operation, pathologic condition, complications, and disease-free and overall survival. Results: Of 273 patients with PETs, 46 (17%) had pre-operative computed tomography evidence of major vascular involvement. The mean size for the primary PET was 5.0 cm. The involved major vessel was as follows: portal vein (n = 20), superior mesenteric vein or superior mesenteric artery (n = 16), inferior vena cava (n = 4), splenic vein (n = 4), and heart (n = 2). Forty-two of 46 patients had a PET removed: 12 (27%) primary only, 30 (68%) with lymph nodes, and 18 (41%) with liver metastases. PETs were removed by either enucleation (n = 7) or resection (n = 35). Resections included distal or subtotal pancreatectomy in 23, Whipple in 10, and total in 2. Eighteen patients had concomitant liver resection: 10 wedge resection and 8 anatomic resections. Nine patients had vascular reconstruction: each had reconstruction of the superior mesenteric vein and portal vein, and 1 had concomitant reconstruction of the superior mesenteric artery. There were no deaths, but 12 patients had complications. Eighteen patients (41%) were immediately disease free, and 5 recurred with follow-up, leaving 13 (30%) disease-free long term. The 10-year overall survival was 60%. Functional tumors were associated with a better overall survival (P < .001), and liver metastases decreased overall survival (P < .001). Conclusion: These findings suggest that surgical resection of PETs with vascular abutment/invasion and nodal or distant metastases is indicated. C1 [Norton, Jeffrey A.] Stanford Univ, Med Ctr, Dept Surg, Stanford, CA 94305 USA. [Jensen, Robert T.] NIH, Bethesda, MD 20892 USA. RP Norton, JA (reprint author), Stanford Univ, Med Ctr, Dept Surg, 300 Pasteur Dr,Room H-3591, Stanford, CA 94305 USA. EM janorton@stanford.edu FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This study was partially supported by intramural funds of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 99 TC 34 Z9 35 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD JUN PY 2011 VL 146 IS 6 BP 724 EP 732 PG 9 WC Surgery SC Surgery GA 780JI UT WOS:000291851500018 PM 21690450 ER PT J AU Ward, MM AF Ward, Michael M. TI Sulfasalazine for the Treatment of Ankylosing Spondylitis: Relic or Niche Medication? SO ARTHRITIS AND RHEUMATISM LA English DT Editorial Material ID PLACEBO; TRIAL C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS NR 12 TC 0 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD JUN PY 2011 VL 63 IS 6 BP 1472 EP 1474 DI 10.1002/art.30225 PG 3 WC Rheumatology SC Rheumatology GA 778EH UT WOS:000291683200002 PM 21630241 ER PT J AU Orman, ES Conjeevaram, HS Vuppalanchi, R Freston, JW Rochon, J Kleiner, DE Hayashi, PH AF Orman, Eric S. Conjeevaram, Hari S. Vuppalanchi, Raj Freston, James W. Rochon, James Kleiner, David E. Hayashi, Paul H. CA DILIN Res Grp TI Clinical and Histopathologic Features of Fluoroquinolone-Induced Liver Injury SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE ALT; Drug Toxicity; Side Effect; Antibiotics; Adverse Reaction ID FULMINANT HEPATIC-FAILURE; CIPROFLOXACIN-INDUCED HEPATOTOXICITY; CHOLESTATIC HEPATITIS; CAUSALITY ASSESSMENT; SAFETY PROFILE; HYPERSENSITIVITY REACTIONS; ADVERSE REACTIONS; UNITED-STATES; LEVOFLOXACIN; PATIENT AB BACKGROUND & AIMS: Fluoroquinolone-induced liver injury is rare; no prospective studies of well-characterized case series have been published. We studied patients with fluoroquinolone-induced hepatotoxicity from the Drug-Induced Liver Injury Network (DILIN) to characterize injury patterns, outcomes, and associated features. METHODS: We identified subjects with fluoroquinolone hepatotoxicity enrolled in the DILIN from September 2004 to January 2010. Demographic, clinical, and laboratory data were analyzed by descriptive statistical methods. RESULTS: Of the 679 registrants in the DILIN prospective study, 12 had fluoroquinolone hepatotoxicity (6 ciprofloxacin, 4 moxifloxacin, 1 levofloxacin, and 1 gatifloxacin). Seven were women; median age was 57 years (range, 23-80 years), and median time from fluoroquinolone start to symptoms was only 4 days (range, 1-39 days). Nine patients developed symptoms on medication; 3 did so 2, 8, and 32 days after stopping the medication. Cases were equally distributed among hepatocellular injury (predominantly increased levels of alanine aminotransferase), cholestatic injury (predominantly increased levels of alkaline phosphatase), and both. Seven patients had immunoallergic features. Patients with mixed hepatocellular and cholestatic injury had mild disease without jaundice; all recovered. In contrast, 2 of 4 patients with hepatocellular injury and jaundice died, 1 of acute liver failure. One patient with cholestatic injury developed vanishing bile duct syndrome and required liver transplantation; another had a persistently increased serum level of alkaline phosphatase. CONCLUSIONS: Fluoroquinolone liver injury is rapid in onset and often has immunoallergic features, indicating a hypersensitivity reaction. The pattern of injury can be hepatocellular, cholestatic, or mixed; mixed cases are the least severe. Acute and chronic liver failure can occur. C1 [Hayashi, Paul H.] Univ N Carolina, UNC Liver Ctr, Div Gastroenterol & Hepatol, Chapel Hill, NC 27599 USA. [Conjeevaram, Hari S.] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Vuppalanchi, Raj] Indiana Univ Sch Med, Div Gastroenterol, Indianapolis, IN USA. [Freston, James W.] Univ Connecticut, Div Gastroenterol, Hlth Sci Ctr, Farmington, CT USA. [Rochon, James] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Hayashi, PH (reprint author), Univ N Carolina, UNC Liver Ctr, Div Gastroenterol & Hepatol, CB 7584 Bumett Womack Bldg,Rm 8011, Chapel Hill, NC 27599 USA. EM paul_hayashi@med.unc.edu OI Vuppalanchi, Raj/0000-0003-0637-1577; Kleiner, David/0000-0003-3442-4453 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [2U01-DK065176-06 (Duke), 2U01-DK065201-06 (UNC), 2U01-DK065184-06 (Michigan), 2U01-DK065211-06 (Indiana), 5U01DK065193-04 (UConn), 5U01-DK065238-08 (UCSF/CPMC), 1U01-DK083023-01 (UTSW), 1U01-DK083027-01 (TJH/UPenn), 1U01-DK082992-01 (Mayo), 1U01-DK083020-01 (USC)]; CTSA [UL1 RR025761 (Indiana), UL1 RR025747 (UNC), UL1 RR024134 (UPenn), UL1 RR024986 (Michigan), UL1 RR024982 (UTSW), UL1 RR024150 (Mayo)]; NIH, National Cancer Institute FX The DILIN Network is structured as a U01 cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grants: 2U01-DK065176-06 (Duke), 2U01-DK065201-06 (UNC), 2U01-DK065184-06 (Michigan), 2U01-DK065211-06 (Indiana), 5U01DK065193-04 (UConn), 5U01-DK065238-08 (UCSF/CPMC), 1U01-DK083023-01 (UTSW), 1U01-DK083027-01 (TJH/UPenn), 1U01-DK082992-01 (Mayo), 1U01-DK083020-01 (USC). Additional funding is provided by CTSA grants: UL1 RR025761 (Indiana), UL1 RR025747 (UNC), UL1 RR024134 (UPenn), UL1 RR024986 (Michigan), UL1 RR024982 (UTSW), UL1 RR024150 (Mayo) and in part by the Intramural Research Program of the NIH, National Cancer Institute. NR 54 TC 37 Z9 41 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD JUN PY 2011 VL 9 IS 6 BP 517 EP U101 DI 10.1016/j.cgh.2011.02.019 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 778HA UT WOS:000291693300019 PM 21356330 ER PT J AU Sacks, DB Arnold, M Bakris, GL Bruns, DE Horvath, AR Kirkman, MS Lernmark, A Metzger, BE Nathan, DM AF Sacks, David B. Arnold, Mark Bakris, George L. Bruns, David E. Horvath, Andrea Rita Kirkman, M. Sue Lernmark, Ake Metzger, Boyd E. Nathan, David M. TI Position Statement Executive Summary: Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus SO DIABETES CARE LA English DT Article ID US AB BACKGROUND-Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. APPROACH-An expert committee compiled evidence-based recommendations for the use of laboratory analysis in patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. A draft of the guidelines was posted on the Internet, and the document was modified in response to comments. The guidelines were reviewed by the joint Evidence-Based Laboratory Medicine Committee of the AACC and the National Academy of Clinical Biochemistry and were accepted after revisions by the Professional Practice Committee and subsequent approval by the Executive Committee of the American Diabetes Association. CONTENT-In addition to the long-standing criteria based on measurement of venous plasma glucose, diabetes can be diagnosed by demonstrating increased hemoglobin A(1c) (HbA(1c)) concentrations in the blood. Monitoring of glycemic control is performed by the patients measuring their own plasma or blood glucose with meters and by laboratory analysis of HbA(1c). The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY-The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended. C1 [Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Arnold, Mark] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. [Bakris, George L.] Univ Chicago, Dept Med, Hypertens Dis Unit, Sect Endocrinol Diabet & Metab, Chicago, IL 60637 USA. [Bruns, David E.] Univ Virginia, Sch Med, Dept Pathol, Charlottesville, VA 22908 USA. [Horvath, Andrea Rita] Univ Sydney, Prince Wales Hosp, SEALS Dept Clin Chem, Screening & Test Evaluat Program,Sch Publ Hlth, Sydney, NSW 2006, Australia. [Kirkman, M. Sue] Amer Diabet Assoc, Alexandria, VA USA. [Lernmark, Ake] Lund Univ, Dept Clin Sci, Skane Univ Hosp, CRC, Malmo, Sweden. [Metzger, Boyd E.] Northwestern Univ, Feinberg Sch Med, Div Endocrinol, Chicago, IL 60611 USA. [Nathan, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nathan, David M.] Harvard Univ, Sch Med, Ctr Diabet, Boston, MA USA. RP Sacks, DB (reprint author), NIH, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. EM sacksdb@mail.nih.gov OI Sacks, David/0000-0003-3100-0735 FU ASL Analytical, Inc.; GlaxoSmithKline; Forest Laboratories; Novartis; Abbott Diagnostics; Siemens; BD FX Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. D.B.S. and D.E.B. reported employment or leadership positions with Clinical Chemistry, AACC. M.A. reported employment or leadership positions with, research funding from, and stock ownership in ASL Analytical, Inc. G.L.B. reported consultant or advisory role for Novartis, Takeda, Johnson & Johnson, and Merck and received research funding from GlaxoSmithKline, Forest Laboratories, and Novartis. D.E.B. received research funding from Abbott Diagnostics, Siemens, and BD. A.R.H. reported honoraria from MediLab Ltd. (Hungary) and received other remuneration from Diagon Ltd. Hungary, Roche Diagnostics (Hungary), and Becton Dickinson. A.L. reported consultant or advisory role for Diamyd Medical AB and Probi AB. No other potential conflicts of interest relevant to this article were reported. NR 8 TC 51 Z9 59 U1 2 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2011 VL 34 IS 6 BP 1419 EP 1423 DI 10.2337/dc11-9997 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 780HX UT WOS:000291846200036 PM 21617111 ER PT J AU Horvath, KA Mazilu, D Kocaturk, O Li, M AF Horvath, Keith A. Mazilu, Dumitru Kocaturk, Ozgur Li, Ming TI Transapical aortic valve replacement under real-time magnetic resonance imaging guidance: experimental results with balloon-expandable and self-expanding stents SO EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY LA English DT Article DE Transcatheter aortic valve implantation; rtMRI guidance; Self-expanding stent; Balloon-expandable stent ID INTERACTIVE MRI; IMPLANTATION; FEASIBILITY; PROSTHESIS; EXPERIENCE; STENOSIS; RETROGRADE; THERAPIES; DISEASE; HUMANS AB Objective: Aortic valves have been implanted on self-expanding (SE) and balloon-expandable (BE) stents minimally invasively. We have demonstrated the advantages of transapical aortic valve implantation (tAVI) under real-time magnetic resonance imaging (rtMRI) guidance. Whether there are different advantages to SE or BE stents is unknown. We report rtMRI-guided tAVI in a porcine model using both SE and BE stents, and compare the differences between the stents. Methods: A total of 22 Yucatan pigs (45-57 kg) underwent tAVI. Commercially available stentless bioprostheses (21-25 mm) were mounted on either BE platinum-iridium stents or SE-nitinol stents. rtMRI guidance was employed as the intraoperative imaging. Markers on both types of stents were used to enhance visualization in rtMRI. Pigs were allowed to survive and had follow-up MRI scans and echocardiography at 1, 3, and 6 months postoperatively. Results: rtMRI provided excellent visualization of the aortic valve implantation mounted on both stent types. The implantation times were shorter with the SE stents (60 +/- 14 s) than with the BE stents (74 +/- 18 s), (p = 0.027). The total procedure time was 31 and 37 min, respectively (p = 0.12). It was considerably easier to manipulate the SE stent during deployment, without hemodynamic compromise. This was not always the case with the BE stent, and its placement occasionally resulted in coronary obstruction and death. Long-term results demonstrated stability of the implants with preservation of myocardial perfusion and function over time for both stents. Conclusions: SE stents were easier to position and deploy, thus leading to fewer complications during tAVI. Future optimization of SE stent design should improve clinical results. (C) 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. C1 [Horvath, Keith A.; Mazilu, Dumitru; Li, Ming] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Kocaturk, Ozgur] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Horvath, KA (reprint author), NHLBI, Cardiothorac Surg Res Program, NIH, Bldg 10,2N246,10 Ctr Dr, Bethesda, MD 20892 USA. EM horvathka@mail.nih.gov RI Kocaturk, Ozgur/A-1419-2016 FU National Heart, Lung, and Blood Institute, NIH, DHHS FX The authors are supported through the Intramural Research Program of the National Heart, Lung, and Blood Institute, NIH, DHHS. NR 23 TC 16 Z9 16 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1010-7940 J9 EUR J CARDIO-THORAC JI Eur. J. Cardio-Thorac. Surg. PD JUN PY 2011 VL 39 IS 6 BP 822 EP 828 DI 10.1016/j.ejcts.2010.09.030 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 777BA UT WOS:000291586500014 PM 20971017 ER PT J AU Bolukbas, S Eberlein, M Eckhoff, J Schirren, J AF Boeluekbas, Servet Eberlein, Michael Eckhoff, Jennifer Schirren, Joachim TI Short-term effects of inhalative tiotropium/formoterol/budenoside versus tiotropium/formoterol in patients with newly diagnosed chronic obstructive pulmonary disease requiring surgery for lung cancer: a prospective randomized trial SO EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY LA English DT Article; Proceedings Paper CT 18th European Conference on General Thoracic Surgery of the European-Society-of-Thoracic-Surgeons CY MAY 30-JUN 02, 2010 CL Valladolid, SPAIN SP European Soc Thorac Surg DE COPD; NSCLC; RCT; Surgery ID INHALED TIOTROPIUM; PRIMARY-CARE; COPD; PREVALENCE; THERAPY; UNDERDIAGNOSIS; COMPLICATIONS; COMBINATION; SALMETEROL; RISK AB Objective: A new diagnosis of chronic obstructive pulmonary disease (COPD) is often made during the evaluation of patients requiring a surgical intervention for lung cancer. Based on initial impaired lung function, these untreated patients are often considered not fit for lung surgery. There is limited information on the short-term effectiveness of preoperative pharmacologic treatment strategies in patients with newly diagnosed COPD before lung surgery. Methods: A prospective randomized study was conducted comparing 1-week-treatment periods of tiotropium/formoterol/budenoside (GR1) with tiotropium/formoterol (GR2) in conjunction with smoking cessation and chest physiotherapy. No patients had been previously treated for COPD. The primary end point was body plethysmography (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and airway resistance (RAW)) at the end of each treatment period. Secondary end points were improvement of >= 10% in FEV1 (% predicted) and improvement of the severity of COPD after the 1-week treatment, as well as the rate of pulmonary complications after surgery. Results: A total of 46 patients were randomized in GR1 (n = 24) and GR2 (n = 22). Both groups were comparable with regard to age, height, weight, smoking history, baseline body plethysmography (FVC, FEV1, and RAW), and the severity of COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) staging, respectively. However, the short-term effects of the treatment with regard to FEV1 (2.0 l vs 1.7 l; p = 0.031) and increase of FEV1 (0.31 l vs 0.10 l; p = 0.02) were better in GR1. More patients in GR1 had an improvement of >= 10% in FEV1 (p = 0.004) and improvement of the severity of COPD (p = 0.012) after the 1-week treatment. Fewer pulmonary complications (11.1% vs 42.9%, p = 0.04) were observed in GR1 after surgery. Conclusions: Both therapies resulted in an improvement of lung function. There is benefit from adding inhalative budenoside to tiotropium and formoterol in terms of an improvement in FEV1 and the severity of COPD. These beneficial results might lead to less pulmonary complications in the postoperative period. (C) 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B. V. All rights reserved. C1 [Boeluekbas, Servet; Eckhoff, Jennifer; Schirren, Joachim] Dr Horst Schmidt Klin, Dept Thorac Surg, D-65199 Wiesbaden, Germany. [Eberlein, Michael] Johns Hopkins Univ Sch Med, Div Pulm & Crit Care Med, Baltimore, MD USA. [Eberlein, Michael] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Bolukbas, S (reprint author), Dr Horst Schmidt Klin, Dept Thorac Surg, Ludwig Erhard Str 100, D-65199 Wiesbaden, Germany. EM Dr.Bolukbas@gmx.de NR 24 TC 10 Z9 12 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1010-7940 J9 EUR J CARDIO-THORAC JI Eur. J. Cardio-Thorac. Surg. PD JUN PY 2011 VL 39 IS 6 BP 995 EP 1000 DI 10.1016/j.ejcts.2010.09.025 PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 777BA UT WOS:000291586500042 PM 20970351 ER PT J AU Sallinen, J Stenholm, S Rantanen, T Helioaara, M Sainio, P Koskinen, S AF Sallinen, J. Stenholm, S. Rantanen, T. Helioaara, M. Sainio, P. Koskinen, S. TI Effect of age on the association between body fat percentage and maximal walking speed SO JOURNAL OF NUTRITION HEALTH & AGING LA English DT Article DE Older adults; obesity; mobility; body composition ID SKELETAL-MUSCLE MASS; CARDIOVASCULAR HEALTH; OLDER PERSONS; OBESITY; WOMEN; INDEX; LIMITATION; MEN; DISABILITY; MOBILITY AB To study the effect of age on the association between body fat percentage and maximal walking speed in older people. Cross-sectional analysis of data collected in the Finnish population-based Health 2000 Survey involving 916 men and 1 222 women aged 55 years and older with complete data on body composition and a walking speed test. Body fat percentage was assessed using bioelectrical impedance analysis and maximal walking speed based on a timed walking test over a distance of 6.1 meters. Linear regression models were used to study the effect of age on association between body fat percentage and maximal walking speed. The association between body fat percentage quartiles and maximal walking speed differed significantly between persons of different ages (p for age interaction = 0.027). In the agestratified analyses, the association between body fat percentage and maximal walking speed remained significant among 60-69-year olds and 70-79-year olds, but disappeared among 55-59-year-olds and 80-year and older after adjustment for potential covariates. Body fat percentage explained 11% of the variation in maximal walking speed among 55-59-year-olds, 21% among 60-69-year-olds, 17% among 70-79-year-olds and 11% among 80-year and older. Association between body fat percentage and maximal walking speed was strongest between the ages of 60 and 79 years. The results suggest that the effects of excess body fatness are especially harmful for physical functioning among adults in their sixties and seventies and they could benefit from interventions. C1 [Stenholm, S.; Helioaara, M.; Sainio, P.; Koskinen, S.] Natl Inst Hlth & Welf, Funct Capac Unit, Dept Hlth Funct Capac & Welf, Helsinki, Finland. [Stenholm, S.] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Sallinen, J.; Rantanen, T.] Univ Jyvaskyla, Dept Hlth Sci, Gerontol Res Ctr, SF-40351 Jyvaskyla, Finland. RP Sallinen, J (reprint author), VTT Tech Res Ctr Finland, POB 1199, FIN-70211 Kuopio, Finland. EM Janne.Sallinen@vtt.fi RI Stenholm, Sari/G-6940-2011; Rantanen, Taina/O-6579-2016 OI Rantanen, Taina/0000-0002-1604-1945 FU Ministry of Education, Finland; NIH, National Institute on Aging; Finnish Academy [125494] FX Janne Sallinen was supported by a research grant from the Ministry of Education, Finland. This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging and by a grant from the Finnish Academy (no. 125494, Sari Stenholm). Taina Rantanen, Markku Heliovaara, Paivi Sainio and Seppo Koskinen have no conflicts of interest to report. The sponsor of this research had no role in the design, methodology, analysis of data, or preparation of the manuscript. NR 29 TC 4 Z9 6 U1 0 U2 2 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 1279-7707 J9 J NUTR HEALTH AGING JI J. Nutr. Health Aging PD JUN PY 2011 VL 15 IS 6 BP 427 EP 432 DI 10.1007/s12603-010-0140-8 PG 6 WC Geriatrics & Gerontology; Nutrition & Dietetics SC Geriatrics & Gerontology; Nutrition & Dietetics GA 777VM UT WOS:000291653200001 PM 21623462 ER PT J AU Rid, A Wendler, D AF Rid, Annette Wendler, David TI A Framework for Risk-Benefit Evaluations in Biomedical Research SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID CANCER CLINICAL-TRIALS; BOARD IRB MEMBERS; MINIMAL RISK; RESEARCH ETHICS; THERAPEUTIC MISCONCEPTION; INTEGRATIVE APPROACH; PEDIATRIC RESEARCH; EQUIPOISE; STANDARD; CARE AB Essentially all guidelines and regulations require that biomedical research studies have an acceptable risk-benefit profile. However, these documents offer little concrete guidance for implementing this requirement and determining when it is satisfied. As a result, those charged with risk-benefit evaluations currently assess the risk-benefit profile of biomedical research studies in unsystematic ways, raising concern that some research participants are not being protected from excessive risks and that some valuable studies involving acceptable risk are being rejected. The present paper aims to address this situation by delineating the first comprehensive framework, which is based on existing guidelines and regulations as well as the relevant literature, for risk-benefit evaluations in biomedical research. C1 [Rid, Annette] Univ Zurich, Inst Biomed Eth, CH-8006 Zurich, Switzerland. [Wendler, David] NIH, Unit Vulnerable Populat, Dept Bioeth, Ctr Clin, Bethesda, MD USA. [Wendler, David] Natl Inst Drug Abuse, IRB, Lexington, KY USA. [Wendler, David] NIH, Bioeth Consultat Serv, Bethesda, MD USA. RP Rid, A (reprint author), Univ Zurich, Inst Biomed Eth, CH-8006 Zurich, Switzerland. NR 64 TC 31 Z9 31 U1 3 U2 16 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 JUN PY 2011 VL 21 IS 2 BP 141 EP 179 PG 39 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 778NS UT WOS:000291712000002 PM 21696094 ER PT J AU Zhang, DP Iyer, LM Aravind, L AF Zhang, Dapeng Iyer, Lakshminarayan M. Aravind, L. TI A novel immunity system for bacterial nucleic acid degrading toxins and its recruitment in various eukaryotic and DNA viral systems SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; HUMAN CYTOMEGALOVIRUS TRS1; CELL-WALL SYNTHESIS; PROTEIN-KINASE-R; SECY-INTERACTING PROTEIN; STRANDED-RNA BINDING; CRYSTAL-STRUCTURE; MURINE CYTOMEGALOVIRUS; STRUCTURE PREDICTION; ESCHERICHIA-COLI AB The use of nucleases as toxins for defense, offense or addiction of selfish elements is widely encountered across all life forms. Using sensitive sequence profile analysis methods, we characterize a novel superfamily (the SUKH superfamily) that unites a diverse group of proteins including Smi1/Knr4, PGs2, FBXO3, SKIP16, Syd, herpesviral US22, IRS1 and TRS1, and their bacterial homologs. Using contextual analysis we present evidence that the bacterial members of this superfamily are potential immunity proteins for a variety of toxin systems that also include the recently characterized contact-dependent inhibition (CDI) systems of proteobacteria. By analyzing the toxin proteins encoded in the neighborhood of the SUKH superfamily we predict that they possess domains belonging to diverse nuclease and nucleic acid deaminase families. These include at least eight distinct types of DNases belonging to HNH/EndoVII- and restriction endonuclease-fold, and RNases of the EndoU-like and colicin E3-like cytotoxic RNases-folds. The N-terminal domains of these toxins indicate that they are extruded by several distinct secretory mechanisms such as the two-partner system (shared with the CDI systems) in proteobacteria, ESAT-6/WXG-like ATP-dependent secretory systems in Gram-positive bacteria and the conventional Sec-dependent system in several bacterial lineages. The hedgehog-intein domain might also release a subset of toxic nuclease domains through auto-proteolytic action. Unlike classical colicin-like nuclease toxins, the overwhelming majority of toxin systems with the SUKH superfamily is chromosomally encoded and appears to have diversified through a recombination process combining different C-terminal nuclease domains to N-terminal secretion-related domains. Across the bacterial superkingdom these systems might participate in discriminating `self' or kin from `non-self' or non-kin strains. Using structural analysis we demonstrate that the SUKH domain possesses a versatile scaffold that can be used to bind a wide range of protein partners. In eukaryotes it appears to have been recruited as an adaptor to regulate modification of proteins by ubiquitination or polyglutamylation. Similarly, another widespread immunity protein from these toxin systems, namely the suppressor of fused (SuFu) superfamily has been recruited for comparable roles in eukaryotes. In animal DNA viruses, such as herpesviruses, poxviruses, iridoviruses and adenoviruses, the ability of the SUKH domain to bind diverse targets has been deployed to counter diverse anti-viral responses by interacting with specific host proteins. C1 [Zhang, Dapeng; Iyer, Lakshminarayan M.; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU National Institutes of Health; National Library of Medicine at the National Institutes of Health, USA; National Institutes of Health, USA FX National Institutes of Health Postdoctoral Visiting Fellowship; intramural funds of the National Library of Medicine at the National Institutes of Health, USA. Funding for open access charge: Intramural funds of the National Institutes of Health, USA. NR 98 TC 51 Z9 51 U1 2 U2 11 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 JUN PY 2011 VL 39 IS 11 BP 4532 EP 4552 DI 10.1093/nar/gkr036 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 779CF UT WOS:000291755000008 PM 21306995 ER PT J AU Pandey, SP Minesinger, BK Kumar, J Walker, GC AF Pandey, Shree P. Minesinger, Brenda K. Kumar, Janesh Walker, Graham C. TI A highly conserved protein of unknown function in Sinorhizobium meliloti affects sRNA regulation similar to Hfq SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ESCHERICHIA-COLI; MESSENGER-RNA; CRYSTAL-STRUCTURE; LIGAND-BINDING; RIBOSOMAL-RNA; CHAPERONE HFQ; RHIZOBIUM-LEGUMINOSARUM; NICOTIANA-ATTENUATA; STRESS PROTECTION; NONCODING RNAS AB The SMc01113/YbeY protein, belonging to the UPF0054 family, is highly conserved in nearly every bacterium. However, the function of these proteins still remains elusive. Our results show that SMc01113/YbeY proteins share structural similarities with the MID domain of the Argonaute (AGO) proteins, and might similarly bind to a small-RNA (sRNA) seed, making a special interaction with the phosphate on the 5'-side of the seed, suggesting they may form a component of the bacterial sRNA pathway. Indeed, eliminating SMc01113/YbeY expression in Sinorhizobium meliloti produces symbiotic and physiological phenotypes strikingly similar to those of the hfq mutant. Hfq, an RNA chaperone, is central to bacterial sRNA-pathway. We evaluated the expression of 13 target genes in the smc01113 and hfq mutants. Further, we predicted the sRNAs that may potentially target these genes, and evaluated the accumulation of nine sRNAs in WT and smc01113 and hfq mutants. Similar to hfq, smc01113 regulates the accumulation of sRNAs as well as the target mRNAs. AGOs are central components of the eukaryotic sRNA machinery and conceptual parallels between the prokaryotic and eukaryotic sRNA pathways have long been drawn. Our study provides the first line of evidence for such conceptual parallels. Furthermore, our investigation gives insights into the sRNA-mediated regulation of stress adaptation in S. meliloti. C1 [Pandey, Shree P.; Minesinger, Brenda K.; Walker, Graham C.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Kumar, Janesh] NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Walker, GC (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM gwalker@mit.edu OI /0000-0001-7243-8261 FU National Institutes of Health [GM31030, F32 GM078966]; MIT Center for Environmental Health Sciences NIEHS [P30 ES002109] FX National Institutes of Health grant GM31030 (to G. C. W.); MIT Center for Environmental Health Sciences NIEHS P30 ES002109; National Institutes of Health fellowship F32 GM078966 (to B. K. M.). Funding for open access charge: National Institute of Health grant GM31030. NR 98 TC 40 Z9 41 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN PY 2011 VL 39 IS 11 BP 4691 EP 4708 DI 10.1093/nar/gkr060 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 779CF UT WOS:000291755000020 PM 21325267 ER PT J AU Iben, JR Epstein, JA Bayfield, MA Bruinsma, MW Hasson, S Bacikova, D Ahmad, D Rockwell, D Kittler, ELW Zapp, ML Maraia, RJ AF Iben, James R. Epstein, Jonathan A. Bayfield, Mark A. Bruinsma, Monique W. Hasson, Samuel Bacikova, Dagmar Ahmad, Daniel Rockwell, Denise Kittler, Ellen L. W. Zapp, Maria L. Maraia, Richard J. TI Comparative whole genome sequencing reveals phenotypic tRNA gene duplication in spontaneous Schizosaccharomyces pombe La mutants SO NUCLEIC ACIDS RESEARCH LA English DT Article ID POLYMERASE-III TRANSCRIPTS; SERINE TRANSFER-RNA; FISSION YEAST; CELL-CYCLE; SACCHAROMYCES-CEREVISIAE; MITOCHONDRIAL GENOME; CHAPERONE ACTIVITY; PROTEIN; MATURATION; RECOGNITION AB We used a genetic screen based on tRNA-mediated suppression (TMS) in a Schizosaccharomyces pombe La protein (Sla1p) mutant. Suppressor pre-tRNA(Ser)UCA-C47:6U with a debilitating substitution in its variable arm fails to produce tRNA in a sla1-rrm mutant deficient for RNA chaperone-like activity. The parent strain and spontaneous mutant were analyzed using Solexa sequencing. One synonymous single-nucleotide polymorphism (SNP), unrelated to the phenotype, was identified. Further sequence analyses found a duplication of the tRNA(Ser)UCA-C47:6U gene, which was shown to cause the phenotype. Ninety percent of 28 isolated mutants contain duplicated tRNA(Ser)UCA-C47:6U genes. The tRNA gene duplication led to a disproportionately large increase in tRNA(Ser)UCA-C47:6U levels in sla1-rrm but not sla1-null cells, consistent with non-specific low-affinity interactions contributing to the RNA chaperone-like activity of La, similar to other RNA chaperones. Our analysis also identified 24 SNPs between ours and S. pombe 972h- strain yFS101 that was recently sequenced using Solexa. By including mitochondrial (mt) DNA in our analysis, overall coverage increased from 52% to 96%. mtDNA from our strain and yFS101 shared 14 mtSNPs relative to a 'reference' mtDNA, providing the first identification of these S. pombe mtDNA discrepancies. Thus, strain-specific and spontaneous phenotypic mutations can be mapped in S. pombe by Solexa sequencing. C1 [Iben, James R.; Epstein, Jonathan A.; Bayfield, Mark A.; Bruinsma, Monique W.; Hasson, Samuel; Bacikova, Dagmar; Ahmad, Daniel; Rockwell, Denise; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program Genom Differentiat, NIH, Worcester, MA USA. [Kittler, Ellen L. W.; Zapp, Maria L.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Maraia, Richard J.] US PHS, Commissioned Corps, Washington, DC USA. RP Maraia, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program Genom Differentiat, NIH, Worcester, MA USA. EM maraiar@mail.nih.gov FU NICHD; National Institutes of Health FX The Intramural Research Program of the NICHD; National Institutes of Health. Funding for open access charge: National Institutes of Health. NR 72 TC 6 Z9 6 U1 0 U2 3 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 JUN PY 2011 VL 39 IS 11 BP 4728 EP 4742 DI 10.1093/nar/gkr066 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 779CF UT WOS:000291755000023 PM 21317186 ER PT J AU Takeda, Y Kang, HS Angers, M Jetten, AM AF Takeda, Yukimasa Kang, Hong Soon Angers, Martin Jetten, Anton M. TI Retinoic acid-related orphan receptor gamma directly regulates neuronal PAS domain protein 2 transcription in vivo SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MAMMALIAN CIRCADIAN CLOCK; REV-ERB-ALPHA; BROWN ADIPOSE-TISSUE; X-RAY-STRUCTURE; NUCLEAR RECEPTOR; ROR-ALPHA; GENE-EXPRESSION; TARGET GENE; NPAS2; METABOLISM AB Retinoic acid-related orphan receptors (RORs) and the basic helix-loop-helix-PAS transcription factor Npas2 have been implicated in the control of circadian rhythm. In this study, we demonstrate that ROR gamma directly regulates Npas2 expression in vivo. Although the rhythmicity of Npas2 mRNA expression was maintained in ROR gamma(-/-) mice, the peak level of expression was significantly reduced in several tissues, while loss of ROR alpha had little effect. Inversely, overexpression of ROR gamma in hepatoma Hepa1-6 cells greatly induced the expression of Npas2. ROR gamma-activated Npas2 transcription directly by binding two ROREs in its proximal promoter. ChIP analysis demonstrated that ROR gamma was recruited to this promoter in the liver of wild-type mice, but not ROR gamma-deficient mice. Activation of Npas2 correlated positively with chromatin accessibility and level of H3K9 acetylation. The activation of Npas2 by ROR gamma was repressed by co-expression with Rev-Erb alpha or addition of the ROR inverse agonist T0901317. Npas2 expression was also significantly enhanced during brown adipose differentiation and that this induction was greatly suppressed in adipose cells lacking ROR gamma. Our results indicate that ROR gamma and Rev-Erb alpha are part of a feed-back loop that regulates the circadian expression of Npas2 suggesting a regulatory role for these receptors in Npas2-dependent physiological processes. C1 [Takeda, Yukimasa; Kang, Hong Soon; Angers, Martin; Jetten, Anton M.] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU National Institute of Environmental Health Sciences, the National Institutes of Health [Z01-ES-101586]; National Institutes of Health FX Intramural Research Program of the National Institute of Environmental Health Sciences, the National Institutes of Health (Z01-ES-101586). Funding for open access charge: National Institutes of Health. NR 62 TC 22 Z9 22 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 JUN PY 2011 VL 39 IS 11 BP 4769 EP 4782 DI 10.1093/nar/gkq1335 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 779CF UT WOS:000291755000026 PM 21317191 ER PT J AU Pitts, SL Liou, GF Mitchenall, LA Burgin, AB Maxwell, A Neuman, KC Osheroff, N AF Pitts, Steven L. Liou, Grace F. Mitchenall, Lesley A. Burgin, Alex B. Maxwell, Anthony Neuman, Keir C. Osheroff, Neil TI Use of divalent metal ions in the DNA cleavage reaction of topoisomerase IV SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ESCHERICHIA-COLI; IIA TOPOISOMERASES; STRUCTURAL BASIS; QUINOLONE ACTION; MECHANISM; GYRASE; POLYMERASE; COMPLEXES; SUBSTRATE; RESISTANCE AB It has long been known that type II topoisomerases require divalent metal ions in order to cleave DNA. Kinetic, mutagenesis and structural studies indicate that the eukaryotic enzymes utilize a novel variant of the canonical two-metal-ion mechanism to promote DNA scission. However, the role of metal ions in the cleavage reaction mediated by bacterial type II enzymes has been controversial. Therefore, to resolve this critical issue, this study characterized the DNA cleavage reaction of Escherichia coli topoisomerase IV. We utilized a series of divalent metal ions with varying thiophilicities in conjunction with oligonucleotides that replaced bridging and non-bridging oxygen atoms at (and near) the scissile bond with sulfur atoms. DNA scission was enhanced when thiophilic metal ions were used with substrates that contained bridging sulfur atoms. In addition, the metal-ion dependence of DNA cleavage was sigmoidal in nature, and rates and levels of DNA cleavage increased when metal ion mixtures were used in reactions. Based on these findings, we propose that topoisomerase IV cleaves DNA using a two-metal-ion mechanism in which one of the metal ions makes a critical interaction with the 3'-bridging atom of the scissile phosphate and facilitates DNA scission by the bacterial type II enzyme. C1 [Pitts, Steven L.; Osheroff, Neil] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. [Liou, Grace F.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Mitchenall, Lesley A.; Maxwell, Anthony] John Innes Ctr Plant Sci Res, Dept Biol Chem, Norwich NR4 7UH, Norfolk, England. [Burgin, Alex B.] Emerald BioStruct, Bainbridge Isl, WA 98110 USA. [Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Osheroff, Neil] Vanderbilt Univ, Sch Med, Dept Med Hematol Oncol, Nashville, TN 37232 USA. RP Osheroff, N (reprint author), Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. EM neil.osheroff@vanderbilt.edu RI Neuman, Keir/F-7400-2011; OI Neuman, Keir/0000-0002-0863-5671; Maxwell, Anthony/0000-0002-5756-6430 FU National Institutes of Health [GM033944]; NHLBI of the National Institutes of Health; Biotechnology and Biological Sciences Research Council (BBSRC), UK; Laboratory Development Funds FX National Institutes of Health grant GM033944 (to N.O.); the NHLBI Intramural Research Program of the National Institutes of Health (to K.C.N.); Biotechnology and Biological Sciences Research Council (BBSRC), UK (to A.M.). Funding for open access charge: National Institutes of Health grant GM033944; Laboratory Development Funds (to N.O.). NR 52 TC 11 Z9 13 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 JUN PY 2011 VL 39 IS 11 BP 4808 EP 4817 DI 10.1093/nar/gkr018 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 779CF UT WOS:000291755000029 PM 21300644 ER PT J AU Castle, PE Rausa, A Walls, T Gravitt, PE Partridge, EE Olivo, V Niwa, S Morrissey, KG Tucker, L Katki, H Scarinci, I AF Castle, Philip E. Rausa, Alfio Walls, Tameka Gravitt, Patti E. Partridge, Edward E. Olivo, Vanessa Niwa, Shelley Morrissey, Kerry Grace Tucker, Laura Katki, Hormuzd Scarinci, Isabel TI Comparative community outreach to increase cervical cancer screening in the Mississippi Delta SO PREVENTIVE MEDICINE LA English DT Article DE Pap; Cervical intraepithelial neoplasia (CIN); Cervical cancer; Human papillomavirus (HPV); Atypical squamous cells of undetermined significance (ASC-US); Hybrid Capture 2 (HC2); Health disparities; Cervical cancer screening ID COLLECTED VAGINAL SAMPLES; HUMAN-PAPILLOMAVIRUS DNA; QUADRIVALENT VACCINE; WOMEN; SPECIMENS; FEASIBILITY; RISK AB Objective. The aim of the study was to increase participation in cervical cancer screening of under-screened women living in the Mississippi Delta, a U.S. population at high risk for cervical cancer. Methods. We conducted a door-to-door feasibility study of women living in the Mississippi Delta to increase participation in cervical cancer screening in 2009-10. Women (n = 119) aged 26-65 years who had not been screened in last 3 years or more, were not pregnant, and had a cervix were offered a cost-free choice: clinic-based Pap testing or home self-collection with HPV DNA testing. Results. Seventy-seven women (64.7%) chose self-collection with HPV testing, of which sixty-two (80.5%) returned their self-collected specimen. By comparison, 42 women (35.3%) chose Pap testing, of which 17 (40.5%) attended their clinic appointment. Thus there was an almost 4-fold greater participation of under-mscreened women in self-collection with HPV testing than in free Pap testing (78.4% vs. 21.5%). Conclusions. We found that offering self-collection will increase participation in cervical cancer screening among under-screened populations living in the Mississippi Delta. Based on these preliminary results, we suggest that self-collection with HPV DNA testing might complement current Pap testing programs to reach under-screened populations of women, such as those living in the Mississippi Delta. Published by Elsevier Inc. C1 [Castle, Philip E.; Katki, Hormuzd] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Castle, Philip E.] Amer Soc Clin Pathol Inst, Washington, DC USA. [Rausa, Alfio; Tucker, Laura] Mississippi Dept Hlth, Jackson, MS USA. [Walls, Tameka; Olivo, Vanessa; Niwa, Shelley; Morrissey, Kerry Grace] Westat Corp, Rockville, MD USA. [Gravitt, Patti E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Partridge, Edward E.; Scarinci, Isabel] UAB Comprehens Canc Ctr, Birmingham, AL USA. [Scarinci, Isabel] Univ Alabama, Dept Prevent Med, Birmingham, AL USA. RP Castle, PE (reprint author), Amer Soc Clin Pathol Inst, 1225 New York Ave NW,Suite 250, Washington, DC 20005 USA. EM philip.castle@ascp.org RI Katki, Hormuzd/B-4003-2015 FU NIH, NCI; NCI Center for Reducing Cancer Health Disparities (CRCHD) FX This research was supported by the Intramural Research Program of the NIH, NCI and by the NCI Center for Reducing Cancer Health Disparities (CRCHD). The authors acknowledge former members of CRCHD, Dr. Harold Freeman and Ms. Jane Daye for their unwavering support of this effort. NR 19 TC 30 Z9 30 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 0091-7435 J9 PREV MED JI Prev. Med. PD JUN 1 PY 2011 VL 52 IS 6 BP 452 EP 455 DI 10.1016/j.ypmed.2011.03.018 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 779DQ UT WOS:000291758700011 PM 21497619 ER PT J AU Mas, FS Olivarez, A Jacobson, HE Hsu, CE Miller, J AF Mas, Francisco Soto Olivarez, Arturo Jacobson, Holly E. Hsu, Chiewen Ed Miller, Jerry TI Risk communication and college students: The 2009 H1N1 pandemic influenza SO PREVENTIVE MEDICINE LA English DT Letter DE H1N1 influenza; College students; Risk communication C1 [Mas, Francisco Soto] Univ Texas El Paso, Translat Hispan Hlth Res Initiat, Coll Educ, EDUC 601, El Paso, TX 79968 USA. [Jacobson, Holly E.] Univ New Mexico, Natl Inst Minor Hlth & Hlth Dispar, NIH, Dept Linguist, Albuquerque, NM 87131 USA. [Hsu, Chiewen Ed; Miller, Jerry] Univ Texas Sch Biomed Informat, Houston, TX 77030 USA. RP Mas, FS (reprint author), Univ Texas El Paso, Translat Hispan Hlth Res Initiat, Coll Educ, EDUC 601, El Paso, TX 79968 USA. EM fsoto3@utep.edu NR 9 TC 5 Z9 5 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD JUN 1 PY 2011 VL 52 IS 6 BP 473 EP 474 DI 10.1016/j.ypmed.2011.04.004 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 779DQ UT WOS:000291758700019 ER PT J AU Ibrahim, L Diazgranados, N Luckenbaugh, DA Machado-Vieira, R Baumann, J Mallinger, AG Zarate, CA AF Ibrahim, Lobna Diazgranados, Nancy Luckenbaugh, David A. Machado-Vieira, Rodrigo Baumann, Jacqueline Mallinger, Alan G. Zarate, Carlos A., Jr. TI Rapid decrease in depressive symptoms with an N-methyl-D-aspartate antagonist in ECT-resistant major depression SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE Depression; Electroconvulsive therapy; Glutamate; NMDA; Treatment-resistant ID ELECTROCONVULSIVE-THERAPY; KETAMINE; TRIAL; STIMULATION; INPATIENTS; EFFICACY; ANESTHESIA; DISORDERS; ALGORITHM; RELAPSE AB Background: Ketamine rapidly improves depressive symptoms in patients with treatment-resistant major depressive disorder (MDD) who do not respond to multiple standard antidepressants. However, it remains unknown whether ketamine is equally effective in patients with MDD who previously also did not respond to electroconvulsive therapy (ECT). Methods: This study compared 17 patients with treatment-resistant MDD who previously did not respond to ECT and 23 patients with treatment-resistant MDD who had not previously received ECT. All subjects received a single open-label infusion of ketamine (0.5 mg/kg). Patients were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline (60 min before the infusion), as well as at 40, 80, 120, and 230 min after infusion. Results: Depressive symptoms were significantly improved in the ECT-resistant group at 230 minutes with a moderate effect size (p<.001, d=0.50, 95% C.I.: 0.21-0.80). At 230 minutes, the non-ECT exposed group showed significant improvement with a large effect size (p<.001, d=1.00, 95% CI.: 0.71-1.29). Conclusion: Ketamine appears to improve depressive symptoms in patients with MDD who had previously not responded to ECT. These preliminary results encourage further investigation with a larger sample size to determine effectiveness compared to other treatment-resistant patients with MDD. Published by Elsevier Inc. C1 [Ibrahim, Lobna; Luckenbaugh, David A.; Baumann, Jacqueline; Mallinger, Alan G.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Diazgranados, Nancy] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Machado-Vieira, Rodrigo] Univ Sao Paulo, Inst & Dept Psychiat, BR-05508 Sao Paulo, Brazil. RP Zarate, CA (reprint author), Mark O Hatfield Clin Res Ctr, 10 Ctr Dr,Unit 7 SE,Rm 7-3465, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU National Institute of Mental Health, National Institutes of Health, and Department of Health & Human Services (IRP-NIMH-NIH-DHHS) FX The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, and Department of Health & Human Services (IRP-NIMH-NIH-DHHS). Dr. Machado-Vieira would also like to thank the Stanley Medical Research Institute (SMRI). loline Henter provided outstanding editorial assistance. NR 30 TC 79 Z9 82 U1 2 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 EI 1878-4216 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD JUN 1 PY 2011 VL 35 IS 4 BP 1155 EP 1159 DI 10.1016/j.pnpbp.2011.03.019 PG 5 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 780IO UT WOS:000291848000052 PM 21466832 ER PT J AU Gao, HM Hong, JS AF Gao, Hui-Ming Hong, Jau-Shyong TI Gene-environment interactions: Key to unraveling the mystery of Parkinson's disease SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE Parkinson's disease; Neurodegenerative disorders; Animal models; Genetics of PD; Environmental cause of PD; Neuroinflammation; Microglia; Neurodegeneration; Disease progression; Crosstalk among PD-associated genetic pathways; Gene-environment interactions ID DOPAMINERGIC NEURON LOSS; HUMAN ALPHA-SYNUCLEIN; UBIQUITIN-PROTEIN LIGASE; RAT SUBSTANTIA-NIGRA; INDUCED CELL-DEATH; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; EARLY-ONSET PARKINSONISM; INCLUSION-BODY FORMATION; GENOME-WIDE ASSOCIATION; G2019S LRRK2 MUTATION AB Parkinson's disease (PD) is the second most common neurodegenerative disease. The gradual, irreversible loss of dopamine neurons in the substantia nigra is the signature lesion of PD. Clinical symptoms of PD become apparent when 50-60% of nigral dopamine neurons are lost. PD progresses insidiously for 5-7 years (preclinical period) and then continues to worsen even under the symptomatic treatment. To determine what triggers the disease onset and what drives the chronic, self-propelling neurodegenerative process becomes critical and urgent, since lack of such knowledge impedes the discovery of effective treatments to retard PD progression. At present, available therapeutics only temporarily relieve PD symptoms. While the identification of causative gene defects in familial PD uncovers important genetic influences in this disease, the majority of PD cases are sporadic and idiopathic. The current consensus suggests that PD develops from multiple risk factors including aging, genetic predisposition, and environmental exposure. Here, we briefly review research on the genetic and environmental causes of PD. We also summarize very recent genome-wide association studies on risk gene polymorphisms in the emergence of PD. We highlight the new converging evidence on gene-environment interplay in the development of PD with an emphasis on newly developed multiple-hit PD models involving both genetic lesions and environmental triggers. Published by Elsevier Ltd. C1 [Gao, Hui-Ming; Hong, Jau-Shyong] NIEHS, Lab Toxicol & Pharmacol, Neuropharmacol Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Gao, HM (reprint author), NIEHS, Lab Toxicol & Pharmacol, Neuropharmacol Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM gao2@niehs.nih.gov; huiminggao@yahoo.com RI gao, huiming/C-8454-2012 FU National Institutes of Health, the National Institute of Environmental Health Sciences FX The authors thank Dr. Honglei Chen for the helpful comments on the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences. NR 316 TC 63 Z9 64 U1 1 U2 27 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD JUN PY 2011 VL 94 IS 1 BP 1 EP 19 DI 10.1016/j.pneurobio.2011.03.005 PG 19 WC Neurosciences SC Neurosciences & Neurology GA 778BA UT WOS:000291670800001 PM 21439347 ER PT J AU Engel, AR Mitzel, DN Hanson, CT Wolfinbarger, JB Bloom, ME Pletnev, AG AF Engel, Amber R. Mitzel, Dana N. Hanson, Christopher T. Wolfinbarger, James B. Bloom, Marshall E. Pletnev, Alexander G. TI Chimeric Tick-Borne Encephalitis/Dengue Virus Is Attenuated in Ixodes scapularis Ticks and Aedes aegypti Mosquitoes SO VECTOR-BORNE AND ZOONOTIC DISEASES LA English DT Article DE Aedes aegypti; Dengue; Flavivirus; Ixodes scapularis; Live attenuated vaccine; Tick-borne encephalitis virus ID COMPLETE ACTIVE VACCINATION; CELL-LINES; GROWTH-CHARACTERISTICS; STRUCTURAL GENES; RHESUS-MONKEYS; LANGAT VIRUS; DENGUE; FLAVIVIRUSES; REPLICATION; CANDIDATE AB In an effort to derive an efficacious live attenuated vaccine against tick-borne encephalitis, we generated a chimeric virus bearing the structural protein genes of a Far Eastern subtype of tick-borne encephalitis virus (TBEV) on the genetic background of recombinant dengue 4 (DEN4) virus. Introduction of attenuating mutations into the TBEV envelope protein gene, as well as the DEN4 NS5 protein gene and 3' noncoding region in the chimeric genome, results in decreased neurovirulence and neuroinvasiveness in mice, and restricted replication in mouse brain. Since TBEV and DEN4 viruses are transmitted in nature by ticks and mosquitoes, respectively, it was of interest to investigate the infectivity of the chimeric virus for both arthropod vectors. Therefore, parental and chimeric viruses were tested for growth in mosquito and tick cells and for oral infection in vivo. Although all chimeric viruses demonstrated moderate levels of replication in C6/36 mosquito cells, they were unable to replicate in ISE6 tick cells. Further, the chimeric viruses were unable to infect or replicate in Aedes aegypti mosquitoes and Ixodes scapularis tick larvae. The poor infectivity for both potential vectors reinforces the safety of chimeric virus-based vaccine candidates for the environment and for use in humans. C1 [Engel, Amber R.; Hanson, Christopher T.; Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Mitzel, Dana N.; Wolfinbarger, James B.; Bloom, Marshall E.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Pletnev, AG (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 33,Room 3W10A,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM apletnev@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 42 TC 13 Z9 13 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-3667 J9 VECTOR-BORNE ZOONOT JI Vector-Borne Zoonotic Dis. PD JUN PY 2011 VL 11 IS 6 BP 665 EP 674 DI 10.1089/vbz.2010.0179 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 778PV UT WOS:000291717500012 PM 21142950 ER PT J AU Moraski, GC Markley, LD Hipskind, PA Boshoff, H Cho, S Franzblau, SG Miller, MJ AF Moraski, Garrett C. Markley, Lowell D. Hipskind, Philip A. Boshoff, Helena Cho, Sanghyun Franzblau, Scott G. Miller, Marvin J. TI Advent of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculosis Activity SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Antituberculosis; imidazo[1,2-a]pyridine-3-carboxamides; MDR-TB; XDR-TB ID MYCOBACTERIUM-TUBERCULOSIS; DERIVATIVES; ASSAY AB A set of nine 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides and one 2,6-dimethylimidazo[1,2-a]pyrimidine-3-carboxamide were synthesized. The compounds were evaluated for their in vitro antituberculosis activity versus replicating, nonreplicating, multi- and extensive drug resistant Mtb strains. The MIC(90) values of seven of these agents were <= mu M against the various tuberculosis strains tested. A representative compound of this class (1) was screened against seven nontubercular strains as well as other nonmycobacteria organisms and demonstrated remarkable microbe selectivity. A transcriptional profiling experiment of Mtb treated with compound 1 was performed to give a preliminary indication of the mode of action. Lastly, the in vivo ADME properties of compounds 1, 3, 4, and 6 were assessed. The 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides are a druglike and synthetically accessible class of anti-TB agents that have excellent selective potency against multi- and extensive drug resistant TB and encouraging pharmacokinetics. C1 [Moraski, Garrett C.; Markley, Lowell D.; Miller, Marvin J.] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. [Hipskind, Philip A.] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. [Boshoff, Helena] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Cho, Sanghyun; Franzblau, Scott G.] Univ Illinois, Coll Pharm, Inst TB Res, Chicago, IL 60612 USA. RP Miller, MJ (reprint author), Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. EM mmiller1@nd.edu OI Franzblau, Scott/0000-0002-8698-0243; Moraski, Garrett/0000-0002-6992-5584 FU National Institutes of Health (NIH) [AI054193, 2R01AI054193]; Dow AgroSciences; NSF [CHE-0741793]; NIH, NIAID FX Funding was provided by NIH AI054193, Dow AgroSciences, and NSF CHE-0741793. This research was supported in part by the Intramural Research Program of the NIH, NIAID, and by Grant 2R01AI054193 from the National Institutes of Health (NIH) and in part by intermediates provided from Dow AgroSciences. We thank the University of Notre Dame, especially the Mass Spectrometry and Proteomics Facility (Bill Boggess, Michelle Joyce, and Nonka Sevova), which is supported by Grant CHE-0741793 from the NSF. NR 23 TC 67 Z9 67 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD JUN PY 2011 VL 2 IS 6 BP 466 EP 470 DI 10.1021/ml200036r PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 776WB UT WOS:000291568400011 PM 21691438 ER PT J AU Conde-Agudelo, A Romero, R Kusanovic, JP Hassan, SS AF Conde-Agudelo, Agustin Romero, Roberto Kusanovic, Juan Pedro Hassan, Sonia S. TI Supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia and other adverse maternal and perinatal outcomes: a systematic review and metaanalysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE abruptio placentae; antioxidants; gestational hypertension; premature rupture of membranes ID RANDOMIZED-CONTROLLED-TRIAL; PRETERM PREMATURE RUPTURE; PLACEBO-CONTROLLED TRIAL; ANTIOXIDANT STATUS; ASCORBIC-ACID; HIGH-RISK; WOMEN; COMPLICATIONS; HYPERTENSION; MEMBRANES AB OBJECTIVE: To determine whether supplementation with vitamins C and E during pregnancy reduces the risk of preeclampsia and other adverse maternal and perinatal outcomes. STUDY DESIGN: Systematic review and metaanalysis of randomized controlled trials. RESULTS: Nine trials involving a total of 19,810 women were included. Overall, there were no significant differences between the vitamin and placebo groups in the risk of preeclampsia (9.6% vs 9.6%; relative risk, 1.00, 95% confidence interval, 0.92-1.09). Similar results were obtained when subgroup analyses were restricted to women at high risk or low/moderate risk for preeclampsia. Women supplemented with vitamins C and E were at increased risk of developing gestational hypertension and premature rupture of membranes, and decreased risk of abruptio placentae. There were no significant differences between the vitamin and placebo groups in the risk of other adverse maternal or fetal/perinatal outcomes. CONCLUSION: Supplementation with vitamins C and E during pregnancy does not prevent preeclampsia. C1 [Conde-Agudelo, Agustin; Romero, Roberto; Kusanovic, Juan Pedro; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Conde-Agudelo, Agustin; Romero, Roberto; Kusanovic, Juan Pedro; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, Ctr Mol Med & Genet, Detroit, MI USA. [Romero, Roberto; Kusanovic, Juan Pedro; Hassan, Sonia S.] Wayne State Univ, Hutzel Womens Hosp, Dept Obstet & Gynecol, Detroit, MI USA. [Kusanovic, Juan Pedro] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. [Kusanovic, Juan Pedro] Hosp Dr Sotero del Rio, Ctr Perinatal Res, Santiago, Chile. RP Conde-Agudelo, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. FU 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 by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 46 TC 4 Z9 5 U1 1 U2 17 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 JUN PY 2011 VL 204 IS 6 AR 503.e1 DI 10.1016/j.ajog.2011.02.020 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 775QL UT WOS:000291477300024 PM 21529757 ER PT J AU Greer, LG Leff, RD Rogers, VL Roberts, SW McCracken, GH Wendel, GD Sheffield, JS AF Greer, Laura G. Leff, Richard D. Rogers, Vanessa Laibl Roberts, Scott W. McCracken, George H., Jr. Wendel, George D., Jr. Sheffield, Jeanne S. TI Pharmacokinetics of oseltamivir in breast milk and maternal plasma SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE breast milk pharmacokinetics; oseltamivir; oseltamivir excretion ID INFLUENZA A(H1N1) VIRUS; 2009 H1N1 INFLUENZA; PREGNANT-WOMEN; ACTIVE METABOLITE; A H1N1; VOLUNTEERS; CALIFORNIA; INFECTION AB OBJECTIVE: Women in the postpartum period are at high risk for complications from influenza. Pharmacokinetic data of oseltamivir phosphate in postpartum women, however, are lacking. STUDY DESIGN: Seven healthy patients within 48 hours of delivery were recruited. Each woman received 75 mg of oseltamivir phosphate. Plasma and breast milk samples were obtained at times 0, 0.5, 1, 2, 4, 8, 12, and 24 hours after the first dose. The samples were analyzed for oseltamivir and oseltamivir carboxylate levels. Using a noncompartmental model, area under the curve (AUC), maximum concentration (C(max)), time to maximum concentration, and half-life were estimated. RESULTS: Oseltamivir phosphate and oseltamivir carboxylate were found in breast milk, although later and in lower levels than that found in plasma. The C(max) and AUC 0-24 was higher for the active metabolite than for the prodrug in both plasma and breast milk. CONCLUSION: Oseltamivir carboxylate was present in breast milk but in concentrations significantly lower than considered therapeutic in infants. C1 [Greer, Laura G.; Rogers, Vanessa Laibl; Roberts, Scott W.; Wendel, George D., Jr.; Sheffield, Jeanne S.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [McCracken, George H., Jr.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [McCracken, George H., Jr.] NICHHD, Dallas, TX USA. [McCracken, George H., Jr.] Pediat Pharmacol Res Unit Network, Dallas, TX USA. [Leff, Richard D.] Texas Tech Univ Hlth Sci Ctr, Sch Pharm, Dallas, TX USA. RP Greer, LG (reprint author), Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. FU Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center; National Institutes of Health [5-U10-HD046000-05] FX This study was supported in part by the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, and by Grant no. 5-U10-HD046000-05 from the National Institutes of Health supporting the Pediatric Pharmacology Research Unit Network. NR 19 TC 0 Z9 0 U1 0 U2 3 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 JUN PY 2011 VL 204 IS 6 AR 524.e1 DI 10.1016/j.ajog.2011.01.056 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 775QL UT WOS:000291477300033 PM 21457910 ER PT J AU Laughlin, SK Hartmann, KE Baird, DD AF Laughlin, Shannon K. Hartmann, Katherine E. Baird, Donna D. TI Postpartum factors and natural fibroid regression SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE breastfeeding; leiomyoma; pregnancy; progesterone; ultrasound ID REPRODUCTIVE FACTORS; UTERINE FIBROIDS; PREGNANCY; RISK; LEIOMYOMATA; INVOLUTION; GROWTH AB OBJECTIVE: Many fibroids regress with pregnancy or postpartum involution. We sought to identify factors that might inhibit or enhance this natural regression. STUDY DESIGN: We used a prospective cohort of women with fibroids (n = 494) determined by ultrasound screening during the early first trimester identified from the Right from the Start study. Ultrasounds were repeated 3-6 months postpartum (n = 279). Logistic regression analyses were used to identify factors associated with fibroid regression (>50% reduction in volume). RESULTS: Postpartum progestin users had significantly less fibroid regression (P = .01), whereas there was no association for combined estrogen-progestin use. Cesarean delivery and fever (hypothesized to inhibit regression) and breast feeding (hypothesized to enhance regression) were not associated with fibroid regression. CONCLUSION: Progestin use in the postpartum period may limit regression of fibroids, consistent with prior literature on progesterone's role in fibroid development. Research into progestin-only treatments in critical reproductive periods is needed. C1 [Laughlin, Shannon K.] Mayo Clin, Dept Obstet & Gynecol, Rochester, MN 55905 USA. [Laughlin, Shannon K.; Baird, Donna D.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. [Hartmann, Katherine E.] Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, Nashville, TN 37232 USA. [Hartmann, Katherine E.] Vanderbilt Univ, Med Ctr, Inst Med & Publ Hlth, Nashville, TN 37232 USA. RP Laughlin, SK (reprint author), Mayo Clin, Dept Obstet & Gynecol, Rochester, MN 55905 USA. RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Pfizer; NICHD [RO1 HD043883, R01 HD049675]; NIH; National Institute of Environmental Health Sciences [P30ES10126] FX The work was conducted as part of the Right from the Start study. The parent study received support from the Pfizer Scholars Grants for Faculty Development in Clinical Epidemiology (Dr Hartmann) and NICHD RO1 HD043883 and R01 HD049675. Dr Laughlin was supported by the NIH Women's Health Fellowships in Intramural Women's Health Research. The postpartum data collection research was supported in part by the Intramural Research Program of the NIH and the National Institute of Environmental Health Sciences (P30ES10126). NR 16 TC 3 Z9 3 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 JUN PY 2011 VL 204 IS 6 AR 496.e1 DI 10.1016/j.ajog.2011.02.018 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 775QL UT WOS:000291477300022 PM 21492823 ER PT J AU Mertz, HL Mele, L Spong, CY Dudley, DJ Wapner, RJ Iams, JD Sorokin, Y Peaceman, A Leveno, KJ Caritis, SN Miodovnik, M Mercer, BM Thorp, JM O'Sullivan, MJ Ramin, SM Carpenter, M Rouse, DJ Sibai, B AF Mertz, Heather L. Mele, Lisa Spong, Catherine Y. Dudley, Donald J. Wapner, Ronald J. Iams, Jay D. Sorokin, Yoram Peaceman, Alan Leveno, Kenneth J. Caritis, Steve N. Miodovnik, Menachem Mercer, Brian M. Thorp, John M. O'Sullivan, Mary J. Ramin, Susan M. Carpenter, Marshall Rouse, Dwight J. Sibai, Baha CA Eunice Kennedy Shriver Natl Inst TI Placental endothelial nitric oxide synthase in multiple and single dose betamethasone exposed pregnancies SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE betamethasone; eNOS; placenta ID ADVANCED MATERNAL AGE; ANTENATAL CORTICOSTEROIDS; ANGIOGENESIS; ENOS; EXPRESSION; GROWTH; CELLS AB OBJECTIVE: To compare endothelial nitric oxide synthase expression and capillary density (CDS) in placentas exposed to single or multiple courses of betamethasone. STUDY DESIGN: Placental specimens exposed to single vs repeat courses of betamethasone were analyzed through immunohistochemistry and digital image quantification for endothelial nitric oxide synthase and CD34. Quantified endothelial nitric oxide synthase staining, calculated capillary density, ratio of endothelial nitric oxide synthase to capillary density, and clinical characteristics were compared. Linear regression was performed with these as dependent variables. RESULTS: Mean and maximum capillary density were increased (P = 0.13 and .005) and the ratio of endothelial nitric oxide synthase to capillary density decreased (P = .016) in specimens exposed to 4 courses of betamethasone compared with 1 to 3 courses. Exposure to 4 courses of betamethasone was associated with increased capillary density, but not with endothelial nitric oxide synthase expression. CONCLUSION: Exposure to 4 courses of betamethasone is associated with increased placental capillary density. The placental effects of multiple courses of betamethasone are unrelated to endothelial nitric oxide synthase expression. C1 [Mertz, Heather L.] Wake Forest Hlth Sci, Dept Obstet, Winston Salem, NC USA. [Mertz, Heather L.] Wake Forest Hlth Sci, Dept Gynecol, Winston Salem, NC USA. [Mele, Lisa] George Washington Univ, Ctr Biostat, Washington, DC USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Dudley, Donald J.] Univ Utah, Salt Lake City, UT USA. [Wapner, Ronald J.] Drexel Univ, Philadelphia, PA 19104 USA. [Iams, Jay D.] Ohio State Univ, Columbus, OH 43210 USA. [Sorokin, Yoram] Wayne State Univ, Detroit, MI USA. [Peaceman, Alan] Northwestern Univ, Chicago, IL 60611 USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Caritis, Steve N.] Univ Pittsburgh, Pittsburgh, PA USA. [Miodovnik, Menachem] Columbia Univ, New York, NY USA. [Miodovnik, Menachem] Univ Cincinnati, Cincinnati, OH USA. [Mercer, Brian M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Thorp, John M.] Univ N Carolina, Chapel Hill, NC USA. [O'Sullivan, Mary J.] Univ Miami, Miami, FL USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Carpenter, Marshall] Brown Univ, Providence, RI 02912 USA. [Rouse, Dwight J.] Univ Alabama Birmingham, Birmingham, AL USA. [Sibai, Baha] Univ Tennessee, Memphis, TN USA. RP Mertz, HL (reprint author), Wake Forest Hlth Sci, Dept Obstet, Winston Salem, NC USA. OI caritis, steve/0000-0002-2169-0712; Peaceman, Alan/0000-0002-4515-4850; Berghella, Vincenzo/0000-0003-2854-0239 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD21410, HD21414, HD27869, HD27917, HD27905, HD27860, HD27861, HD27915, HD34122, HD34116, HD34208, HD34136, HD40500, HD40485, HD40544, HD40545, HD40560, HD40512, HD36801]; National Center for Research Resources [M01-RR-000080] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD21410, HD21414, HD27869, HD27917, HD27905, HD27860, HD27861, HD27915, HD34122, HD34116, HD34208, HD34136, HD40500, HD40485, HD40544, HD40545, HD40560, HD40512, HD36801) and M01-RR-000080 from the National Center for Research Resources. NR 22 TC 0 Z9 0 U1 0 U2 3 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 JUN PY 2011 VL 204 IS 6 AR 545.e11 DI 10.1016/j.ajog.2011.02.021 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 775QL UT WOS:000291477300046 PM 21529755 ER PT J AU Yi, HW Oh, SJ Hong, JJ Kim, DH Choi, MG Noh, JH Sohn, TS Bae, JM Kim, S AF Yi, Ha Woo Oh, Seung Jong Hong, Jenny Jimmy Kim, Dae Hoon Choi, Min Gew Noh, Jae Hyung Sohn, Tae Sung Bae, Jae Moon Kim, Sung TI GASTRIC GASTROINTESTINAL STROMAL TUMOR (GIST): DOES THE NEWLY PROPOSED UICC TNM SYSTEM PROVIDE A BETTER PROGNOSTIC ABILITY THAN THE NIH CONSENSUS CRITERIA? SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT European-Society-for-Medical-Oncology (ESMO) 13th World Congress on Gastrointestinal Cancer CY JUN 22-25, 2011 CL Barcelona, SPAIN SP European Soc Med Oncol C1 [Yi, Ha Woo; Oh, Seung Jong; Kim, Dae Hoon; Choi, Min Gew; Noh, Jae Hyung; Sohn, Tae Sung; Bae, Jae Moon; Kim, Sung] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Hong, Jenny Jimmy] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUN PY 2011 VL 22 SU 5 BP v44 EP v44 PG 1 WC Oncology SC Oncology GA 772TR UT WOS:000291260100121 ER PT J AU Romero, R Kusanovic, JP Chaiworapongsa, T Hassan, SS AF Romero, Roberto Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Hassan, Sonia S. TI Placental bed disorders in preterm labor, preterm PROM, spontaneous abortion and abruptio placentae SO BEST PRACTICE & RESEARCH CLINICAL OBSTETRICS & GYNAECOLOGY LA English DT Article DE failure of physiologic transformation; spiral arteries; maternal-fetal interface ID ULTRASONOGRAPHIC CERVICAL LENGTH; GESTATIONAL DIABETES-MELLITUS; SPIRAL ARTERY TRANSFORMATION; MATERNAL FLOOR INFARCTION; RENIN-ANGIOTENSIN SYSTEM; ANTI-ANGIOGENIC FACTORS; AMNIOTIC-FLUID SLUDGE; CLINICAL-SIGNIFICANCE; PREMATURE RUPTURE; TROPHOBLAST INVASION AB Failure of physiologic transformation of the spiral arteries has been studied using placental bed biopsies in several obstetrical syndromes. Contrary to what was originally believed, this lesion is not restricted to preeclampsia and/or intrauterine growth restriction. A review of published evidence indicates that failure of physiologic transformation can be observed in women with spontaneous second trimester abortions, preterm labor with intact membranes, preterm prelabor rupture of membranes and abruptio placentae. Therefore, disorders of deep placentation are present in a wide range of complications of pregnancy, emphasizing the importance of understanding the physiology and pathology of transformation of the spiral arteries. We propose that changes in the population and function of immunocytes at the maternal-fetal interface can be part of the mechanism of disease of obstetrical disorders, and this requires further investigation. Published by Elsevier Ltd. C1 [Romero, Roberto; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Romero, Roberto; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 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, NIH, DHHS FX This research was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 112 TC 32 Z9 35 U1 0 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6934 EI 1532-1932 J9 BEST PRACT RES CL OB JI Best Pract. Res. Clin. Obstet. Gynaecol. PD JUN PY 2011 VL 25 IS 3 BP 313 EP 327 DI 10.1016/j.bpobgyn.2011.02.006 PG 15 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 776WH UT WOS:000291570000007 PM 21388889 ER PT J AU Longmire, MR Ogawa, M Choyke, PL Kobayashi, H AF Longmire, Michelle R. Ogawa, Mikako Choyke, Peter L. Kobayashi, Hisataka TI Biologically Optimized Nanosized Molecules and Particles: More than Just Size SO BIOCONJUGATE CHEMISTRY LA English DT Review ID MR CONTRAST AGENTS; MAGNETIC-RESONANCE LYMPHANGIOGRAPHY; POLYAMIDOAMINE DENDRIMER CORE; SENTINEL LYMPH-NODE; NEUTRON-CAPTURE THERAPY; ACUTE-RENAL-FAILURE; DRUG-DELIVERY; QUANTUM DOTS; PHARMACOKINETIC PROPERTIES; POLYMERIC NANOPARTICLES AB The expanded biological and medical applications of nanomaterials place a premium on better understanding of the chemical and physical determinants of in vivo particles. Nanotechnology allows us to design a vast array of molecules with distinct chemical and biological characteristics, each with a specific size, charge, hydrophilicity, shape, and flexibility. To date, much research has focused on the role of particle size as a determinant of biodistribution and clearance. Additionally, much of what we know about the relationship between nanoparticle traits and pharmacokinetics has involved research limited to the gross average hydrodynamic size. Yet, other features such as particle shape and flexibility affect in vivo behavior and become increasingly important for designing and synthesizing nanosized molecules. Herein, we discuss determinants of in vivo behavior of nanosized molecules used as imaging agents with a focus on dendrimer-based contrast agents. We aim to discuss often overlooked or, yet to be considered, factors that affect in vivo behavior of synthetic nanosized molecules, as well as aim to highlight important gaps in current understanding. C1 [Longmire, Michelle R.; Ogawa, Mikako; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, NIH, Bldg 10,Room B3B69,MSC 1088,10 Ctr Dr, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 75 TC 87 Z9 87 U1 4 U2 65 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JUN PY 2011 VL 22 IS 6 BP 993 EP 1000 DI 10.1021/bc200111p PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 776VZ UT WOS:000291568200001 PM 21513351 ER PT J AU Zhu, L Xie, J Swierczewska, M Zhang, F Lin, X Fang, XX Niu, G Lee, S Chen, XY AF Zhu, Lei Xie, Jin Swierczewska, Magdalena Zhang, Fan Lin, Xin Fang, Xuexun Niu, Gang Lee, Seulki Chen, Xiaoyuan TI Dual-Functional, Receptor-Targeted Fluorogenic Probe for In Vivo, Imaging of Extracellular Protease Expressions SO BIOCONJUGATE CHEMISTRY LA English DT Article ID CANCER AB Herein, we report a new type of in vivo fluorogenic probe that enables simultaneous and active targeting of overexpressed receptors, alpha(v)beta(3) integrins, and extracellular proteases, matrix metalloproteinases (MMPs), in the tumor regions. This c(RGDyK)-conjugated MMP fluorogenic probe efficiently targets the tumor regions with high retention time while maintaining receptor binding affinity and substrate activity. The probe minimizes nonspecific accumulation, thus demonstrating improved tumor-to-background signal ratio (T/N) in both alpha(v)beta(3) integrin- and MMP-overexpressing U87MG tumor-bearing mouse model. This strategy can be easily tuned for a wide array of applications targeting various receptors and extracellular proteases in vivo. C1 [Zhu, Lei; Xie, Jin; Swierczewska, Magdalena; Zhang, Fan; Lin, Xin; Niu, Gang; Lee, Seulki; Chen, Xiaoyuan] NIBIB, NIH, Bethesda, MD 20892 USA. [Zhu, Lei; Fang, Xuexun] Jilin Univ, Key Lab Mol Enzymol & Enzyme Engn, Changchun 130021, Peoples R China. [Swierczewska, Magdalena] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. RP Lee, S (reprint author), NIBIB, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM Seulki.Lee@nih.gov; Shawn.Chen@nih.gov RI Xie, Jin/E-8193-2010; Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Science Foundation of China (NSFC) [81028009] 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), and the International Cooperative Program of National Science Foundation of China (NSFC) (81028009). NR 25 TC 8 Z9 9 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JUN PY 2011 VL 22 IS 6 BP 1001 EP 1005 DI 10.1021/bc200005w PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 776VZ UT WOS:000291568200002 PM 21574650 ER PT J AU Kecskes, A Tosh, DK Wei, Q Gao, ZG Jacobson, KA AF Kecskes, Angela Tosh, Dilip K. Wei, Qiang Gao, Zhan-Guo Jacobson, Kenneth A. TI GPCR Ligand Dendrimer (GLiDe) Conjugates: Adenosine Receptor Interactions of a Series of Multivalent Xanthine Antagonists SO BIOCONJUGATE CHEMISTRY LA English DT Article ID HIGH-AFFINITY; FUNCTIONALIZED CONGENERS; DERIVATIVES; AGONISTS; BINDING; RADIOLIGAND; CHEMISTRY; EFFICIENT; ANALOGS; TARGETS AB Previously, G protein-coupled receptor (GPCR) agonists were tethered from polyamidoamine (PAMAM) dendrimers to provide high receptor affinity and selectivity. Here, we prepared GPCR ligand-dendrimer (GLiDe) conjugates from a potent adenosine receptor (AR) antagonist; such agents are of interest for treating Parkinson's disease, asthma, and other conditions. Xanthine amine congener (XAC) was appended with an alkyne group on an extended C8 substituent for coupling by Cu(I)-catalyzed click chemistry to azide-derivatized G4 (fourth-generation) PAMAM dendrimers to form triazoles. These conjugates also contained triazole-linked PEG groups (8 or 22 moieties per 64 terminal positions) for increasing water-solubility and optionally prosthetic groups for spectroscopic characterization and affinity labeling. Human AR binding affinity increased progressively with the degree of xanthine substitution to reach K(i) values in the nanomolar range. The order of affinity of each conjugate was hA(2A)AR > hA(3)AR > hA(1)AR, while the corresponding monomer was ranked hA(2A)AR > hA(1)AR >= hA(3)AR. The antagonist activity of the most potent conjugate 14 (34 xanthines per dendrimer) was examined at the G(i)-coupled A(1)AR Conjugate 14 at 100 nM right-shifted the AR agonist concentration-response curve in a cyclic AMP functional assay in a parallel manner, but at 10 nM (lower than its K(i) value), it significantly suppressed the maximal agonist effect in calcium mobilization. This is the first systematic probing of a potent AR antagonist tethered on a dendrinier and its activity as a function of variable loading. C1 [Kecskes, Angela; Tosh, Dilip K.; Wei, Qiang; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH, NIDDK FX We thank Dr. John Lloyd and Dr. Noel Whittaker (NIDDK) for the mass spectral determinations, Dr. Martin Garraffo (NIDDK) for FT-IR measurements, and Khai Phan (NIDDK) for pharmacological measurements. We thank Dr. Francesca Deflorian (NIDDK), Dr. Michael Kilbey, III, and Dr. Kunlun Hong (Oak Ridge National Laboratory, Knoxville TN) for helpful discussions. This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 43 TC 15 Z9 16 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JUN PY 2011 VL 22 IS 6 BP 1115 EP 1127 DI 10.1021/bc1005812 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 776VZ UT WOS:000291568200016 PM 21539392 ER PT J AU Song, HA Kang, CS Baidoo, KE Milenic, DE Chen, YW Dai, AZ Brechbiel, MW Chong, HS AF Song, Hyun A. Kang, Chi Soo Baidoo, Kwamena E. Milenic, Diane E. Chen, Yunwei Dai, Anzhi Brechbiel, M. W. Chong, Hyun-Soon TI Efficient Bifunctional Decadentate Ligand 3p-C-DEPA for Targeted alpha-Radioimmunotherapy Applications SO BIOCONJUGATE CHEMISTRY LA English DT Article ID DISSEMINATED PERITONEAL DISEASE; MONOCLONAL-ANTIBODY; MYELOID-LEUKEMIA; THERAPY; GENERATOR; CANCER; ANTI-CD33; RADIATION; MELANOMA; AC-225 AB A new bifunctional ligand 3p-C-DEPA was synthesized and evaluated for use in targeted alpha-radioimmunotherapy. 3p-C-DEPA was efficiently prepared via regiospecific ring opening of an aziridinium ion and conjugated with trastuzumab. The 3p-C-DEPA-trastuzumab conjugate was extremely rapid in binding (205/6)Bi, and the corresponding (205/6)Bi-3p-C-DEPA-trastuzumab complex was stable in human serum. Biodistribution studies were performed to evaluate in vivo stability and tumor targeting of (205/6)Bi-3p-C-DEPA-trastuzumab conjugate in tumor bearing athymic mice. (205/6)Bi-3p-C-DEPA-trastuzumab conjugate displayed excellent in vivo stability and targeting as evidenced by low organ uptake and high tumor uptake. The results of the in vitro and in vivo studies indicate that 3p-C-DEPA is a promising chelator for radioimmunotherapy of (212)Bi and (213)Bi. C1 [Song, Hyun A.; Kang, Chi Soo; Chen, Yunwei; Dai, Anzhi; Chong, Hyun-Soon] IIT, Div Chem, Biol Chem & Phys Sci Dept, Chicago, IL 60616 USA. [Baidoo, Kwamena E.; Milenic, Diane E.; Brechbiel, M. W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Chong, HS (reprint author), IIT, Div Chem, Biol Chem & Phys Sci Dept, 3101 S Dearborn St,LS 182, Chicago, IL 60616 USA. EM Chong@iit.edu FU National Institutes of Health [R01CA112503]; Illinois Institute of Technology FX We acknowledge financial support from the National Institutes of Health (R01CA112503). This work was partly supported by intramural research program of NIH. Hyun A Song is the recipient of 2009 Illinois Institute of Technology Kilpatrick Fellowship. NR 27 TC 14 Z9 14 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JUN PY 2011 VL 22 IS 6 BP 1128 EP 1135 DI 10.1021/bc100586y PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 776VZ UT WOS:000291568200017 PM 21604692 ER PT J AU Finkel, T Quyyumi, AA AF Finkel, Toren Quyyumi, Arshed A. TI Genetic Links Between Circulating Cells and Cardiovascular Risk SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Editorial Material DE Editorials; genome-wide association study ID ENDOTHELIAL PROGENITOR CELLS; CORONARY-ARTERY-DISEASE; ATHEROSCLEROSIS; ASSOCIATION C1 [Finkel, Toren] NHLBI, Ctr Mol Med, Bethesda, MD 20892 USA. [Quyyumi, Arshed A.] Emory Sch Med, Div Cardiol, Atlanta, GA USA. RP Finkel, T (reprint author), NIH, Bldg 10 CRC 5-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU Intramural NIH HHS [Z01 HL005012-12] NR 17 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD JUN PY 2011 VL 4 IS 3 BP 218 EP 220 DI 10.1161/CIRCGENETICS.111.960310 PG 3 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 777CV UT WOS:000291593100002 PM 21673309 ER PT J AU Shaw, SY Cheng, SS Cupples, LA Larson, MG McCabe, EL Ngwa, JS Wang, YA Martin, RP Klein, RJ Hashmi, B Ajijola, OA Lau, E O'Donnell, CJ Vasan, RS Cohen, KS Wang, TJ AF Shaw, Stanley Y. Cheng, Susan Cupples, L. Adrienne Larson, Martin G. McCabe, Elizabeth L. Ngwa, Julius S. Wang, Ying A. Martin, Roderick P. Klein, Rachael J. Hashmi, Basma Ajijola, Olujimi A. Lau, Evan O'Donnell, Christopher J. Vasan, Ramachandran S. Cohen, Kenneth S. Wang, Thomas J. TI Genetic and Clinical Correlates of Early-Outgrowth Colony-Forming Units SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE genetics; epidemiology; coronary disease; cardiovascular disease; cells ID ENDOTHELIAL PROGENITOR CELLS; CORONARY-HEART-DISEASE; NITRIC-OXIDE SYNTHASE; MYOCARDIAL-INFARCTION; CARDIOVASCULAR RISK; MIGRATORY ACTIVITY; GENDER-DIFFERENCES; VASCULAR REPAIR; ARTERY-DISEASE; ATHEROSCLEROSIS AB Background-Several bone marrow-derived cell populations may have angiogenic activity, including cells termed endothelial progenitor cells. Decreased numbers of circulating angiogenic cell populations have been associated with increased cardiovascular risk. However, few data exist from large, unselected samples, and the genetic determinants of these traits are unclear. Methods and Results-We examined the clinical and genetic correlates of early-outgrowth colony-forming units (CFUs) in 1799 participants of the Framingham Heart Study (mean age, 66 years; 54% women). Among individuals without cardiovascular disease (n = 1612), CFU number was inversely related to advanced age (P = 0.004), female sex (P = 0.04), and triglycerides (P = 0.008) and positively related to hormone replacement (P = 0.008) and statin therapy (P = 0.027) in stepwise multivariable analyses. Overall, CFU number was inversely related to the Framingham risk score (P = 0.01) but not with prevalent cardiovascular disease. In genome-wide association analyses in the entire sample, polymorphisms were associated with CFUs at the MOSC1 locus (P = 3.3 x 10(-7)) and at the SLC22A3-LPAL2-LPA locus (P = 4.9 x 10(-7)), a previously replicated susceptibility locus for myocardial infarction. Furthermore, alleles at the SLC22A3-LPAL2-LPA locus that were associated with decreased CFUs were also related to increased risk of myocardial infarction (P = 1.1 x 10(-4)). Conclusions-In a community-based sample, early-outgrowth CFUs are inversely associated with select cardiovascular risk factors. Furthermore, genetic variants at the SLC22A3-LPAL2-LPA locus are associated with both decreased CFUs and an increased risk of myocardial infarction. These findings are consistent with the hypothesis that decreased circulating angiogenic cell populations promote susceptibility to myocardial infarction. (Circ Cardiovasc Genet. 2011;4:296-304.) C1 [Shaw, Stanley Y.; Cheng, Susan; McCabe, Elizabeth L.; O'Donnell, Christopher J.; Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Div Cardiol, Sch Med, Boston, MA 02114 USA. [Shaw, Stanley Y.] Harvard Univ, Massachusetts Gen Hosp, Ctr Syst Biol, Sch Med, Boston, MA 02114 USA. [Cheng, Susan; Cupples, L. Adrienne; Larson, Martin G.; McCabe, Elizabeth L.; Ngwa, Julius S.; Wang, Ying A.; O'Donnell, Christopher J.; Vasan, Ramachandran S.; Wang, Thomas J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Cheng, Susan] Harvard Univ, Massachusetts Gen Hosp, Div Cardiovasc Med, Sch Med, Boston, MA 02114 USA. [Cheng, Susan] Harvard Univ, Beth Israel Deaconness Med Ctr, Clin Investigator Training Program, Sch Med, Boston, MA 02114 USA. [Cupples, L. Adrienne; Ngwa, Julius S.; Wang, Ying A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Harvard Univ, Sch Med, Dept Prevent Med, Boston, MA 02115 USA. [Martin, Roderick P.] Genzyme Corp, Cambridge, MA USA. [Martin, Roderick P.; Klein, Rachael J.; Cohen, Kenneth S.] Harvard Univ, Massachusetts Gen Hosp, Ctr Regenerat Med, Sch Med, Boston, MA 02114 USA. [Hashmi, Basma] Harvard Univ, Dept Bioengn, Boston, MA 02115 USA. [Ajijola, Olujimi A.] Univ Calif Los Angeles, Med Ctr, Div Cardiol, Los Angeles, CA 90024 USA. [Lau, Evan] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [O'Donnell, Christopher J.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Cohen, Kenneth S.] Univ Chicago, Med Ctr, Hematol Oncol Sect, Chicago, IL 60637 USA. RP Wang, TJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Cardiol, Sch Med, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM kcohen@medicine.bsd.uchicago.edu; tjwang@partners.org OI Cupples, L. Adrienne/0000-0003-0273-7965; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, R01-HL083197, R01-HL93328]; de Gunzburg Family Foundation at Massachusetts General Hospital; Ellison Foundation FX This work was supported in part by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195), grant R01-HL083197 (Dr Wang), and grant R01-HL93328 (Dr Vasan). Dr Shaw is supported by the de Gunzburg Family Foundation at Massachusetts General Hospital. Dr Cheng is supported by a grant from the Ellison Foundation. NR 55 TC 8 Z9 9 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD JUN PY 2011 VL 4 IS 3 BP 296 EP U174 DI 10.1161/CIRCGENETICS.110.958470 PG 23 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 777CV UT WOS:000291593100012 PM 21493818 ER PT J AU Paul, BM Vassmer, D Taylor, A Magenheimer, L Carlton, CG Piontek, KB Germino, GG Heuvel, GBV AF Paul, Binu M. Vassmer, Dianne Taylor, Aaron Magenheimer, Lynn Carlton, Carol G. Piontek, Klaus B. Germino, Gregory G. Heuvel, Gregory B. Vanden TI Ectopic Expression of Cux1 is Associated with Reduced p27 Expression and Increased Apoptosis During Late Stage Cyst Progression Upon Inactivation of Pkd1 in Collecting Ducts SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Cux1; polycystic kidney disease; apoptosis; p27 ID POLYCYSTIC KIDNEY-DISEASE; HOMEODOMAIN PROTEIN CUX1; AUTOSOMAL-DOMINANT; CELL-CYCLE; TRANSCRIPTION FACTORS; P27(KIP1) EXPRESSION; P110 CUX1; CPK MICE; S-PHASE; ACTIVATION AB Polycystic kidney diseases (PKD) are inherited disorders characterized by fluid-filled cysts primarily in the kidneys. We previously reported differences between the expression of Cux1, p21, and p27 in the cpk and Pkd1 null mouse models of PKD. Embryonic lethality of Pkd1 null mice limits its study to early stages of kidney development. Therefore, we examined mice with a collecting duct specific deletion in the Pkd1 gene. Cux1 was ectopically expressed in the cyst lining epithelial cells of newborn, P7 and P15 Pkd1(CD) mice. Cux1 expression correlated with cell proliferation in early stages of cystogenesis, however, as the disease progressed, fewer cyst lining cells showed increased cell proliferation. Rather, Cux1 expression in late stage cystogenesis was associated with increased apoptosis. Taken together, our results suggest that increased Cux1 expression associated with apoptosis is a common feature of late stage cyst progression in both the cpk and Pkd1(CD) mouse models of PKD. Developmental Dynamics 240:1493-1501, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Paul, Binu M.; Vassmer, Dianne; Taylor, Aaron; Carlton, Carol G.; Heuvel, Gregory B. Vanden] Univ Kansas, Med Ctr, Dept Anat & Cell Biol, Kansas City, KS 66160 USA. [Paul, Binu M.; Taylor, Aaron; Magenheimer, Lynn; Carlton, Carol G.; Heuvel, Gregory B. Vanden] Univ Kansas, Med Ctr, Kidney Inst, Kansas City, KS 66160 USA. [Vassmer, Dianne] Univ Kansas, Med Ctr, Dept Clin Lab Sci, Kansas City, KS 66160 USA. [Piontek, Klaus B.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Germino, Gregory G.] NIDDK, NIH, Bethesda, MD USA. RP Heuvel, GBV (reprint author), Univ Kansas, Med Ctr, Dept Anat & Cell Biol, 5020B Wahl Hall E, Kansas City, KS 66160 USA. EM gvandenheuvel@kumc.edu OI Germino, Gregory/0000-0002-3609-5588 FU NIH [RO1-DK58377, P50-DK57301, RO1-DK48006]; KUMC FX Grant sponsor: NIH; Grant numbers: RO1-DK58377, P50-DK57301, RO1-DK48006.; We thank Rosetta Barkley and Jennifer Brantley for their expert technical assistance. We thank Dr. Madhulika Sharma for many helpful discussions and expert technical advice. G.B.V.H. and G.G.G. were funded by the NIH and B.M.P. received a KUMC biomedical research training program fellowship. NR 33 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD JUN PY 2011 VL 240 IS 6 BP 1493 EP 1501 DI 10.1002/dvdy.22625 PG 9 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 776TG UT WOS:000291560300017 PM 21465620 ER PT J AU Harrell, PT Montoya, ID Preston, KL Juliano, LM Gorelick, DA AF Harrell, P. T. Montoya, I. D. Preston, K. L. Juliano, L. M. Gorelick, D. A. TI Cigarette smoking and short-term addiction treatment outcome SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Cigarettes; Nicotine; Cocaine; Opioids; Opiates; Treatment outcome ID METHADONE-MAINTENANCE; NICOTINE DEPENDENCE; COCAINE DEPENDENCE; TOBACCO SMOKING; DRUG-USE; CESSATION TREATMENT; SUBSTANCE-ABUSERS; FOLLOW-UP; RATS; MECAMYLAMINE AB Cigarette smoking is common among patients in cocaine and opioid dependence treatment, and may influence treatment outcome. We addressed this issue in a secondary analysis of data from an outpatient clinical trial of buprenorphine treatment for concurrent cocaine and opioid dependence (13 weeks, N=200). The association between cigarette smoking (lifetime cigarette smoking status, number of cigarettes smoked per day prior to study entry) and short-term treatment outcome (% of urine samples positive for cocaine or opioids, treatment retention) was evaluated with analysis of covariance, bivariate correlations, and multivariate linear regression. Nicotine-dependent smokers (66% of participants) had a significantly higher percentage of cocaine-positive urine samples than non-smokers (12% of participants) (76% vs. 62%), but did not differ in percentage of opioid-positive urine samples or treatment retention. Number of cigarettes smoked per day at baseline was positively associated with percentage of cocaine-positive urine samples, even after controlling for baseline sociodemographic and drug use characteristics, but was not significantly associated with percentage of opioid-positive urine samples or treatment retention. These results suggest that cigarette smoking is associated with poorer short-term outcome of outpatient treatment for cocaine dependence, but perhaps not of concurrent opioid dependence, and support the importance of offering smoking cessation treatment to cocaine-dependent patients. Published by Elsevier Ireland Ltd. C1 [Harrell, P. T.; Preston, K. L.; Gorelick, D. A.] NIDA, Intramural Res Program, N1H, Baltimore, MD 21224 USA. [Harrell, P. T.; Juliano, L. M.] American Univ, Dept Psychol, Washington, DC 20016 USA. [Montoya, I. D.] NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. RP Gorelick, DA (reprint author), NIDA IRP, 251 Bayview Blvd,200, Baltimore, MD 21224 USA. EM dgorelic@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU National Institutes of Health, National Institute on Drug Abuse FX This research was supported by the Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse. We thank Dr. David Epstein for help with statistical analysis. NR 60 TC 6 Z9 6 U1 0 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN 1 PY 2011 VL 115 IS 3 BP 161 EP 166 DI 10.1016/j.drugalcdep.2010.08.017 PG 6 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 775HI UT WOS:000291449200001 PM 21163592 ER PT J AU Copeland, WE Magnusson, A Goransson, M Heilig, MA AF Copeland, William E. Magnusson, Asa Goransson, Mona Heilig, Markus A. TI Genetic moderators and psychiatric mediators of the link between sexual abuse and alcohol dependence SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Sexual abuse; Psychiatric comorbidity; Genetics; Alcohol dependence ID NATIONAL COMORBIDITY SURVEY; IDENTIFICATION TEST AUDIT; SUBSTANCE USE DISORDERS; MENTAL-HEALTH; RECEPTOR GENE; CHILD-ABUSE; ADULT WOMEN; CONSUMPTION; HISTORY; SAMPLE AB Background/objective: This study used a case-control female sample to test psychiatric mediators and genetic moderators of the effect of sexual abuse on later alcohol dependence. The study also tested differences between alcohol dependent women with or without a history of sexual abuse on variables that might affect treatment planning. Methods: A case-control design compared 192 treatment-seeking alcohol dependent women with 177 healthy population controls. All participants were assessed for alcohol-related behaviors, sexual abuse history, psychiatric problems, and personality functioning. Markers were genotyped in the CRHR1, MAO-A and OPRM1 genes. Results: The association of sexual abuse with alcohol dependence was limited to the most severe category of sexual abuse involving anal or vaginal penetration. Of the five psychiatric disorders tested, anxiety, anorexia nervosa, and bulimia met criteria as potential mediators of the abuse-alcohol dependence association. Severe sexual abuse continued to have an independent effect on alcohol dependence status even after accounting for these potential mediators. None of the candidate genetic markers moderated the association between sexual abuse and alcohol dependence. Of alcohol dependent participants, those with a history of severe abuse rated higher on alcoholism severity, and psychiatric comorbidities. Conclusion: Sexual abuse is associated with later alcohol problems directly as well as through its effect on psychiatric problems. Treatment-seeking alcohol dependent women with a history of abuse have distinct features as compared to other alcohol dependent women. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Copeland, William E.] Duke Univ, Ctr Dev Epidemiol, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Magnusson, Asa; Goransson, Mona; Heilig, Markus A.] Karolinska Inst, Dept Clin Neurosci, S-17176 Stockholm, Sweden. [Heilig, Markus A.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. RP Copeland, WE (reprint author), Duke Univ, Ctr Dev Epidemiol, Med Ctr, Dept Psychiat & Behav Sci, Box 3454, Durham, NC 27710 USA. EM William.Copeland@duke.edu RI copeland, william/N-5413-2014 FU County of Stockholm; National Institute on Alcohol Abuse and Alcoholism; NIMH [K23 MH080230-02] FX This work was supported by funding from the County of Stockholm, National Institute on Alcohol Abuse and Alcoholism intramural research funds, and an NIMH career development award (K23 MH080230-02; Copeland, PI). The County of Stockholm and NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication NR 44 TC 3 Z9 4 U1 3 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN 1 PY 2011 VL 115 IS 3 BP 183 EP 189 DI 10.1016/j.drugalcdep.2010.10.024 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 775HI UT WOS:000291449200004 PM 21193270 ER PT J AU Zuber, SM Kantorovich, V Pacak, K AF Zuber, Samuel M. Kantorovich, Vitaly Pacak, Karel TI Hypertension in Pheochromocytoma: Characteristics and Treatment SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Pheochromocytoma; Paraganglioma; Hypertension; Sustained; Catecholamine; Cardiovascular diseases ID DOPAMINE-SECRETING PHEOCHROMOCYTOMA; ADRENAL PHEOCHROMOCYTOMA; ANESTHETIC MANAGEMENT; ARTERIAL STIFFNESS; BETA-ADRENOCEPTOR; CLINICAL-PRACTICE; DIAGNOSIS; PARAGANGLIOMAS; DESENSITIZATION; MANIFESTATIONS AB Pheochromocytoma is a tumor of the chromaffin cells in the adrenal medulla and sympathetic paraganglia, which synthesizes and secretes catecholamines. Norepinephrine, epinephrine, and dopamine all act on their target receptors, which causes a physiologic change in the body. High circulating levels of catecholamines can lead to severe hypertension and can have devastating effects on multiple body systems (eg, cardiovascular, cerebrovascular), and can lead to death if untreated. Although surgical treatment represents the only modality of ultimate cure, pharmacologic preoperative treatment remains' the mainstay of successful outcome. C1 [Zuber, Samuel M.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Kantorovich, Vitaly] Univ Arkansas Med Sci, Div Endocrinol & Metab, Little Rock, AR 72205 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Program Reprod & Adult Endocrinol, NIH, Bldg 10-CRC,1East,Room 3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural NIH HHS [Z01 HD008735-07] NR 98 TC 8 Z9 13 U1 1 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 JUN PY 2011 VL 40 IS 2 BP 295 EP + DI 10.1016/j.ecl.2011.02.002 PG 18 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 776VW UT WOS:000291567800005 PM 21565668 ER PT J AU Sharma, ST Nieman, LK AF Sharma, Susmeeta T. Nieman, Lynnette K. TI Cushing's Syndrome: All Variants, Detection, and Treatment SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Cushing's syndrome; Hypertension; Glucocorticoids; Ectopic ACTH secretion; 11 Beta-hydroxysteroid dehydrogenase; Hypercortisolemia ID ECTOPIC ADRENOCORTICOTROPIN SYNDROME; CORTISOL-INDUCED HYPERTENSION; VASCULAR SMOOTH-MUSCLE; BLOOD-PRESSURE; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; CARDIOVASCULAR RISK; GLUCOCORTICOID EXCESS; NITRIC-OXIDE; DISEASE; SECRETION AB Diagnosis of Cushing's syndrome involves a step-wise approach and establishing the cause can be challenging. Several pathogenic mechanisms have been proposed for glucocorticoid-induced hypertension, including a functional mineralocorticoid excess state, upregulation of the renin angiotensin system, and deleterious effects of cortisol on the vasculature. Surgical excision of the cause of excess glucocorticoids remains the optimal treatment. Antiglucocorticoid and antihypertensive agents and steroidogenesis inhibitors can be used as adjunctive treatment modalities in preparation for surgery and in cases where surgery is contraindicated or has not led to cure. C1 [Sharma, Susmeeta T.; Nieman, Lynnette K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bldg 10,1East,Room 3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM niemanl@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 62 TC 18 Z9 18 U1 2 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8529 EI 1558-4410 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD JUN PY 2011 VL 40 IS 2 BP 379 EP + DI 10.1016/j.ecl.2011.01.006 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 776VW UT WOS:000291567800010 PM 21565673 ER PT J AU Mahadevan, B Snyder, RD Waters, MD Benz, RD Kemper, RA Tice, RR Richard, AM AF Mahadevan, Brinda Snyder, Ronald D. Waters, Michael D. Benz, R. Daniel Kemper, Raymond A. Tice, Raymond R. Richard, Ann M. TI Genetic Toxicology in the 21st Century: Reflections and Future Directions SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Review DE genotoxicity; mutagenicity; toxicogenomics; high throughput screening ID DISCRIMINATE RODENT CARCINOGENS; VITRO GENOTOXICITY TESTS; SALMONELLA-MICROSOME TEST; DNA INTERCALATING AGENTS; E-STATE INDEXES; MDL-QSAR; NONGENOTOXIC CARCINOGENS; ENVIRONMENTAL CHEMICALS; DEVELOPMENTAL TOXICITY; RELATIVE PREDICTIVITY AB A symposium at the 40th anniversary of the Environmental Mutagen Society, held from October 24-28, 2009 in St. Louis, MO, surveyed the current status and future directions of genetic toxicology. This article summarizes the presentations and provides a perspective on the future. An abbreviated history is presented, highlighting the current standard battery of genotoxicity assays and persistent challenges. Application of computational toxicology to safety testing within a regulatory setting is discussed as a means for reducing the need for animal testing and human clinical trials, and current approaches and applications of in silico genotoxicity screening approaches across the pharmaceutical industry were surveyed and are reported here. The expanded use of toxicogenomics to illuminate mechanisms and bridge genotoxicity and carcinogenicity, and new public efforts to use high-throughput screening technologies to address lack of toxicity evaluation for the backlog of thousands of industrial chemicals in the environment are detailed. The Tox21 project involves coordinated efforts of four U. S. Government regulatory/research entities to use new and innovative assays to characterize key steps in toxicity pathways, including genotoxic and nongenotoxic mechanisms for carcinogenesis. Progress to date, highlighting preliminary test results from the National Toxicology Program is summarized. Finally, an overview is presented of ToxCast (TM), a related research program of the U. S. Environmental Protection Agency, using a broad array of high throughput and high content technologies for toxicity profiling of environmental chemicals, and computational toxicology modeling. Progress and challenges, including the pressing need to incorporate metabolic activation capability, are summarized. Environ. Mol. Mutagen. 52: 339-354, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Mahadevan, Brinda; Snyder, Ronald D.] Merck Res Labs, Genet Toxicol, Mech & Predict Toxicol, Summit, NJ USA. [Waters, Michael D.] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Benz, R. Daniel] US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Appl Pharmacol Res, Silver Spring, MD USA. [Kemper, Raymond A.] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT USA. [Tice, Raymond R.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Res Triangle Pk, NC USA. [Richard, Ann M.] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Mahadevan, B (reprint author), Abbott Labs Inc, Global Occupat Toxicol, Abbott Qual & Regulatory Dept, 03QW Bldg,AP6B-2,100 Abbott Pk Rd, Abbott Pk, IL 60064 USA. EM brinda.mahadevan@abbott.com FU Intramural NIH HHS [Z99 ES999999] NR 81 TC 39 Z9 41 U1 8 U2 36 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD JUN PY 2011 VL 52 IS 5 BP 339 EP 354 DI 10.1002/em.20653 PG 16 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 776SR UT WOS:000291558700001 PM 21538556 ER PT J AU Paules, RS Aubrecht, J Corvi, R Garthoff, B Kleinjans, JC AF Paules, Richard S. Aubrecht, Jiri Corvi, Raffaella Garthoff, Bernward Kleinjans, Jos C. TI Moving Forward in Human Cancer Risk Assessment SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material DE cancer; human; omics technologies; risk assessment; systems biology ID DISCRIMINATE RODENT CARCINOGENS; GENE-EXPRESSION SIGNATURES; VITRO GENOTOXICITY TESTS; BREAST-CANCER; MARKETED PHARMACEUTICALS; NONGENOTOXIC CARCINOGENS; RELATIVE PREDICTIVITY; CONNECTIVITY MAP; PROFILES; NONCARCINOGENS AB BACKGROUND: The current safety paradigm for assessing carcinogenic properties of drugs, cosmetics, industrial chemicals, and environmental exposures relies mainly on in vitro genotoxicity testing followed by 2-year rodent bioassays. This testing battery is extremely sensitive but has low specificity. Furthermore, rodent bioassays are associated with high costs, high animal burden, and limited predictive value for human risks. OBJECTIVES: We provide a response to a growing appeal for a paradigm change in human cancer risk assessment. METHODS: To facilitate development of a road map for this needed paradigm change in carcinogenicity testing, a workshop titled "Genomics in Cancer Risk Assessment" brought together toxicologists from academia and industry and government regulators and risk assessors from the United States and the European Union. Participants discussed the state-of-the-art in developing alternative testing strategies for carcinogenicity, with emphasis on potential contributions from omics technologies. RESULTS AND CONCLUSIONS: The goal of human risk assessment is to decide whether a given exposure to an agent is acceptable to human health and to provide risk management measures based on evaluating and predicting the effects of exposures on human health. Although exciting progress is being made using genomics approaches, a new paradigm that uses these methods and human material when possible would provide mechanistic insights that may inform new predictive approaches (e. g., in vitro assays) and facilitate the development of genomics-derived biomarkers. Regulators appear to be willing to accept such approaches where use is clearly defined, evidence is strong, and approaches are qualified for regulatory use. C1 [Paules, Richard S.] NIEHS, Environm Stress & Canc Grp, Lab Toxicol & Pharmacol, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Aubrecht, Jiri] Pfizer Inc, Groton, CT 06340 USA. [Corvi, Raffaella] European Commiss Joint Res Ctr, Inst Hlth & Consumer Protect, European Ctr Validat Alternat Methods, In Vitro Methods Unit, Ispra, Italy. [Garthoff, Bernward] BIO NRW Cluster Biotechnol N Rhine Westphalia, Dusseldorf, Germany. [Kleinjans, Jos C.] Maastricht Univ, Maastricht, Netherlands. RP Paules, RS (reprint author), NIEHS, Environm Stress & Canc Grp, Lab Toxicol & Pharmacol, NIH,Dept Hlth & Human Serv, 111 TW Alexander Dr,Room D-266B,Box 12233,Mail Dr, Res Triangle Pk, NC 27709 USA. EM paules@niehs.nih.gov RI Kleinjans, Jos/E-7241-2015 FU Intramural NIH HHS NR 42 TC 12 Z9 12 U1 0 U2 5 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 JUN PY 2011 VL 119 IS 6 BP 739 EP 743 DI 10.1289/ehp.1002735 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 771JC UT WOS:000291152000014 PM 21147607 ER PT J AU Gao, HM Zhang, F Zhou, H Kam, W Wilson, B Hong, JS AF Gao, Hui-Ming Zhang, Feng Zhou, Hui Kam, Wayneho Wilson, Belinda Hong, Jau-Shyong TI Neuroinflammation and alpha-Synuclein Dysfunction Potentiate Each Other, Driving Chronic Progression of Neurodegeneration in a Mouse Model of Parkinson's Disease SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE oxidase; neuro degeneration; oxidative stress; Parkinson's disease ID DOPAMINERGIC NEURODEGENERATION; MICROGLIAL ACTIVATION; NADPH OXIDASE; LEWY BODIES; NEURON LOSS; CELL-DEATH; MUTATION; MICE; SUSCEPTIBILITY; NEUROTOXICITY AB BACKGROUND: Mechanisms whereby gene-environment interactions mediate chronic, progressive neuro degenerative processes in Parkinson's disease (PD)-the second most common neuro-degenerative disease-remain elusive. OBJECTIVE: We created a two-hit [neuro inflammation and mutant alpha-synuclein (alpha-syn) overexpression] animal model to investigate mechanisms through which mutant alpha-syn and inflammation work in concert to mediate chronic PD neuro degeneration. METHODS: We used an intraperitoneal injection of the inflammogen lipopolysaccharide (LPS; 3 x 10(6) EU/kg) to initiate systemic and brain inflammation in wild-type (WT) mice and transgenic (Tg) mice over expressing human A53T mutant alpha-syn. We then evaluated nigral dopaminergic neurodegeneration, alpha-syn pathology, and neuro inflammation. RESULTS: After LPS injection, both WT and Tg mice initially displayed indistinguishable acute neuro inflammation; however, only Tg mice developed persistent neuro inflammation, chronic progressive degeneration of the nigrostriatal dopamine pathway, accumulation of aggregated, nitrated alpha-syn, and formation of Lewy body-like inclusions in nigral neurons. Further mechanistic studies indicated that 4-week infusion of two inhibitors of inducible nitric oxide synthase and NADPH oxidase, major free radical-generating enzymes in activated microglia, blocked nigral alpha-syn pathology and neuro degeneration in LPS-injected Tg mice. CONCLUSIONS: Microglia-derived oxidative stress bridged neuro inflammation and alpha-syn pathogenic alteration in mediating chronic PD progression. Our two-hit animal model involving both a genetic lesion and an environmental trigger reproduced key features of PD and demonstrated synergistic effects of genetic predisposition and environmental exposures in the development of PD. The chronic progressive nature of dopaminergic neuro degeneration, which is absent in most existing PD models, makes this new model invaluable for the study of mechanisms of PD progression. C1 [Gao, Hui-Ming; Zhang, Feng; Zhou, Hui; Kam, Wayneho; Wilson, Belinda; Hong, Jau-Shyong] NIEHS, Lab Toxicol & Pharmacol, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Gao, HM (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, Dept Hlth & Human Serv, 111 TW Alexander Dr,MD F1-01, Res Triangle Pk, NC 27709 USA. EM gao2@niehs.nih.gov RI gao, huiming/C-8454-2012 FU National Institute of Environmental Health Sciences, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 45 TC 79 Z9 82 U1 1 U2 23 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 JUN PY 2011 VL 119 IS 6 BP 807 EP 814 DI 10.1289/ehp.1003013 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 771JC UT WOS:000291152000024 PM 21245015 ER PT J AU Gohlke, JM Thomas, R Woodward, A Campbell-Lendrum, D Pruss-Ustun, A Hales, S Portier, CJ AF Gohlke, Julia M. Thomas, Reuben Woodward, Alistair Campbell-Lendrum, Diarmid Pruess-Uestuen, Annette Hales, Simon Portier, Christopher J. TI Estimating the Global Public Health Implications of Electricity and Coal Consumption SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE air pollution; climate change; coal; electricity; energy policy; global health; health impact modeling; infant mortality; life expectancy; time series ID CLIMATE-CHANGE; AIR-POLLUTION; ENERGY; MORTALITY; BENEFITS AB BACKGROUND: The growing health risks associated with greenhouse gas emissions highlight the need for new energy policies that emphasize efficiency and low-carbon energy intensity. OBJECTIVES: We assessed the relationships among electricity use, coal consumption, and health outcomes. METHODS: Using time-series data sets from 41 countries with varying development trajectories between 1965 and 2005, we developed an autoregressive model of life expectancy (LE) and infant mortality (IM) based on electricity consumption, coal consumption, and previous year's LE or IM. Prediction of health impacts from the Greenhouse Gas and Air Pollution Interactions and Synergies (GAINS) integrated air pollution emissions health impact model for coal-fired power plants was compared with the time-series model results. RESULTS: The time-series model predicted that increased electricity consumption was associated with reduced IM for countries that started with relatively high IM (> 100/1,000 live births) and low LE (< 57 years) in 1965, whereas LE was not significantly associated with electricity consumption regardless of IM and LE in 1965. Increasing coal consumption was associated with increased IM and reduced LE after accounting for electricity consumption. These results are consistent with results based on the GAINS model and previously published estimates of disease burdens attributable to energy-related environmental factors, including indoor and outdoor air pollution and water and sanitation. CONCLUSIONS: Increased electricity consumption in countries with IM < 100/1,000 live births does not lead to greater health benefits, whereas coal consumption has significant detrimental health impacts. C1 [Gohlke, Julia M.; Thomas, Reuben; Portier, Christopher J.] Natl Inst Environm Hlth Sci, Mol Toxicol Lab, Res Triangle Pk, NC USA. [Woodward, Alistair] Univ Auckland, Sch Populat Hlth, Auckland 1, New Zealand. [Campbell-Lendrum, Diarmid; Pruess-Uestuen, Annette; Hales, Simon] World Hlth Org, Dept Publ Hlth & Environm, Geneva, Switzerland. RP Gohlke, JM (reprint author), Univ Alabama, Dept Environm Hlth Sci, RPHB 530,1530 3rd Ave S, Birmingham, AL 35294 USA. EM jgohlke@uab.edu RI Portier, Christopher/A-3160-2010; OI Portier, Christopher/0000-0002-0954-0279; Woodward, Alistair/0000-0001-5425-6018; Gohlke, Julia/0000-0002-6984-2893 FU National Institutes of Health, National Institute of Environmental Health Sciences FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 40 TC 11 Z9 11 U1 2 U2 26 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 JUN PY 2011 VL 119 IS 6 BP 821 EP 826 DI 10.1289/ehp.1002241 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 771JC UT WOS:000291152000026 PM 21339091 ER PT J AU Tanner, CM Kamel, F Ross, GW Hoppin, JA Goldman, SM Korell, M Marras, C Bhudhikanok, GS Kasten, M Chade, AR Comyns, K Richards, MB Meng, C Priestley, B Fernandez, HH Cambi, F Umbach, DM Blair, A Sandler, DP Langston, JW AF Tanner, Caroline M. Kamel, Freya Ross, G. Webster Hoppin, Jane A. Goldman, Samuel M. Korell, Monica Marras, Connie Bhudhikanok, Grace S. Kasten, Meike Chade, Anabel R. Comyns, Kathleen Richards, Marie Barber Meng, Cheryl Priestley, Benjamin Fernandez, Hubert H. Cambi, Franca Umbach, David M. Blair, Aaron Sandler, Dale P. Langston, J. William TI Rotenone, Paraquat, and Parkinson's Disease SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE aging; agricultural epidemiology; environmental epidemiology; epidemiology; fungicides; herbicides; insecticides; persistent organic pollutants; pesticides ID ENVIRONMENTAL RISK-FACTORS; AGRICULTURAL HEALTH; INTERNATIONAL WORKSHOP; DIAGNOSTIC-CRITERIA; PESTICIDE EXPOSURE; ESSENTIAL TREMOR; COMPLEX I; INHIBITORS; PATHOLOGY; ACCURACY AB BACKGROUND: Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson's disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. OBJECTIVES: Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. METHODS: We assessed lifetime use of pesticides selected by mechanism in a case-control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls: one case. RESULTS: In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0-2.8] including rotenone (OR = 2.5; 95% CI, 1.3-4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2-3.6), including paraquat (OR = 2.5; 95% CI, 1.4-4.7). CONCLUSIONS: PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally-those that impair mitochondrial function and those that increase oxidative stress-supporting a role for these mechanisms in PD pathophysiology. C1 [Tanner, Caroline M.; Goldman, Samuel M.; Korell, Monica; Bhudhikanok, Grace S.; Comyns, Kathleen; Meng, Cheryl; Priestley, Benjamin; Langston, J. William] Parkinsons Inst, Sunnyvale, CA 94085 USA. [Kamel, Freya; Hoppin, Jane A.; Richards, Marie Barber; Sandler, Dale P.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Ross, G. Webster] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Marras, Connie] Univ Toronto, Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. [Kasten, Meike] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Kasten, Meike] Univ Lubeck, Dept Clin & Mol Neurogenet, Lubeck, Germany. [Chade, Anabel R.] Favaloro Univ, Inst Neurosci, Inst Cognit Neurol, Buenos Aires, DF, Argentina. [Richards, Marie Barber] Westat Corp, Durham, NC USA. [Fernandez, Hubert H.] Cleveland Clin, Ctr Neurol Restorat, Cleveland, OH 44106 USA. [Cambi, Franca] Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA. [Umbach, David M.] Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Blair, Aaron] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tanner, CM (reprint author), Parkinsons Inst, 675 Almanor Ave, Sunnyvale, CA 94085 USA. EM ctannermd@aol.com RI Goldman, Samuel/A-2225-2014; OI Goldman, Samuel/0000-0002-3039-9927; Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health [National Institute of Environmental Health Sciences (NIEHS)] [Z01-ES044007, Z01-ES049030]; National Institutes of Health [National Cancer Institute] [Z01-CP010119]; NIEHS [R01-ES10803] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health [National Institute of Environmental Health Sciences (NIEHS) grants Z01-ES044007 and Z01-ES049030, National Cancer Institute grant Z01-CP010119], NIEHS grant R01-ES10803, and James and Sharron Clark. NR 60 TC 314 Z9 318 U1 17 U2 95 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 JUN PY 2011 VL 119 IS 6 BP 866 EP 872 DI 10.1289/ehp.1002839 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 771JC UT WOS:000291152000033 PM 21269927 ER PT J AU Isoda, M Hikosaka, O AF Isoda, Masaki Hikosaka, Okihide TI Cortico-basal ganglia mechanisms for overcoming innate, habitual and motivational behaviors SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Review DE automaticity; behavioral switching; executive function; monkey; saccade ID SUPPLEMENTARY EYE FIELD; PRIMATE SUPERIOR COLLICULUS; NIGRA PARS RETICULATA; MEDIAL FRONTAL-CORTEX; LATERAL INTRAPARIETAL AREA; EVENT-RELATED FMRI; PRESUPPLEMENTARY MOTOR AREA; VISUALLY-GUIDED SACCADES; HUMAN PREFRONTAL CORTEX; CM-PF COMPLEX AB Most of the human behaviors are executed automatically under familiar circumstances. These behaviors are prepotent in that they take precedence over any other potential alternatives. Yet, humans are also capable of engaging cognitive resources to inhibit such a prepotent behavior and replace it with an alternative controlled behavior in response to an unforeseen situation. This remarkable capability to switch behaviors in a short period of time is the hallmark of executive functions. In this article, we first argue that the prepotent automaticity could emerge at least in three different domains - innate, habitual and motivational. We then review neurophysiological findings on how the brain might realize its switching functions in each domain, primarily by focusing on the monkey oculomotor system as the experimental model. Emerging evidence now suggests that multiple neuronal populations in the shared cortico-basal ganglia network contribute to overriding prepotent eye movement, be its origin innate, habitual or motivational. This consideration suggests the general versatility of the cortico-basal ganglia network as the neural mechanism whereby humans and other animals keep themselves from becoming subservient to reflex, habit and motivational impulses. C1 [Isoda, Masaki] Okinawa Inst Sci & Technol, Unit Neural Syst & Behav, Okinawa 9040412, Japan. [Isoda, Masaki] RIKEN Brain Sci Inst, Lab Symbol Cognit Dev, Wako, Saitama, Japan. [Isoda, Masaki] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama, Japan. [Hikosaka, Okihide] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Isoda, M (reprint author), Okinawa Inst Sci & Technol, Unit Neural Syst & Behav, Okinawa 9040412, Japan. EM masaki.isoda@oist.jp NR 178 TC 32 Z9 32 U1 3 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUN PY 2011 VL 33 IS 11 BP 2058 EP 2069 DI 10.1111/j.1460-9568.2011.07698.x PG 12 WC Neurosciences SC Neurosciences & Neurology GA 774QD UT WOS:000291400300012 PM 21645101 ER PT J AU Freedman, ND Curto, TM Lindsay, KL Wright, EC Sinha, R Everhart, JE AF Freedman, Neal D. Curto, Teresa M. Lindsay, Karen L. Wright, Elizabeth C. Sinha, Rashmi Everhart, James E. CA HALT-C Trial Grp TI Coffee Consumption Is Associated With Response to Peginterferon and Ribavirin Therapy in Patients With Chronic Hepatitis C SO GASTROENTEROLOGY LA English DT Article DE Liver Fibrosis; Diet; Risk Factor; Caffeine ID GAMMA-GLUTAMYL-TRANSFERASE; ALPHA-2B PLUS RIBAVIRIN; PEGYLATED INTERFERON; VIROLOGICAL RESPONSE; GENETIC-VARIATION; INSULIN-RESISTANCE; SUSTAINED RESPONSE; SERUM-LIPIDS; IL28B; VIRUS AB BACKGROUND & AIMS: High-level coffee consumption has been associated with reduced progression of pre-existing liver diseases and lower risk of hepatocellular carcinoma. However, its relationship with therapy for hepatitis C virus infection has not been evaluated. METHODS: Patients (n=885) from the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial recorded coffee intake before retreatment with peginterferon alpha-2a (180 mu g/wk) and ribavirin (1000-1200 mg/day). We assessed patients for early virologic response (2 log(10) reduction in level of hepatitis C virus RNA at week 12; n=466), and undetectable hepatitis C virus RNA at weeks 20 (n=320), 48 (end of treatment, n=284), and 72 (sustained virologic response; n=157). RESULTS: Median log(10) drop from baseline to week 20 was 2.0 (interquartile range [IQR], 0.6-3.9) among nondrinkers and 4.0 (IQR, 2.1-4.7) among patients that drank 3 or more cups/day of coffee (P trend<.0001). After adjustment for age, race/ethnicity, sex, alcohol, cirrhosis, ratio of aspartate aminotransferase to alanine aminotransferase, the IL28B polymorphism rs12979860, dose reduction of peginterferon, and other covariates, odds ratios for drinking 3 or more cups/day vs nondrinking were 2.0 (95% confidence interval [CI]: 1.1-3.6; P trend=.004) for early virologic response, 2.1 (95% CI: 1.1-3.9; P trend=.005) for week 20 virologic response, 2.4 (95% CI: 1.3-4.6; P trend=.001) for end of treatment, and 1.8 (95% CI: 0.8-3.9; P trend=.034) for sustained virologic response. CONCLUSIONS: High-level consumption of coffee (more than 3 cups per day) is an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with hepatitis C. C1 [Freedman, Neal D.; Sinha, Rashmi] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Rockville, MD 20852 USA. New England Res Inst, Watertown, MA 02172 USA. [Lindsay, Karen L.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Wright, Elizabeth C.] NIDDK, Off Director, NIH, US Dept HHS, Bethesda, MD USA. [Everhart, James E.] NIDDK, Div Digest Dis & Nutr, NIH, US Dept HHS, Bethesda, MD USA. RP Freedman, ND (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, 6120 Execut Blvd,EPS-320,MSC 7232, Rockville, MD 20852 USA. EM freedmanne@mail.nih.gov RI Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015 OI Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098 FU University of Massachusetts Medical Center, Worcester, MA [N01-DK-9-2326]; University of Connecticut Health Center, Farmington, CT [M01RR-06192]; Saint Louis University School of Medicine, St Louis, MO [N01-DK-9-2324]; Massachusetts General Hospital, Boston, MA [N01-DK-9-2319, M01RR-01066, 1 UL1 RR025758-01]; University of Colorado Denver, School of Medicine, Aurora, CO [N01-DK-9-2327, M01RR-00051, 1 UL1 RR 025780-01]; University of California-Irvine, Irvine, CA [N01-DK-9-2320, M01RR-00827]; University of Texas Southwestern Medical Center, Dallas, TX [N01-DK-9-2321, M01RR-00633, 1 UL1 RR024982-01]; University of Southern California, Los Angeles, CA [N01-DK-9-2325, M01RR-00043]; University of Michigan Medical Center, Ann Arbor, MI [N01-DK-9-2323, M01RR-00042, 1 UL1 RR024986]; Virginia Commonwealth University Health System, Richmond, VA [N01-DK-9-2322, M01RR-00065]; University of Washington, Seattle, WA [N01-DK-9-2318]; New England Research Institutes, Watertown, MA [N01-DK-9-2328]; Hoffmann-La Roche, Inc. (now Genentech); National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Research Resources, National Institutes of Health; National Institutes of Health; Hoffmann-La Roche, Inc. (now Genentech), through a Cooperative Research and Development Agreement (CRADA); National Cancer Institute FX In addition to the authors of this article, the following individuals were instrumental in the planning, conduct, and/or care of patients enrolled in this study at each of the participating institutions as follows: University of Massachusetts Medical Center, Worcester, MA (Contract N01-DK-9-2326): Gyongyi Szabo, MD, Barbara F. Banner, MD, Maureen Cormier, RN, Donna Giansiracusa, RN; University of Connecticut Health Center, Farmington, CT (Grant M01RR-06192): Herbert L. Bonkovsky, MD, Gloria Borders, RN, Michelle Kelley, RN, ANP; Saint Louis University School of Medicine, St Louis, MO (Contract N01-DK-9-2324): Adrian M. Di Bisceglie, MD, Bruce Bacon, MD, Brent Neuschwander-Tetri, MD, Elizabeth M. Brunt, MD, Debra King, RN; Massachusetts General Hospital, Boston, MA (Contract N01-DK-9-2319, Grant M01RR-01066; Grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center): Jules L. Dienstag, MD, Raymond T. Chung, MD, Andrea E. Reid, MD, Atul K. Bhan, MD, Wallis A. Molchen, David P. Lundmark; University of Colorado Denver, School of Medicine, Aurora, CO (Contract N01-DK-9-2327, Grant M01RR-00051, Grant 1 UL1 RR 025780-01): Gregory T. Everson, MD, Thomas Trouillot, MD, Marcelo Kugelmas, MD, S. Russell Nash, MD, Jennifer DeSanto, RN, Carol McKinley, RN; University of California-Irvine, Irvine, CA (Contract N01-DK-9-2320, Grant M01RR-00827): Timothy R. Morgan, MD, John C. Hoefs, MD, John R. Craig, MD, M. Mazen Jamal, MD, MPH, Muhammad Sheikh, MD, Choon Park, RN; University of Texas Southwestern Medical Center, Dallas, TX (Contract N01-DK-9-2321, Grant M01RR-00633, Grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational Science Initiative): William M. Lee, MD, Thomas E. Rogers, MD, Peter F. Malet, MD, Janel Shelton, Nicole Crowder, LVN, Rivka Elbein, RN, BSN, Nancy Liston, MPH; University of Southern California, Los Angeles, CA (Contract N01-DK-9-2325, Grant M01RR-00043): Sugantha Govindarajan, MD, Carol B. Jones, RN, Susan L. Milstein, RN; University of Michigan Medical Center, Ann Arbor, MI (Contract N01-DK-9-2323, Grant M01RR-00042, Grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research): Anna S. Lok, MD, Robert J. Fontana, MD, Joel K. Greenson, MD, Pamela A. Richtmyer, LPN, CCRC, R. Tess Bonham, BS; Virginia Commonwealth University Health System, Richmond, VA (Contract N01-DK-9-2322, Grant M01RR-00065): Mitchell L. Shiffman, MD, Richard K. Sterling, MD, MSc, Melissa J. Contos, MD, A. Scott Mills, MD, Charlotte Hofmann, RN, Paula Smith, RN; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD: Marc G. Ghany, MD, T. Jake Liang, MD, David Kleiner, MD, PhD, Yoon Park, RN, Elenita Rivera, RN, Vanessa Haynes-Williams, RN; National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD: Leonard B. Seeff, MD, Patricia R. Robuck, PhD, Jay H. Hoofnagle, MD; University of Washington, Seattle, WA (Contract N01-DK-9-2318): Chihiro Morishima, MD, David R. Gretch, MD, PhD, Minjun Chung Apodaca, BS, ASCP, Rohit Shankar, BC, ASCP, Natalia Antonov, MEd; New England Research Institutes, Watertown, MA (Contract N01-DK-9-2328): Kristin K. Snow, MSc, ScD, Anne M. Stoddard, ScD; Inova Fairfax Hospital, Falls Church, VA: Zachary D. Goodman, MD, PhD, Fanny Monge, Michelle Parks. Data and Safety Monitoring Board Members (Chair): Gary L. Davis, MD, Guadalupe Garcia-Tsao, MD, Michael Kutner, PhD, Stanley M. Lemon, MD, Robert P. Perrillo, MD.; This author discloses the following: Dr Lindsay was a consultant and received research support from Hoffmann-La Roche, Inc. (now Genentech) during this study and is now an employee of Tibotec, Inc. (a subsidiary of Johnson and Johnson), Titusville, NJ.; This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (contract numbers are listed in the Acknowledgments). Additional support was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed in the Acknowledgments). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc. (now Genentech), through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health. This research was also supported in part by the Intramural Research Program of the National Cancer Institute. The funding organizations had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. NR 46 TC 31 Z9 31 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2011 VL 140 IS 7 BP 1961 EP 1969 DI 10.1053/j.gastro.2011.02.061 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 774LR UT WOS:000291388200030 PM 21376050 ER PT J AU Taylor, M Qu, AJ Anderson, ER Matsubara, T Martin, A Gonzalez, FJ Shah, YM AF Taylor, Matthew Qu, Aijuan Anderson, Erik R. Matsubara, Tsutomu Martin, Angelical Gonzalez, Frank J. Shah, Yatrik M. TI Hypoxia-Inducible Factor-2 alpha Mediates the Adaptive Increase of Intestinal Ferroportin During Iron Deficiency in Mice SO GASTROENTEROLOGY LA English DT Article DE Chromatin Immunoprecipitation Assay; ChIP Assay; Hepcidin; Diet; Metabolism ID AUTOSOMAL-DOMINANT HEMOCHROMATOSIS; EPITHELIAL-CELLS; OVERLOAD DISORDERS; PEPTIDE HEPCIDIN; GENE-EXPRESSION; HIF-ALPHA; MUTATION; TRANSPORTER; METABOLISM; ABSORPTION AB BACKGROUND & AIMS: Iron deficiency and iron overload affect over a billion people worldwide. Dietary iron absorption in the small intestine is required for systemic iron homeostasis. Ferroportin (FPN) is the only characterized, mammalian, basolateral iron exporter. Despite the importance of FPN in maintaining iron homeostasis, its in vivo mechanisms of regulation are unclear. METHODS: Systemic iron homeostasis was assessed in mice with intestine-specific disruption of genes encoding the von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (HIF)-1 alpha, HIF-2 alpha, and aryl hydrocarbon nuclear translocator (ARNT). RESULTS: We observed biphasic regulation of Fpn during iron deficiency. Fpn was rapidly induced under conditions of low iron, which required the transcription factor HIF-2 alpha. Targeted disruption of HIF-2 alpha in the intestine inhibited Fpn induction in mice with low iron, through loss of transcriptional activation. Analysis of the Fpn promoter and in vivo chromatin immunoprecipitation assays demonstrated that HIF-2 alpha directly binds to the Fpn promoter and induces its expression, indicating a mechanism of transcriptional regulation of Fpn following changes in systemic levels of iron. During chronic iron deficiency, FPN protein levels also increased, via increased stability through a HIF-2 alpha-independent pathway. CONCLUSIONS: In mice, expression of the gene that encodes Fpn and its protein levels are regulated by distinct pathways to provide a rapid and sustained response to acute and chronic iron deficiency. Therapies that target FPN might be developed for patients with iron-related disorders. C1 [Shah, Yatrik M.] Univ Michigan, Dept Internal Med, Dept Mol & Integrat Physiol, Div Gastroenterol, Ann Arbor, MI 48109 USA. NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Shah, YM (reprint author), Univ Michigan, Dept Internal Med, Dept Mol & Integrat Physiol, Div Gastroenterol, Ann Arbor, MI 48109 USA. EM shahy@umich.edu FU National Institutes of Health [CA148828]; University of Michigan Gastrointestinal Peptide Center FX Supported by grants from the National Institutes of Health (CA148828) and The University of Michigan Gastrointestinal Peptide Center (to Y.M.S). NR 46 TC 71 Z9 72 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2011 VL 140 IS 7 BP 2044 EP 2055 DI 10.1053/j.gastro.2011.03.007 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 774LR UT WOS:000291388200038 PM 21419768 ER PT J AU Kim, MS Lee, KP Yang, DK Shin, DM Abramowitz, J Kiyonaka, S Birnbaumer, L Mori, Y Muallem, S AF Kim, Min Seuk Lee, Kyu Pil Yang, Dongki Shin, Dong Min Abramowitz, Joel Kiyonaka, Shigeki Birnbaumer, Lutz Mori, Yasuo Muallem, Shmuel TI Genetic and Pharmacologic Inhibition of the Ca2+ Influx Channel TRPC3 Protects Secretory Epithelia From Ca2+-Dependent Toxicity SO GASTROENTEROLOGY LA English DT Article DE Ca2+ Influx; Inflammation; Cell Death; Therapeutics ID PANCREATIC ACINAR-CELLS; SJOGRENS-SYNDROME; CALCIUM; ACTIVATION; MICRODOMAINS; TRYPSINOGEN; CROSSTALK; AUTOPHAGY; ALCOHOL; DISEASE AB BACKGROUND & AIMS: Excessive Ca2+ influx mediates many cytotoxic processes, including those associated with autoimmune inflammatory diseases such as acute pancreatitis and Sjogren syndrome. Transient receptor potential (canonical) channel (TRPC) 3 is a major Ca2+ influx channel in pancreatic and salivary gland cells. We investigated whether genetic or pharmacologic inhibition of TRPC3 protects pancreas and salivary glands from Ca2+-dependent damage. METHODS: We developed a Ca2+-dependent model of cell damage for salivary gland acini. Acute pancreatitis was induced by injection of cerulein into wild-type and Trpc3(-/-) mice. Mice were also given the Trpc3-selective inhibitor pyrazole 3 (Pyr3). RESULTS: Salivary glands and pancreas of Trpc3(-/-) mice were protected from Ca2+-mediated cell toxicity. Analysis of Ca2+ signaling in wild-type and Trpc3(-/-) acini showed that Pyr3 is a highly specific inhibitor of Tprc3; it protected salivary glands and pancreas cells from Ca2+-mediated toxicity by inhibiting the Trpc3-mediated component of Ca2+ influx. CONCLUSIONS: TRPC3-mediated Ca2+ influx mediates damage to pancreas and salivary glands. Pharmacologic inhibition of TRPC3 with the highly selective TRPC3 inhibitor Pyr3 might be developed for treatment of patients with acute pancreatitis and Sjogren syndrome. C1 [Kim, Min Seuk; Lee, Kyu Pil; Yang, Dongki; Muallem, Shmuel] Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20814 USA. Yonsei Univ, Coll Dent, Brain Korea Project 21, Dept Oral Biol, Seoul 120749, South Korea. [Abramowitz, Joel; Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC USA. [Kiyonaka, Shigeki; Mori, Yasuo] Kyoto Univ, Grad Sch Engn, Dept Synthet Chem & Biol Chem, Kyoto, Japan. RP Muallem, S (reprint author), Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bldg 10,Room 1N-113, Bethesda, MD 20814 USA. EM shmuel.muallem@nih.gov RI Abramowitz, Joel/A-2620-2015; rchnds, rchnds/D-7595-2016 FU National Institutes of Health National Institute of Dental and Craniofacial Research/Division of Intramural Research [Z01-ES-101684]; National Research Foundation of Korea; Ministry of Education, Science and Technology [2011-0001167, 2010-0000315] FX Supported by the Intramural Research Program of the National Institutes of Health National Institute of Dental and Craniofacial Research/Division of Intramural Research (S. M.), grant Z01-ES-101684 (to L. B.), the Science Research Program of the National Research Foundation of Korea, and the Ministry of Education, Science and Technology grants 2011-0001167 and 2010-0000315 (to D.M.S.). NR 44 TC 47 Z9 47 U1 1 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2011 VL 140 IS 7 BP 2107 EP U346 DI 10.1053/j.gastro.2011.02.052 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 774LR UT WOS:000291388200044 PM 21354153 ER PT J AU Parkman, HP Hasler, WL Nguyen, L Pasricha, PJ Snape, WJ Farrugia, G Koch, KL Abell, TL McCallum, RW Yates, K Lee, L Unalp-Arida, A Tonascia, J Hamilton, F AF Parkman, Henry P. Hasler, William L. Nguyen, Linda Pasricha, Pankaj J. Snape, William J. Farrugia, Gianrico Koch, Kenneth L. Abell, Thomas L. McCallum, Richard W. Yates, Katherine Lee, Linda Unalp-Arida, Aynur Tonascia, James Hamilton, Frank TI Idiopathic Gastroparesis or Functional Dyspepsia With Delayed Gastric Emptying: Where Is the Difference? Reply SO GASTROENTEROLOGY LA English DT Letter C1 [Parkman, Henry P.] Temple Univ, Philadelphia, PA 19122 USA. [Hasler, William L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Nguyen, Linda; Pasricha, Pankaj J.] Stanford Univ, Palo Alto, CA 94304 USA. [Snape, William J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Farrugia, Gianrico] Mayo Clin, Rochester, MN USA. [Koch, Kenneth L.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Abell, Thomas L.] Univ Mississippi, Jackson, MS 39216 USA. [McCallum, Richard W.] Univ Texas El Paso, El Paso, TX 79968 USA. [Yates, Katherine; Lee, Linda; Unalp-Arida, Aynur; Tonascia, James] Johns Hopkins Univ, Baltimore, MD USA. [Hamilton, Frank] Natl Inst Diabet Digest & Kidney Dis, Bethesda, MD USA. RP Parkman, HP (reprint author), Temple Univ, Philadelphia, PA 19122 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2011 VL 140 IS 7 BP 2146 EP 2148 DI 10.1053/j.gastro.2011.04.040 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 774LR UT WOS:000291388200048 ER PT J AU Bauer, TR Olson, EM Huo, Y Tuschong, LM Allen, JM Li, Y Burkholder, TH Russell, DW AF Bauer, T. R., Jr. Olson, E. M. Huo, Y. Tuschong, L. M. Allen, J. M. Li, Y. Burkholder, T. H. Russell, D. W. TI Treatment of canine leukocyte adhesion deficiency by foamy virus vectors expressing CD18 from a PGK promoter SO GENE THERAPY LA English DT Article DE foamy virus; retrovirus; immunodeficiency; hematopoietic stem cell; canine ID SEVERE COMBINED IMMUNODEFICIENCY; NOD/SCID-REPOPULATING CELLS; HEMATOPOIETIC STEM-CELLS; GENE-THERAPY; RETROVIRAL VECTORS; LENTIVIRAL VECTOR; HUMAN GENOME; MOUSE MODEL; LONG-TERM; INTEGRATION AB Proto-oncogene activation caused by retroviral vector integration can cause malignancies in gene therapy trials. This has led investigators to search for less genotoxic vectors with minimal enhancer activity and a decreased risk of influencing neighboring chromosomal gene expression after integration. We previously showed that foamy virus (FV) vectors expressing the canine CD18 gene from an internal murine stem cell virus (MSCV) promoter could cure canine leukocyte adhesion deficiency (LAD). Here, we have repeated these studies using a FV vector expressing canine CD18 from a phosphoglycerate kinase (PGK) gene promoter. In vitro analysis showed that this vector did not contain an enhancer that activated neighboring genes, and it expressed CD18 efficiently in canine neutrophils and CD34+ cells. However, dogs that received hematopoietic stem cells transduced with the PGK-CD18 vector continued to suffer from LAD, and sometimes died prematurely of the disease. These studies show that the PGK promoter cannot effectively replace the MSCV promoter in CD18-expressing FV vectors, and they suggest that vectors containing a strong promoter-enhancer may be necessary for the treatment of human LAD. Gene Therapy (2011) 18, 553-559; doi: 10.1038/gt.2010.169; published online 13 January 2011 C1 [Olson, E. M.; Huo, Y.; Allen, J. M.; Li, Y.; Russell, D. W.] Univ Washington, Dept Med, Div Hematol, Seattle, WA 98195 USA. [Bauer, T. R., Jr.; Tuschong, L. M.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Burkholder, T. H.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. [Russell, D. W.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. RP Russell, DW (reprint author), Univ Washington, Dept Med, Div Hematol, Mailstop 357720, Seattle, WA 98195 USA. EM drussell@u.washington.edu FU US National Institutes of Health [HL53750, HL085107]; US National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by US National Institutes of Health grants HL53750 and HL085107 and the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. We thank Raisa Stolitenko for technical assistance, William Telford and Veena Kapoor for help with flow cytometry, and Dennis Hickstein for support and advice. NR 40 TC 11 Z9 11 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD JUN PY 2011 VL 18 IS 6 BP 553 EP 559 DI 10.1038/gt.2010.169 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 775DP UT WOS:000291438900004 PM 21228879 ER PT J AU Dall'Armellina, E Karia, N Lindsay, A Karamitsos, TD Ferreira, V Robson, MD Kellman, P Francis, JM Forfar, C Prendergast, B Banning, AP Channon, K Kharbanda, RJ Neubauer, S Choudhury, RP AF Dall'Armellina, E. Karia, N. Lindsay, A. Karamitsos, T. D. Ferreira, V. Robson, M. D. Kellman, P. Francis, J. M. Forfar, C. Prendergast, B. Banning, A. P. Channon, K. Kharbanda, R. J. Neubauer, S. Choudhury, R. P. TI DYNAMIC CHANGES OF OEDEMA AND LATE GADOLINIUM ENHANCEMENT AFTER ACUTE MYOCARDIAL INFARCTION AND THEIR RELATIONSHIP TO FUNCTIONAL RECOVERY AND SALVAGE INDEX SO HEART LA English DT Meeting Abstract CT Annual Conference of the British-Cardiovascular-Society (BCS) CY JUN 13-15, 2011 CL Manchester, ENGLAND SP British Cardiovasc Soc C1 [Dall'Armellina, E.; Karia, N.; Lindsay, A.; Karamitsos, T. D.; Ferreira, V.; Robson, M. D.; Francis, J. M.; Channon, K.; Neubauer, S.; Choudhury, R. P.] Univ Oxford, NIHR Biomed Res Ctr, Dept Cardiovasc Med, Oxford, England. [Kellman, P.] NIH, Bethesda, MD 20892 USA. [Forfar, C.; Prendergast, B.; Banning, A. P.; Kharbanda, R. J.] John Radcliffe Hosp, NIHR Biomed Res Ctr, Dept Cardiol, Oxford OX3 9DU, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 J9 HEART JI Heart PD JUN PY 2011 VL 97 SU 1 MA 14 BP A12 EP A13 DI 10.1136/heartjnl-2011-300198.14 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 775NZ UT WOS:000291468400015 ER PT J AU Barese, CN Dunbar, CE AF Barese, Cecilia N. Dunbar, Cynthia E. TI Contributions of Gene Marking to Cell and Gene Therapies SO HUMAN GENE THERAPY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; HEMATOPOIETIC STEM-CELLS; GREEN FLUORESCENT PROTEIN; SEVERE COMBINED IMMUNODEFICIENCY; ADENOSINE-DEAMINASE DEFICIENCY; CHRONIC GRANULOMATOUS-DISEASE; NONHUMAN PRIMATE MODELS; RHESUS PERIPHERAL-BLOOD; GRAFT-VERSUS-LEUKEMIA; ASSESSED IN-VIVO AB The first human genetic modification studies used replication-incompetent integrating vector vectors to introduce marker genes into T lymphocytes and subsequently into hematopoietic stem cells. Such studies have provided numerous insights into the biology of hematopoiesis and immune reconstitution and contributed to clinical development of gene and cell therapies. Tracking of hematopoietic reconstitution and analysis of the origin of residual malignant disease after hematopoietic transplantation has been possible via gene marking. Introduction of selectable marker genes has enabled preselection of specific T-cell populations for tumor and viral immunotherapy and reduced the threat of graft-versus-host disease, improving the survival of patients after allogeneic marrow transplantation. Marking studies in humans, murine xenografts, and large animals have helped optimize conditions for gene transfer into CD34(+) hematopoietic progenitors, contributing to the achievement of gene transfer efficiencies sufficient for clinical benefit in several serious genetic diseases such as X-linked severe combined immunodeficiency and adrenoleukodystropy. When adverse events linked to insertional mutagenesis arose in clinical gene therapy trials for inherited immunodeficiencies, additional animal studies using gene-marking vectors have greatly increased our understanding of genotoxicity. The knowledge gained from these studies is being translated into new vector designs and clinical protocols, which we hope will continue to improve the efficiency, effectiveness and safety of these promising therapeutic approaches. C1 [Barese, Cecilia N.; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20852 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, CRC Bldg 10,Room 4E-5132,10 Ctr Dr, Bethesda, MD 20852 USA. EM dunbarc@nhlbi.nih.gov RI BARESE, CECILIA/G-8843-2011 NR 103 TC 13 Z9 13 U1 2 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUN PY 2011 VL 22 IS 6 BP 659 EP 668 DI 10.1089/hum.2010.237 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 774LS UT WOS:000291388300077 PM 21261461 ER PT J AU Hunter, MJ Zhao, HF Tuschong, LM Bauer, TR Burkholder, TH Persons, DA Hickstein, DD AF Hunter, Michael J. Zhao, Huifen Tuschong, Laura M. Bauer, Thomas R., Jr. Burkholder, Tanya H. Persons, Derek A. Hickstein, Dennis D. TI Gene Therapy for Canine Leukocyte Adhesion Deficiency with Lentiviral Vectors Using the Murine Stem Cell Virus and Human Phosphoglycerate Kinase Promoters SO HUMAN GENE THERAPY LA English DT Article ID P150,95 GLYCOPROTEINS; TRANSGENE EXPRESSION; HEMATOPOIETIC-CELLS; TRANSPLANTATION; DISEASE; LFA-1; MAC-1; TRANSDUCTION; INTEGRATION; FEATURES AB Children with leukocyte adhesion deficiency type 1 (LAD-1) and dogs with canine LAD (CLAD) develop life-threatening bacterial infections due to mutations in the leukocyte integrin CD18. Here, we compared the human phosphoglycerate kinase (hPGK) promoter to the murine stem cell virus (MSCV) promoter/enhancer in a self-inactivating HIV-1-derived lentiviral vector to treat animals with CLAD. Four CLAD dogs were infused with CD34(+) cells transduced with the hPGK vector, and two CLAD dogs received MSCV vector-transduced CD34(+) cells. Infusions were preceded by a nonmyeloablative dose of 200 cGy total body irradiation. Comparable numbers of transduced cells were infused in each group of animals. Only one of four CLAD animals treated with the hPGK-cCD18 vector had reversal of CLAD, whereas both MSCV-cCD18 vector-treated dogs had reversal of the phenotype. Correction of CLAD depends both upon the percentage of CD18(+) myeloid cells and the level of expression of CD18 on individual myeloid cells. In this regard, the hPGK promoter directed low levels of expression of CD18 on neutrophils compared to the MSCV promoter, likely contributing to the suboptimal clinical outcome with the hPGK vector. C1 [Hunter, Michael J.; Tuschong, Laura M.; Bauer, Thomas R., Jr.; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zhao, Huifen; Persons, Derek A.] St Jude Childrens Hosp, Dept Hematol, Div Expt Hematol, Memphis, TN 38105 USA. [Burkholder, Tanya H.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Hunter, MJ (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,MSC1203,Bldg 10-CRC,Room 3-3264, Bethesda, MD 20892 USA. EM huntermj@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. We wish to thank Veena Kapoor, National Cancer Institute, for assistance with flow cytometry. NR 26 TC 13 Z9 13 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUN PY 2011 VL 22 IS 6 BP 689 EP 696 DI 10.1089/hum.2010.130 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 774LS UT WOS:000291388300080 PM 21275758 ER PT J AU Lindahl, K Barnes, AM Fratzl-Zelman, N Whyte, MP Hefferan, TE Makareeva, E Brusel, M Yaszemski, MJ Rubin, CJ Kindmark, A Roschger, P Klaushofer, K McAlister, WH Mumm, S Leikin, S Kessler, E Boskey, AL Ljunggren, O Marini, JC AF Lindahl, Katarina Barnes, Aileen M. Fratzl-Zelman, Nadja Whyte, Michael P. Hefferan, Theresa E. Makareeva, Elena Brusel, Marina Yaszemski, Michael J. Rubin, Carl-Johan Kindmark, Andreas Roschger, Paul Klaushofer, Klaus McAlister, William H. Mumm, Steven Leikin, Sergey Kessler, Efrat Boskey, Adele L. Ljunggren, Osten Marini, Joan C. TI COL1 C-Propeptide Cleavage Site Mutations Cause High Bone Mass Osteogenesis Imperfecta SO HUMAN MUTATION LA English DT Article DE osteogenesis imperfecta; C-propeptide; collagen; C-proteinase; mineralization; high bone mass ID MINERALIZATION DENSITY DISTRIBUTION; EHLERS-DANLOS-SYNDROME; CARBOXYL-TERMINAL PROPEPTIDE; I COLLAGEN; PARTIAL-PURIFICATION; GROWING CHILDREN; NORMATIVE DATA; PROTEINASE; PROCOLLAGEN; HISTOMORPHOMETRY AB Osteogenesis imperfecta (OI) is most often caused by mutations in the type I procollagen genes (COL1A1/COL1A2). We identified two children with substitutions in the type I procollagen C-propeptide cleavage site, which disrupt a unique processing step in collagen maturation and define a novel phenotype within OI. The patients have mild OI caused by mutations in COL1A1 (Patient 1: p.Asp1219Asn) or COL1A2 (Patient 2: p.Ala1119Thr), respectively. Patient 1 L1-L4 DXA Z-score was +3.9 and pQCT vBMD was +3.1; Patient 2 had L1-L4 DXA Z-score of 0.0 and pQCT vBMD of -1.8. Patient BMD contrasts with radiographic osteopenia and histomorphometry without osteosclerosis. Mutant procollagen processing is impaired in pericellular and in vitro assays. Patient dermal collagen fibrils have irregular borders. Incorporation of pC-collagen into matrix leads to increased bone mineralization. FTIR imaging confirms elevated mineral/matrix ratios in both patients, along with increased collagen maturation in trabecular bone, compared to normal or OI controls. Bone mineralization density distribution revealed a marked shift toward increased mineralization density for both patients. Patient 1 has areas of higher and lower bone mineralization than controls; Patient 2's bone matrix has a mineral content exceeding even classical OI bone. These patients define a new phenotype of high BMD OI and demonstrate that procollagen C-propeptide cleavage is crucial to normal bone mineralization. Hum Mutat 32:598-609, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Lindahl, Katarina; Rubin, Carl-Johan; Kindmark, Andreas; Ljunggren, Osten] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Barnes, Aileen M.; Marini, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD USA. [Fratzl-Zelman, Nadja; Roschger, Paul; Klaushofer, Klaus] Hanusch Hosp, Ludwig Boltzmann Inst Osteol, WGKK & AUVA Trauma Ctr Meidling, Dept Med 1, Vienna, Austria. [Whyte, Michael P.; McAlister, William H.; Mumm, Steven] Shriners Hosp Children, St Louis, MO USA. [Whyte, Michael P.; McAlister, William H.; Mumm, Steven] Washington Univ, Sch Med, St Louis, MO USA. [Hefferan, Theresa E.; Yaszemski, Michael J.] Mayo Clin, Dept Orthoped, Rochester, MN USA. [Makareeva, Elena; Leikin, Sergey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Phys Biochem, NIH, Bethesda, MD USA. [Brusel, Marina; Kessler, Efrat] Tel Aviv Univ, Sackler Fac Med, Maurice & Gabriela Goldschleger Eye Res Inst, Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Boskey, Adele L.] Cornell Univ, Hosp Special Surg, Weill Med Coll, New York, NY 10021 USA. RP Marini, JC (reprint author), NICHD, Bone & Extracellular Matrix Branch, NIH, Bldg 10,Rm 10N260,9000 Rockville Pike, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov RI Makareeva, Elena/F-5183-2011; Leikin, Sergey/A-5518-2008; OI Leikin, Sergey/0000-0001-7095-0739; Boskey, Adele/0000-0002-6181-2219 FU NICHD; Swedish research council [207-2946]; Israel Science Foundation [1360/07]; NIH [DE04141, AR041325]; AUVA (Austrian workers compensation board); WGKK FX Contract grant sponsors: NICHD Intramural Funding (to J.C.L. and S.L.); The Swedish research council; Contract grant number: 207-2946 (to K.L. and O.L.); Contract grant sponsor: The Israel Science Foundation; Contract grant number: 1360/07 (to E.K.); Contract grant sponsor: NIH; Contract grant numbers: DE04141; AR041325 (to A.L.B.); Contract grant sponsors: AUVA (Research funds of the Austrian workers compensation board); WGKK (Viennese sickness insurance funds) (to N.F.-Z., P.R., and K.K.). NR 40 TC 54 Z9 59 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD JUN PY 2011 VL 32 IS 6 BP 598 EP 609 DI 10.1002/humu.21475 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 776UO UT WOS:000291564000011 PM 21344539 ER PT J AU Wei, XM Moncada-Pazos, A Cal, S Soria-Valles, C Gartner, J Rudloff, U Lin, JC Rosenberg, SA Lopez-Otin, C Samuels, Y AF Wei, Xiaomu Moncada-Pazos, Angela Cal, Santiago Soria-Valles, Clara Gartner, Jared Rudloff, Udo Lin, Jimmy C. Rosenberg, Steven A. Lopez-Otin, Carlos Samuels, Yardena CA NISC Comparative Sequencing TI Analysis of the Disintegrin-metalloproteinases Family Reveals ADAM29 and ADAM7 Are Often Mutated in Melanoma SO HUMAN MUTATION LA English DT Article DE Somatic mutation; Melanoma; ADAM7; ADAM29 ID CANCER; INACTIVATION; METZINCINS; MUTATIONS; PATHWAYS; PROTEINS; GENES AB We performed a mutational analysis of the 19 disintegrin-metalloproteinases (ADAMs) genes in human cutaneous metastatic melanoma and identified eight to be somatically mutated in 79 samples, affecting 34% of the melanoma tumors analyzed. Functional analysis of the two frequently mutated ADAM genes, ADAM29 and ADAM7 demonstrated that the mutations affect adhesion of melanoma cells to specific extracellular matrix proteins and in some cases increase their migration ability. This suggests that mutated ADAM genes could play a role in melanoma progression. (C) 2011 Wiley-Liss, Inc. C1 [Wei, Xiaomu; Gartner, Jared; Samuels, Yardena] Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Moncada-Pazos, Angela; Cal, Santiago; Soria-Valles, Clara; Lopez-Otin, Carlos] Univ Oviedo, Dept Bioquim & Biol Mol, Inst Univ Oncol IUOPA, E-33006 Oviedo, Spain. [Rudloff, Udo; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Lin, Jimmy C.] Johns Hopkins Kimmel Canc Ctr, Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD 21231 USA. [Lin, Jimmy C.] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD 21231 USA. [NISC Comparative Sequencing] Natl Human Genome Res Inst, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Samuels, Y (reprint author), Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM samuelsy@mail.nih.gov RI Lopez-Otin, Carlos/C-6657-2013; OI Lopez-Otin, Carlos/0000-0001-6964-1904; MONCADA PAZOS, ANGELA/0000-0002-3871-2965 FU National Human Genome Research Institute, National Institutes of Health; Ministerio de Ciencia e Innovacion-Spain; Fundacion "M. Botin"; European Union FX We thank Dr. R. Weinberg for the Mel-STR cell line and Dr. W. Gahl and W. Westbroek (National Institutes of Health) for normal melanocytes RNA. We thank T. Prickett and V. Walia for their helpful comments on the manuscript. We also thank members of the NISC Comparative Sequencing Program for providing leadership in the generation of the sequence data analyzed here. Funded by the National Human Genome Research Institute, National Institutes of Health to Y.S. and Ministerio de Ciencia e Innovacion-Spain, Fundacion "M. Botin", and European Union (FP7 MicroEnviMet) to C.L-O. NR 34 TC 22 Z9 30 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD JUN PY 2011 VL 32 IS 6 BP E2148 EP E2175 DI 10.1002/humu.21477 PG 28 WC Genetics & Heredity SC Genetics & Heredity GA 776UO UT WOS:000291564000002 PM 21618342 ER PT J AU Klaschik, S Tross, D Klinman, DM AF Klaschik, S. Tross, D. Klinman, D. M. TI INDUCTIVE AND SUPPRESSIVE NETWORKS REGULATE TLR9-DEPENDENT GENE EXPRESSION IN VIVO SO INFLAMMATION RESEARCH LA English DT Meeting Abstract CT 10th World Congress on Inflammation CY JUN 25-29, 2011 CL Paris, FRANCE SP Int Assoc Inflammation Soc, Grp Res & Study Mediators Inflammat C1 [Klaschik, S.] Univ Bonn, Dept Anesthesiol, D-5300 Bonn, Germany. [Tross, D.; Klinman, D. M.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1023-3830 J9 INFLAMM RES JI Inflamm. Res. PD JUN PY 2011 VL 60 SU 1 BP 165 EP 165 PG 1 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 774CM UT WOS:000291358900449 ER PT J AU Czachorowski, M de Maturana, EL Kishore, S Herranz, J Silverman, D Morente, M Rothman, N Kogevinas, M Real, F Malats, N AF Czachorowski, M. Lopez de Maturana, E. Kishore, S. Herranz, J. Silverman, D. Morente, M. Rothman, N. Kogevinas, M. Real, F. Malats, N. TI IDENTIFICATION OF GENETIC SUSCEPTIBILITY FACTORS IN SUBGROUPS OF BLADDER CANCER CHARACTERIZED BY DIFFERENTIAL EXPRESSION OF CYCLOOXYGENASE-2 (COX-2) SO INFLAMMATION RESEARCH LA English DT Meeting Abstract CT 10th World Congress on Inflammation CY JUN 25-29, 2011 CL Paris, FRANCE SP Int Assoc Inflammation Soc, Grp Res & Study Mediators Inflammat C1 [Morente, M.] Ctr Nacl Invest Oncol, Tumor Bank Unit, E-08003 Madrid, Spain. [Silverman, D.; Rothman, N.] Natl Canc Inst, Bethesda, MD USA. [Kogevinas, M.] Inst Municipal Invest Med, Barcelona, Spain. [Real, F.] Ctr Nacl Invest Oncol, Epithelial Carcinogenesis Grp, Madrid, Spain. RI Kogevinas, Manolis/C-3918-2017 NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1023-3830 J9 INFLAMM RES JI Inflamm. Res. PD JUN PY 2011 VL 60 SU 1 BP 192 EP 192 PG 1 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 774CM UT WOS:000291358900526 ER PT J AU Canhamero, T Reines, B Borrego, A Correa, MA Jensen, JR Cabrera, WH Ribeiro, OG Starobinas, N Ibanez, OM De Franco, M AF Canhamero, T. Reines, B. Borrego, A. Correa, M. A. Jensen, J. R. Cabrera, W. H. Ribeiro, O. G. Starobinas, N. Ibanez, O. M. De Franco, M. TI EARLY INFLAMMATORY EVENTS DURING EAR TISSUE REGENERATION IN MICE SO INFLAMMATION RESEARCH LA English DT Meeting Abstract CT 10th World Congress on Inflammation CY JUN 25-29, 2011 CL Paris, FRANCE SP Int Assoc Inflammation Soc, Grp Res & Study Mediators Inflammat C1 [Canhamero, T.; Borrego, A.; Correa, M. A.; Jensen, J. R.; Cabrera, W. H.; Ribeiro, O. G.; Starobinas, N.; Ibanez, O. M.; De Franco, M.] Inst Butantan, Lab Imunogenet, Sao Paulo, Brazil. [Reines, B.] NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RI Starobinas, Nancy/B-9178-2015; Ribeiro, Orlando/B-5241-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1023-3830 J9 INFLAMM RES JI Inflamm. Res. PD JUN PY 2011 VL 60 SU 1 BP 275 EP 275 PG 1 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 774CM UT WOS:000291358900760 ER PT J AU Nugent, AC Bain, EE Thayer, JF Sollers, JJ Drevets, WC AF Nugent, Allison C. Bain, Earle E. Thayer, Julian F. Sollers, John J. Drevets, Wayne C. TI Sex differences in the neural correlates of autonomic arousal: A pilot PET study SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE Autonomic; HRV; PET; Sex; Amygdala ID HEART-RATE-VARIABILITY; MEDIAL PREFRONTAL CORTEX; TEND-AND-BEFRIEND; SPECTRAL-ANALYSIS; GENDER-DIFFERENCES; CINGULATE CORTEX; CENTRAL AMYGDALA; NERVOUS-SYSTEM; FOREBRAIN; RESPONSES AB Electrophysiology, behavioral, and neuroimaging studies have revealed sex-related differences in autonomic cardiac control, as reflected in measurements of heart rate variability (HRV). Imaging studies indicate that the neurobiological correlates of autonomic nervous system (ANS) function can be investigated by measuring indices of HRV during the performance of mildly strenuous motor tasks or mildly stressful cognitive tasks. In this preliminary study, fifteen male and seven female healthy subjects underwent (H2O)-O-15-positron emission tomography (PET) and electrocardiograph (ECG) recording while performing a handgrip motor task and an n-back task. Indices of HRV were calculated and correlated with regional cerebral blood flow (rCBF). We hypothesized that sex differences would be evident in brain regions known to participate in autonomic regulation: the anterior insula, the anterior cingulate cortex, the orbitofrontal cortex, and the amygdala. Our study found that associations between rCBF and parasympathetic indices differed significantly between female and male subjects in the amygdala. Females showed a positive correlation between rCBF and parasympathetic indices while males exhibited negative correlations. This differential correlation of amygdala rCBF and parasympathetic activity between males and females may reflect differences in parasympathetic/sympathetic balance between sexes, consistent with known sexual dimorphism in the amygdala and closely related structures such as the hypothalamus. These preliminary imaging results are consistent with earlier reports of significant correlation between brain activity and HRV, and extend these findings by demonstrating prominent sex differences in the neural control of the ANS. While the generalizability of our results was limited by the small size of the study samples, the relatively robust effect size of the differences found between groups encourages further work in larger samples to characterize sex differences in the neural correlates of autonomic arousal. Published by Elsevier B.V. C1 [Nugent, Allison C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Bain, Earle E.] Abbott Labs, Neurosci & Anesthesia Dev, Abbott Pk, IL 60064 USA. [Thayer, Julian F.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [Sollers, John J.] Univ Auckland, Dept Psychol Med, Auckland 1, New Zealand. [Drevets, Wayne C.] Univ Oklahoma, Coll Med, Laureate Inst Brain Res, Tulsa, OK USA. RP Nugent, AC (reprint author), NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, 9 Mem Dr,MSC 0940, Bethesda, MD 20892 USA. EM nugenta@mail.nih.gov OI Nugent, Allison/0000-0003-2569-2480 FU Intramural NIH HHS [Z99 MH999999] NR 62 TC 22 Z9 23 U1 3 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 EI 1872-7697 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD JUN PY 2011 VL 80 IS 3 BP 182 EP 191 DI 10.1016/j.ijpsycho.2011.03.001 PG 10 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 774HS UT WOS:000291376900002 PM 21414364 ER PT J AU Sinicrope, FA Foster, NR Thibodeau, SN Marsoni, S Monges, G Labianca, R Yothers, G Allegra, C Moore, MJ Gallinger, S Sargent, DJ AF Sinicrope, Frank A. Foster, Nathan R. Thibodeau, Stephen N. Marsoni, Silvia Monges, Genevieve Labianca, Roberto Yothers, Greg Allegra, Carmen Moore, Malcolm J. Gallinger, Steven Sargent, Daniel J. TI DNA Mismatch Repair Status and Colon Cancer Recurrence and Survival in Clinical Trials of 5-Fluorouracil-Based Adjuvant Therapy SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NONPOLYPOSIS COLORECTAL-CANCER; ISLAND METHYLATOR PHENOTYPE; MICROSATELLITE-INSTABILITY; LYNCH SYNDROME; FLUOROURACIL; CHEMOTHERAPY; CARCINOMA; EXPRESSION; LEVAMISOLE; PROGNOSIS AB Background Approximately 15% of colorectal cancers develop because of defective function of the DNA mismatch repair (MMR) system. We determined the association of MMR status with colon cancer recurrence and examined the impact of 5-fluorouracil (FU)-based adjuvant therapy on recurrence variables. Methods We included stage II and III colon carcinoma patients (n = 2141) who were treated in randomized trials of 5-FU-based adjuvant therapy. Tumors were analyzed for microsatellite instability by polymerase chain reaction and/or for MMR protein expression by immunohistochemistry to determine deficient MMR (dMMR) or proficient MMR (pMMR) status. Associations of MMR status and/or 5-FU-based treatment with clinicopathologic and recurrence covariates were determined using chi(2) or Fisher Exact or Wilcoxon rank-sum tests. Time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) were analyzed using univariate and multivariable Cox models, with the latter adjusted for covariates. Tumors showing dMMR were categorized by presumed germline vs sporadic origin and were assessed for their prognostic and predictive impact. All statistical tests were two-sided. Results In this study population, dMMR was detected in 344 of 2141 (16.1%) tumors. Compared with pMMR tumors, dMMR was associated with reduced 5-year recurrence rates (33% vs 22%; P < .001), delayed TTR (P < .001), and fewer distant recurrences (22% vs 12%; P < .001). In multivariable models, dMMR was independently associated with delayed TTR (hazard ratio = 0.72, 95% confidence interval = 0.56 to 0.91, P = .005) and improved DFS (P = .035) and OS (P = .031). In stage III cancers, 5-FU-based treatment vs surgery alone or no 5-FU was associated with reduced distant recurrence for dMMR tumors (11% vs 29%; P = .011) and reduced recurrence to all sites for pMMR tumors (P < .001). The dMMR tumors with suspected germline mutations were associated with improved DFS after 5-FU-based treatment compared with sporadic tumors where no benefit was observed (P = .006). Conclusions Patients with dMMR colon cancers have reduced rates of tumor recurrence, delayed TTR, and improved survival rates, compared with pMMR colon cancers. Distant recurrences were reduced by 5-FU-based adjuvant treatment in dMMR stage III tumors, and a subset analysis suggested that any treatment benefit was restricted to suspected germline vs sporadic tumors. C1 [Sinicrope, Frank A.] Mayo Clin, Div Oncol, Rochester, MN 55905 USA. [Sinicrope, Frank A.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA. [Thibodeau, Stephen N.] Mayo Clin, Div Lab Med & Pathol, Rochester, MN 55905 USA. [Foster, Nathan R.; Sargent, Daniel J.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Yothers, Greg; Allegra, Carmen] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Marsoni, Silvia] SENDO Fdn, Milan, Italy. [Monges, Genevieve] Inst J Paoli I Calmettes, F-13009 Marseille, France. [Labianca, Roberto] Osped Riuniti Bergamo, I-24100 Bergamo, Italy. [Gallinger, Steven] Univ Hlth Network, Toronto, ON, Canada. [Moore, Malcolm J.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. RP Sinicrope, FA (reprint author), Mayo Clin, Div Oncol, 200 1st St SW, Rochester, MN 55905 USA. EM sinicrope.frank@mayo.edu RI Gallinger, Steven/E-4575-2013; Labianca, Roberto/N-1847-2016; OI Labianca, Roberto/0000-0001-7149-822X; Sargent, Daniel/0000-0002-2684-4741; Yothers, Greg/0000-0002-7965-7333 FU National Cancer Institute [CA104683-02, 1 K05 CA142885-01]; Mayo Clinic Cancer Center [CA15083] FX National Cancer Institute (CA104683-02 and 1 K05 CA142885-01 to FAS); Mayo Clinic Cancer Center (CA15083). NR 48 TC 171 Z9 172 U1 0 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JUN PY 2011 VL 103 IS 11 BP 863 EP 875 DI 10.1093/jnci/djr153 PG 13 WC Oncology SC Oncology GA 775VG UT WOS:000291490900008 PM 21597022 ER PT J AU Dinse, GE AF Dinse, Gregg E. TI An EM Algorithm for Fitting a Four-Parameter Logistic Model to Binary Dose-Response Data SO JOURNAL OF AGRICULTURAL BIOLOGICAL AND ENVIRONMENTAL STATISTICS LA English DT Article DE Binomial data; Hill model; Logistic regression; Quantal response ID CARCINOGENICITY AB This article is motivated by the need of biological and environmental scientists to fit a popular nonlinear model to binary dose-response data. The four-parameter logistic model, also known as the Hill model, generalizes the usual logistic regression model to allow the lower and upper response asymptotes to be greater than zero and less than one, respectively. This article develops an EM algorithm, which is naturally suited for maximum likelihood estimation under the Hill model after conceptualizing the problem as a mixture of subpopulations in which some subjects respond regardless of dose, some fail to respond regardless of dose, and some respond with a probability that depends on dose. The EM algorithm leads to a pair of functionally independent two-parameter optimizations and is easy to program. Not only can this approach be computationally appealing compared to simultaneous optimization with respect to all four parameters, but it also facilitates estimating covariances, incorporating predictors, and imposing constraints. This article is motivated by, and the EM algorithm is illustrated with, data from a toxicology study of the dose effects of selenium on the death rates of flies. Other biological and environmental applications, as well as medical and agricultural applications, are also described briefly. Computer code for implementing the EM algorithm is available as supplemental material online. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Dinse, GE (reprint author), NIEHS, Biostat Branch, Mail Drop A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. EM dinse@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01-ES-102685] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-102685). I am very grateful to Shyamal Peddada, David Umbach, Clarice Weinberg, the editors, and the referees for their valuable suggestions. NR 10 TC 3 Z9 4 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1085-7117 J9 J AGR BIOL ENVIR ST JI J. Agric. Biol. Environ. Stat. PD JUN PY 2011 VL 16 IS 2 BP 221 EP 232 DI 10.1007/s13253-010-0045-3 PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 777GN UT WOS:000291604000005 PM 21769246 ER PT J AU Findling, RL Kafantaris, V Pavuluri, M McNamara, NK McClellan, J Frazier, JA Sikich, L Kowatch, R Lingler, J Faber, J Rowles, BM Clemons, TE Taylor-Zapata, P AF Findling, Robert L. Kafantaris, Vivian Pavuluri, Mani McNamara, Nora K. McClellan, Jon Frazier, Jean A. Sikich, Linmarie Kowatch, Robert Lingler, Jacqui Faber, Jon Rowles, Brieana M. Clemons, Traci E. Taylor-Zapata, Perdita TI Dosing Strategies for Lithium Monotherapy in Children and Adolescents with Bipolar I Disorder SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID SCHOOL-AGE-CHILDREN; DIVALPROEX SODIUM; RATING-SCALE; DOUBLE-BLIND; ACUTE MANIA; RELIABILITY; VALIDITY; PLACEBO; VERSION; PHARMACOKINETICS AB Objective: The primary goal of this exploratory study was to obtain data that could lead to evidence-based dosing strategies for lithium in children and adolescents suffering from bipolar I disorder. Methods: Outpatients aged 7-17 years meeting Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnostic criteria for bipolar I disorder (manic or mixed) were eligible for 8 weeks of open label treatment with lithium in one of three dosing arms. In Arm I, participants began treatment at a dose of 300 mg of lithium twice daily. The starting dose of lithium in Arms II and III was 300 mg thrice daily. Patients in Arms I and II could have their dose increased by 300 mg/day, depending on clinical response, at weekly visits. Patients in Arm III also had mid-week telephone interviews after which they could also have their dose of lithium increased by 300 mg per day. Youths weighing <30 kg were automatically assigned to Arm I, whereas youths weighing >= 30 kg were randomly assigned to Arm I, II, or III. Randomization was balanced by age (7-11 years, 12-17 years) and sex in approximately equal numbers. A priori response criteria were defined as a Clinical Global Impressions-Improvement scale score of <= 2 and a 50% decrease from baseline on the Young Mania Rating Scale. Results: Of the 61 youths [32 males (52.5%)] who received open-label lithium, 60 youths completed at least 1 week of treatment and returned for a postbaseline assessment. Most patients had a >= 50% improvement in Young Mania Rating Scale score, and more than half of the patients (58%) achieved response. Overall, lithium was well tolerated. All three treatment arms had similar effectiveness, side effect profiles, and tolerability of lithium. Conclusions: On the basis of these results, a dosing strategy in which pediatric patients begin lithium at a dose of 300 mg thrice daily (with an additional 300 mg increase during the first week), followed by 300 mg weekly increases until a priori stopping criteria are met, will be used in an upcoming randomized, placebo-controlled trial. C1 [Findling, Robert L.; McNamara, Nora K.; Lingler, Jacqui; Faber, Jon; Rowles, Brieana M.] Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Kafantaris, Vivian] Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Feinstein Inst Med Res N Shore, Long Isl City, NY USA. [Pavuluri, Mani] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [McClellan, Jon] Univ Washington, Seattle, WA 98195 USA. [Frazier, Jean A.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Sikich, Linmarie] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Kowatch, Robert] Cincinnati Childrens Hosp, Dept Psychiat, Cincinnati, OH USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Taylor-Zapata, Perdita] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Findling, RL (reprint author), Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, 10524 Euclid Ave,Suite 1155, Cleveland, OH 44106 USA. EM robert.findling@uhhospitals.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services [HHSN275200503406C]; Abbott; Addrenex; AstraZeneca; Biovail; Bristol-Myers Squibb; Forest; GlaxoSmithKline; Johnson Johnson; KemPharm Lilly; Lundbeck; Neuropharm; Novartis; Noven; Organon; Otsuka; Pfizer; Sanofi-Aventis; Sepracore; Schering-Plough; Shire; Solvay; Supernus Pharmaceuticals; Validus; Wyeth; Eli Lilly Co; Glaxo-Smith Kline; Janssen Pharmaceuticals; NIMH; NICHD; Dana Foundation; NARSAD; AFSP; Marshall Reynolds Foundation; Otsuka America Pharmaceutical; Pfizer Inc.; Janssen; Curemark; Seaside Pharmaceuticals; Medscale; National Alliance for Research on Schizophrenia and Depression; Physicians Postgraduate Press; Stanley Foundation FX Dr. Findling receives or has received research support, acted as a consultant, and/or served on a speaker's bureau for Abbott, Addrenex, AstraZeneca, Biovail, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Johnson & Johnson, KemPharm Lilly, Lundbeck, Neuropharm, Novartis, Noven, Organon, Otsuka, Pfizer, Sanofi-Aventis, Sepracore, Schering-Plough, Shire, Solvay, Supernus Pharmaceuticals, Validus, and Wyeth.; Dr. Kafantaris has received research support from AstraZeneca, Eli Lilly & Co, Glaxo-Smith Kline, Janssen Pharmaceuticals, and Pfizer.; Dr. Pavuluri's work unrelated to this article is currently supported by NIMH, NICHD, Dana Foundation, NARSAD, AFSP, and Marshall Reynolds Foundation.; Dr. Frazier receives or has received research support from Bristol-Myers Squibb, Eli Lilly & Co, Johnson & Johnson, Neuropharm, Otsuka America Pharmaceutical, and Pfizer Inc.; Dr. Sikich has a current financial interest in that she receives research funding or participates in clinical trials with Janssen, Pfizer, Bristol Myers-Squibb, Neuropharm, Curemark, and Seaside Pharmaceuticals, and received software for a computer intervention in schizophrenia from Posit Science; in the past, Dr. Sikich received research funding from Eli Lilly, Janssen, Pfizer, Otsuka, and Astra Zeneca, and has served as a consultant for Sanofi Aventis and ABT Associates.; Dr. Kowatch receives or has received research support, acted as a consultant, and/or served on a speaker's bureau for AstraZeneca, Forest, Medscale, National Alliance for Research on Schizophrenia and Depression, NICHD, NIMH, Physicians Postgraduate Press, and the Stanley Foundation.; This project has been funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275200503406C. NR 47 TC 11 Z9 11 U1 1 U2 7 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD JUN PY 2011 VL 21 IS 3 BP 195 EP 205 DI 10.1089/cap.2010.0084 PG 11 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 775NI UT WOS:000291466000001 PM 21663422 ER PT J AU Schrauwen, EJA Bestebroer, TM Munster, VJ de Wit, E Herfst, S Rimmelzwaan, GF Osterhaus, ADME Fouchier, RAM AF Schrauwen, Eefje J. A. Bestebroer, Theo M. Munster, Vincent J. de Wit, Emmie Herfst, Sander Rimmelzwaan, Guus F. Osterhaus, Albert D. M. E. Fouchier, Ron A. M. TI Insertion of a multibasic cleavage site in the haemagglutinin of human influenza H3N2 virus does not increase pathogenicity in ferrets SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID A VIRUS; REVERSE GENETICS; H5N1 VIRUSES; VIRULENCE; PATHOGENESIS; INFECTION; CONJUNCTIVITIS; CLEAVABILITY; REASSORTMENT; GENERATION AB A multibasic cleavage site (MBCS) in the haemagglutinin (HA) protein of influenza A virus is a key determinant of pathogenicity in chickens, and distinguishes highly pathogenic avian influenza (HPAI) viruses from low pathogenic avian influenza viruses (LPAI). An MBCS has only been detected in viruses of the H5 and H7 subtypes. Here we investigated the phenotype of a human H3N2 virus with an MBCS in HA. Insertion of an MBCS in the H3N2 virus resulted in cleavage of HA and efficient replication in Madin-Darby canine kidney cells in the absence of exogenous trypsin in vitro, similar to HPAI H5N1 virus. However, studies in ferrets demonstrated that insertion of the MBCS into HA did not result in increased virus shedding, cellular host range, systemic replication or pathogenicity, as compared with wild-type virus. This study indicates that acquisition of an MBCS alone is insufficient to increase pathogenicity of a prototypical seasonal human H3N2 virus. C1 [Schrauwen, Eefje J. A.; Bestebroer, Theo M.; Munster, Vincent J.; de Wit, Emmie; Herfst, Sander; Rimmelzwaan, Guus F.; Osterhaus, Albert D. M. E.; Fouchier, Ron A. M.] Erasmus MC, Natl Influenza Ctr, Rotterdam, Netherlands. [Schrauwen, Eefje J. A.; Bestebroer, Theo M.; Munster, Vincent J.; de Wit, Emmie; Herfst, Sander; Rimmelzwaan, Guus F.; Osterhaus, Albert D. M. E.; Fouchier, Ron A. M.] Erasmus MC, Dept Virol, Rotterdam, Netherlands. [Munster, Vincent J.; de Wit, Emmie] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. RP Fouchier, RAM (reprint author), Erasmus MC, Natl Influenza Ctr, Rotterdam, Netherlands. EM r.fouchier@erasmusmc.nl RI Fouchier, Ron/A-1911-2014; OI Fouchier, Ron/0000-0001-8095-2869; Osterhaus, Albert/0000-0002-6074-1172; de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; ZonMW [91896613]; National Institute of Allergy and Infectious Diseases-NIH [HHSN266200700010C] FX We thank R. Dias-D'Ullois, D. de Meulder, S. Chutinimitkul, P. van Run and M. de Graaf for excellent technical assistance, and E. Sorrell for helpful discussions. V. J. M. and E. d W. are currently supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. This research was financed through VICI grant 91896613 from ZonMW and National Institute of Allergy and Infectious Diseases-NIH contract HHSN266200700010C. NR 41 TC 18 Z9 18 U1 3 U2 6 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD JUN PY 2011 VL 92 BP 1410 EP 1415 DI 10.1099/vir.0.030379-0 PN 6 PG 6 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 774FI UT WOS:000291370100018 PM 21346026 ER PT J AU Sharma, K Ix, JH Mathew, AV Cho, M Pflueger, A Dunn, SR Francos, B Sharma, S Falkner, B McGowan, TA Donohue, M RamachandraRao, S Xu, RH Fervenza, FC Kopp, JB AF Sharma, Kumar Ix, Joachim H. Mathew, Anna V. Cho, Monique Pflueger, Axel Dunn, Stephen R. Francos, Barbara Sharma, Shoba Falkner, Bonita McGowan, Tracy A. Donohue, Michael RamachandraRao, Satish Xu, Ronghui Fervenza, Fernando C. Kopp, Jeffrey B. TI Pirfenidone for Diabetic Nephropathy SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID MATRIX GENE-EXPRESSION; RENAL-FUNCTION; ANGIOTENSIN-II; TRANSFORMING GROWTH-FACTOR-BETA-1; KIDNEY-DISEASE; BETA ANTIBODY; TNF-ALPHA; TGF-BETA; FIBROSIS; EXPANSION AB Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebo-controlled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m(2)). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (+3.3 +/- 8.5 ml/min per 1.73 m(2)) whereas the mean eGFR decreased in the placebo group (-2.2 +/- 4.8 ml/min per 1.73 m(2); P = 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (-1.9 +/- 6.7 ml/min per 1.73 m(2)). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P = 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy. C1 [Sharma, Kumar] Univ Calif San Diego, Vet Affairs Med Ctr, Ctr Renal Translat Med, Vet Affairs San Diego Healthcare Syst,Dept Med, La Jolla, CA 92093 USA. [Sharma, Kumar; Donohue, Michael; Xu, Ronghui] Univ Calif San Diego, Clin & Translat Res Inst, La Jolla, CA 92093 USA. [Sharma, Kumar; Ix, Joachim H.; Mathew, Anna V.; RamachandraRao, Satish] Univ Calif San Diego, Div Nephrol, La Jolla, CA 92093 USA. [Cho, Monique; Kopp, Jeffrey B.] Mayo Clin, Rochester, MN USA. [Pflueger, Axel; Fervenza, Fernando C.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. [Dunn, Stephen R.; Francos, Barbara; Falkner, Bonita] Thomas Jefferson Univ, Dept Med, Philadelphia, PA 19107 USA. [Dunn, Stephen R.] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [McGowan, Tracy A.] Johnson & Johnson Inc, Horsham, PA USA. RP Sharma, K (reprint author), Univ Calif San Diego, Vet Affairs Med Ctr, Ctr Renal Translat Med, Vet Affairs San Diego Healthcare Syst,Dept Med, La Jolla, CA 92093 USA. EM kumarsharma@ucsd.edu OI Mathew, Anna/0000-0002-7043-4221; Pflueger, Axel/0000-0002-9938-5208; Kopp, Jeffrey/0000-0001-9052-186X FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH) [R01DK063017]; Juvenile Diabetes Research Foundation Academic Research and Development award; NIDDK, NIH [ZO1-DK043308]; General Clinical Research Centers Program [M01 RR00827]; NIH/National Center for Research Resources [1UL1 RR031980-01]; Inter-Mune, Inc.; Merck FX This study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (R01DK063017 to K.S.); a Juvenile Diabetes Research Foundation Academic Research and Development award (to K.S.); the Intramural Research Program, NIDDK, NIH (ZO1-DK043308 to J.B.K.); the General Clinical Research Centers Program (M01 RR00827); the Clinical and Translational Science Awards Program (1UL1 RR031980-01) from NIH/National Center for Research Resources (to R.X. and M.D.); and supplemental funding from Inter-Mune, Inc. We thank Christina Petyo, Louise Enderle, Linda Nocella, and Dr. Joseph Cheung of Thomas Jefferson University for assisting in the completion of the trial. We thank the Clinical and Translational Research Institute and SriKrishna Khandrika at the University of California-San Diego for assistance in performing the measurement of plasma biomarkers. We thank InterMune, Inc. for providing the study drug.; Dr. Sharma received research support from InterMune, Inc., before the completion of the clinical study. Dr. Falkner received consulting fees from Merck. Dr. McGowan is currently an employee of Johnson and Johnson. InterMune, Inc., provided study medication but had no role in study design, data analysis, data interpretation, or manuscript review. NR 41 TC 101 Z9 107 U1 1 U2 10 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 JUN PY 2011 VL 22 IS 6 BP 1144 EP 1151 DI 10.1681/ASN.2010101049 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 776XP UT WOS:000291574400022 PM 21511828 ER PT J AU Warren, JL Barbera, L Bremner, KE Yabroff, KR Hoch, JS Barrett, MJ Luo, J Krahn, MD AF Warren, Joan L. Barbera, Lisa Bremner, Karen E. Yabroff, K. Robin Hoch, Jeffrey S. Barrett, Michael J. Luo, Jin Krahn, Murray D. TI End-of-Life Care for Lung Cancer Patients in the United States and Ontario SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SEER-MEDICARE DATA; PROSTATE-CANCER; CANADA; POPULATION; DEATH; AGGRESSIVENESS; UROLOGISTS; MANAGEMENT; STAGE; AREAS AB Background Both the United States and Canada offer government-financed health insurance for the elderly, but few studies have compared care at the end of life for cancer patients between the two systems. Methods We identified care for non-small cell lung cancer (NSCLC) patients who died of cancer at age 65 years and older during 1999-2003. Patients were identified from US Surveillance, Epidemiology, and End Results (SEER)Medicare data (N = 13 533) and the Ontario Cancer Registry (N = 8100). Health claims during the last 5 months of life identified chemotherapy and emergency room use, hospitalizations, and supportive care. We estimated rates per person-months (PM) for short-term survivors (died <6 months after diagnosis) and longer-term survivors (died = 6 months after diagnosis), adjusting for demographic differences. To test whether monthly rates in Ontario were statistically significantly different from the United States, standardized differences were computed, and a 99% confidence interval (CI) was constructed to account for the multiple tests performed. All statistical tests were two-sided. Results Rates of chemotherapy use were statistically significantly higher for SEER-Medicare patients than Ontario patients in every month before death (short-term survivors at 5 months before death: SEER-Medicare, 33.2 patients per 100 PM vs Ontario, 9.5 per 100 PM, rate difference = 23.7 per 100 PM, 99% CI = 18.3 to 29.1 per 100 PM, P < .001; longer-term survivors at 5 months before death: SEER-Medicare, 24.4 patients per 100 PM vs Ontario, 14.5 per 100 PM, rate difference = 9.9 per 100 PM, 99% CI = 7.7 to 12.1 per 100 PM, P < .001). During the last 30 days of life, fewer SEER-Medicare than Ontario patients were hospitalized (short-term survivors, 49.9 vs 78.6 patients per 100 PM, rate difference = 28.6 per 100 PM, 95% CI = 22.9 to 34.4 per 100 PM, P <. 001; longer-term survivors, 44.1 vs 67.1 patients per 100 PM, rate difference = 23.0 per 100 PM, 95% CI = 18.5 to 27.5 per 100 PM, P < .001). Conclusions NSCLC patients in both Ontario and the United States used extensive end-of-life care. Limited availability of hospice care in Ontario and differing attitudes between the United States and Ontario regarding end-of-life care may explain the differences in practice patterns. C1 [Warren, Joan L.] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Barbera, Lisa] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada. [Bremner, Karen E.; Krahn, Murray D.] Univ Hlth Network, Toronto Gen Res Inst, Toronto, ON, Canada. [Hoch, Jeffrey S.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Canadian Ctr Appl Res Canc Control, Toronto, ON M5B 1W8, Canada. [Barrett, Michael J.] Informat Management Serv Inc, Silver Spring, MD USA. [Luo, Jin; Krahn, Murray D.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Krahn, Murray D.] Univ Toronto, Fac Pharm, Toronto, ON, Canada. RP Warren, JL (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Rm 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM joan_warren@nih.gov OI Krahn, Murray/0000-0001-5836-397X; Yabroff, K. Robin/0000-0003-0644-5572; Hoch, Jeffrey/0000-0002-4880-4281 FU Cancer Care Ontario; Ontario Institute for Cancer Research; F. Norman Hughes Chair in Pharmacoeconomics, Faculty of Pharmacy, University of Toronto; Institute for Clinical Evaluative Sciences FX There was no external funding for the SEER-Medicare work. Funding for the Ontario arm of the study was provided by research grants from Cancer Care Ontario, the Ontario Institute for Cancer Research, and a career support award through the F. Norman Hughes Chair in Pharmacoeconomics, Faculty of Pharmacy, University of Toronto. This study was also supported by the Institute for Clinical Evaluative Sciences. Institute for Clinical Evaluative Sciences is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. NR 35 TC 42 Z9 44 U1 1 U2 10 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 JUN PY 2011 VL 103 IS 11 BP 853 EP 862 DI 10.1093/jnci/djr145 PG 10 WC Oncology SC Oncology GA 775VG UT WOS:000291490900007 PM 21593012 ER PT J AU Ou, W Delisle, J Konduru, K Bradfute, S Radoshitzky, SR Retterer, C Kota, K Bavari, S Kuhn, JH Jahrling, PB Kaplan, G Wilson, CA AF Ou, Wu Delisle, Josie Konduru, Krishnamurthy Bradfute, Steven Radoshitzky, Sheli R. Retterer, Cary Kota, Krishna Bavari, Sina Kuhn, Jens H. Jahrling, Peter B. Kaplan, Gerardo Wilson, Carolyn A. TI Development and characterization of rabbit and mouse antibodies against ebolavirus envelope glycoproteins SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Ebola; Ebolavirus; Envelope glycoprotein; Filovirus; sGP ID VIRUS INFECTION; MONOCLONAL-ANTIBODIES; PASSIVE TRANSFER; EPITOPES; ELISA; CELL; GP AB Ebolaviruses are the etiologic agents of severe viral hemorrhagic fevers in primates, including humans, and could be misused for the development of biological weapons. The ability to rapidly detect and differentiate these viruses is therefore crucial. Antibodies that can detect reliably the ebolavinis surface envelope glycoprotein GP(1,2) or a truncated variant that is secreted from infected cells (sGP) are required for advanced development of diagnostic assays such as sandwich ELISAs or Western blots (WB). We used a GP(1,2) peptide conserved among Bundibugyo, Ebola, Reston, Sudan, and Tai Forest viruses and a mucin-like domain-deleted Sudan virus GP(1,2) (SudanGP Delta Muc) to immunize mice or rabbits, and developed a panel of antibodies that either cross-react or are virus-specific. These antibodies detected full-length GP(1,2) and sGP in different assays such as ELISA, FACS, or WB. In addition, some of the antibodies were shown to have potential clinical relevance, as they detected ebolavirus-infected cells by immunofluorescence assay and gave a specific increase in signal by sandwich ELISA against sera from mouse-adapted Ebola virus-infected mice over uninfected mouse sera. Rabbit anti-SudanGP Delta Muc polyclonal antibody neutralized gammaretroviral particles pseudotyped with Sudan virus GP(1,2), but not particles pseudotyped with other ebolavirus GP(1,2). Together, our results suggest that this panel of antibodies may prove useful for both in vitro analyses of ebolavirus GP(1,2), as well as analysis of clinically relevant samples. Published by Elsevier B.V. C1 [Ou, Wu; Delisle, Josie; Wilson, Carolyn A.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Konduru, Krishnamurthy; Kaplan, Gerardo] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Bradfute, Steven; Radoshitzky, Sheli R.; Retterer, Cary; Kota, Krishna; Bavari, Sina] USA, Med Res Inst Infect Dis, Div Toxicol, Frederick, MD USA. [Kuhn, Jens H.; Jahrling, Peter B.] NIH NIAID Integrated Res Facil Ft Detrick, Frederick, MD USA. RP Wilson, CA (reprint author), US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bldg 29B,Room 5NN22,8800 Rockville Pike, Bethesda, MD 20892 USA. EM carolyn.wilson@fda.hhs.gov RI Kuhn, Jens H./B-7615-2011 OI Kuhn, Jens H./0000-0002-7800-6045 FU CBER/NIAID Interagency Agreement (IAG); Biomedical Advanced Research and Development Authority (BARDA); Joint Science and Technology Office Transformational Medical Technologies [TMT10048_09_RD_T]; Defense Threat Reduction Agency [4.10022_08_RD_B]; NIAID [HHSN2722002000161] FX We are grateful to Seton Pariser, Bertram W. Maidment III, and Evan Ewers for their technical assistance. This research was partially supported by CBER/NIAID Interagency Agreement (IAG) and the Biomedical Advanced Research and Development Authority (BARDA). This research was partially supported by the Joint Science and Technology Office Transformational Medical Technologies (proposal # TMT10048_09_RD_T) and Defense Threat Reduction Agency (proposal #4.10022_08_RD_B) to SB. JHK performed this work as an employee of Tunnel(Consulting, Inc., a subcontractor to Battelle Memorial Institute under its prime contract with NIAID, under Contract No. HHSN2722002000161. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the US Army, the US Department of Health and Human Services or of the institutions and companies affiliated with the authors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 5 Z9 7 U1 4 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD JUN PY 2011 VL 174 IS 1-2 BP 99 EP 109 DI 10.1016/j.jviromet.2011.04.003 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 776FX UT WOS:000291521000016 PM 21513741 ER PT J AU Shaked, A Feng, S Punch, J Reyes, J Levitsky, J Klintmalm, G Zimmerman, M Kopetskie, H DePaulis, M Bridges, N DesMarais, M Sayre, P AF Shaked, A. Feng, S. Punch, J. Reyes, J. Levitsky, J. Klintmalm, G. Zimmerman, M. Kopetskie, H. DePaulis, M. Bridges, N. DesMarais, M. Sayre, P. TI Lessons Learned from the ITN030ST Immunosuppression Withdrawal (ISW) Trial in Liver Transplant Recipients SO LIVER TRANSPLANTATION LA English DT Meeting Abstract CT Joint International Congress of ILTS, ELITA, and LICAGE CY JUN 22-25, 2011 CL Valencia, SPAIN C1 [Shaked, A.] UPenn, Philadelphia, PA USA. [Feng, S.; DesMarais, M.; Sayre, P.] UCSF, San Francisco, CA USA. [Punch, J.] U MI, Ann Arbor, MI USA. [Reyes, J.] U WA, Seattle, WA USA. [Levitsky, J.] NW U, Chicago, IL USA. [Klintmalm, G.] Baylor, Dallas, TX USA. [Zimmerman, M.] U CO, Denver, CO USA. [Kopetskie, H.] RhoFed, Chapel Hill, NC USA. [DePaulis, M.; Bridges, N.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD JUN PY 2011 VL 17 IS 6 SU 1 BP S84 EP S84 PG 1 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 773RK UT WOS:000291326800019 ER PT J AU Karev, GP Novozhilov, AS Berezovskaya, FS AF Karev, Georgy P. Novozhilov, Artem S. Berezovskaya, Faina S. TI On the asymptotic behaviour of the solutions to the replicator equation SO MATHEMATICAL MEDICINE AND BIOLOGY-A JOURNAL OF THE IMA LA English DT Article DE replicator equation; selection system; singular value decomposition; Newton diagram; power asymptotes ID GAME DYNAMICS; POPULATION; SELECTION; MODELS; EQUILIBRIUM; STABILITY; SYSTEMS AB Selection systems and the corresponding replicator equations model the evolution of replicators with a high level of abstraction. In this paper, we apply novel methods of analysis of selection systems to the replicator equations. To be suitable for the suggested algorithm, the interaction matrix of the replicator equation should be transformed; in particular, the standard singular value decomposition allows us to rewrite the replicator equation in a convenient form. The original n-dimensional problem is reduced to the analysis of asymptotic behaviour of the solutions to the so-called escort system, which in some important cases can be of significantly smaller dimension than the original system. The Newton diagram methods are applied to study the asymptotic behaviour of the solutions to the escort system, when interaction matrix has Rank 1 or 2. A general replicator equation with the interaction matrix of Rank 1 is fully analysed; the conditions are provided when the asymptotic state is a polymorphic equilibrium. As an example of the system with the interaction matrix of Rank 2, we consider the problem from Adams & Sornborger (2007, Analysis of a certain class of replicator equations. J. Math. Biol., 54, 357-384), for which we show, for an arbitrary dimension of the system and under some suitable conditions, that generically one globally stable equilibrium exits on the 1-skeleton of the simplex. C1 [Karev, Georgy P.; Novozhilov, Artem S.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Novozhilov, Artem S.] Moscow State Univ Railway Engn, Dept Appl Math 1, Moscow 127994, Russia. [Berezovskaya, Faina S.] Howard Univ, Dept Math, Washington, DC 20059 USA. RP Karev, GP (reprint author), NIH, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM karev@ncbi.nlm.nih.gov; anovozhilov@gmail.com; fberezovskaya@howard.edu RI Novozhilov, Artem/D-7544-2012; Novozhilov, Artem/C-9248-2013 OI Novozhilov, Artem/0000-0001-5469-2557 FU Department of Health and Human Services, (National Institutes of Health, National Library of Medicine) FX Department of Health and Human Services intramural program (National Institutes of Health, National Library of Medicine) to K.G.P. and A.S.N. NR 32 TC 11 Z9 11 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1477-8599 J9 MATH MED BIOL JI Math. Med. Biol. PD JUN PY 2011 VL 28 IS 2 SI SI BP 89 EP 110 DI 10.1093/imammb/dqq006 PG 22 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 775XZ UT WOS:000291498100002 PM 20435663 ER PT J AU Dokmanovic, M Shen, Y Bonacci, TM Hirsch, DS Wu, WJ AF Dokmanovic, Milos Shen, Yi Bonacci, Tabetha M. Hirsch, Dianne S. Wu, Wen Jin TI Trastuzumab Regulates IGFBP-2 and IGFBP-3 to Mediate Growth Inhibition: Implications for the Development of Predictive Biomarkers for Trastuzumab Resistance SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID BREAST-CANCER CELLS; FACTOR-BINDING PROTEIN-2; FACTOR-I RECEPTOR; THERAPEUTIC TARGET; EPITHELIAL-CELLS; HERCEPTIN; DEGRADATION; APOPTOSIS; MARKER; CDC42 AB Activation of insulin-like growth factor-I receptor (IGF-IR) signaling is an important mechanism for trastuzumab resistance. IGF-binding proteins (IGFBP) modulate IGF-IR signaling and play important roles in the control of breast cancer progression. In this article, we report that trastuzumab treatment enhances the expression and secretion of IGFBP-3 in SKBR3 cells, a trastuzumab-sensitive breast cancer cell line, and that this upregulation of IGFBP-3 induced by trastuzumab correlates with trastuzumab-mediated growth inhibition. We describe a new role for IGFBP-3 in the regulation of IGF-I-mediated cross-talk between IGF-IR and ErbB2 signaling pathways. In particular, treatment of SKBR3 cells with recombinant IGFBP-3 blocks IGF-I-induced activation of IGF-IR and ErbB2, and stable expression of IGFBP-3 inhibits SKBR3 cell growth. We find an inverse relationship in the levels of secreted IGFBP-3 such that high levels of IGFBP-3 are associated with trastuzumab-sensitive breast cancer cells (SKBR3 and BT-474), whereas low levels of IGFBP-3 are found in trastuzumab-resistant cells (clone 3 and JIMT-1). In contrast to IGFBP-3, the secretion and expression of IGFBP-2 are upregulated in trastuzumab-resistant SKBR3 cells. Furthermore, we show that IGFBP-2 stimulates activation of ErbB2 and that trastuzumab reduces IGFBP-2-stimulated ErbB2 activation. Based on our data, we propose a novel mechanism of action whereby trastuzumab enhances the expression and secretion of IGFBP-3, which interferes with IGF-I-mediated mitogenic signaling via autocrine and paracrine mechanisms and reduces IGFBP-2-induced ErbB2 activation to mediate growth inhibition. Changes in secretion profiles of IGFBP-2 and IGFBP-3 in trastuzumab-sensitive and trastuzumab-resistant cells may promote the development of IGFBP-2 and IGFBP-3 as predictive biomarkers for trastuzumab resistance. Mol Cancer Ther; 10(6); 917-28. (C)2011 AACR. C1 [Dokmanovic, Milos; Shen, Yi; Bonacci, Tabetha M.; Hirsch, Dianne S.; Wu, Wen Jin] US FDA, Div Monoclonal Antibodies, Off Biotechnol Prod, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Wu, WJ (reprint author), US FDA, Div Monoclonal Antibodies, Off Biotechnol Prod, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, HFD 123,29 Lincoln Dr,NIH Bldg 29B,Room 3 NN-15, Bethesda, MD 20892 USA. EM wen.wu@fda.hhs.gov FU U.S. Food and Drug Administration; National Cancer Institute (NIH) FX This study was supported by the U.S. Food and Drug Administration Critical Path Funding for FY2009 and FY2010 and the Interagency Oncology Task Force (IOTF) Joint Fellowship Program sponsored by the U.S. Food and Drug Administration and National Cancer Institute (NIH). T. M. Bonacci is an IOTF fellow. NR 43 TC 13 Z9 13 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2011 VL 10 IS 6 BP 917 EP 928 DI 10.1158/1535-7163.MCT-10-0980 PG 12 WC Oncology SC Oncology GA 775AI UT WOS:000291428000001 PM 21487052 ER PT J AU O'Brien, K Troendle, J Gochuico, BR Markello, TC Salas, J Cardona, H Yao, JH Bernardini, I Hess, R Gahl, WA AF O'Brien, Kevin Troendle, James Gochuico, Bernadette R. Markello, Thomas C. Salas, Jose Cardona, Hilda Yao, Jianhua Bernardini, Isa Hess, Richard Gahl, William A. TI Pirfenidone for the treatment of Hermansky-Pudlak syndrome pulmonary fibrosis SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Hermansky Pudlak syndrome; Albinism; Pulmonary function tests; Pulmonary fibrosis; Puerto Rico; Pirfenidone ID BLEOMYCIN-HAMSTER MODEL; LUNG FIBROSIS; DISEASE; GENE; FORM; TRAFFICKING; ORGANELLES; MUTATIONS; PROTEINS; SUBUNIT AB Hermansky-Pudlak syndrome (HPS) is a rare disorder of oculocutaneous albinism, platelet dysfunction, and in some subtypes, fatal pulmonary fibrosis. There is no effective treatment for the pulmonary fibrosis except lung transplantation, but an initial trial using pirfenidone, an anti-fibrotic agent, showed promising results. The current, randomized, placebo-controlled, prospective, double-blind trial investigated the safety and efficacy of pirfenidone for mild to moderate HPS-1 and 4 pulmonary fibrosis. Subjects were evaluated every 4 months at the National Institutes of Health Clinical Center, and the primary outcome parameter was change in forced vital capacity using repeated measures analysis with random coefficients. Thirty-five subjects with HPS-1 pulmonary fibrosis were enrolled during a 4-year interval; 23 subjects received pirfenidone and 12 received placebo. Four subjects withdrew from the trial, 3 subjects died, and 10 serious adverse events were reported. Both groups experienced similar side effects, especially gastroesophageal reflux. Interim analysis of the primary outcome parameter, performed 12 months after 30 patients were enrolled, showed no statistical difference between the placebo and pirfenidone groups, and the study was stopped due to futility. There were no significant safety concerns. Other clinical trials are indicated to identify single or multiple drug regimens that may be effective in treatment for progressive HPS-1 pulmonary fibrosis. Published by Elsevier Inc. C1 [O'Brien, Kevin; Salas, Jose; Cardona, Hilda; Gahl, William A.] NHGRI, NIH, Bethesda, MD 20892 USA. [O'Brien, Kevin] NIH, Off Rare Dis Res, Bethesda, MD 20892 USA. [Troendle, James] NHLBI, Off Biostat Res, DCVS, NIH, Bethesda, MD 20892 USA. [Gochuico, Bernadette R.; Markello, Thomas C.; Bernardini, Isa; Hess, Richard; Gahl, William A.] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Yao, Jianhua] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP O'Brien, K (reprint author), NHGRI, NIH, 10 Ctr Dr,Bldg 10-CRC,Room 3-2551, Bethesda, MD 20892 USA. EM obrienke@mail.nih.gov FU National Human Genome Research Institute; Eunice Kennedy Shriver National Institute of Child Health & Human Development; Clinical Center, National Institutes of Health FX We would like to acknowledge the efforts of the Clinical Center pharmacists Judy Starling and George Grimes of the Pharmaceutical Development Service. We thank the members of the Hermansky-Pudlak syndrome network for their support, and most importantly, we thank our patients for their contributions to this research. This study was supported by the Intramural Research Programs of the National Human Genome Research Institute, the Eunice Kennedy Shriver National Institute of Child Health & Human Development, and the Clinical Center, National Institutes of Health. NR 31 TC 16 Z9 17 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 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2011 VL 103 IS 2 BP 128 EP 134 DI 10.1016/j.ymgme.2011.02.003 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 775JZ UT WOS:000291456900004 PM 21420888 ER PT J AU Chakkera, HA Hanson, RL Kobes, S Millis, MP Robert, GNB Knowler, WC DiStefano, JK AF Chakkera, Harini A. Hanson, Robert L. Kobes, Sayuko Millis, Meredith P. Nelson, Robert G. Knowler, William C. DiStefano, Johanna K. TI Association of variants in the carnosine peptidase 1 gene (CNDP1) with diabetic nephropathy in American Indians SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Kidney disease; Single nucleotide polymorphism; Proteinuria ID STAGE RENAL-DISEASE; PIMA-INDIANS; LEUCINE REPEAT; AFRICAN-AMERICANS; LINKAGE ANALYSIS; FINELY MAP; MELLITUS; GENOME; SUSCEPTIBILITY; POLYMORPHISMS AB CNDP1 is located on 18q22.3, where linkage with diabetic nephropathy has been observed in several populations, including Pima Indians. However, evidence for association between CNDP1 alleles and diabetic nephropathy is equivocal and population-dependent. This study investigated CNDP1 as a candidate for diabetic kidney disease in Pima Indians. Nineteen tag single nucleotide polymorphisms spanning the CNDP1 locus were selected using genotype data from Chinese individuals in the HapMap resource along with 2 variants previously associated with diabetic nephropathy. All variants were genotyped in 3 different samples including a diabetic end-stage renal disease (ESRD) case-control study, a family-based study of diabetic individuals who participated in the linkage study for nephropathy, and a cohort of diabetic individuals in whom longitudinal measures of glomerular filtration rates (GFR) were performed. There was no statistically significant evidence for association with diabetic ESRD. However, nominal evidence for association was found in the family study, where markers rs12957330 (Odds ratio [OR] = 0.29 per copy of G allele; p = 0.04) and rs17817077 (OR = 0.46 per copy of G allele; p = 0.05) were associated with diabetic nephropathy. In addition, markers rs12964454, rs7244647, and rs7229005 were associated with changes in GFR (-8.5 ml/min per copy of the G allele; p = 0.04; 18.8 ml/min per copy of the C allele; p = 0.03; and -13.4 ml/min per copy of the C allele; p = 0.001, respectively). These findings provide nominal evidence supporting a role between CNDP1 variants and diabetic kidney disease. 2011 Elsevier Inc. All rights reserved. C1 [Chakkera, Harini A.] Mayo Clin, Div Nephrol, Phoenix, AZ USA. [Chakkera, Harini A.] Mayo Clin, Div Transplantat, Phoenix, AZ USA. [Chakkera, Harini A.; Hanson, Robert L.; Kobes, Sayuko; Nelson, Robert G.; Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ 85014 USA. [Millis, Meredith P.; DiStefano, Johanna K.] Translat Genom Res Inst, Diabet Cardiovasc & Metab Dis Div, Phoenix, AZ 85004 USA. RP Chakkera, HA (reprint author), Mayo Clin Hosp, Div Transplantat, 5777 E Mayo Blvd, Phoenix, AZ 85054 USA. EM chakkera.harini@mayo.edu RI Nelson, Robert/B-1470-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Center for Research Resources (NCRR), National Institutes of Health (NIH) [1 KL2 RR024151]; NIH; National Institute of Diabetes and Digestive and Kidney Diseases FX This publication was made possible by Grant Number 1 KL2 RR024151 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Additionally, this research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 39 TC 10 Z9 10 U1 1 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 JUN PY 2011 VL 103 IS 2 BP 185 EP 190 DI 10.1016/j.ymgme.2011.02.010 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 775JZ UT WOS:000291456900014 PM 21393041 ER PT J AU Valera, VA Merino, MJ AF Valera, Vladimir A. Merino, Maria J. TI Misdiagnosis of clear cell renal cell carcinoma SO NATURE REVIEWS UROLOGY LA English DT Review ID FINE-NEEDLE-ASPIRATION; HOGG-DUBE-SYNDROME; PERCUTANEOUS BIOPSY; GUIDED BIOPSY; KIDNEY CANCER; HELICAL CT; MOLECULAR CLASSIFICATION; PATHOLOGICAL CORRELATION; EPITHELIAL NEOPLASMS; DIAGNOSTIC PROBLEMS AB Clear cell renal cell carcinoma (RCC) represents the most common histological subtype of malignant kidney tumors. Based on symptoms alone, clear cell RCC is indistinguishable from other histological classes of RCC unless the tumor is present in the context of an RCC syndrome. Histopathological examination is, therefore, important to accurately identify clear cell RCC. Clear cell RCCs have characteristic morphological criteria; these tumors can be easily identified upon typical presentation, but diagnosis can be challenging when tumor cell pattern is unusual or when availability of tissue samples is limited. In this Review, the clinical, radiological and pathological characteristics of clear cell RCCs are described, as well as the potential tumors that can be confused with clear cell RCC and need to be considered in the differential diagnoses. Finally, the importance of an accurate diagnosis is highlighted in the context of the increasing use of preoperative tissue sampling and the prevalence of clear cell tumors associated with hereditary syndromes, which could have different therapeutic and prognostic implications for patients and their families. C1 [Valera, Vladimir A.; Merino, Maria J.] NCI, Translat Surg Pathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Merino, MJ (reprint author), NCI, Translat Surg Pathol Sect, Pathol Lab, Ctr Canc Res,NIH, 10 Ctr Dr,Bldg 10,MSC Room 2B44, Bethesda, MD 20892 USA. EM mjmerino@mail.nih.gov FU National Cancer Institute, NIH FX This research was supported in part by the Intramural Research Program of the National Cancer Institute, NIH. 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 83 TC 8 Z9 9 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4812 J9 NAT REV UROL JI Nat. Rev. Urol. PD JUN PY 2011 VL 8 IS 6 BP 321 EP 333 DI 10.1038/nrurol.2011.64 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 776OO UT WOS:000291546200006 PM 21587224 ER PT J AU Fischbeck, KH Pulst, SM AF Fischbeck, Kenneth H. Pulst, Stefan M. TI Amyotrophic lateral sclerosis and spinocerebellar ataxia 2 SO NEUROLOGY LA English DT Editorial Material ID MUTATIONS; ALS; PARKINSONISM; ASSOCIATION; EXPANSIONS; GENE; VEGF C1 [Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD USA. [Pulst, Stefan M.] Univ Utah, Dept Neurol, Salt Lake City, UT USA. RP Fischbeck, KH (reprint author), 35-2A1000,35 Convent Dr, Bethesda, MD 20892 USA. EM kf@ninds.nih.gov NR 15 TC 8 Z9 8 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 JUN PY 2011 VL 76 IS 24 BP 2050 EP 2051 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 777BR UT WOS:000291588800005 PM 21562249 ER PT J AU Pearson, J AF Pearson, Jane TI Implications for Civilian Postvention Research and Practice SO PSYCHIATRY-INTERPERSONAL AND BIOLOGICAL PROCESSES LA English DT Editorial Material ID SUICIDE; CONTAGION C1 NIMH, Suicide Res Consortium, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Pearson, J (reprint author), NIMH, Suicide Res Consortium, Div Serv & Intervent Res, Rm 7139,MSC 9635,6001 Execut Blvd, Bethesda, MD 20892 USA. EM jp36u@nih.gov NR 10 TC 0 Z9 0 U1 0 U2 2 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0033-2747 J9 PSYCHIATRY JI Psychiatry-Interpers. Biol. Process. PD SUM PY 2011 VL 74 IS 2 BP 118 EP 120 PG 3 WC Psychiatry SC Psychiatry GA 776UR UT WOS:000291564400005 PM 21688961 ER PT J AU Gorospe, M Abdelmohsen, K AF Gorospe, Myriam Abdelmohsen, Kotb TI MicroRegulators come of age in senescence SO TRENDS IN GENETICS LA English DT Review ID ONCOGENE-INDUCED SENESCENCE; REPLICATIVE LIFE-SPAN; DIPLOID CELL STRAINS; PREMATURE SENESCENCE; MULTIPLE MICRORNAS; TUMOR SUPPRESSION; HUMAN FIBROBLASTS; GENE-EXPRESSION; AGING PRIMATES; GROWTH ARREST AB Cellular senescence was first reported five decades ago as a state of long-term growth inhibition in viable, metabolically active cells cultured in vitro. However, evidence that senescence occurs in vivo and underlies pathophysiologic processes has only emerged over the past few years. Coincident with this increased knowledge, understanding of the mechanisms that control senescent-cell gene expression programs has also recently escalated. Such mechanisms include a prominent group of regulatory factors (miRNA), a family of small, noncoding RNAs that interact with select target mRNAs and typically repress their expression. Here, we review recent reports that miRNAs are key modulators of cellular senescence, and we examine their influence upon specific senescence-regulatory proteins. We discuss evidence that dysregulation of miRNA-governed senescence programs underlies age-associated diseases, including cancer. C1 [Gorospe, Myriam; Abdelmohsen, Kotb] NIA, Lab Mol Biol & Immunol, IRP, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Lab Mol Biol & Immunol, IRP, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov OI abdelmohsen, Kotb/0000-0001-6240-5810 FU National Institute on Aging-National Institutes of Health FX MG and KA are supported by the National Institute on Aging-Intramural Research Program of the National Institutes of Health. NR 99 TC 53 Z9 53 U1 1 U2 11 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JUN PY 2011 VL 27 IS 6 BP 233 EP 241 DI 10.1016/j.tig.2011.03.005 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 776VS UT WOS:000291567400004 PM 21592610 ER PT J AU Beigi, RH Han, K Venkataramanan, R Hankins, GD Clark, S Hebert, MF Easterling, T Zajicek, A Ren, Z Mattison, DR Caritis, SN AF Beigi, Richard H. Han, Kelong Venkataramanan, Raman Hankins, Gary D. Clark, Shannon Hebert, Mary F. Easterling, Thomas Zajicek, Anne Ren, Zhaoxia Mattison, Donald R. Caritis, Steve N. CA Obstetric-Fetal Pharmacology Res TI Pharmacokinetics of oseltamivir among pregnant and nonpregnant women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE influenza; oseltamivir; pregnancy; treatment ID BREAST-FEEDING WOMEN; 2009 H1N1 INFLUENZA; PANDEMIC INFLUENZA; A H1N1; VIRUS; INFECTION; HOSPITALIZATIONS; EPIDEMIC AB We sought to delineate the pharmacokinetics (PK) of oseltamivir and its active metabolite oseltamivir carboxylate during pregnancy. Physiologic changes of pregnancy, including increased renal filtration and secretion, may increase the clearance of oseltamivir carboxylate. Sixteen pregnant women taking oseltamivir for prophylaxis or treatment of suspected/proven influenza infection were enrolled. Twenty-three nonpregnant reproductive-age females served as the control group. The primary PK endpoint was area under the plasma concentration time curve for oseltamivir carboxylate. Pregnancy did not alter the PK parameters of the parent compound, oseltamivir. However, for oseltamivir carboxylate the area under the plasma concentration time curve was significantly lower (P = .007) and the apparent clearance significantly higher (P = .006) in pregnant women compared with nonpregnant women. Pregnancy produces lower systemic levels of oseltamivir carboxylate. Increasing the dose and/or dosing frequency of oseltamivir during pregnancy may be necessary to achieve comparable exposure in pregnant and nonpregnant women. C1 [Beigi, Richard H.; Caritis, Steve N.] Univ Pittsburgh, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Med Ctr,Div Reprod Infect Dis, Pittsburgh, PA 15213 USA. [Beigi, Richard H.; Caritis, Steve N.] Univ Pittsburgh, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Med Ctr,Div Maternal Fetal Med, Pittsburgh, PA 15213 USA. [Han, Kelong; Venkataramanan, Raman] Univ Pittsburgh, Sch Med, Dept Pathol, Dept Pharmaceut Sci,Sch Pharm, Pittsburgh, PA USA. [Hankins, Gary D.; Clark, Shannon] Univ Texas Med Branch, Dept Obstet & Gynecol, Div Maternal Fetal Med, Galveston, TX USA. [Hebert, Mary F.; Easterling, Thomas] Univ Washington, Sch Med, Dept Pharm & Obstet & Gynecol, Seattle, WA USA. [Zajicek, Anne; Ren, Zhaoxia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Obstet & Pediat Pharmacol Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD USA. [Mattison, Donald R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. RP Beigi, RH (reprint author), Univ Pittsburgh, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Med Ctr,Div Reprod Infect Dis, Pittsburgh, PA 15213 USA. RI HAN, KyoungHoon/D-4588-2011; Han, Kelong/J-5233-2014; Mattison, Donald/L-4661-2013; OI Mattison, Donald/0000-0001-5623-0874; caritis, steve/0000-0002-2169-0712 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD047905, HD047891, HD047892]; Office of Research on Women's Health, National Institutes of Health (NIH); NICHD, NIH; NIH National Center for Research Resources [UL1RR025014]; Centers for Disease Control and Prevention; Association of Maternal and Child Health Programs FX This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD047905, HD047891, HD047892) and by the Office of Research on Women's Health, National Institutes of Health (NIH). Dr Mattison was supported by funds from the intramural program of NICHD, NIH. In addition, this work was supported in part by Grant no. UL1RR025014 from the NIH National Center for Research Resources. Drs Beigi, Han, Venkataramanan, Hankins, Clark, Hebert, Easterling, Zajicek, Ren, and Caritis have no conflicts to report.; Publication of this article was supported by the Centers for Disease Control and Prevention and the Association of Maternal and Child Health Programs. NR 28 TC 34 Z9 35 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 JUN PY 2011 VL 204 IS 6 SU 1 BP S84 EP S88 DI 10.1016/j.ajog.2011.03.002 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 772AF UT WOS:000291201100014 PM 21492826 ER PT J AU Sezgin, E van Natta, ML Ahuja, A Lyon, A Srivastava, S Troyer, JL O'Brien, SJ Jabs, DA AF Sezgin, Efe van Natta, Mark L. Ahuja, Alka Lyon, Alice Srivastava, Sunil Troyer, Jennifer L. O'Brien, Stephen J. Jabs, Douglas A. CA Studies Ocular Complications AIDS TI Association of Host Genetic Risk Factors With the Course of Cytomegalovirus Retinitis in Patients Infected With Human Immunodeficiency Virus SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; CELL-DERIVED FACTOR-1; ENDOTHELIAL GROWTH-FACTOR; VISUAL-ACUITY LOSS; DISEASE PROGRESSION; HIV-1 INFECTION; OCULAR COMPLICATIONS; 1-INFECTED PATIENTS; AIDS PROGRESSION; NATURAL-HISTORY AB PURPOSE: To evaluate the effects of previously reported host genetics factors that influence cytomegalovirus (CMV) retinitis incidence, progression to acquired immune deficiency syndrome (AIDS), and efficacy of highly active antiretroviral therapy (HAART) for mortality, retinitis progression, and retinal detachment in patients with CMV retinitis and AIDS in the era of HAART. DESIGN: Prospective, multicenter, observational study. METHODS: Cox proportional hazards model based genetic association tests examined the influence of IL-10R1_S420L, CCR5-Delta 32, CCR2-V64I, CCR5 promoter, and SDF-3'A polymorphisms among patients with mortality, retinitis progression, and retinal detachment. Participants were 203 European-American and 117 African-American patients with AIDS and CMV retinitis. RESULTS: European-American patients with the CCR5 + .P1. + promoter haplotype showed increased risk for mortality (hazard ratio [HR] = 1.83; 95% confidence interval [CI]: 1.00-3.40; P = .05). Although the same haplotype also trended for increased risk for mortality in African-American patients, the result was not significant (HR = 2.28; 95% CI: 0.93-5.60; P = .07). However, this haplotype was associated with faster retinitis progression in African Americans (HR = 5.22; 95% CI: 1.54-17.71; P = .007). Increased risk of retinitis progression was also evident for African-American patients with the SDF1-3'A variant (HR = 3.89; 95% CI: 1.42-10.60; P = .008). In addition, the SDF1-3'A variant increased the retinal detachment risk in this patient group (HR = 3.05; 95% CI: 1.01-9.16; P = .05). CONCLUSION: Besides overall immune health, host genetic factors influence mortality, retinitis progression, and retinal detachment in patients with AIDS and CMV retinitis that are receiving HAART. (Am J Ophthalmol 2011;151:999-1006. Published by Elsevier Inc.) C1 [Sezgin, Efe; Troyer, Jennifer L.] NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. [van Natta, Mark L.; Ahuja, Alka; Jabs, Douglas A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lyon, Alice] Northwestern Univ, Dept Ophthalmol, Feinberg Sch Med, Chicago, IL 60611 USA. [Srivastava, Sunil] Emory Univ, Sch Med, Dept Ophthalmol, Atlanta, GA 30322 USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. RP Sezgin, E (reprint author), NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. EM efe.sezgin@nih.gov RI Troyer, Jennifer/B-8415-2012; Sezgin, Efe/B-8418-2012 OI Sezgin, Efe/0000-0002-8000-7485 FU NATIONAL CANCER Institute [N01-CO-12400]; National Eye Institute, National Institutes of Health, Bethesda, Maryland [U10 EY08057]; Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland [U10 EY-08067]; University of Wisconsin, Madison, Madison, Wisconsin [U10 EY08067] FX PUBLICATION OF THIS ARTICLE WAS SUPPORTED IN PART BY CONTRACT N01-CO-12400 FROM THE NATIONAL CANCER Institute to the Laboratory of Genomic Diversity, Frederick, Maryland, and cooperative agreements from the National Eye Institute, National Institutes of Health, Bethesda, Maryland, to the Mount Sinai School of Medicine, New York, New York (U10 EY08057); the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (U10 EY-08067); and the University of Wisconsin, Madison, Madison, Wisconsin (U10 EY08067). NR 59 TC 6 Z9 7 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUN PY 2011 VL 151 IS 6 BP 999 EP 1006 DI 10.1016/j.ajo.2010.11.029 PG 8 WC Ophthalmology SC Ophthalmology GA 773GQ UT WOS:000291295400013 PM 21396623 ER PT J AU Maltsev, VA Vinogradova, TM Stern, MD Lakatta, EG AF Maltsev, Victor A. Vinogradova, Tatiana M. Stern, Michael D. Lakatta, Edward G. TI "Validating the requirement for beat-to-beat coupling of the Ca2+ clock and M clock in pacemaker cell normal automaticity" SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Letter ID PIG SINOATRIAL NODE; RYANODINE RECEPTOR; MECHANISMS; MYOCYTES C1 [Maltsev, Victor A.; Vinogradova, Tatiana M.; Stern, Michael D.; Lakatta, Edward G.] Gerontol Res Ctr, Cardiovasc Sci Lab, Baltimore, MD USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, IRP, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM lakattae@grc.nia.nih.gov NR 11 TC 8 Z9 8 U1 0 U2 8 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 JUN PY 2011 VL 300 IS 6 BP H2323 EP H2324 DI 10.1152/ajpheart.00110.2011 PG 2 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 772CS UT WOS:000291209300040 PM 21632980 ER PT J AU Zhang, XL Shi, J Zhao, LY Sun, LL Wang, J Wang, GB Epstein, DH Lu, L AF Zhang, Xiao-li Shi, Jie Zhao, Li-yan Sun, Li-li Wang, Jun Wang, Gui-bin Epstein, David H. Lu, Lin TI Effects of Stress on Decision-Making Deficits in Formerly Heroin-Dependent Patients After Different Durations of Abstinence SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID VENTROMEDIAL PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; COCAINE DEPENDENCE; STRIA TERMINALIS; BED NUCLEUS; ADDICTION; RESPONSES; EMOTION; ABUSERS; VULNERABILITY AB Objective: Drug abuse is associated with substantial impairments in decision making. However, little is known about the time course of changes in decision-making ability after abstinence or about the effects of stress on decision making in individuals recovering from heroin dependence after different durations of abstinence. Method: First, the authors assessed decision-making performance with the original card version of the Iowa Gambling Task in formerly heroin-dependent patients who had been abstinent for 3, 7, 15, or 30 days or 3, 6, 12, or 24 months. Second, patients who had been abstinent from heroin for 15 or 30 days or 3, 12, or 24 months were challenged with acute stress induced by the Trier Social Stress Test. Third, the beta-adrenoceptor antagonist propranolol (40 mg) was administered 1 hour before stress to those who had been abstinent for 30 days or 12 or 24 months. Results: The short-term abstinence groups (3-30 days) performed worse on the Iowa Gambling Task compared with the long-term abstinence groups (3-24 months). Psychosocial stress unmasked a latent impairment in decision making in the 24-month abstinence group, which seemed to perform identically to healthy comparison subjects in the absence of stress. Propranolol blocked the stress-induced impairment of decision making, which was seen only in the formerly heroin-dependent patients. Conclusions: Stress can exacerbate an already existing impairment of decision making or unmask a latent one in individuals recovering from heroin dependence. The beta-adrenergic blockade reduces this effect and might hold promise for treatment of substance use disorders. C1 [Shi, Jie; Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 100191, Peoples R China. Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. RP Shi, J (reprint author), Peking Univ, Natl Inst Drug Dependence, 38 Xue Yuan Rd, Beijing 100191, Peoples R China. EM shijie@bjmu.edu.cn; linlu@bjmu.edu.cn FU National Basic Research Program of China [2009CB522000]; Natural Science Foundation of China [30725016]; Natural Science Foundation of Beijing Municipality [09G0762, 7092058] FX Supported in part by the National Basic Research Program of China (grant number: 2009CB522000), the Natural Science Foundation of China (grant number: 30725016), and the Natural Science Foundation of Beijing Municipality (grants: 09G0762 and 7092058). NR 41 TC 19 Z9 22 U1 5 U2 15 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 JUN PY 2011 VL 168 IS 6 BP 610 EP 616 DI 10.1176/appi.ajp.2010.10040499 PG 7 WC Psychiatry SC Psychiatry GA 772OJ UT WOS:000291242900009 PM 21406465 ER PT J AU Bertuccio, P La Vecchia, C Silverman, DT Petersen, GM Bracci, PM Negri, E Li, D Risch, HA Olson, SH Gallinger, S Miller, AB Bueno-de-Mesquita, HB Talamini, R Polesel, J Ghadirian, P Baghurst, PA Zatonski, W Fontham, ET Bamlet, WR Holly, EA Lucenteforte, E Hassan, M Yu, H Kurtz, RC Cotterchio, M Su, J Maisonneuve, P Duell, EJ Bosetti, C Boffetta, P AF Bertuccio, P. La Vecchia, C. Silverman, D. T. Petersen, G. M. Bracci, P. M. Negri, E. Li, D. Risch, H. A. Olson, S. H. Gallinger, S. Miller, A. B. Bueno-de-Mesquita, H. B. Talamini, R. Polesel, J. Ghadirian, P. Baghurst, P. A. Zatonski, W. Fontham, E. T. Bamlet, W. R. Holly, E. A. Lucenteforte, E. Hassan, M. Yu, H. Kurtz, R. C. Cotterchio, M. Su, J. Maisonneuve, P. Duell, E. J. Bosetti, C. Boffetta, P. TI Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4) SO ANNALS OF ONCOLOGY LA English DT Article DE cigar; pancreatic cancer; pooled analysis; smokeless tobacco; tobacco; pipe ID DIRECT INTERVIEWS; RISK-FACTORS; COHORT AB Background: Cigarette smoking is the best-characterized risk factor for pancreatic cancer. However, data are limited for other tobacco smoking products and smokeless tobacco. Materials and methods: We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and risk of pancreatic cancer using data from 11 case-control studies (6056 cases and 11 338 controls) within the International Pancreatic Cancer Case-Control Consortium (PanC4). Pooled odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression models adjusted for study center and selected covariates. Results: Compared with never tobacco users, the OR for cigar-only smokers was 1.6 (95% CI: 1.2-2.3), i.e. comparable to that of cigarette-only smokers (OR 1.5; 95% CI 1.4-1.6). The OR was 1.1 (95% CI 0.69-1.6) for pipe-only smokers. There was some evidence of increasing risk with increasing amount of cigar smoked per day (OR 1.82 for 10 grams of tobacco), although not with duration. The OR for ever smokeless tobacco users as compared with never tobacco users was 0.98 (95% CI 0.75-1.3). Conclusion: This collaborative analysis provides evidence that cigar smoking is associated with an excess risk of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless tobacco use. C1 [Boffetta, P.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Bertuccio, P.; La Vecchia, C.; Negri, E.; Lucenteforte, E.; Bosetti, C.] Ist Ric Farmacol Mario Negri, Dept Epidemiol, Milan, Italy. [Bertuccio, P.; La Vecchia, C.; Lucenteforte, E.] Univ Milan, Dept Occupat Hlth, Sect Med Stat, Milan, Italy. [Silverman, D. T.; Su, J.] NCI, Bethesda, MD 20892 USA. [Petersen, G. M.; Bamlet, W. R.] Mayo Clin, Rochester, MN 55905 USA. [Bracci, P. M.; Holly, E. A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Li, D.; Hassan, M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Risch, H. A.; Yu, H.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Olson, S. H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Gallinger, S.] Toronto Gen Hosp, Toronto, ON, Canada. [Miller, A. B.; Cotterchio, M.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Bueno-de-Mesquita, H. B.] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. B.] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Talamini, R.; Polesel, J.] Ctr Riferimento Oncol, Unit Epidemiol & Biostat, I-33081 Aviano, Italy. [Ghadirian, P.] Res Ctr CRCHUM, Epidemiol Res Unit, Montreal, PQ, Canada. [Baghurst, P. A.] Womens & Childrens Hosp, Adelaide, SA, Australia. [Zatonski, W.] Ctr Canc, Warsaw, Poland. [Zatonski, W.] Inst Oncol, Warsaw, Poland. [Fontham, E. T.] Louisiana State Univ, Sch Publ Hlth, New Orleans, LA USA. [Kurtz, R. C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Cotterchio, M.] Canc Care Ontario, Toronto, ON, Canada. [Maisonneuve, P.] European Inst Oncol, Milan, Italy. [Duell, E. J.] Catalan Inst Oncol ICO, Barcelona, Spain. [Boffetta, P.] Int Prevent Res Inst, Lyon, France. RP Boffetta, P (reprint author), Mt Sinai Sch Med, Tisch Canc Inst, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM paolo.boffetta@mssm.edu RI Negri, Eva/B-7244-2013; Gallinger, Steven/E-4575-2013; OI Negri, Eva/0000-0001-9712-8526; Duell, Eric J/0000-0001-5256-0163; Polesel, Jerry/0000-0001-9381-1520; La Vecchia, Carlo/0000-0003-1441-897X; Lucenteforte, Ersilia/0000-0001-5608-5902; Maisonneuve, Patrick/0000-0002-5309-4704 FU Louisiana Board of Regents Millennium Trust Health Excellence Fund [HEF 2000-05]; Prevention, Control, and Population Research Goldstein Award; Society of MSKCC; Geoffrey Beene Cancer Research Fund; National Institute of Health, NCI, Division of Cancer Epidemiology and Genetics [N01-CP-51090, N01-CP-51089, N01-CP-51092, N01-CP-05225, N01-CP-31022, N01-CP-05227]; NCI [CA59706, CA108370, CA109767, CA89726, CA098889, 5R01-CA098870]; Rombauer Pancreatic Cancer Research Fund; NCI's Surveillance, Epidemiology and End Results Program [N01-PC-35136]; Association for Cancer Research (AIRC); Cancer Research Society; NCI of Canada; Dutch Ministry of Public Health, Welfare and Sports (formerly Welfare, Health and Culture); Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS-European Union) FX The LSU study was supported by the Louisiana Board of Regents Millennium Trust Health Excellence Fund (Project 5: HEF 2000-05, Genetics Studies in the Acadian Population). The Pancreatic Cancer Family Registry at Memorial Sloan-Kettering Cancer Center (MSKCC) has been supported by the Prevention, Control, and Population Research Goldstein Award; the Society of MSKCC; and the Geoffrey Beene Cancer Research Fund. The NCI study was supported by the Intramural Research Program of the National Institute of Health, NCI, Division of Cancer Epidemiology and Genetics (contract numbers: N01-CP-51090, N01-CP-51089, N01-CP-51092, N01-CP-05225, N01-CP-31022, N01-CP-05227). The UCSF study work was supported in part by NCI grants (CA59706, CA108370, CA109767, CA89726, CA098889) (EAH, PI) and by the Rombauer Pancreatic Cancer Research Fund. Cancer incidence data collection in the UCSF study was supported by the California Department of Public Health, the NCI's Surveillance, Epidemiology and End Results Program contract N01-PC-35136 awarded to the Northern California Cancer Center. The Italian and Milan studies were supported by the Italian Association for Cancer Research (AIRC). The Montreal investigation in the SEARCH study was supported by the Cancer Research Society; the Toronto contribution was supported by the NCI of Canada, and The Netherlands investigation was supported by the Dutch Ministry of Public Health, Welfare and Sports (formerly Welfare, Health and Culture). The Yale Connecticut Study was supported by NCI grant 5R01-CA098870 (HAR, PI). The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access for the Yale Connecticut study is gratefully acknowledged. The Yale study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in the Yale study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data.; The authors thank Mrs I. Garimoldi for editorial assistance. PB was supported by Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS-European Union, Sixth Framework Program [FP6] Network of Excellence). NR 29 TC 37 Z9 38 U1 0 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUN PY 2011 VL 22 IS 6 BP 1420 EP 1426 DI 10.1093/annonc/mdq613 PG 7 WC Oncology SC Oncology GA 770BA UT WOS:000291060800024 PM 21245160 ER PT J AU Kim, AJ Kim, HJ Jee, HJ Song, N Kim, M Bae, YS Chung, JH Yun, J AF Kim, Ae Jeong Kim, Hyun-Ju Jee, Hye Jin Song, Naree Kim, Minjee Bae, Yoe-Sik Chung, Jay H. Yun, Jeanho TI Glucose deprivation is associated with Chk1 degradation through the ubiquitin-proteasome pathway and effective checkpoint response to replication blocks SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Chk1; Glucose deprivation; Protein stability; Ubiquitin-proteasome pathway; Genomic instability ID COLORECTAL-CANCER CELLS; DNA-DAMAGE CHECKPOINT; MAMMALIAN-CELLS; TUMOR HYPOXIA; KINASE; PHOSPHORYLATION; EXPRESSION; STRESS; ATR; MUTAGENESIS AB Chk1 plays a key role in the DNA replication checkpoint and in preserving genomic integrity. Previous studies have shown that reduced Chk1 function leads to defects in the checkpoint response and is closely associated with tumorigenesis. Here, we report that glucose deprivation caused the degradation of Chk1 protein without perturbing cell cycle progression. The induction of Chk1 degradation in response to glucose deprivation was observed in various cancer cell lines and in normal human fibroblasts. Therefore, it appears to be a universal phenomenon in mammalian cells. A specific proteasome inhibitor blocked glucose deprivation-induced Chk1 degradation. Ubiquitination of Chk1 was detected, indicating that the proteasome-ubiquitin pathway mediates Chk1 degradation upon glucose deprivation. Mechanistic studies have demonstrated that ATR-dependent phosphorylation of Chk1 at the Ser317 and Ser345 sites is not required, suggesting that the molecular mechanism for Chk1 degradation upon glucose deprivation is distinct from genotoxic stress-induced degradation. Under conditions of glucose deprivation, the cells manifested a defective checkpoint response to replication stress, camptothecin or hydroxyurea. The forced expression of Myc-Chk1 partially rescued the defective response to the replication block upon glucose deprivation. Taken together, our results indicate that glucose deprivation induces ubiquitin-mediated Chk1 degradation and defective checkpoint responses, implying its potential role in genomic instability and tumor development. (C) 2011 Elsevier B.V. All rights reserved. C1 [Kim, Ae Jeong; Kim, Hyun-Ju; Jee, Hye Jin; Song, Naree; Kim, Minjee; Yun, Jeanho] Dong A Univ, Coll Med, Dept Biochem, Pusan 602714, South Korea. [Kim, Ae Jeong; Kim, Hyun-Ju; Jee, Hye Jin; Song, Naree; Kim, Minjee; Yun, Jeanho] Dong A Univ, Coll Med, Mitochondria Hub Regulat Ctr, Pusan 602714, South Korea. [Bae, Yoe-Sik] Sungkyunkwan Univ, Dept Biol Sci, Suwon 440746, South Korea. [Chung, Jay H.] NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Yun, J (reprint author), Dong A Univ, Coll Med, Dept Biochem, Pusan 602714, South Korea. EM yunj@dau.ac.kr FU Korean Government (MOEHRD) [KRF-2008-512-E00012]; Ministry for Health, Welfare & Family Affairs, Republic of Korea [A090331]; Korea government (MEST) [2009-0093197] FX We thank Dr. Yolanda Sanchez, and Dr. Helen Piwnica-Worms for providing expression plasmids. This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2008-512-E00012) by a grant of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A090331), and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2009-0093197). NR 47 TC 4 Z9 4 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JUN PY 2011 VL 1813 IS 6 BP 1230 EP 1238 DI 10.1016/j.bbamcr.2011.03.012 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 771PG UT WOS:000291172600011 PM 21440578 ER PT J AU Capitini, CM Davis, JPE Larabee, SM Herby, S Nasholm, NM Fry, TJ AF Capitini, Christian M. Davis, Jessica P. E. Larabee, Shannon M. Herby, Sarah Nasholm, Nicole M. Fry, Terry J. TI Extracorporeal Photopheresis Attenuates Murine Graft-versus-Host Disease via Bone Marrow-Derived Interleukin-10 and Preserves Responses to Dendritic Cell Vaccination SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic bone marrow transplantation; Donor lymphocyte infusion; Immune reconstitution; Vaccine ID REGULATORY T-CELLS; CONTACT HYPERSENSITIVITY; AUTOIMMUNE-DISEASE; APOPTOTIC CELLS; ANIMAL-MODEL; PHOTOCHEMOTHERAPY; TRANSPLANTATION; IMMUNITY; ULTRAVIOLET; MATURATION AB Extracorporeal photopheresis (ECP) is emerging as a therapy for graft-versus-host-disease (GVHD), but the full mechanism of action and the impact on immunity have not been fully established. After murine minor histocompatibility antigen-mismatched bone marrow (BM) transplantation (allo-BMT), coinfusion of ECP-treated splenocytes with T cell-replete BM attenuated GVHD irrespective of the donor strain of the ECP-treated splenocytes, and was associated with increased numbers of regulatory T cells. Coculture of myeloid dendritic cells (DCs) with ECP-treated splenocytes resulted in increased interleukin (IL)-10 production after submaximal stimulation with lipopolysaccharide. Furthermore, male myeloid DCs exposed to ECP-treated splenocytes were less potent at inducing CD8(+) HY responses when used as a vaccine in vivo. The efficacy of ECP-treated splenocytes was enhanced when administered just before delayed donor lymphocyte infusion following T cell-depleted allo-BMT, allowing for the administration of sufficient numbers of T cells to respond to myeloid DC vaccination in the absence of a thymus. Finally, the therapeutic effect of ECP-treated splenocytes was lost in recipients of IL-10 deficient BM. We demonstrate that ECP-treated splenocytes attenuate GVHD irrespective of the source of ECP-treated cells via a mechanism that likely involves modulation of DCs and requires IL-10 produced by BM-derived cells. Importantly, the attenuation of GVHD by ECP-treated splenocytes permits donor lymphocyte infusion dependent responses to DC vaccines after allo-BMT. Biol Blood Marrow Transplant 17: 790-799 (2011) Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation C1 [Capitini, Christian M.; Davis, Jessica P. E.; Larabee, Shannon M.; Herby, Sarah; Nasholm, Nicole M.; Fry, Terry J.] NCI, Immunol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Capitini, CM (reprint author), NCI, Immunol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bldg 10,MSC 1104,10 Ctr Dr, Bethesda, MD 20892 USA. EM capitinic@mail.nih.gov OI Capitini, Christian/0000-0002-2276-6731 FU National Institutes of Health; Children's Cancer Foundation; Lisa's Heart Kids Cancer Research Fund FX This work was supported by the National Institutes of Health's Intramural Research Program and grants from the Children's Cancer Foundation and Lisa's Heart Kids Cancer Research Fund (to Terry J. Fry). The contents of this article do 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 38 TC 13 Z9 13 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUN PY 2011 VL 17 IS 6 BP 790 EP 799 DI 10.1016/j.bbmt.2010.12.712 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 771XM UT WOS:000291194000002 PM 21216299 ER PT J AU Melenhorst, JJ Scheinberg, P Williams, A Ambrozak, DR Keyvanfar, K Smith, M McCoy, JP Hensel, NF Douek, DC Barrett, AJ AF Melenhorst, J. Joseph Scheinberg, Phillip Williams, Ann Ambrozak, David R. Keyvanfar, Keyvan Smith, Melody McCoy, J. Philip, Jr. Hensel, Nancy F. Douek, Daniel C. Barrett, A. John TI Alloreactivity Across HLA Barriers Is Mediated by Both Naive and Antigen-Experienced T Cells SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Cross-reactivity; Clonotype; Graft-versus-host disease ID VERSUS-HOST-DISEASE; TOXIC LYMPHOCYTES-T; CYTOMEGALOVIRUS-SPECIFIC CD4(+); CROSS-REACTIVITY; HISTOCOMPATIBILITY ANTIGENS; VIRUS; PEPTIDE; RECOGNITION; LEUKEMIA; CLONES AB T cell responses to allogeneic targets arise predominantly from the naive pool. However, in humans, the risk of graft-versus-host disease is increased if the donor has circulating T cells recognizing multiple persistent DNA viruses, suggesting that memory T cells also contribute to the alloresponse. To examine HLA alloreactivity, we used flow cytometry-based proliferation and cytokine production assays. We identified the clonal identity of virus-specific T cells cross-reacting with HLA-disparate targets by sequencing the T cell receptor 13 chains in virus-specific T cell lines restimulated with cognate and HLA-disparate targets and sorting these chains according to cytokine response. We confirmed that naive T cells from cord blood and adult individuals responded to HLA-mismatched target cells. In addition, in adults, we identified memory T cells responding by cytokine release to HLA-mismatched targets both in direct assays and after 8 days of culture with allogeneic stimulator cells. Epstein-Barr virus specific and cytomegalovirus-specific T cells, tested against a panel of 30 T cell antigen-presenting cells with a broad coverage of the most prominent HLA types, displayed specificity for certain mismatched HLA alleles. Sequencing of the T cell receptor beta chain demonstrated a clonotypic identity of cells that responded to both viral and allogeneic stimulation. These findings show conclusively that alloresponses in humans are not confined to the naive T cell subset, and that memory viral antigen-specific T cells can cross-react with specific mismatched HLA-peptide complexes not presenting with cytomegalovirus or Epstein-Barr virus peptides. Biol Blood Marrow Transplant 17: 800-809 (2011) Published by Elsevier Inc. on behalf of American Society fir Blood and Marrow Transplantation C1 [Melenhorst, J. Joseph] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Williams, Ann; McCoy, J. Philip, Jr.] NHLBI, Flow Cytometry Core Facil, Bethesda, MD 20892 USA. [Ambrozak, David R.] NIAID, Immunol Sect, NIH, Bethesda, MD 20892 USA. [Scheinberg, Phillip; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Melenhorst, JJ (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10-CRC,Room 3-5320,10 Ctr Dr, Bethesda, MD 20892 USA. EM melenhoj@nhlbi.nih.gov RI Scheinberg, Phillip/H-5251-2012; OI Scheinberg, Phillip/0000-0002-9047-4538 FU National Institutes of Health, National Heart, Lung, and Blood Institute; Vaccine Research Center, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute and by the Vaccine Research Center, National Institute of Allergy and Infectious Diseases. NR 60 TC 12 Z9 12 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUN PY 2011 VL 17 IS 6 BP 800 EP 809 DI 10.1016/j.bbmt.2010.12.711 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 771XM UT WOS:000291194000003 PM 21215812 ER PT J AU Yamamoto, M Sato, T Beren, J Verthelyi, D Klinman, DM AF Yamamoto, Masaki Sato, Takashi Beren, Joel Verthelyi, Daniela Klinman, Dennis M. TI The acceleration of wound healing in primates by the local administration of immunostimulatory CpG oligonucleotides SO BIOMATERIALS LA English DT Article DE CpG oligonucleotide; Primate; TLR9; Wound healing ID PLASMACYTOID DENDRITIC CELLS; BACTERIAL-DNA; GROWTH-FACTOR; ACTIVATION; SKIN; MOTIFS; REPAIR; ALPHA; OLIGODEOXYNUCLEOTIDES; IDENTIFICATION AB The process of wound healing involves complex interactions between circulating immune cells and local epithelial and endothelial cells. Studies in murine models indicate that cells of the innate immune system activated via their Toll-like receptors (TLR) can accelerate wound healing. This work examines whether immunostimulatory CpG oligodeoxynucleotides (ODN) designed to trigger human immune cells via TLR9 can promote the healing of excisional skin biopsies in rhesus macaques. Results indicate that 'K' type CpG ODN significantly accelerate wound closure in non-human primates (p < 0.05). Contributing to this outcome was a CpG-dependent increase in both the production of basic fibroblast growth factor and in keratinocyte migration. Of interest, IL-1 alpha and TGF alpha normally present at sites of skin injury facilitated these effects. Current findings support the conclusion that the local administration of CpG ODN may provide an effective strategy for accelerating wound healing in humans. Published by Elsevier Ltd. C1 [Yamamoto, Masaki; Sato, Takashi; Klinman, Dennis M.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Beren, Joel] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20894 USA. [Verthelyi, Daniela] US FDA, Ctr Drug Evaluat & Res, Bethesda, MD 20894 USA. RP Klinman, DM (reprint author), NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU National Cancer Institute of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health. NR 44 TC 10 Z9 11 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD JUN PY 2011 VL 32 IS 18 BP 4238 EP 4242 DI 10.1016/j.biomaterials.2011.02.043 PG 5 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 771OW UT WOS:000291171600008 PM 21421264 ER PT J AU Cramer, SC Sur, M Dobkin, BH O'Brien, C Sanger, TD Trojanowski, JQ Rumsey, JM Hicks, R Cameron, J Chen, DF Chen, WG Cohen, LG deCharms, C Duffy, CJ Eden, GF Fetz, EE Filart, R Freund, M Grant, SJ Haber, S Kalivas, PW Kolb, B Kramer, AF Lynch, M Mayberg, HS McQuillen, PS Nitkin, R Pascual-Leone, A Reuter-Lorenz, P Schiff, N Sharma, A Shekim, L Stryker, M Sullivan, EV Vinogradov, S AF Cramer, Steven C. Sur, Mriganka Dobkin, Bruce H. O'Brien, Charles Sanger, Terence D. Trojanowski, John Q. Rumsey, Judith M. Hicks, Ramona Cameron, Judy Chen, Daofen Chen, Wen G. Cohen, Leonardo G. deCharms, Christopher Duffy, Charles J. Eden, Guinevere F. Fetz, Eberhard E. Filart, Rosemarie Freund, Michelle Grant, Steven J. Haber, Suzanne Kalivas, Peter W. Kolb, Bryan Kramer, Arthur F. Lynch, Minda Mayberg, Helen S. McQuillen, Patrick S. Nitkin, Ralph Pascual-Leone, Alvaro Reuter-Lorenz, Patricia Schiff, Nicholas Sharma, Anu Shekim, Lana Stryker, Michael Sullivan, Edith V. Vinogradov, Sophia TI Harnessing neuroplasticity for clinical applications SO BRAIN LA English DT Review DE neuroplasticity; retraining; therapeutics; clinical assessment ID DEEP BRAIN-STIMULATION; TRANSCRANIAL MAGNETIC STIMULATION; RANDOMIZED CONTROLLED-TRIAL; SPINAL-CORD-INJURY; TREATMENT-RESISTANT DEPRESSION; INDUCED MOVEMENT THERAPY; FUNCTION FOLLOWING HEMISPHERECTOMY; CROSS-MODAL PLASTICITY; SURROGATE END-POINTS; REAL-TIME FMRI AB Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies. C1 [Cramer, Steven C.] Univ Calif Irvine, Dept Neurol, Irvine, CA 92967 USA. [Cramer, Steven C.] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92967 USA. [Sur, Mriganka] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Dobkin, Bruce H.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. [O'Brien, Charles; Trojanowski, John Q.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [O'Brien, Charles; Trojanowski, John Q.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Sanger, Terence D.] Univ So Calif, Los Angeles, CA 90089 USA. [Rumsey, Judith M.; Freund, Michelle] NIMH, Rockville, MD 20852 USA. [Hicks, Ramona; Chen, Daofen; Cohen, Leonardo G.] NINDS, Bethesda, MD 20824 USA. [Cameron, Judy] Oregon Hlth & Sci Univ, Dept Physiol, Portland, OR 97239 USA. [Cameron, Judy] Oregon Hlth & Sci Univ, Dept Pharmacol, Portland, OR 97239 USA. [Chen, Wen G.] NIA, Bethesda, MD 20892 USA. [deCharms, Christopher] Omneuron Inc, Menlo Pk, CA 94025 USA. [Duffy, Charles J.; Haber, Suzanne] Univ Rochester, Dept Neurogeriatr, Rochester, NY 14627 USA. [Duffy, Charles J.; Haber, Suzanne] Univ Rochester, Dept Pharmacol & Physiol, Rochester, NY 14627 USA. [Eden, Guinevere F.] Georgetown Univ, Dept Pediat, Washington, DC 20057 USA. [Fetz, Eberhard E.] Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA. [Filart, Rosemarie] Natl Ctr Res Resources, Bethesda, MD 20892 USA. [Grant, Steven J.; Lynch, Minda] NIDA, Rockville, MD 20852 USA. [Kalivas, Peter W.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Kolb, Bryan] Univ Lethbridge, Dept Neurosci, Lethbridge, AB T1K 3M4, Canada. [Kramer, Arthur F.] Univ Illinois, Dept Psychol, Urbana, IL 61801 USA. [Mayberg, Helen S.] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Mayberg, Helen S.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [McQuillen, Patrick S.; Stryker, Michael; Vinogradov, Sophia] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94102 USA. [McQuillen, Patrick S.; Stryker, Michael; Vinogradov, Sophia] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94102 USA. [McQuillen, Patrick S.; Stryker, Michael; Vinogradov, Sophia] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94102 USA. [Nitkin, Ralph] NICHHD, Bethesda, MD 20892 USA. [Pascual-Leone, Alvaro] Beth Israel Deaconess Med, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA USA. [Pascual-Leone, Alvaro] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Reuter-Lorenz, Patricia] Univ Michigan, Dept Psychol, Dearborn, MI 48128 USA. [Reuter-Lorenz, Patricia] Univ Michigan, Dept Neurosci, Dearborn, MI 48128 USA. [Schiff, Nicholas] Cornell Univ, Dept Neurol, Weill Cornell Med Coll, New York, NY 10065 USA. [Sharma, Anu] Univ Colorado, Dept Speech Language & Hearing Sci, Boulder, CO 80305 USA. [Shekim, Lana] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD 20892 USA. [Sullivan, Edith V.] Stanford Univ, Dept Psychiat & Behav Sci, Menlo Pk, CA USA. RP Cramer, SC (reprint author), UC Irvine Med Ctr, 101 City Dr S,Bldg 53,Rm 203, Orange, CA 92868 USA. EM scramer@uci.edu RI Winstein, Carolee/A-8375-2008; Cameron, Judy/J-6682-2013; OI Stryker, Michael/0000-0003-1546-5831 FU National Institutes of Health Blueprint for Neuroscience Research; GlaxoSmithKline; Stem Cell Therapeutics; Panasonic; Pfizer; Photothera; Allergan; Asubio FX This work is based on a workshop sponsored by the National Institutes of Health Blueprint for Neuroscience Research and held in April, 2009. The views expressed herein do not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Health and Human Services, or any other agency of the United States Government.; Conflict of interest: Steven Cramer has received grant support from GlaxoSmithKline, Stem Cell Therapeutics and Panasonic and has received consulting income from GlaxoSmithKline, Stem Cell Therapeutics, Pfizer, Photothera, Allergan and Asubio. Christopher deCharms is an employee and stockholder in Omneuron, Inc., a research company that develops neuroimaging approaches for diagnosing and treating neurologic and psychiatric diseases. Helen S. Mayberg holds intellectual property in the field of deep brain stimulation for depression and is a consultant for St Jude Medical. Charles O'Brien has served as a consultant in the past year to Gilead, Alkermes, Reckitt and Embera. Alvaro Pascual-Leone serves on the medical advisory board for Nexstim, Neuronix, Neosync and Starlab. NR 225 TC 227 Z9 229 U1 20 U2 160 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD JUN PY 2011 VL 134 BP 1591 EP 1609 DI 10.1093/brain/awr039 PN 6 PG 19 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 770CF UT WOS:000291063900004 PM 21482550 ER PT J AU Cui, CH Grandison, L Noronha, A AF Cui, Changhai Grandison, Lindsey Noronha, Antonio TI Neuroimmune mechanisms of brain function and alcohol related disorders SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Editorial Material C1 [Cui, Changhai; Grandison, Lindsey; Noronha, Antonio] NIAAA, Div Neurosci & Behav, Bethesda, MD 20892 USA. RP Cui, CH (reprint author), NIAAA, Div Neurosci & Behav, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM changhai.cui@nih.gov NR 17 TC 6 Z9 6 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD JUN PY 2011 VL 25 SU 1 BP S1 EP S3 DI 10.1016/j.bbi.2011.03.005 PG 3 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 771XQ UT WOS:000291194400001 PM 21397684 ER PT J AU Cross, AJ Major, JM Sinha, R AF Cross, Amanda J. Major, Jacqueline M. Sinha, Rashmi TI Urinary Biomarkers of Meat Consumption SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID 3-METHYLHISTIDINE EXCRETION; TAURINE LEVELS; PROTEIN; DIET; 1-METHYLHISTIDINE; DERIVATIVES; METABOLISM; CREATININE; DISEASE; MARKER AB Background: Meat intake has been positively associated with incidence and mortality of chronic diseases, including diabetes, heart disease, and several different cancers, in observational studies by using self-report methods of dietary assessment; however, these dietary assessment methods are subject to measurement error. One method to circumvent such errors is the use of biomarkers of dietary intake, but currently there are no accepted biomarkers for meat intake. Methods: We investigated four analytes (creatinine, taurine, 1-methylhistidine, and 3-methylhistidine) specifically found in meat and excreted in urine. Twenty-four-hour urine samples were collected from 17 individuals on controlled diets containing varying levels of meat: vegetarian (0 g/d), low red meat (60 g/d), medium red meat (120 g/d), and high red meat (420 g/d), as part of two randomized crossover feeding studies. Results: When compared with the low red meat diet or the vegetarian diet, the urinary levels of all four analytes were significantly higher in urine samples collected after 15 days of a high red meat diet (P < 0.0001). Only urinary 1-methylhistidine and 3-methylhistidine were statistically significantly different for every diet type, increasing as the amount of meat in the diet increased (P < 0.01 for 1-methylhistidine and P < 0.05 for 3-methylhistidine). Furthermore, urinary excretion of 1-methylhistidine and 3-methylhistidine elevated with increasing meat intake in every individual. Conclusion: Urinary 1-methylhistidine and 3-methylhistidine may be good biomarkers of meat intake. Impact: To determine the public health impact of red meat on cancer risk, biomarkers are crucial to estimate true intake; these potential biomarkers should be further investigated in free-living populations. Cancer Epidemiol Biomarkers Prev; 20(6); 1107-11. (C)2011 AACR. C1 [Cross, Amanda J.; Major, Jacqueline M.; Sinha, Rashmi] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Cross, AJ (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd EPS,Suite 320, Rockville, MD 20852 USA. EM crossa@mail.nih.gov RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU Intramural NIH HHS [Z99 CA999999] NR 26 TC 35 Z9 36 U1 1 U2 16 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 JUN PY 2011 VL 20 IS 6 BP 1107 EP 1111 DI 10.1158/1055-9965.EPI-11-0048 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 773LK UT WOS:000291308600007 PM 21527577 ER PT J AU Scollen, S Luccarini, C Baynes, C Driver, K Humphreys, MK Garcia-Closas, M Figueroa, J Lissowska, J Pharoah, PD Easton, DF Hesketh, R Metcalfe, JC Dunning, AM AF Scollen, Serena Luccarini, Craig Baynes, Caroline Driver, Kristy Humphreys, Manjeet K. Garcia-Closas, Montserrat Figueroa, Jonine Lissowska, Jolanta Pharoah, Paul D. Easton, Douglas F. Hesketh, Robin Metcalfe, James C. Dunning, Alison M. TI TGF-beta Signaling Pathway and Breast Cancer Susceptibility SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; POLYGENIC SUSCEPTIBILITY; RECEPTOR; RISK; LOCI; VARIANT; STATE AB Background: TGF-beta acts as a suppressor of primary tumor initiation but has been implicated as a promoter of the later malignant stages. Here associations with risk of invasive breast cancer are assessed for single-nucleotide polymorphisms (SNP) tagging 17 genes in the canonical TGF-beta ALK5/SMADs 2&3 and ALK1/SMADs 1&5 signaling pathways: LTBP1, LTBP2, LTBP4, TGFB1, TGFB2, TGFB3, TGFBR1(ALK5), ALK1, TGFBR2, Endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, and SMAD7 [Approved Human Gene Nomenclature Committee gene names: ACVRL1 (for ALK1) and ENG (for Endoglin)]. Methods: Three-hundred-fifty-four tag SNPs (minor allele frequency > 0.05) were selected for genotyping in a staged study design using 6,703 cases and 6,840 controls from the Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) study. Significant associations were meta-analyzed with data from the NCI Polish Breast Cancer Study (PBCS; 1,966 cases and 2,347 controls) and published data from the Breast Cancer Association Consortium (BCAC). Results: Associations of three SNPs, tagging TGFB1 (rs1982073), TGFBR1 (rs10512263), and TGFBR2 (rs4522809), were detected in SEARCH; however, associations became weaker in meta-analyses including data from PBCS and BCAC. Tumor subtype analyses indicated that the TGFB1 rs1982073 association may be confined to increased risk of developing progesterone receptor negative (PR(-)) tumors [1.18 (95% CI: 1.09-1.28), 4.1 x 10(-5) (P value for heterogeneity of ORs by PR status = 2.3 x 10(-4))]. There was no evidence for breast cancer risk associations with SNPs in the endothelial-specific pathway utilizing ALK1/SMADs 1&5 that promotes angiogenesis. Conclusion: Common variation in the TGF-beta ALK5/SMADs 2&3 signaling pathway, which initiates signaling at the cell surface to inhibit cell proliferation, might be related to risk of specific tumor subtypes. Impact: The subtype specific associations require very large studies to be confirmed. Cancer Epidemiol Biomarkers Prev; 20(6); 1112-9. (c) 2011 AACR. C1 [Scollen, Serena; Hesketh, Robin; Metcalfe, James C.] Univ Cambridge, Dept Biochem, Cambridge CB2 1TN, England. [Luccarini, Craig; Baynes, Caroline; Driver, Kristy; Humphreys, Manjeet K.; Pharoah, Paul D.; Easton, Douglas F.; Dunning, Alison M.] Univ Cambridge, Dept Publ Hlth & Primary Care, Dept Oncol, Strangeways Res Lab, Cambridge, England. [Garcia-Closas, Montserrat; Figueroa, Jonine] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Sect Epidemiol & Canc Genet, London SW3 6JB, England. [Garcia-Closas, Montserrat] Breakthrough Breast Canc Res Ctr, London, England. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. RP Scollen, S (reprint author), Pfizer PGRD, Sandwich Lab, Ramsgate Rd, Sandwich, Kent, England. EM serena.scollen@pfizer.com RI Garcia-Closas, Montserrat /F-3871-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Scollen, Serena/0000-0002-9311-1337; Lissowska, Jolanta/0000-0003-2695-5799 FU Breast Cancer Campaign [2003: 747]; Cancer, Research-UK [C8197/A10123, C490/A11021, C1287/A10118, C8197/A10865]; EU [Health-F2-2009-223175-COGS] FX Financial support provided by Breast Cancer Campaign grant number 2003: 747, Cancer, Research-UK grant numbers C8197/A10123, C490/A11021, C1287/A10118, C8197/A10865, and EU FP7 Health-F2-2009-223175-COGS. NR 25 TC 25 Z9 26 U1 1 U2 6 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 JUN PY 2011 VL 20 IS 6 BP 1112 EP 1119 DI 10.1158/1055-9965.EPI-11-0062 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 773LK UT WOS:000291308600008 PM 21527583 ER PT J AU Cooney, RV Dai, Q Gao, YT Chow, WH Franke, AA Shu, XO Li, HL Ji, BT Cai, QY Chai, WW Zheng, W AF Cooney, Robert V. Dai, Qi Gao, Yu-Tang Chow, Wong-Ho Franke, Adrian A. Shu, Xiao-Ou Li, Honglan Ji, Butian Cai, Qiuyin Chai, Weiwen Zheng, Wei TI Low Plasma Coenzyme Q(10) Levels and Breast Cancer Risk in Chinese Women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID TAMOXIFEN THERAPY; CONTROLLED-TRIAL; TOCOPHEROL; SUPPLEMENTATION; INFLAMMATION; METABOLISM; OXIDATION; CHILDREN; CELLS AB Background: Low circulating levels of coenzyme Q(10) (CoQ(10)) have been associated with increased cancer incidence and poor prognosis for a number of cancer types, while a recent prospective study observed a positive association for CoQ(10) with breast cancer risk. Methods: We prospectively examined the association of plasma CoQ(10) with breast cancer risk in a nested case-control study of Chinese women within the Shanghai Women's Health Study (SWHS). Prediagnostic plasma samples were obtained from 340 cases and 653 age-matched controls and analyzed for total CoQ(10). Results: A borderline significant inverse association for breast cancer incidence with plasma CoQ(10) level was observed by a conditional logistic regression model adjusted for age and age at first live birth, which became significant after elimination of cases diagnosed within 1 year of blood draw (P-trend = 0.03). This association was independent of menopausal status. Plasma CoQ(10) levels were also observed to be significantly associated with circulating gamma-tocopherol (r = 0.50; P < 0.0001) and alpha-tocopherol (r = 0.38; P < 0.0001) levels. Conclusions: Circulating levels of CoQ(10) were generally low in this population and the observed association with breast cancer risk may be limited to those women with exceptionally low values. Impact: This study reports an inverse relationship between circulating CoQ(10) and breast cancer risk, while the only other prospective study of CoQ(10) and breast cancer to date found a positive association. Lower levels of CoQ(10) in the SWHS population suggest that the 2 studies may not be contradictory and indicate a possible nonlinear (U-shaped) association of CoQ(10) with risk. Cancer Epidemiol Biomarkers Prev; 20(6); 1124-30. (C)2011 AACR. C1 [Cooney, Robert V.] Univ Hawaii Manoa, John A Burns Sch Med, Off Publ Hlth Studies, Honolulu, HI 96822 USA. [Franke, Adrian A.] Univ Hawaii Manoa, Canc Res Ctr, Honolulu, HI 96822 USA. [Dai, Qi; Shu, Xiao-Ou; Cai, Qiuyin; Zheng, Wei] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Gao, Yu-Tang; Li, Honglan] Shanghai Canc Inst, Shanghai, Peoples R China. [Chow, Wong-Ho; Ji, Butian] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Cooney, RV (reprint author), Univ Hawaii Manoa, John A Burns Sch Med, Off Publ Hlth Studies, 1960 East West Rd, Honolulu, HI 96822 USA. EM rvcooney@hawaii.edu FU NIH [CA132149, CA106591, CA90956, CA71789, CA70867]; Vanderbilt-Ingram Cancer Center [P30 CA68485] FX This work was supported by NIH Grants CA132149 (RVC), CA106591 (QD), CA90956 (WC), CA71789 (AAF), and CA70867 (WZ). Sample preparations were performed at the Survey and Biospecimen Core, which is supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). NR 34 TC 6 Z9 6 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2011 VL 20 IS 6 BP 1124 EP 1130 DI 10.1158/1055-9965.EPI-10-1261 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 773LK UT WOS:000291308600010 PM 21467235 ER PT J AU Arem, H Weinstein, SJ Horst, RL Virtamo, J Yu, K Albanes, D Abnet, CC AF Arem, Hannah Weinstein, Stephanie J. Horst, Ronald L. Virtamo, Jarmo Yu, Kai Albanes, Demetrius Abnet, Christian C. TI Serum 25-Hydroxyvitamin D and Risk of Oropharynx and Larynx Cancers in Finnish Men SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID VITAMIN-D STATUS; PROSTATE-CANCER; PANCREATIC-CANCER; OVARIAN-CANCER; NECK-CANCER; MORTALITY; PLASMA; ESOPHAGEAL; STABILITY; SMOKING AB Background: Published studies suggesting a relationship between vitamin D and some common cancers sparked interest in the association of vitamin D with head and neck cancers. Prolonged darker months in Finland are associated with lower levels of ultraviolet B radiation, raising concerns about low vitamin D levels. Methods: We used a nested case-control study in the prospective Alpha-Tocopherol Beta Carotene (ATBC) Study of male smokers in Finland, to examine the relationship between serum 25(OH) D and risk of developing squamous cancers of the head and neck. Using conditional logistic regression, we calculated the multivariate adjusted ORs and CIs comparing those with serum 25(OH) D adequate levels of 50 to <75 nmol/L to those <25.0. Results: We identified incident cancers of the oral cavity (n = 134), pharynx (n = 48), and larynx (n = 158). Median serum vitamin D was 31 nmol/L (interquartile range: 21-48), which is below the 50 nmol/L cutoff point was considered adequate for bone and overall health. Comparing those with serum 25(OH) D below 25 nmol/L to those 50 to <75 nmol/L as the referent, the OR was 1.35 (95% CI: 0.53-3.43, P(trend) = 0.65) for overall head and neck cancers. Stratification by cancer subsites of the oral cavity, pharynx, and larynx (P(trend) = 0.93, 0.78, 0.26, respectively) or by season of blood draw also showed no association. Conclusions: Our study showed no association between serum 25(OH) D and risk of head and neck cancers. Impact: This study does not support the hypothesis that greater vitamin D exposure would reduce the risk of developing head and neck squamous cancers. Cancer Epidemiol Biomarkers Prev; 20(6); 1178-84. (C)2011 AACR. C1 [Abnet, Christian C.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Horst, Ronald L.] Heartland Assays, Ames, IA USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Arem, Hannah] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. RP Abnet, CC (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Room 320,6120 Execut Blvd,MSC 7232, Rockville, MD 20852 USA. EM abnetc@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU USPHS, National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; NIH; National Cancer Institute; [T32 CA105666] FX This work was supported by USPHS (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 the Intramural Research Program of the NIH, National Cancer Institute. This work was also supported in part by the training grant T32 CA105666. NR 33 TC 6 Z9 6 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2011 VL 20 IS 6 BP 1178 EP 1184 DI 10.1158/1055-9965.EPI-11-0153 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 773LK UT WOS:000291308600015 PM 21527582 ER PT J AU FitzGerald, LM Kwon, EM Conomos, MP Kolb, S Holt, SK Levine, D Feng, ZD Ostrander, EA Stanford, JL AF FitzGerald, Liesel M. Kwon, Erika M. Conomos, Matthew P. Kolb, Suzanne Holt, Sarah K. Levine, David Feng, Ziding Ostrander, Elaine A. Stanford, Janet L. TI Genome-wide Association Study Identifies a Genetic Variant Associated with Risk for More Aggressive Prostate Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SEQUENCE VARIANTS; CHROMOSOME 8Q24; LINKAGE SCAN; SUSCEPTIBILITY LOCI; AFRICAN-AMERICANS; MULTIPLE; HERC2; REPLICATION; CONFIRMATION; POPULATIONS AB Background: Of the 200,000 U. S. men annually diagnosed with prostate cancer, approximately 20% to 30% will have clinically aggressive disease. Although factors such as Gleason score and tumor stage are used to assess prognosis, there are no biomarkers to identify men at greater risk for developing aggressive prostate cancer. We therefore undertook a search for genetic variants associated with risk of more aggressive disease. Methods: A genome-wide scan was conducted in 202 prostate cancer cases with a more aggressive phenotype and 100 randomly sampled, age-matched prostate-specific antigen screened negative controls. Analysis of 387,384 autosomal single nucleotide polymorphisms (SNPs) was followed by validation testing in an independent set of 527 cases with more aggressive and 595 cases with less aggressive prostate cancer, and 1,167 age-matched controls. Results: A variant on 15q13, rs6497287, was confirmed to be most strongly associated with more aggressive (P(discovery) = 5.20 x 10(-5), P(validation) = 0.004) than less aggressive disease (P = 0.14). Another SNP on 3q26, rs3774315, was found to be associated with prostate cancer risk; however, the association was not stronger for more aggressive disease. Conclusions: This study provides suggestive evidence for a genetic predisposition to more aggressive prostate cancer and highlights the fact that larger studies are warranted to confirm this supposition and identify further risk variants. Impact: These findings raise the possibility that assessment of genetic variation may one day be useful to discern men at higher risk for developing clinically significant prostate cancer. Cancer Epidemiol Biomarkers Prev; 20(6); 1196-203. (C)2011 AACR. C1 [FitzGerald, Liesel M.; Kolb, Suzanne; Holt, Sarah K.; Feng, Ziding; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Conomos, Matthew P.; Levine, David] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Kwon, Erika M.; Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Kwon, Erika M.] Johns Hopkins Univ, Sch Med, Program Human Genet & Mol Biol, Baltimore, MD USA. RP Stanford, JL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, M4-B874,POB 19024, Seattle, WA 98109 USA. EM jstanfor@fhcrc.org OI Ostrander, Elaine/0000-0001-6075-9738 FU National Cancer Institute, NIH [RO1 CA056678, R01 CA092579, R03 CA121871, R03 CA137799, GM T32 81062, HG U01 004464, P50 CA097186]; Fred Hutchinson Cancer Research Center; National Human Genome Research Institute; Prostate Cancer Foundation FX This work was partially supported by grants RO1 CA056678 (J.L. Stanford), R01 CA092579 (J.L. Stanford), R03 CA121871 (J.L. Stanford), R03 CA137799 (J.L. Stanford), GM T32 81062 (M.P. Conomos), HG U01 004464 (D. Levine), and P50 CA097186 (J.L. Stanford and L.M. FitzGerald) from the National Cancer Institute, NIH. Additional support was provided by the Fred Hutchinson Cancer Research Center, the Intramural Program of the National Human Genome Research Institute, and the Prostate Cancer Foundation Young Investigator Award Grant (S.K. Holt). NR 50 TC 31 Z9 32 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2011 VL 20 IS 6 BP 1196 EP 1203 DI 10.1158/1055-9965.EPI-10-1299 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 773LK UT WOS:000291308600018 PM 21467234 ER PT J AU Wentzensen, IM Mirabello, L Pfeiffer, RM Savage, SA AF Wentzensen, Ingrid M. Mirabello, Lisa Pfeiffer, Ruth M. Savage, Sharon A. TI The Association of Telomere Length and Cancer: a Meta-analysis SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID INCIDENT COLORECTAL-CARCINOMA; BREAST-CANCER; CIGARETTE-SMOKING; BLOOD-CELLS; DYSKERATOSIS-CONGENITA; PREDISPOSITION FACTOR; QUANTITATIVE PCR; BLADDER-CANCER; INCREASED RISK; DNA-CONTENT AB Background: Telomeres shorten with each cell division and are essential for chromosomal stability. Short telomeres in surrogate tissues (e. g., blood cells) are associated with increased cancer risk in several case-control studies, but findings are inconsistent in prospective studies. Methods: We systematically reviewed studies published prior to August 30, 2010, on the association between telomere length (TL) in surrogate tissues and cancer. There were 27 reports on 13 cancers and/or incident cancer investigating this association. The majority, 16, were retrospective case-control studies, 11 were prospective studies. Meta-analyses were conducted to determine ORs and 95% CIs for these studies. Results: Studies on bladder, esophageal, gastric, head and neck, ovarian, renal, and overall incident cancer found associations between short telomeres and these cancers. Non-Hodgkin lymphoma, breast, lung, and colorectal cancer reports were inconsistent. Single studies on endometrial, prostate, and skin cancers were null. In a random-effects meta-analysis, short TL was significantly associated with cancer in retrospective studies (pooled OR for the shortest TL quartile compared with the longest: 2.9, 95% CI: 1.75-4.8, P < 0.0001). The pooled OR for prospective studies was 1.16 (95% CI: 0.87-1.54, P = 0.32). All studies combined yielded a pooled OR of 1.96 (95% CI: 1.37-2.81, P = 0.0001) for the association of short TL and cancer. Conclusion and Impact: There is suggestive evidence that short surrogate tissue TL is associated with cancer; the strongest evidence exists for bladder, esophageal, gastric, and renal cancers. Additional prospective studies with consistent methodology are needed to confirm this hypothesis. Cancer Epidemiol Biomarkers Prev; 20(6); 1238-50. (C)2011 AACR. C1 [Wentzensen, Ingrid M.; Mirabello, Lisa; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS-7018, Rockville, MD 20852 USA. EM savagesh@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services FX This work was supported by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services. NR 63 TC 169 Z9 169 U1 1 U2 32 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 JUN PY 2011 VL 20 IS 6 BP 1238 EP 1250 DI 10.1158/1055-9965.EPI-11-0005 PG 13 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 773LK UT WOS:000291308600023 PM 21467229 ER PT J AU Sinicrope, FA Broaddus, R Joshi, N Gerner, E Half, E Kirsch, I Lewin, J Morlan, B Hong, WK AF Sinicrope, Frank A. Broaddus, Russell Joshi, Nina Gerner, Eugene Half, Elizabeth Kirsch, Ilan Lewin, Jan Morlan, Bruce Hong, Waun Ki TI Evaluation of Difluoromethylornithine for the Chemoprevention of Barrett's Esophagus and Mucosal Dysplasia SO CANCER PREVENTION RESEARCH LA English DT Article ID PRODUCT OTOACOUSTIC EMISSIONS; SPORADIC COLORECTAL ADENOMAS; ALPHA-DIFLUOROMETHYLORNITHINE; ORNITHINE-DECARBOXYLASE; CANCER-CELLS; POLYAMINE CONTENTS; HEARING-LOSS; CYCLIN-E; EXPRESSION; ADENOCARCINOMA AB Patients with Barrett's esophagus (BE) and dysplasia are candidates for chemopreventive strategies to reduce cancer risk. We determined the effects of difluoromethylornithine (DMFO) on mucosal polyamines, gene expression, and histopathology in BE. Ten patients with BE and low-grade dysplasia participated in a single-arm study of DFMO (0.5 g/m(2)/d) given continuously for 6 months. Esophagoscopy with biopsies was conducted at baseline, 3, 6, and 12 months. Dysplasia was graded by a gastrointestinal pathologist. Audiology was assessed (at baseline and at 6 months). Mucosal polyamines were measured by high-performance liquid chromatography. Microarray-based gene expression was analyzed using a cDNA two-color chip. DFMO suppressed levels of the polyamines putrescine (P = 0.02) and spermidine (P = 0.02) and the spermidine/spermine ratio (P < 0.01) in dysplastic BE (6 months vs. baseline) that persisted at 6 months following drug cessation. Among the top 25 modulated genes, we found those regulating p53-mediated cell signaling (RPL11), cell-cycle regulation (cyclin E2), and cell adhesion and invasion (Plexin1). DFMO downregulated Kruppel-like factor 5 (KLF5), a transcription factor promoting cell proliferation, and suppressed RFC5 whose protein interacts with proliferating cell nuclear antigen. Histopathology showed regression of dysplasia (n = 1), stable disease (n = 8), and progression to high-grade dysplasia (n = 1). Polyamines were suppressed in the responder to a greater extent than in stable cases. DFMO was well tolerated, and one patient had subclinical, unilateral ototoxicity. DFMO suppressed mucosal polyamines and modulated genes that may be mechanistically related to its chemopreventive effect. Further study of DFMO for the chemoprevention of esophageal cancer in BE patients is warranted. Cancer Prev Res; 4(6); 829-39. (C) 2011 AACR. C1 [Broaddus, Russell; Half, Elizabeth; Lewin, Jan; Hong, Waun Ki] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Joshi, Nina; Kirsch, Ilan] NCI, Bethesda, MD 20892 USA. [Gerner, Eugene] Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. [Sinicrope, Frank A.; Morlan, Bruce] Mayo Clin, Rochester, MN 55905 USA. RP Sinicrope, FA (reprint author), Mayo Clin, 200 1st St SW,Guggenheim 10, Rochester, MN 55905 USA. EM sinicrope.frank@mayo.edu FU Ilex Pharmaceuticals FX This study was supported in part by Ilex Pharmaceuticals. NR 51 TC 11 Z9 11 U1 2 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 JUN PY 2011 VL 4 IS 6 BP 829 EP 839 DI 10.1158/1940-6207.CAPR-10-0243 PG 11 WC Oncology SC Oncology GA 771ZR UT WOS:000291199700008 PM 21636549 ER PT J AU Permuth-Wey, J Kim, D Tsai, YY Lin, HY Chen, YA Barnholtz-Sloan, J Birrer, MJ Bloom, G Chanock, SJ Chen, ZH Cramer, DW Cunningham, JM Dagne, G Ebbert-Syfrett, J Fenstermacher, D Fridley, BL Garcia-Closas, M Gayther, SA Ge, W Gentry-Maharaj, A Gonzalez-Bosquet, J Goode, EL Iversen, E Jim, H Kong, W McLaughlin, J Menon, U Monteiro, ANA Narod, SA Pharoah, PDP Phelan, CM Qu, XT Ramus, SJ Risch, H Schildkraut, JM Song, HL Stockwell, H Sutphen, R Terry, KL Tyrer, J Vierkant, RA Wentzensen, N Lancaster, JM Cheng, JQ Sellers, TA AF Permuth-Wey, Jennifer Kim, Donghwa Tsai, Ya-Yu Lin, Hui-Yi Chen, Y. Ann Barnholtz-Sloan, Jill Birrer, Michael J. Bloom, Gregory Chanock, Stephen J. Chen, Zhihua Cramer, Daniel W. Cunningham, Julie M. Dagne, Getachew Ebbert-Syfrett, Judith Fenstermacher, David Fridley, Brooke L. Garcia-Closas, Montserrat Gayther, Simon A. Ge, William Gentry-Maharaj, Aleksandra Gonzalez-Bosquet, Jesus Goode, Ellen L. Iversen, Edwin Jim, Heather Kong, William McLaughlin, John Menon, Usha Monteiro, Alvaro N. A. Narod, Steven A. Pharoah, Paul D. P. Phelan, Catherine M. Qu, Xiaotao Ramus, Susan J. Risch, Harvey Schildkraut, Joellen M. Song, Honglin Stockwell, Heather Sutphen, Rebecca Terry, Kathryn L. Tyrer, Jonathan Vierkant, Robert A. Wentzensen, Nicolas Lancaster, Johnathan M. Cheng, Jin Q. Sellers, Thomas A. CA OCAC TI LIN28B Polymorphisms Influence Susceptibility to Epithelial Ovarian Cancer SO CANCER RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; MICRORNA-RELATED GENES; RISK; LOCI; CARCINOMA; VARIANTS; PATHWAYS; IDENTIFICATION; TRANSFORMATION; METAANALYSIS AB Defective microRNA (miRNA) biogenesis contributes to the development and progression of epithelial ovarian cancer (EOC). In this study, we examined the hypothesis that single nucleotide polymorphisms (SNP) in miRNA biogenesis genes may influence EOC risk. In an initial investigation, 318 SNPs in 18 genes were evaluated among 1,815 EOC cases and 1,900 controls, followed up by a replicative joint meta-analysis of data from an additional 2,172 cases and 3,052 controls. Of 23 SNPs from 9 genes associated with risk (empirical P < 0.05) in the initial investigation, the meta-analysis replicated 6 SNPs from the DROSHA, FMR1, LIN28, and LIN28B genes, including rs12194974 (G>A), an SNP in a putative transcription factor binding site in the LIN28B promoter region (summary OR = 0.90, 95% CI: 0.82-0.98; P = 0.015) which has been recently implicated in age of menarche and other phenotypes. Consistent with reports that LIN28B overexpression in EOC contributes to tumorigenesis by repressing tumor suppressor let-7 expression, we provide data from luciferase reporter assays and quantitative RT-PCR to suggest that the inverse association among rs12194974 A allele carriers may be because of reduced LIN28B expression. Our findings suggest that variants in LIN28B and possibly other miRNA biogenesis genes may influence EOC susceptibility. Cancer Res; 71(11); 3896-903. (C) 2011 AACR. C1 [Permuth-Wey, Jennifer; Tsai, Ya-Yu; Phelan, Catherine M.; Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Canc Epidemiol Program, Div Populat Sci, Tampa, FL 33682 USA. [Kim, Donghwa; Kong, William; Cheng, Jin Q.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Interdisciplinary Oncol, Tampa, FL 33682 USA. [Lin, Hui-Yi; Chen, Y. Ann] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Biostat, Tampa, FL 33682 USA. [Bloom, Gregory; Chen, Zhihua; Fenstermacher, David; Ge, William; Qu, Xiaotao] Univ S Florida, H Lee Moffitt Canc Ctr, Dept iomed Informat, Tampa, FL 33682 USA. [Ebbert-Syfrett, Judith; Gonzalez-Bosquet, Jesus; Lancaster, Johnathan M.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Womens Oncol, Tampa, FL 33682 USA. [Jim, Heather] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Hlth Outcomes & Behav, Tampa, FL 33682 USA. [Permuth-Wey, Jennifer; Dagne, Getachew; Stockwell, Heather] Univ S Florida, Dept Epidemiol & Biostat, Coll Publ Hlth, Tampa, FL 33682 USA. [Sutphen, Rebecca] Univ S Florida, Pediat Epidemiol Ctr, Coll Med, Tampa, FL 33682 USA. Case Sch Med, Case Comprehens Canc Ctr, Cleveland, OH USA. [Birrer, Michael J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barnholtz-Sloan, Jill; Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Epidemiol Ctr, Boston, MA 02115 USA. [Chanock, Stephen J.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Cunningham, Julie M.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Fridley, Brooke L.; Goode, Ellen L.; Vierkant, Robert A.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Garcia-Closas, Montserrat] UCL, EGA Inst Womens Hlth, Inst Canc Res, Sect Epidemiol, London, England. [Garcia-Closas, Montserrat] UCL, EGA Inst Womens Hlth, Inst Canc Res, Sect Genet, London, England. [Garcia-Closas, Montserrat] UCL, EGA Inst Womens Hlth, Breakthrough Breast Canc Res Ctr, London, England. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, EGA Inst Womens Hlth, Dept Gynecol Oncol, London, England. [Gayther, Simon A.; Ramus, Susan J.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Iversen, Edwin] Duke Univ, Dept Stat Sci, Durham, NC USA. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [McLaughlin, John] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Narod, Steven A.] Ctr Res Womens Hlth, Toronto, ON, Canada. [Pharoah, Paul D. P.; Song, Honglin; Tyrer, Jonathan] Univ Cambridge, Dept Oncol, Cambridge, England. [Risch, Harvey] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. RP Sellers, TA (reprint author), MRC CANCONT, Moffitt Res Inst, Dept Epidemiol & Genet, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM thomas.sellers@moffitt.org RI McLaughlin, John/E-4577-2013; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; OI Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; Monteiro, Alvaro/0000-0002-8448-4801; Vierkant, Robert/0000-0001-6242-5221; Ramus, Susan/0000-0003-0005-7798 FU Moffitt Cancer Center/University of South Florida; Cancer Center [P30-CA0762-92]; Mayo Foundation; American Cancer Society [CRTG-00-196-01-CCE]; Advanced Cancer Detection Center, Department of Defense [DAMD-17-98-1-8659]; Canadian Cancer Society; NIH [R01-CA-63682, R01-CA-63678]; National Cancer Institute [P30-CA-15083]; NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Center for Cancer Research; Cancer Research U.K.; Eve Appeal; OAK Foundation; Department of Health's NIHR Biomedical Research Centre; [R01-CA-114343]; [R01-CA114343-S1]; [R01-CA-122443]; [P50-CA-136393]; [R01-CA-76016]; [R01-CA-106414]; [CA-54419]; [P50 CA105009] FX The genotyping, bioinformatic, and biostatistical data analysis for stage 1 was supported by R01-CA-114343 and R01-CA114343-S1 and the Moffitt Cancer Center/University of South Florida Anna Valentine Fund and Cancer Center Support Grant P30-CA0762-92. The MAY study is supported by R01-CA-122443 and P50-CA-136393 and funding from the Mayo Foundation. The NCO study is supported by R01-CA-76016. The TBO study is supported by R01-CA-106414, the American Cancer Society (CRTG-00-196-01-CCE), and the Advanced Cancer Detection Center Grant, Department of Defense (DAMD-17-98-1-8659). The TOR study is supported by grants from the Canadian Cancer Society and the NIH (R01-CA-63682 and R01-CA-63678). The Mayo Clinic Genotyping Shared Resource is supported by the National Cancer Institute (P30-CA-15083).; Of studies that participated in stage 2, the NEC study is supported by grants CA-54419 and P50 CA105009. The POL study was supported by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the Center for Cancer Research. The SEA study is funded by a program grant from Cancer Research U.K. The UKO study is supported by funding from Cancer Research U.K., the Eve Appeal, and the OAK Foundation. Some of this work was undertaken at UCLH/UCL, who received some funding from the Department of Health's NIHR Biomedical Research Centre funding scheme. U.K. genotyping and data analysis was supported by a project grant from Cancer Research U.K. U.K. studies also make use of data generated by the Wellcome Trust Case-Control consortium. A list of investigators who contributed to the generation of data is available at www.wtccc.org.uk. NR 40 TC 50 Z9 52 U1 0 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2011 VL 71 IS 11 BP 3896 EP 3903 DI 10.1158/0008-5472.CAN-10-4167 PG 8 WC Oncology SC Oncology GA 771JR UT WOS:000291153500019 PM 21482675 ER PT J AU Liu, YF Ye, YH AF Liu, Yanfen Ye, Yihong TI Proteostasis regulation at the endoplasmic reticulum: a new perturbation site for targeted cancer therapy SO CELL RESEARCH LA English DT Review DE retrotranslocation/ERAD/dislocation; ER stress/UPR; proteasome; BH3-only protein; IRE1; PERK; ubiquitin; p97/Cdc48; targeted cancer therapy; bortezomib/Velcade ID UNFOLDED-PROTEIN RESPONSE; ER-ASSOCIATED DEGRADATION; VALOSIN-CONTAINING PROTEIN; MANTLE-CELL LYMPHOMA; E3 UBIQUITIN LIGASE; NF-KAPPA-B; DEUBIQUITINATING ENZYME ATAXIN-3; SIGNAL PEPTIDE PEPTIDASE; STRESS-INDUCED APOPTOSIS; RECOGNIZES SUGAR CHAINS AB To deal with the constant challenge of protein misfolding in the endoplasmic reticulum (ER), eukaryotic cells have evolved an ER protein quality control (ERQC) mechanism that is integrated with an adaptive stress response. The ERQC pathway is comprised of factors residing in the ER lumen that function in the identification and retention of aberrantly folded proteins, factors in the ER membrane for retrotranslocation of misfolded polypeptides, and enzymes in the cytosol that degrade retrotranslocated proteins. The integrated stress response (termed ER stress or unfolded protein response, UPR) contains several signaling branches elicited from the ER membrane, which fine-tune the rate of protein synthesis and entry into the ER to match the ER folding capacity. The fitness of the cell, particularly those bearing a high secretory burden, is critically dependent on functional integrity of the ER, which in turn relies on these stress-attenuating mechanisms to maintain protein homeostasis, or proteostasis. Aberrant proteostasis can trigger cellular apoptosis, making these adaptive stress response systems attractive targets for perturbation in treatment of cell malignancies. Here, we review our current understanding of how the cell preserves ER proteostasis and discuss how we may harness the mechanistic information on this process to develop new cancer therapeutics. C1 [Liu, Yanfen; Ye, Yihong] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov FU NIH; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX The authors' research is supported by the NIH intramural AIDS Targeted Antiviral Program (IATAP) and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). We thank Michael Krause (NIDDK) for critical reading of the manuscript. We also thank the Developmental Therapeutics Program (DTP)/Division of Cancer Treatment and Diagnosis (DCTD) at National Cancer Institute (NCI) (http://dtp.cancer.gov) for testing compounds in the NCI 60 cancer cell lines. We apologize for not being able to cite all the relevant publications due to space limits. NR 197 TC 41 Z9 41 U1 1 U2 12 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 EI 1748-7838 J9 CELL RES JI Cell Res. PD JUN PY 2011 VL 21 IS 6 BP 867 EP 883 DI 10.1038/cr.2011.75 PG 17 WC Cell Biology SC Cell Biology GA 772AK UT WOS:000291201600004 PM 21537343 ER PT J AU Mossoba, ME Onda, M Taylor, J Massey, PR Treadwell, S Sharon, E Hassan, R Pastan, I Fowler, DH AF Mossoba, Miriam E. Onda, Masanori Taylor, Justin Massey, Paul R. Treadwell, Shirin Sharon, Elad Hassan, Raffit Pastan, Ira Fowler, Daniel H. TI Pentostatin Plus Cyclophosphamide Safely and Effectively Prevents Immunotoxin Immunogenicity in Murine Hosts SO CLINICAL CANCER RESEARCH LA English DT Article ID STEM-CELL TRANSPLANTATION; PHASE-I TRIAL; ANTI-MESOTHELIN IMMUNOTOXIN; RECOMBINANT IMMUNOTOXIN; T-CELL; RFB4(DSFV)-PE38 BL22; DEAMINASE DEFICIENCY; ANTITUMOR-ACTIVITY; EXPRESSION; LEUKEMIA AB Purpose: The success of immunotoxin therapy of cancer is limited by host production of neutralizing antibodies, which are directed toward the Pseudomonas exotoxin A (PE) component. In this proof-of-principle study using a well-established murine model, we hypothesized that a newly developed immune depletion regimen consisting of pentostatin plus cyclophosphamide would abrogate anti-immunotoxin reactivity. Experimental Design: BALB/c hosts were injected weekly with recombinant immunotoxin (RIT) SS1P, which is an antimesothelin Fv antibody fragment genetically fused to a 38 kDa portion of PE, and has been evaluated in clinical trials. Experimental cohorts received induction chemotherapy consisting of pentostatin (P) plus cyclophosphamide (C) prior to initial RIT exposure; some cohorts received further maintenance PC therapy of varying intensity just prior to each weekly RIT challenge. Cohorts were monitored for T, B, myeloid cell depletion, and for total anti-SS1P antibody (Ab) formation. Results: Controls uniformly developed anti-SS1P Ab after the third RIT exposure. Induction PC therapy reduced the frequency of hosts with anti-SS1P Ab. Abrogation of antibody generation was improved by maintenance PC therapy: nearly 100% of recipients of intensive PC maintenance were free of anti-SS1P Ab after 9 weekly RIT doses. The most effective PC regimen yielded the greatest degree of host B-cell depletion, moderate T-cell depletion, and minimal myeloid cell depletion. Conclusions: Induction and maintenance PC chemotherapy safely prevented anti-immunotoxin antibody formation with uniform efficacy. These data suggest that immunotoxin therapy might be used in combination with pentostatin plus cyclophosphamide chemotherapy to improve the targeted therapy of cancer. Clin Cancer Res; 17(11); 3697-705. (C)2011 AACR. C1 [Mossoba, Miriam E.; Taylor, Justin; Massey, Paul R.; Treadwell, Shirin; Fowler, Daniel H.] NIH, Ctr Canc Res, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Onda, Masanori; Sharon, Elad; Hassan, Raffit; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Fowler, DH (reprint author), NIH, Ctr Canc Res, Expt Transplantat & Immunol Branch, Bldg 10, Bethesda, MD 20892 USA. EM fowlerda@mail.nih.gov FU Intramural NIH HHS [Z01 SC010288-11] NR 47 TC 19 Z9 19 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2011 VL 17 IS 11 BP 3697 EP 3705 DI 10.1158/1078-0432.CCR-11-0493 PG 9 WC Oncology SC Oncology GA 772AC UT WOS:000291200800020 PM 21521777 ER PT J AU Rimsza, LM Wright, G Schwartz, M Chan, WC Jaffe, ES Gascoyne, RD Campo, E Rosenwald, A Ott, G Cook, JR Tubbs, RR Braziel, RM Delabie, J Miller, TP Staudt, LM AF Rimsza, Lisa M. Wright, George Schwartz, Mark Chan, Wing C. Jaffe, Elaine S. Gascoyne, Randy D. Campo, Elias Rosenwald, Andreas Ott, German Cook, James R. Tubbs, Raymond R. Braziel, Rita M. Delabie, Jan Miller, Tom P. Staudt, Louis M. TI Accurate Classification of Diffuse Large B-Cell Lymphoma into Germinal Center and Activated B-Cell Subtypes Using a Nuclease Protection Assay on Formalin-Fixed, Paraffin-Embedded Tissues SO CLINICAL CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION; SUBGROUPS; SURVIVAL; PREDICTION; MICROARRAY; PROFILES AB Classification of diffuse large B-cell lymphoma (DLBCL) into cell-of-origin (COO) subtypes based on gene expression profiles has well-established prognostic value. These subtypes, termed germinal center B cell (GCB) and activated B cell (ABC) also have different genetic alterations and overexpression of different pathways that may serve as therapeutic targets. Thus, accurate classification is essential for analysis of clinical trial results and planning new trials by using targeted agents. The current standard for COO classification uses gene expression profiling (GEP) of snap frozen tissues, and a Bayesian predictor algorithm. However, this is generally not feasible. In this study, we investigated whether the qNPA technique could be used for accurate classification of COO by using formalin-fixed, paraffin-embedded (FFPE) tissues. We analyzed expression levels of 14 genes in 121 cases of R-CHOP-treated DLBCL that had previously undergone GEP by using the Affymetrix U133 Plus 2.0 microarray and had matching FFPE blocks. Results were evaluated by using the previously published algorithm with a leave-one-out cross-validation approach. These results were compared with COO classification based on frozen tissue GEP profiles. For each case, a probability statistic was generated indicating the likelihood that the classification by using qNPA was accurate. When data were dichotomized into GCB or non-GCB, overall accuracy was 92%. The qNPA technique accurately categorized DLBCL into GCB and ABC subtypes, as defined by GEP. This approach is quantifiable, applicable to FFPE tissues with no technical failures, and has potential for significant impact on DLBCL research and clinical trial development. Clin Cancer Res; 17(11); 3727-32. (C)2011 AACR. C1 [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. [Schwartz, Mark; Staudt, Louis M.] High ThroughPut Genom, Tucson, AZ USA. [Miller, Tom P.] Arizona Canc Ctr, Tucson, AZ USA. [Wright, George; Jaffe, Elaine S.] NIH, Metab Branch, Bethesda, MD 20892 USA. [Chan, Wing C.] Univ Nebraska, Dept Pathol, Omaha, NE 68182 USA. [Cook, James R.; Tubbs, Raymond R.] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44106 USA. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Campo, Elias] Univ Barcelona, Dept Pathol, Barcelona, Spain. [Rosenwald, Andreas] Univ Wurzburg, Dept Pathol, D-8700 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Inst Pathol, Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-7000 Stuttgart, Germany. [Delabie, Jan] Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. RP Rimsza, LM (reprint author), Univ Arizona, Dept Pathol, 1501 N Campbell Ave,Room 5208A,POB 245043, Tucson, AZ 85724 USA. EM lrimsza@email.arizona.edu OI Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301; Campo, elias/0000-0001-9850-9793 FU NCI NIH HHS [U01 CA084967-01] NR 21 TC 32 Z9 33 U1 2 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2011 VL 17 IS 11 BP 3727 EP 3732 DI 10.1158/1078-0432.CCR-10-2573 PG 6 WC Oncology SC Oncology GA 772AC UT WOS:000291200800023 PM 21364035 ER PT J AU Pharoah, PDP Palmieri, RT Ramus, SJ Gayther, SA Andrulis, IL Anton-Culver, H Antonenkova, N Antoniou, AC Goldgar, D Beattie, MS Beckmann, MW Birrer, MJ Bogdanova, N Bolton, KL Brewster, W Brooks-Wilson, A Brown, R Butzow, R Caldes, T Caligo, MA Campbell, I Chang-Claude, J Chen, YA Cook, LS Couch, FJ Cramer, DW Cunningham, JM Despierre, E Doherty, JA Dork, T Durst, M Eccles, DM Ekici, AB Easton, D Fasching, PA de Fazio, A Fenstermacher, DA Flanagan, JM Fridley, BL Friedman, E Gao, B Sinilnikova, O Gentry-Maharaj, A Godwin, AK Goode, EL Goodman, MT Gross, J Hansen, TVO Harnett, P Rookus, M Heikkinen, T Hein, R Hogdall, C Hogdall, E Iversen, ES Jakubowska, A Johnatty, SE Karlan, BY Kauff, ND Kaye, SB Chenevix-Trench, G Kelemen, LE Kiemeney, LA Kjaer, SK Lambrechts, D LaPolla, JP Lazaro, C Le, ND Leminen, A Leunen, K Levine, DA Lu, Y Lundvall, L Macgregor, S Marees, T Massuger, LF McLaughlin, JR Menon, U Montagna, M Moysich, KB Narod, SA Nathanson, KL Nedergaard, L Ness, RB Nevanlinna, H Nickels, S Osorio, A Paul, J Pearce, CL Phelan, CM Pike, MC Radice, P Rossing, MA Schildkraut, JM Sellers, TA Singer, CF Song, HL Stram, DO Sutphen, R Lindblom, A Terry, KL Tsai, YY van Altena, AM Vergote, I Vierkant, RA Vitonis, AF Walsh, C Wang-Gohrke, S Wappenschmidt, B Wu, AH Ziogas, A Berchuck, A Risch, HA AF Pharoah, Paul D. P. Palmieri, Rachel T. Ramus, Susan J. Gayther, Simon A. Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia Antoniou, Antonis C. Goldgar, David Beattie, Mary S. Beckmann, Matthias W. Birrer, Michael J. Bogdanova, Natalia Bolton, Kelly L. Brewster, Wendy Brooks-Wilson, Angela Brown, Robert Butzow, Ralf Caldes, Trinidad Caligo, Maria Adelaide Campbell, Ian Chang-Claude, Jenny Chen, Y. Ann Cook, Linda S. Couch, Fergus J. Cramer, Daniel W. Cunningham, Julie M. Despierre, Evelyn Doherty, Jennifer A. Doerk, Thilo Duerst, Matthias Eccles, Diana M. Ekici, Arif B. Easton, Douglas Fasching, Peter A. de Fazio, Anna Fenstermacher, David A. Flanagan, James M. Fridley, Brooke L. Friedman, Eitan Gao, Bo Sinilnikova, Olga Gentry-Maharaj, Aleksandra Godwin, Andrew K. Goode, Ellen L. Goodman, Marc T. Gross, Jenny Hansen, Thomas V. O. Harnett, Paul Rookus, Matti Heikkinen, Tuomas Hein, Rebecca Hogdall, Claus Hogdall, Estrid Iversen, Edwin S. Jakubowska, Anna Johnatty, Sharon E. Karlan, Beth Y. Kauff, Noah D. Kaye, Stanley B. Chenevix-Trench, Georgia Kelemen, Linda E. Kiemeney, Lambertus A. Kjaer, Susanne Krueger Lambrechts, Diether LaPolla, James P. Lazaro, Conxi Le, Nhu D. Leminen, Arto Leunen, Karin Levine, Douglas A. Lu, Yi Lundvall, Lene Macgregor, Stuart Marees, Tamara Massuger, Leon F. McLaughlin, John R. Menon, Usha Montagna, Marco Moysich, Kirsten B. Narod, Steven A. Nathanson, Katherine L. Nedergaard, Lotte Ness, Roberta B. Nevanlinna, Heli Nickels, Stefan Osorio, Ana Paul, Jim Pearce, Celeste Leigh Phelan, Catherine M. Pike, Malcolm C. Radice, Paolo Rossing, Mary Anne Schildkraut, Joellen M. Sellers, Thomas A. Singer, Christian F. Song, Honglin Stram, Daniel O. Sutphen, Rebecca Lindblom, Annika Terry, Kathryn L. Tsai, Ya-Yu van Altena, Anne M. Vergote, Ignace Vierkant, Robert A. Vitonis, Allison F. Walsh, Christine Wang-Gohrke, Shan Wappenschmidt, Barbara Wu, Anna H. Ziogas, Argyrios Berchuck, Andrew Risch, Harvey A. CA BCFR Investigators EMBRACE Investigators GEMO Study Collaborators HEBON Investigators KConFab Investigators Consortium Investigators Modifiers SWE-BRCA Investigators Ovarian Canc Assoc Consortium TI The Role of KRAS rs61764370 in Invasive Epithelial Ovarian Cancer: Implications for Clinical Testing SO CLINICAL CANCER RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; MUTATION CARRIERS; BREAST-CANCER; RISK; CONSORTIUM; SURVIVAL AB Purpose: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3'-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design: Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. Results: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95-1.10), serous EOC (OR = 1.08, 95% CI: 0.98-1.18), familial EOC (OR = 1.09, 95% CI: 0.78-1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88-1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99-1.22), among serous cases (HR = 1.12, 95% CI = 0.99-1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93-1.52). Conclusions: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted. Clin Cancer Res; 17(11); 3742-50. (C)2011 AACR. C1 [Risch, Harvey A.] Yale Univ, Dept Epidemiol & Publ Hlth, Sch Publ Hlth, Sch Med, New Haven, CT 06520 USA. [Wappenschmidt, Barbara] Univ Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Wappenschmidt, Barbara] Univ Cologne, CIO, Cologne, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Lindblom, Annika; SWE-BRCA Investigators] Karolinska Univ Hosp, Stockholm, Sweden. [Singer, Christian F.] Med Univ Vienna, Div Special Gynecol, Vienna, Austria. [Radice, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Radice, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Paul, Jim] Univ Glasgow, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland. [Ness, Roberta B.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Nathanson, Katherine L.] Univ Penn, Sch Med, Dept Med, Med Genet & Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Montagna, Marco] IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy. [Lazaro, Conxi] Inst Catalan Oncol, Hereditary Canc Program, Barcelona, Spain. [LaPolla, James P.] Bayfront Med Ctr, Obstet & Gynecol Residency Program, St Petersburg, FL USA. [LaPolla, James P.] Womens Canc Associates, St Petersburg, FL USA. [Lambrechts, Diether] Vesalius Res Ctr VIB, Louvain, Belgium. [Lambrechts, Diether] Univ Leuven, Louvain, Belgium. [Massuger, Leon F.; van Altena, Anne M.] Radboud Univ Nijmegen, Med Ctr, Dept Gynecol, NL-6525 ED Nijmegen, Netherlands. [Kiemeney, Lambertus A.; Marees, Tamara] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & HTA, NL-6525 ED Nijmegen, Netherlands. [Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB, Canada. [Chenevix-Trench, Georgia; KConFab Investigators] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Kaye, Stanley B.] Inst Canc Res, Med Sect, Sutton, Surrey, England. [Kauff, Noah D.] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, New York, NY 10021 USA. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Johnatty, Sharon E.; Lu, Yi; Macgregor, Stuart; Consortium Investigators Modifiers] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Jakubowska, Anna] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Rookus, Matti; HEBON Investigators] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Nedergaard, Lotte] Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark. [Hogdall, Estrid] Herlev Hosp, Mol Unit, Dept Pathol, Herlev, Denmark. [Hogdall, Estrid; Kjaer, Susanne Krueger] Danish Canc Soc, Inst Canc Epidemiol, Dept Viruses Hormones & Canc, Copenhagen, Denmark. [Hogdall, Claus; Kjaer, Susanne Krueger; Lundvall, Lene] Univ Copenhagen, Rigshosp, Juliane Marie Ctr, Gynecol Clin, DK-2100 Copenhagen, Denmark. [Hansen, Thomas V. O.] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark. [Goodman, Marc T.] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Sinilnikova, Olga; GEMO Study Collaborators] Federat Natl Ctr Lutte Canc, Canc Genet Network Grp Genet & Canc, Lyon, France. [Friedman, Eitan] Chaim Sheba Med Ctr, Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Friedman, Eitan] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [de Fazio, Anna; Gao, Bo; Harnett, Paul] Westmead Hosp, Westmead Millennium Inst, Westmead, NSW 2145, Australia. [de Fazio, Anna; Gao, Bo; Harnett, Paul] Univ Sydney, Westmead Inst Canc Res, Westmead, NSW 2145, Australia. [de Fazio, Anna; Gao, Bo] Westmead Hosp, Dept Gynaecol Oncol, Westmead, NSW 2145, Australia. [Easton, Douglas; EMBRACE Investigators] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge, England. [Eccles, Diana M.] Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England. [Duerst, Matthias] Univ Jena, Clin Obstet & Gynaecol, Jena, Germany. [Doherty, Jennifer A.; Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Despierre, Evelyn; Leunen, Karin; Vergote, Ignace] Univ Leuven, Univ Hosp Leuven, Dept Obstet & Gynaecol, Div Gynaecol Oncol, Leuven, Belgium. [Goode, Ellen L.] Mayo Clin, Coll Med, Div Epidemiol, Rochester, MN USA. [Fridley, Brooke L.; Vierkant, Robert A.] Mayo Clin, Coll Med, Div Biostat, Dept Hlth Sci Res, Rochester, MN USA. [Cunningham, Julie M.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Sutphen, Rebecca] Univ S Florida, Coll Med, Dept Pediat, Tampa, FL 33612 USA. [Chen, Y. Ann; Fenstermacher, David A.; Phelan, Catherine M.; Sellers, Thomas A.; Tsai, Ya-Yu] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stefan] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Campbell, Ian] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [Campbell, Ian] Peter MacCallum Canc Ctr, Ctr Canc Genom & Predict Med, Melbourne, Vic, Australia. [Caligo, Maria Adelaide] Univ Hosp Pisa, Sect Genet Oncol, Pisa, Italy. [Osorio, Ana] Spanish Natl Canc Ctr, Human Canc Genet Programme, Human Genet Grp, Madrid, Spain. [Caldes, Trinidad] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Butzow, Ralf] Univ Helsinki, Dept Pathol, Helsinki, Finland. [Butzow, Ralf; Heikkinen, Tuomas; Leminen, Arto; Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Menon, Usha] UCL, EGA Inst Womens Hlth, Dept Gynaecol Oncol, London, England. [Brown, Robert; Flanagan, James M.; Gentry-Maharaj, Aleksandra] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, Epigenet Unit, London SW7 2AZ, England. [Brooks-Wilson, Angela] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Brewster, Wendy] Univ N Carolina, Sch Med, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Bolton, Kelly L.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bogdanova, Natalia] Hannover Med Sch, Clin Radiat Oncol, D-3000 Hannover, Germany. [Bogdanova, Natalia; Doerk, Thilo] Hannover Med Sch, Clin Obstet & Gynaecol, D-3000 Hannover, Germany. [Cramer, Daniel W.; Terry, Kathryn L.; Vitonis, Allison F.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Birrer, Michael J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Ekici, Arif B.] Friedrich Alexander Univ Erlangen Nuremberg, Inst Human Genet, Erlangen, Bavaria, Germany. [Beckmann, Matthias W.] Univ Hosp Erlangen, Dept Gynecol & Obstet, Erlangen, Germany. [Beattie, Mary S.] Univ Calif San Francisco, Dept Med, Canc Risk Program, San Francisco, CA USA. [Beattie, Mary S.] Univ Calif San Francisco, Dept Epidemiol, Canc Risk Program, San Francisco, CA 94143 USA. [Beattie, Mary S.] Univ Calif San Francisco, Dept Biostat, Canc Risk Program, San Francisco, CA 94143 USA. [Goldgar, David; BCFR Investigators] NCI, Breast Canc Family Registry, Epidemiol & Genet Res Program, DCCPS, Rockville, MD USA. [Antonenkova, Natalia] Byelorussian Inst Oncol & Med Radiol Aleksandrov, Minsk, Byelarus. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Andrulis, Irene L.] Canc Care Ontario, Ontario Canc Genet Network, Toronto, ON, Canada. [Andrulis, Irene L.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, New York, NY USA. [Gross, Jenny; Karlan, Beth Y.; Walsh, Christine] Cedars Sinai Med Ctr, Samual Oschin Comprehens Canc Inst, Womens Canc Res Inst, Los Angeles, CA 90048 USA. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Ramus, Susan J.; Gayther, Simon A.; Pearce, Celeste Leigh; Pike, Malcolm C.; Stram, Daniel O.; Wu, Anna H.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Ramus, Susan J.; Gayther, Simon A.; Pearce, Celeste Leigh; Pike, Malcolm C.; Stram, Daniel O.; Wu, Anna H.] Univ So Calif, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Palmieri, Rachel T.; Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Pharoah, Paul D. P.; Song, Honglin] Univ Cambridge, Dept Oncol, Cambridge, England. RP Risch, HA (reprint author), Yale Univ, Dept Epidemiol & Publ Hlth, Sch Publ Hlth, Sch Med, 60 Coll St, New Haven, CT 06520 USA. EM harvey.risch@yale.edu RI Tang, Macy/B-9798-2014; Harnett, Paul/D-4090-2014; deFazio, Anna/D-3939-2013; Marees, Tamara/D-9867-2011; Lester, Jenny/B-5933-2012; montagna, marco/E-2225-2012; Verdrengh, Evelien/H-4571-2012; Macgregor, Stuart/C-6442-2009; Ekici, Arif/C-3971-2013; Andrulis, Irene/E-7267-2013; McLaughlin, John/E-4577-2013; Radice, Paolo/O-3119-2013; Kiemeney, Lambertus/D-3357-2009; Brooks-Wilson, Angela/E-9399-2012; Osorio, Ana/I-4324-2014; Massuger, Leon/H-8072-2014; Jakubowska, Anna/O-8050-2014; campbell, Ian/F-6006-2011; Fridley, Brooke/D-8315-2015; van Altena, Anne/B-9824-2016; Dork, Thilo/J-8620-2012; Johnatty, Sharon/R-8890-2016; OI Harnett, Paul/0000-0001-7021-0642; deFazio, Anna/0000-0003-0057-4744; montagna, marco/0000-0002-4929-2150; Macgregor, Stuart/0000-0001-6731-8142; Kiemeney, Lambertus/0000-0002-2368-1326; Brooks-Wilson, Angela/0000-0003-1009-6408; Osorio, Ana/0000-0001-8124-3984; Fridley, Brooke/0000-0001-7739-7956; Johnatty, Sharon/0000-0002-7888-1966; Vierkant, Robert/0000-0001-6242-5221; Nathanson, Katherine/0000-0002-6740-0901; Kjaer, Susanne/0000-0002-8347-1398; Ramus, Susan/0000-0003-0005-7798; Kauff, Noah/0000-0001-7242-6156; Nevanlinna, Heli/0000-0002-0916-2976 FU Ovarian Cancer Research Fund; Breast Cancer Family Registry including Cancer Care Ontario; US NIH [5U01-CA069467, 5U01-CA069398, 5U01-CA069631, 5U01-CA069446, 5U01-CA069417, 5U01-CA069638, N02-PC45022]; National Cancer Plan-Action 29; NIH [5R01-CA054419, 5P50-CA105009, 5R01-CA112523]; Ligue National Contre le Cancer; Association Le cancer du sein, parlonsen; Association for International Cancer Research [AICR-07-0454]; German Federal Ministry of Education and Research; Programme of Clinical Biomedical Research [01 GB 9401]; state of Baden-Wurttemberg through the University of Ulm Medical [P.685]; German Cancer Research Center; Helsinki University Central Hospital; Academy of Finland; Finnish Cancer Society; US Army MRMC [DAMD 17-02-1-0669]; Ovarian Cancer Research Foundation; Roswell Park Alliance Foundation; Cancer Australia [628333]; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; American Cancer Society [SIOP-06-258-01-CCE, CRTG-00-196-01-CCE]; L & S Milken Foundation; Mermaid 1; Danish Cancer Society; National Cancer Institute [5R01-CA061107, 5R01-CA122443, 5R01-CA076016, 5R01-CA058860, 5K07-CA092044]; Radboud University Nijmegen Medical Centre; Canadian Institutes of Health Research (CIHR); Workers' Compensation Board of British Columbia; Cancer Research UK [A6689]; Experimental Cancer Research Centres; Advanced Cancer Detection Center; Department of Defense [DAMD 17-98-1-8659]; Celma Mastry Ovarian Cancer Foundation; Canadian Institutes for Health Research; National Cancer Institute of Canada; Canadian Cancer Society; Lon V Smith Foundation [LVS-39420]; Eve Appeal; OAK Foundation; Department of Health's NIHR Biomedical Research Centre; California Cancer Research Program [00-01389V-20170, 2110200]; California Department of Health Services [050-E8709]; Wellcome Trust [076113]; Breast Cancer Research Foundation; Susan G. Komen for the Cure; Eileen Stein Jacoby Fund; Neve Foundation; Project Hope for Ovarian Cancer Research and Education; Australian National Breast Cancer Foundation; National Health and Medical Research Council of Australia FX The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund. Funding for the individual participating studies was provided by: cooperative agreements with the Breast Cancer Family Registry including Cancer Care Ontario, and US NIH grants 5U01-CA069467, 5U01-CA069398, 5U01-CA069631, 5U01-CA069446, 5U01-CA069417, 5U01-CA069638, and N02-PC45022 (BCFR); the National Cancer Plan-Action 29 for the support of Translational Research (BEL); NIH grants 5R01-CA054419 and 5P50-CA105009 (BWH); NIH grants 5R01-CA112523 and 5R01-CA087538 (DOV); the Ligue National Contre le Cancer, the Association "Le cancer du sein, parlonsen!" and research grant AICR-07-0454 from the Association for International Cancer Research (GEMO); the German Federal Ministry of Education and Research, the Programme of Clinical Biomedical Research grant 01 GB 9401, the state of Baden-Wurttemberg through the University of Ulm Medical Faculty grant P.685, and the German Cancer Research Center (GER); the Helsinki University Central Hospital Research Fund, Academy of Finland and the Finnish Cancer Society (HOC); NIH grants 5R01-CA095023, 5R01-CA126841, and 5R03-CA121881, US Army MRMC grant DAMD 17-02-1-0669, and grants from the Ovarian Cancer Research Foundation and the Roswell Park Alliance Foundation (HOP); grant 628333 from Cancer Australia and grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia (kConFab); American Cancer Society Early Detection Professorship grant SIOP-06-258-01-CCE and the L & S Milken Foundation (LAX); Mermaid 1, The Danish Cancer Society and the National Cancer Institute 5R01-CA061107 (MAL); National Cancer Institute 5R01-CA122443 (MAY); National Cancer Institute 5R01-CA076016 (NCO); an Investment Grant of the Radboud University Nijmegen Medical Centre (NTH); grants from the Canadian Institutes of Health Research (CIHR) and the Workers' Compensation Board of British Columbia (OVA); Cancer Research UK (SEA); Experimental Cancer Research Centres and Cancer Research UK A6689 (SRO); NIH grant 5R01-CA106414, American Cancer Society grant CRTG-00-196-01-CCE and an Advanced Cancer Detection Center Grant, Department of Defense grant DAMD 17-98-1-8659, and funding from the Celma Mastry Ovarian Cancer Foundation (TBO); Canadian Institutes for Health Research, the National Cancer Institute of Canada, the Canadian Cancer Society and the NIH grants 5R01-CA063682 and 5R01-CA063678 (TOR); National Cancer Institute grants 5R01-CA058860 and 5K07-CA092044 and the Lon V Smith Foundation LVS-39420 (UCI); Cancer Research UK, the Eve Appeal, the OAK Foundation and the Department of Health's NIHR Biomedical Research Centre funding scheme (UKO); the California Cancer Research Program grants 00-01389V-20170 and 2110200, NIH grants 5P30-CA014089, 5P01-CA017054, 5R01-CA061132, 5R01-CA063464, N01-PC67010, and 5R03-CA113148, and California Department of Health Services sub-contract 050-E8709 (USC); Wellcome Trust award 076113 (WTCCC). Additional support for the TOR, NCO, MAY, TBO, and NCI studies was provided by NIH grant 5R01-CA114343. The Consortium of Investigators of Modifiers of BRCA1/2 GWAS and its participating studies were funded by: the Breast Cancer Research Foundation, Susan G.; Komen for the Cure, the Ovarian Cancer Research Fund, the Eileen Stein Jacoby Fund, NIH grants 5R01-CA128978 and 1R01-CA140323, Cancer Research UK, he Neve Foundation, Project Hope for Ovarian Cancer Research and Education, the Australian National Breast Cancer Foundation, the National Health and Medical Research Council of Australia. NR 16 TC 31 Z9 33 U1 0 U2 17 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 JUN 1 PY 2011 VL 17 IS 11 BP 3742 EP 3750 DI 10.1158/1078-0432.CCR-10-3405 PG 9 WC Oncology SC Oncology GA 772AC UT WOS:000291200800025 PM 21385923 ER PT J AU Puzanov, I Lee, W Chen, AP Calcutt, MW Hachey, DL Vermeulen, WL Spanswick, VJ Liao, CY Hartley, JA Berlin, JD Rothenberg, ML AF Puzanov, Igor Lee, Wooin Chen, Alice P. Calcutt, M. Wade Hachey, David L. Vermeulen, Wendy L. Spanswick, Victoria J. Liao, Chih-Yi Hartley, John A. Berlin, Jordan D. Rothenberg, Mace L. TI Phase I Pharmacokinetic and Pharmacodynamic Study of SJG-136, a Novel DNA Sequence Selective Minor Groove Cross-linking Agent, in Advanced Solid Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID SPECTRUM ANTITUMOR-ACTIVITY; NSC-694501; POTENT AB Purpose: This phase I study assessed the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SJG-136, a sequence-specific DNA cross-linking agent, in patients with advanced cancer. Experimental Design: In schedule A, seven patients received escalating doses of SJG-136 (6, 12, 24, and 48 mg/m(2)) daily for 5 of 21 days. Blood samples were collected for PK analysis on days 1 and 5 of cycle 1. In schedule B, SJG-136 was given daily for 3 of 21 days (N = 17; doses 20, 25, 30, and 35 mg/m(2)). Blood samples were collected on days 1 and 3 of cycles 1 and 2 for PK and PD analysis. Patients in schedule B received dexamethasone and early diuretic care. Results: Schedule A-dose-limiting toxicities included grade 3 edema, dyspnea, fatigue, and delayed liver toxicity (grade 3-4). PK analysis revealed dose-dependent increases in AUC and C(max). Substantial changes in volume of distribution at steady-state occurred after repeated dosing in some patients prior to the onset of edema. Schedule B-the same toxicities were manageable with steroid premedication and diuretic support. No significant myelosuppression occurred on either schedule. DNA interstrand crosslinks correlated with systemic exposure of SJG-136 following the second dose in cycle 1 and were still detectable immediately before cycle 2. Conclusions: The MTD of SJG-136 in this study was 30 mg/m(2) administered on a daily 3x basis with no myelosuppression effects. Coupled with supportive management, SJG-136 is now advancing to a phase II trial in ovarian cancer. Clin Cancer Res; 17(11); 3794-802. (C)2011 AACR. C1 [Puzanov, Igor] Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Lee, Wooin] Univ Kentucky, Coll Pharm, Lexington, KY USA. [Chen, Alice P.] NCI, CTEP, Bethesda, MD 20892 USA. [Spanswick, Victoria J.; Hartley, John A.] UCL Canc Inst, CRUK Drug DNA Interact Res Grp, London, England. RP Puzanov, I (reprint author), Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Vanderbilt Ingram Canc Ctr, 777 PRB,2220 Pierce Ave, Nashville, TN 37232 USA. EM igor.puzanov@vanderbilt.edu RI Lee, Wooin/K-7789-2012 OI Lee, Wooin/0000-0001-7805-869X FU NIH [UO1 CA099177, M01 RR00095]; National Center for Research Resources (NIH) [1UL1 RR024975]; UCL Experimental Cancer Medicine Centre [CR UK C2259/A9994] FX This work was supported in part by the NIH cooperative agreement award UO1 CA099177, M01 RR00095 (MLR), Vanderbilt CTSA grant 1UL1 RR024975 from the National Center for Research Resources (NIH) and UCL Experimental Cancer Medicine Centre, CR UK C2259/A9994. NR 12 TC 14 Z9 14 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2011 VL 17 IS 11 BP 3794 EP 3802 DI 10.1158/1078-0432.CCR-10-2056 PG 9 WC Oncology SC Oncology GA 772AC UT WOS:000291200800030 PM 21346148 ER PT J AU Wang, RX Schwartzman, LM Memoli, MJ Taubenberger, JK AF Wang, Ruixue Schwartzman, Louis M. Memoli, Matthew J. Taubenberger, Jeffery K. TI Detection of seasonal H3N2 influenza A virus by type-specific TaqMan minor groove binder probe assay SO DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE LA English DT Article DE Influenza A virus; H3N2; Real-time PCR ID RAPID SELECTION; A/H3N2 VIRUS; PCR AB Despite the emergence of the pandemic H1N1 influenza A virus in 2009, seasonal H3N2 viruses continue to co-circulate in the population and may even predominate in the coming influenza season. We describe a specific minor groove binder TaqMan assay for H3N2 viruses with a detection limit of 16.5 standard DNA copies. Published by Elsevier Inc. C1 [Wang, Ruixue; Schwartzman, Louis M.; Memoli, Matthew J.; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU NIH; NIAID FX This work was supported by the intramural research funds of the NIH and the NIAID. NR 12 TC 0 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 0732-8893 J9 DIAGN MICR INFEC DIS JI Diagn. Microbiol. Infect. Dis. PD JUN PY 2011 VL 70 IS 2 BP 281 EP 284 DI 10.1016/j.diagmicrobio.2011.01.012 PG 4 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 771CQ UT WOS:000291135200021 PM 21429691 ER PT J AU Plevka, P Battisti, AJ Junjhon, J Winkler, DC Holdaway, HA Keelapang, P Sittisombut, N Kuhn, RJ Steven, AC Rossmann, MG AF Plevka, Pavel Battisti, Anthony J. Junjhon, Jiraphan Winkler, Dennis C. Holdaway, Heather A. Keelapang, Poonsook Sittisombut, Nopporn Kuhn, Richard J. Steven, Alasdair C. Rossmann, Michael G. TI Maturation of flaviviruses starts from one or more icosahedrally independent nucleation centres SO EMBO REPORTS LA English DT Article DE dengue virus 2; maturation; mosaic; mutants; symmetry ID DENGUE VIRUS; PARTICLES; CLEAVAGE AB Flaviviruses assemble as fusion-incompetent immature particles and subsequently undergo conformational change leading to release of infectious virions. Flavivirus infections also produce combined 'mosaic' particles. Here, using cryo-electron tomography, we report that mosaic particles of dengue virus type 2 had glycoproteins organized into two regions of mature and immature structure. Furthermore, particles of a maturation-deficient mutant had their glycoproteins organized into two regions of immature structure with mismatching icosahedral symmetries. It is therefore apparent that the maturation-related reorganization of the flavivirus glycoproteins is not synchronized across the whole virion, but is initiated from one or more nucleation centres. Similar deviation from icosahedral symmetry might be relevant to the asymmetrical mode of genome packaging and cell entry of other viruses. C1 [Plevka, Pavel; Battisti, Anthony J.; Junjhon, Jiraphan; Holdaway, Heather A.; Kuhn, Richard J.; Rossmann, Michael G.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Junjhon, Jiraphan; Sittisombut, Nopporn] Mahidol Univ, Natl Ctr Genet Engn & Biotechnol,Siriraj Hosp, Natl Sci & Technol Dev Agcy,Off Res & Dev, Med Biotechnol Res Unit,Med Mol Biol Div,Fac Med, Bangkok 10700, Thailand. [Winkler, Dennis C.; Steven, Alasdair C.] Natl Inst Arthrit Musculoskeletal & Skin Dis, Lab Struct Biol Res, NIH, Bethesda, MD 20892 USA. [Keelapang, Poonsook; Sittisombut, Nopporn] Chiang Mai Univ, Fac Med, Dept Microbiol, Chiang Mai 50200, Thailand. RP Rossmann, MG (reprint author), Purdue Univ, Dept Biol Sci, 240 S Martin Jischke Dr, W Lafayette, IN 47907 USA. EM mr@purdue.edu RI Plevka, Pavel/H-8661-2014 OI Plevka, Pavel/0000-0003-4215-3315 FU National Institutes of Health [R01 AI 76331, P01 AI 55672]; Thailand Tropical Diseases Research Program [02-2-DEN-03-003]; Medical Biotechnology Network, National Center for Genetic Engineering and Biotechnology, Thailand; Thailand Research Fund [PHD/0225/2546]; NIAMS FX We thank S. Kelly for help with the preparation of the manuscript. This work was supported by National Institutes of Health grants to M. G. R. (R01 AI 76331) and R.J.K. (P01 AI 55672), as well as the Thailand Tropical Diseases Research Program (02-2-DEN-03-003) and the Medical Biotechnology Network, National Center for Genetic Engineering and Biotechnology, Thailand. J.J. was supported by the Thailand Research Fund through the Royal Golden Jubilee PhD program (PHD/0225/2546). This work was also supported in part by the Intramural Research Program of NIAMS. NR 19 TC 41 Z9 43 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD JUN PY 2011 VL 12 IS 6 BP 602 EP 606 DI 10.1038/embor.2011.75 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 771HQ UT WOS:000291148200023 PM 21566648 ER PT J AU Manini, TM Patel, KV Bauer, DC Ziv, E Schoeller, DA Mackey, DC Li, R Newman, AB Nalls, M Zmuda, JM Harris, TB AF Manini, T. M. Patel, K. V. Bauer, D. C. Ziv, E. Schoeller, D. A. Mackey, D. C. Li, R. Newman, A. B. Nalls, M. Zmuda, J. M. Harris, T. B. CA Hlth Aging Body Composition Study TI European ancestry and resting metabolic rate in older African Americans SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE admixture; energy metabolism; body composition; genetic mapping ID ACTIVITY ENERGY-EXPENDITURE; POPULATION-STRUCTURE; GENETIC ADMIXTURE; BODY-COMPOSITION; DISEASE GENES; ADULTS; ASSOCIATION; OBESITY; WEIGHT; HEALTH AB Background/Objectives: Resting metabolic rate (RMR) contributes 60-80% of total energy expenditure and is consistently lower in populations of African descent compared with populations of European populations. Determination of European ancestry (EA) through single nucleotide polymorphism (SNP) analysis would provide an initial step for identifying genetic associations that contribute to low RMR. We sought to evaluate the association between RMR and EA in African Americans. Subjects/Methods: RMR was measured by indirect calorimetry in 141 African American men and women (aged 74.7 +/- 3.0 years) enrolled in a substudy of the Health, Aging and Body Composition Study. Ancestry informative markers were used to estimate individual percent EA. Multivariate regression was used to assess the association between RMR and EA after adjustments for soft tissue fat-free mass (STFFM), fat mass, age, study site, physical activity level and sex. Results: Mean EA was 23.8 +/- 16% (range: 0.1-70.7%) and there were no differences by sex. Following adjustments, each percent EA was associated with a 1.6 kcal/day (95% Confidence interval: 0.42, 2.7 kcal/day) higher RMR (P = 0.008). This equates to a 160 kcal/day lower RMR in a population of completely African ancestry, with one of completely European ancestry. Additional adjustment for trunk STFFM that partially accounts for high-metabolic rate organs did not affect this association. Conclusions: EA in African Americans is strongly associated with higher RMR. The data suggest that population differences in RMR may be due to genetic variants. European Journal of Clinical Nutrition (2011) 65, 663-667; doi:10.1038/ejcn.2011.22; published online 6 April 2011 C1 [Manini, T. M.] Univ Florida, Dept Aging & Geriatr Res, Inst Aging, Gainesville, FL 32611 USA. [Patel, K. V.; Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Schoeller, D. A.] Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. [Mackey, D. C.] Calif Pacific Med Ctr, San Francisco Coordinating Ctr, San Francisco, CA USA. [Newman, A. B.; Zmuda, J. M.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Ziv, E.] Univ Calif San Francisco, Dept Med, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Ziv, E.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Li, R.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Ziv, E.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Nalls, M.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Manini, TM (reprint author), Univ Florida, Dept Aging & Geriatr Res, Inst Aging, 210 E Mowry Rd, Gainesville, FL 32611 USA. EM tmanini@aging.ufl.edu RI Ziv, Elad/L-5396-2014; Newman, Anne B./C-6408-2013 OI Newman, Anne B./0000-0002-0106-1150 FU NIA Claude D Pepper Center [P30AG028740]; Institute on Aging at the University of Florida; NIH, National Institute on Aging [N01-AG-6-2106, N01-AG-6-2101, N01-AG-6-2103] FX This study was supported by The NIA Claude D Pepper Center P30AG028740 and a grant from the Institute on Aging at the University of Florida. The Health, Aging and Body Composition Study was supported by the Intramural Research Program of the NIH, National Institute on Aging contracts N01-AG-6-2106, N01-AG-6-2101 and N01-AG-6-2103 with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases. The National Institute on Aging Intramural Research Program designed the Health ABC study, supervised its conduct and participated in data collection. The coauthors, The Health, Aging, and Body Composition publications committee and representatives from The National Institute on Aging reviewed and approved the manuscript. NR 26 TC 5 Z9 5 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JUN PY 2011 VL 65 IS 6 BP 663 EP 667 DI 10.1038/ejcn.2011.22 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 772FD UT WOS:000291218800001 PM 21468093 ER PT J AU Siddiqui, N Alam, MS Stables, JP AF Siddiqui, Nadeem Alam, M. Shamsher Stables, James P. TI Synthesis and anticonvulsant properties of 1-(amino-N-arylmethanethio)-3-(1-substituted benzyl-2, 3-dioxoindolin-5-yl) urea derivatives SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Isatin; Anticonvulsants; Neurotoxicity ID EARLY IDENTIFICATION; HYDROPHOBIC DOMAIN; ISATIN; INHIBITORS; OXINDOLES; EPILEPSY; TOXICITY; DESIGN AB Various 1-(amino-N-arylmethanethio)-3-(1-substituted benzyl-2, 3-dioxoindolin-5-yl) urea (5a-p) were designed keeping in view the structural requirements suggested in the pharmacophore model for anticonvulsant activity. Their in vivo anticonvulsant screenings were performed by two most adopted seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Compound 5f was found active in MES screening while compounds 5h, 5i, 5k and 5i showed significant anticonvulsant activity in both the screenings and were devoid of any neurotoxicity. Compound 5h and 51 showed marked protection at 300 mg/kg against MES and scPTZ screening. Compound 5i also showed protection against MES screening at the dose of 100 mg/kg. In 6 Hz screening these two compounds showed significant protection and emerged as lead compounds for future investigations. (C) 2011 Elsevier Masson SAS. All rights reserved. C1 [Siddiqui, Nadeem; Alam, M. Shamsher] Hamdard Univ, Dept Pharmaceut Chem, Fac Pharm, New Delhi 110062, India. [Stables, James P.] Natl Inst Neurol Disorders & Stroke, Epilepsy Branch, NIH, Rockville, MD 20892 USA. RP Siddiqui, N (reprint author), Hamdard Univ, Dept Pharmaceut Chem, Fac Pharm, New Delhi 110062, India. EM nadeems_03@yahoo.co.in FU UGC (Govt. of India) FX One of the authors (Md. Shamsher Alam) is thankful to UGC (Govt. of India) for financial assistance in the form of Junior Research Fellowship (JRF). We are also thankful to the Anticonvulsant Screening Project (ASP), National Institute of Neurological Disorders and Stroke, NIH, Rockville, MD 20892-9523, USA. for anticonvulsant testing. NR 29 TC 13 Z9 14 U1 0 U2 5 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 JUN PY 2011 VL 46 IS 6 BP 2236 EP 2242 DI 10.1016/j.ejmech.2011.03.004 PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 770WG UT WOS:000291118600032 PM 21435751 ER PT J AU Gomez-Rodriguez, J Kraus, ZJ Schwartzberg, PL AF Gomez-Rodriguez, Julio Kraus, Zachary J. Schwartzberg, Pamela L. TI Tec family kinases Itk and Rlk/Txk in T lymphocytes: cross-regulation of cytokine production and T-cell fates SO FEBS JOURNAL LA English DT Review DE cytokines; innate lymphocytes; Itk; PLZF; Rlk; Txk; T-helper cells; Th1; Th2; Th17; thymus ID TYROSINE KINASE; IGE PRODUCTION; ACTIVE ITK; EXPRESSION; PHENOTYPE; DIFFERENTIATION; ACTIVATION; RECEPTORS; LINEAGE; ABSENCE AB Developing thymocytes and T cells express the Tec kinases Itk, Rlk/Txk and Tec, which are critical modulators of T-cell receptor signaling, required for full activation of phospholipase C gamma, and downstream Ca2+ and ERK-mediated signaling pathways. Over the last 10 years, data have implicated the Tec family kinases Itk and Rlk/Txk as important regulators of cytokine production by CD4+ effector T-cell populations. Emerging data now suggest that the Tec family kinases not only influence cytokine-producing T-cell populations in the periphery, but also regulate the development of distinct innate-type cytokine-producing T-cell populations in the thymus. Together, these results suggest that the Tec family kinases play critical roles in helping shape immune responses via their effects on the differentiation and function of distinct cytokine-producing, effector T-cell populations. C1 [Gomez-Rodriguez, Julio; Kraus, Zachary J.; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Schwartzberg, PL (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM pams@nhgri.nih.gov FU National Human Genome Research Institute, National Institutes of Health, Bethesda, MD FX The authors are funded by intramural funding from the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD. NR 44 TC 18 Z9 18 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2011 VL 278 IS 12 BP 1980 EP 1989 DI 10.1111/j.1742-4658.2011.08072.x PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 772OH UT WOS:000291242700003 PM 21362139 ER PT J AU Kryndushkin, DS Engel, A Edskes, H Wickner, RB AF Kryndushkin, Dmitry S. Engel, Abbi Edskes, Herman Wickner, Reed B. TI Molecular Chaperone Hsp104 Can Promote Yeast Prion Generation SO GENETICS LA English DT Article ID SACCHAROMYCES-CEREVISIAE; IN-VITRO; URE3 PRION; PSI+ PRION; ANTAGONISTIC INTERACTIONS; PROTEIN DISAGGREGATION; HUNTINGTONS-DISEASE; STRUCTURAL BASIS; CYTOSOLIC HSP70; FORMING DOMAIN AB [URE3] is an amyloid-based prion of Ure2p, a regulator of nitrogen catabolism in Saccharomyces cerevisiae. The Ure2p of the human pathogen Candida albicans can also be a prion in S. cerevisiae. We find that overproduction of the disaggregating chaperone, Hsp104, increases the frequency of de novo [URE3] prion formation by the Ure2p of S. cerevisiae and that of C. albicans. This stimulation is strongly dependent on the presence of the [PIN1] prion, known from previous work to enhance [URE3] prion generation. Our data suggest that transient Hsp104 overproduction enhances prion generation through persistent effects on Rnq1 amyloid, as well as during overproduction by disassembly of amorphous Ure2 aggregates (generated during Ure2p overproduction), driving the aggregation toward the amyloid pathway. Overproduction of other major cytosolic chaperones of the Hsp70 and Hsp40 families (Ssa1p, Sse1p, and Ydj1p) inhibit prion formation, whereas another yeast Hsp40, Sis1p, modulates the effects of Hsp104p on both prion induction and prion curing in a prion-specific manner. The same factor may both enhance de novo prion generation and destabilize existing prion variants, suggesting that prion variants may be selected by changes in the chaperone network. C1 [Kryndushkin, Dmitry S.; Engel, Abbi; Edskes, Herman; Wickner, Reed B.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank D. Masison [National Institutes of Health (NIH), Bethesda, MD] and M. D. Ter-Avanesyan (Cardiology Research Center, Moscow, Russia) for plasmids and strains; D. M. Cyr (University of North Carolina, Chapel Hill, NC) and P. Needham (University of Pittsburgh, Pittsburgh, PA) for kindly sharing antibodies; K. O'Connell (NIH) for help with microscopy; and members of our lab for a critical reading of the paper. This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 82 TC 19 Z9 26 U1 0 U2 5 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUN PY 2011 VL 188 IS 2 BP 339 EP U180 DI 10.1534/genetics.111.127779 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 773XM UT WOS:000291344900008 PM 21467567 ER PT J AU Mondoux, MA Love, DC Ghosh, SK Fukushige, T Bond, M Weerasinghe, GR Hanover, JA Krause, MW AF Mondoux, Michelle A. Love, Dona C. Ghosh, Salil K. Fukushige, Tetsunari Bond, Michelle Weerasinghe, Gayani R. Hanover, John A. Krause, Michael W. TI O-Linked-N-Acetylglucosamine Cycling and Insulin Signaling Are Required for the Glucose Stress Response in Caenorhabditis elegans SO GENETICS LA English DT Article ID LIFE-SPAN; GLCNAC TRANSFERASE; C. ELEGANS; DAUER FORMATION; TETRATRICOPEPTIDE REPEATS; DIABETIC COMPLICATIONS; PROTEIN GLYCOSYLATION; 3T3-L1 ADIPOCYTES; MEXICAN-AMERICANS; SKELETAL-MUSCLE AB In a variety of organisms, including worms, flies, and mammals, glucose homeostasis is maintained by insulin-like signaling in a robust network of opposing and complementary signaling pathways. The hexosamine signaling pathway, terminating in O-linked-N-acetylglucosamine (O-GlcNAc) cycling, is a key sensor of nutrient status and has been genetically linked to the regulation of insulin signaling in Caenorhabditis elegans. Here we demonstrate that O-GlcNAc cycling and insulin signaling are both essential components of the C. elegans response to glucose stress. A number of insulin-dependent processes were found to be sensitive to glucose stress, including fertility, reproductive timing, and dauer formation, yet each of these differed in their threshold of sensitivity to glucose excess. Our findings suggest that O-GlcNAc cycling and insulin signaling are both required for a robust and adaptable response to glucose stress, but these two pathways show complex and interdependent roles in the maintenance of glucose-insulin homeostasis. C1 [Fukushige, Tetsunari; Krause, Michael W.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Love, Dona C.; Ghosh, Salil K.; Bond, Michelle; Weerasinghe, Gayani R.; Hanover, John A.] NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. [Mondoux, Michelle A.] Coll Holy Cross, Dept Biol, Worcester, MA 01610 USA. RP Krause, MW (reprint author), NIDDK, Mol Biol Lab, NIH, Bldg 5,Room B104,5 Mem Dr, Bethesda, MD 20892 USA. EM mwkrause@helix.nih.gov OI Krause, Michael/0000-0001-6127-3940 FU National Institutes of Health, National Institute for Diabetes and Digestive and Kidney Diseases FX We thank Thomas Brodigan for technical assistance and members of the Krause and Hanover laboratories for helpful discussions. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute for Diabetes and Digestive and Kidney Diseases. NR 65 TC 19 Z9 27 U1 1 U2 7 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUN PY 2011 VL 188 IS 2 BP 369 EP 382 DI 10.1534/genetics.111.126490 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 773XM UT WOS:000291344900011 PM 21441213 ER PT J AU Horvath, JE Sheedy, CB Merrett, SL Diallo, AB Swofford, DL Green, ED Willard, HF AF Horvath, Julie E. Sheedy, Christina B. Merrett, Stephanie L. Diallo, Abdoulaye Banire Swofford, David L. Green, Eric D. Willard, Huntington F. CA NISC Comparative Sequencing Progra TI Comparative analysis of the primate X-inactivation center region and reconstruction of the ancestral primate XIST locus SO GENOME RESEARCH LA English DT Article ID PROTEIN-CODING GENE; CHROMOSOME INACTIVATION; HUMAN GENOME; FACULTATIVE HETEROCHROMATIN; SEGMENTAL DUPLICATIONS; MULTIPLE ALIGNMENT; REPEAT HYPOTHESIS; RAPID EVOLUTION; TANDEM REPEATS; NONCODING RNAS AB Here we provide a detailed comparative analysis across the candidate X-Inactivation Center (XIC) region and the XIST locus in the genomes of six primates and three mammalian outgroup species. Since lemurs and other strepsirrhine primates represent the sister lineage to all other primates, this analysis focuses on lemurs to reconstruct the ancestral primate sequences and to gain insight into the evolution of this region and the genes within it. This comparative evolutionary genomics approach reveals significant expansion in genomic size across the XIC region in higher primates, with minimal size alterations across the XIST locus itself. Reconstructed primate ancestral XIC sequences show that the most dramatic changes during the past 80 million years occurred between the ancestral primate and the lineage leading to Old World monkeys. In contrast, the XIST locus compared between human and the primate ancestor does not indicate any dramatic changes to exons or XIST-specific repeats; rather, evolution of this locus reflects small incremental changes in overall sequence identity and short repeat insertions. While this comparative analysis reinforces that the region around XIST has been subject to significant genomic change, even among primates, our data suggest that evolution of the XIST sequences themselves represents only small lineage-specific changes across the past 80 million years. C1 [Horvath, Julie E.; Sheedy, Christina B.; Merrett, Stephanie L.; Swofford, David L.; Willard, Huntington F.] Duke Univ, Duke Inst Genome Sci & Policy, Durham, NC 27708 USA. [Horvath, Julie E.] Duke Univ, Dept Evolutionary Anthropol, Durham, NC 27708 USA. [Diallo, Abdoulaye Banire] Univ Quebec, Dept Informat, Montreal, PQ H3C 3P8, Canada. [Swofford, David L.; Willard, Huntington F.] Duke Univ, Dept Biol, Durham, NC 27708 USA. [Green, Eric D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Green, Eric D.; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr NISC, NIH, Bethesda, MD 20892 USA. RP Horvath, JE (reprint author), Duke Univ, Duke Inst Genome Sci & Policy, Durham, NC 27708 USA. EM juliann.horvath@duke.edu FU National Human Genome Research Institute, National Institutes of Health; Duke Institute for Genome Sciences Policy (IGSP); IGSP Center for Evolutionary Genomics FX We thank Beth Sullivan and members of the Willard laboratory for technical discussions. J.E.H. thanks David Haring of the Duke Lemur Center for providing lemur photographs. This is Duke Lemur Center Publication Number 1199. The work was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, and by funds from the Genome Biology Program of the Duke Institute for Genome Sciences & Policy (IGSP). J.E.H. was supported in part by a fellowship from the IGSP Center for Evolutionary Genomics. NR 82 TC 8 Z9 9 U1 1 U2 3 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 JUN PY 2011 VL 21 IS 6 BP 850 EP 862 DI 10.1101/gr.111849.110 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 771JQ UT WOS:000291153400005 PM 21518738 ER PT J AU Maxwell, GL Hood, BL Day, R Chandran, U Kirchner, D Kolli, VSK Bateman, NW Allard, J Miller, C Sun, M Flint, MS Zahn, C Oliver, J Banerjee, S Litzi, T Parwani, A Sandburg, G Rose, S Becich, MJ Berchuck, A Kohn, E Risinger, JI Conrads, TP AF Maxwell, G. Larry Hood, Brian L. Day, Roger Chandran, Uma Kirchner, David Kolli, V. S. Kumar Bateman, Nicolas W. Allard, Jay Miller, Caela Sun, Mai Flint, Melanie S. Zahn, Chris Oliver, Julie Banerjee, Subhadra Litzi, Tracy Parwani, Anil Sandburg, Glenn Rose, Scott Becich, Michael J. Berchuck, Andrew Kohn, Elise Risinger, John I. Conrads, Thomas P. TI Proteomic analysis of stage I endometrial cancer tissue: Identification of proteins associated with oxidative processes and inflammation SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Endometrial cancer; Laser capture microdissection; Proteomics; Stage I ID GENE-EXPRESSION PROFILES; DIFFERENT HISTOLOGIC TYPES; H2O2-INDUCED CELL-DEATH; HUMAN BREAST-TUMORS; DIFFERENTIAL EXPRESSION; MICROARRAY ANALYSIS; RIBOSOMAL-PROTEINS; PEROXIREDOXIN-I; ANNEXIN A1; CARCINOMA AB Objective. The present study aimed to identify differentially expressed proteins employing a high resolution mass spectrometry (MS)-based proteomic analysis of endometrial cancer cells harvested using laser microdissection. Methods. A differential MS-based proteomic analysis was conducted from discrete epithelial cell populations gathered by laser microdissection from 91 pathologically reviewed stage I endometrial cancer tissue samples (79 endometrioid and 12 serous) and 10 samples of normal endometrium from postmenopausal women. Hierarchical cluster analysis of protein abundance levels derived from a spectral count analysis revealed a number of proteins whose expression levels were common as well as unique to both histologic types. An independent set of endometrial cancer specimens from 394 patients were used to externally validate the differential expression of select proteins. Results. 209 differentially expressed proteins were identified in a comparison of stage I endoimetrial cancers and normal post-menopausal endometrium controls (Q < 0.005). A number of differentially abundant proteins in stage I endometrial cancer were identified and independently validated by western blot and tissue microarray analyses. Multiple proteins identified with elevated abundance in stage I endometrial cancer are functionally associated with inflammation (annexins) and oxidative processes (peroxiredoxins). PRDX1 and ANXA2 were both confirmed as being overexpressed in stage I cancer compared to normal endometrium by independent TMA (Q=0.008 and Q=0.00002 respectively). Conclusions. These data provide the basis for further investigation of previously unrecognized novel pathways involved in early stage endometrial carcinogenesis and provide possible targets for prevention strategies that are inclusive of both endometrioid and serous histologic subtypes. Published by Elsevier Inc. C1 [Maxwell, G. Larry; Allard, Jay; Miller, Caela; Rose, Scott] Walter Reed Army Med Ctr, Div Gynecol Oncol, Washington, DC 20307 USA. [Maxwell, G. Larry; Allard, Jay; Miller, Caela; Oliver, Julie; Banerjee, Subhadra; Litzi, Tracy; Kohn, Elise; Conrads, Thomas P.] NCI, Canc Res Ctr, Walter Reed Lab Gynecol Dis, Bethesda, MD 20892 USA. [Maxwell, G. Larry; Hood, Brian L.; Miller, Caela; Conrads, Thomas P.] Womens Hlth Integrated Res Ctr Inova Hlth Syst, Fairfax, VA USA. [Day, Roger; Chandran, Uma; Bateman, Nicolas W.; Sun, Mai; Flint, Melanie S.; Parwani, Anil; Becich, Michael J.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Kirchner, David; Kolli, V. S. Kumar] Windber Res Inst, Johnstown, PA USA. [Zahn, Chris] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Sandburg, Glenn] Duke Univ, Med Ctr, Armed Forces Inst Pathol, Durham, NC USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Div Gynecol Oncol, Durham, NC USA. [Risinger, John I.] Michigan State Univ, Dept Obstet Gynecol & Reprod Biol, Grand Rapids, MI USA. RP Maxwell, GL (reprint author), Walter Reed Army Med Ctr, Div Gynecol Oncol, 6900 Georgia Ave, Washington, DC 20307 USA. EM george.maxwell@us.army.mil OI Flint, Melanie/0000-0001-5311-3023; parwani, anil/0000-0002-7616-1666 FU Department of Defense Telemedicine and Advanced Technology Center [W81XWH-05-2-0005] FX The opinions expressed in this article represent the private views of the authors and should not be construed as reflecting the official views of the Department of Defense. This study was funded by the Department of Defense Telemedicine and Advanced Technology Center, Award Number W81XWH-05-2-0005. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. NR 45 TC 18 Z9 21 U1 1 U2 1 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 JUN 1 PY 2011 VL 121 IS 3 BP 586 EP 594 DI 10.1016/j.ygyno.2011.02.031 PG 9 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 772NN UT WOS:000291240700030 PM 21458040 ER PT J AU Santangelo, L Marchetti, A Cicchini, C Conigliaro, A Conti, B Mancone, C Bonzo, JA Gonzalez, FJ Alonzi, T Amicone, L Tripodi, M AF Santangelo, Laura Marchetti, Alessandra Cicchini, Carla Conigliaro, Alice Conti, Beatrice Mancone, Carmine Bonzo, Jessica A. Gonzalez, Frank J. Alonzi, Tonino Amicone, Laura Tripodi, Marco TI The Stable Repression of Mesenchymal Program Is Required for Hepatocyte Identity: A Novel Role for Hepatocyte Nuclear Factor 4 alpha SO HEPATOLOGY LA English DT Article ID TRANSCRIPTION FACTOR SNAIL; GENE-EXPRESSION; E-CADHERIN; LIVER; TRANSITIONS; CELLS; DIFFERENTIATION; ACTIVATION; MECHANISMS; PROTEINS AB The concept that cellular terminal differentiation is stably maintained once development is complete has been questioned by numerous observations showing that differentiated epithelium may undergo an epithelial-to-mesenchymal transition (EMT) program. EMT and the reverse process, mesenchymal-to-epithelial transition (MET), are typical events of development, tissue repair, and tumor progression. In this study, we aimed to clarify the molecular mechanisms underlying these phenotypic conversions in hepatocytes. Hepatocyte nuclear factor 4 alpha (HNF4 alpha) was overexpressed in different hepatocyte cell lines and the resulting gene expression profile was determined by real-time quantitative polymerase chain reaction. HNF4 alpha recruitment on promoters of both mesenchymal and EMT regulator genes was determined by way of electrophoretic mobility shift assay and chromatin immunoprecipitation. The effect of HNF4 alpha depletion was assessed in silenced cells and in the context of the whole liver of HNF4 knockout animals. Our results identified key EMT regulators and mesenchymal genes as new targets of HNF4 alpha. HNF4 alpha, in cooperation with its target HNF1 alpha, directly inhibits transcription of the EMT master regulatory genes Snail, Slug, and HMGA2 and of several mesenchymal markers. HNF4 alpha-mediated repression of EMT genes induces MET in hepatomas, and its silencing triggers the mesenchymal program in differentiated hepatocytes both in cell culture and in the whole liver. Conclusion: The pivotal role of HNF4 alpha in the induction and maintenance of hepatocyte differentiation should also be ascribed to its capacity to continuously repress the mesenchymal program; thus, both HNF4 alpha activator and repressor functions are necessary for the identity of hepatocytes. (HEPATOLOGY 2011;53:2063-2074) C1 [Tripodi, Marco] Univ Roma La Sapienza, Dipartimento Biotecnol Cellulari & Ematol, Inst Pasteur, Cenci Bolognetti Fdn,Sez Genet, I-00161 Rome, Italy. [Conti, Beatrice; Mancone, Carmine; Alonzi, Tonino; Tripodi, Marco] Inst Res & Cure Sci Character, Natl Inst Infect Dis L Spallanzani, Rome, Italy. [Bonzo, Jessica A.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Tripodi, M (reprint author), Univ Roma La Sapienza, Dipartimento Biotecnol Cellulari & Ematol, Inst Pasteur, Cenci Bolognetti Fdn,Sez Genet, Viale Regina Elena 324, I-00161 Rome, Italy. EM tripodi@bce.uniroma1.it RI Tripodi, Marco/F-1143-2011; Conigliaro, Alice/J-8717-2016; OI Tripodi, Marco/0000-0001-6135-971X; Conigliaro, Alice/0000-0002-3037-835X; Mancone, Carmine/0000-0002-9569-5030; Amicone, Laura/0000-0002-3487-5740 FU Cancer Research Italian Foundation (FIRC); Ministry of Health; MIUR Ministry of University and Scientific Research; Waldensian Church; "Giorgio Ferraresi'' FIRC Fellowship for Cancer Research; Associazione Italiana per la Ricerca sul Cancro FX Supported by Cancer Research Italian Foundation (FIRC), Ministry of Health, MIUR Ministry of University and Scientific Research, and Waldensian Church. L. S. is recipient of a "Giorgio Ferraresi'' FIRC 2010-2012 Fellowship for Cancer Research. NR 31 TC 48 Z9 48 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUN PY 2011 VL 53 IS 6 BP 2063 EP 2074 DI 10.1002/hep.24280 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 773KX UT WOS:000291307300030 PM 21384409 ER PT J AU Brunt, EM Kleiner, DE Neuschwander-Tetri, BA AF Brunt, Elizabeth M. Kleiner, David E. Neuschwander-Tetri, Brent A. TI Nonalcoholic Fatty Liver Disease Activity Score and Brunt's Pathologic Criteria for the Diagnosis of Nonalcoholic Steatohepatitis: What Do They Mean and Do They Agree? Reply SO HEPATOLOGY LA English DT Letter C1 [Brunt, Elizabeth M.] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63130 USA. [Kleiner, David E.] NCI, Dept Lab Med, NIH, Bethesda, MD 20892 USA. [Neuschwander-Tetri, Brent A.] St Louis Univ, Dept Med, Div Gastroenterol & Hepatol, St Louis, MO 63103 USA. RP Brunt, EM (reprint author), Washington Univ, Dept Pathol & Immunol, St Louis, MO 63130 USA. NR 2 TC 0 Z9 0 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 JUN PY 2011 VL 53 IS 6 BP 2143 EP 2143 DI 10.1002/hep.24345 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 773KX UT WOS:000291307300047 ER PT J AU Hayashi, T Lewis, A Hayashi, E Betenbaugh, MJ Su, TP AF Hayashi, Teruo Lewis, Abasha Hayashi, Eri Betenbaugh, Michael J. Su, Tsung-Ping TI Antigen retrieval to improve the immunocytochemistry detection of sigma-1 receptors and ER chaperones SO HISTOCHEMISTRY AND CELL BIOLOGY LA English DT Article DE Antigen retrieval; Urea; Molecular chaperone; Endoplasmic reticulum; Sigma-1 receptor; ER stress ID UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM; ANDROGEN RECEPTOR; PARAFFIN SECTIONS; MITOCHONDRIA; BIP; IMMUNOHISTOCHEMISTRY; CALRETICULIN; MICRODOMAINS; PRETREATMENT AB Molecular chaperones localized at the endoplasmic reticulum (ER) lumen constitutively or cellular stress-dependently associate with a variety of proteins to promote their proper folding or to inhibit protein misfolding. ER chaperones preferentially form large complexes with co-chaperones and/or misfolded proteins in a highly crowded cellular environment that often hampers their detection by immunocytochemistry (ICC). This study establishes an antigen retrieval (AR) protocol to improve the ICC detection of ER chaperones in cultured cells using widely available antibodies against synthetic peptides. Among ten different antigen retrieval/fixation conditions, only the AR with Tris-HCl (pH 9.5) containing 6 M urea (80 degrees C for 10 min) significantly improved the ICC detection of the novel ER chaperone sigma-1 receptor (Sig-1R) in Chinese hamster ovary cells. Extended fixation with 4% paraformaldehyde for 1 h effectively preserved the morphology of the ER under the AR condition. This method greatly enhanced the signal-to-noise ratio in Sig-1R ICC, thus allowing for semi-quantitative detection of protein upregulation under ER stress. The AR similarly improved the ICC detection of a series of other major ER chaperones, including BiP/GRP78, GRP94, calnexin, calreticulin, ERp57, protein disulfide isomerase, and cyclophilin B. The improved ICC methodology using the urea AR at 80 degrees C may improve ICC of ER molecules as well as visualization of ER structure and substructures. C1 [Hayashi, Teruo; Hayashi, Eri] NIDA, Cellular Stress Signaling Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Lewis, Abasha; Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Lewis, Abasha; Betenbaugh, Michael J.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. RP Hayashi, T (reprint author), NIDA, Cellular Stress Signaling Unit, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM thayashi@intra.nida.nih.gov RI Betenbaugh, Michael J./A-3252-2010 OI Betenbaugh, Michael J./0000-0002-6336-4659 FU National Institute on Drug Abuse, NIH, DHHS FX This work was supported by Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS. Authors thank Dr. Arnold E. Ruoho (University of Wisconsin School of Medicine and Public Health, Madison) for the generous gift of anti-Sig-1R-full antibodies. NR 38 TC 6 Z9 6 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0948-6143 J9 HISTOCHEM CELL BIOL JI Histochem. Cell Biol. PD JUN PY 2011 VL 135 IS 6 BP 627 EP 637 DI 10.1007/s00418-011-0811-5 PG 11 WC Cell Biology; Microscopy SC Cell Biology; Microscopy GA 772GM UT WOS:000291222300009 PM 21573736 ER PT J AU Van Dyke, RB Patel, K Siberry, GK Burchett, SK Spector, SA Chernoff, MC Read, JS Mofenson, LM Seage, GR AF Van Dyke, Russell B. Patel, Kunjal Siberry, George K. Burchett, Sandra K. Spector, Stephen A. Chernoff, Miriam C. Read, Jennifer S. Mofenson, Lynne M. Seage, George R., III CA Pediat HIV AIDS Cohort Study TI Antiretroviral Treatment of US Children With Perinatally Acquired HIV Infection: Temporal Changes in Therapy Between 1991 and 2009 and Predictors of Immunologic and Virologic Outcomes SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE antiretroviral therapy; CD4 count; HIV viral load; Human Immunodeficiency virus; pediatrics ID SHORT-TERM RISK; HIV-1-INFECTED CHILDREN; COMBINATION THERAPY; HAART ERA; DISEASE PROGRESSION; CLINICAL-TRIALS; UNITED-STATES; FOLLOW-UP; ADOLESCENTS; TRANSMISSION AB Background: Advances in therapy have allowed children with perinatal HIV infection in the United States to survive into adolescence. We sought to describe the disease status of a large cohort of such children and identify predictors of their current CD4 count and HIV viral load (VL). Methods: The Pediatric HIV/AIDS Cohort Study AMP Protocol is an ongoing prospective study conducted at 15 sites in the United States. Between 2007 and 2009, we enrolled a population-based sample of 451 children with perinatal HIV who were 7-16 years of age at entry. Results: The median age of subjects at entry was 12.2 years, 53% were female, 70% were African-American, and 24% Hispanic. Their median entry CD4% was 33%, and 78% had a CD4% >= 25%; 68% had a suppressed VL. The more recent birth cohorts (1994-2002) had a significantly higher CD4% over time than the earliest birth cohort (1991-1993). The significant independent predictors of a higher CD4% at entry were a suppressed entry VL, a higher nadir CD4%, and starting antiretroviral therapy at a younger age. The mean CD4% at entry for children with a nadir CD4% $ 25% was 9.5% higher than for those with a nadir CD4%,15% (P < 0.001). Independent predictors of a suppressed entry VL were membership in a recent birth cohort, male gender, highly active combination antiretroviral therapy use at entry, and fewer prior antiretroviral therapy regimens. Conclusions: Most children with perinatal HIV maintain virologic suppression and good CD4 values. Earlier treatment results in better immune outcome. C1 [Van Dyke, Russell B.] Tulane Univ, Hlth Sci Ctr, Dept Pediat, New Orleans, LA 70112 USA. [Patel, Kunjal; Seage, George R., III] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Patel, Kunjal; Chernoff, Miriam C.; Seage, George R., III] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Siberry, George K.; Read, Jennifer S.; Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent Maternal AIDS Branch, NIH, Bethesda, MD USA. [Burchett, Sandra K.] Childrens Hosp, Dept Infect Dis, Boston, MA 02115 USA. [Spector, Stephen A.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. RP Van Dyke, RB (reprint author), Tulane Univ, Hlth Sci Ctr, Dept Pediat, TB 8,1440 Canal St,Suite 1600, New Orleans, LA 70112 USA. EM vandyke@tulane.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse; National Institute of Mental Health, National Institute of Deafness and Other Communication Disorders; National Heart Lung and Blood Institute, National Institute of Neurological Disorders and Stroke; National Institute on Alcohol Abuse and Alcoholism [U01 HD052102-04]; Tulane University School of Medicine [U01 HD052104-01] FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, the National Institute of Mental Health, National Institute of Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, National Institute of Neurological Disorders and Stroke, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (U01 HD052102-04) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (U01 HD052104-01) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Mercy Swatson). NR 31 TC 34 Z9 34 U1 0 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 JUN 1 PY 2011 VL 57 IS 2 BP 165 EP 173 DI 10.1097/QAI.0b013e318215c7b1 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 771MQ UT WOS:000291163100019 PM 21407086 ER PT J AU Andreopoulou, P Dumitrescu, CE Kelly, MH Brillante, BA Peck, CMC Wodajo, FM Chang, R Collins, MT AF Andreopoulou, Panagiota Dumitrescu, Claudia E. Kelly, Marilyn H. Brillante, Beth A. Peck, Carolee M. Cutler Wodajo, Felasfa M. Chang, Richard Collins, Michael T. TI Selective Venous Catheterization for the Localization of Phosphaturic Mesenchymal Tumors SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE FGF-23; OSTEOMALACIA; RICKETS; TUMOR-INDUCED OSTEOMALACIA; ONCOGENIC OSTEOMALACIA ID FIBROBLAST GROWTH FACTOR-23; INDUCED OSTEOMALACIA; FGF23; HYPOPHOSPHATEMIA; FIBROBLAST-GROWTH-FACTOR-23; RICKETS; FGF-23; BONE AB Tumor-induced osteomalacia (TIO) is characterized by renal phosphate wasting, hypophosphatemia, and aberrant vitamin D(3) metabolism and is caused by fibroblast growth factor 23 (FGF-23)-producing mesenchymal tumors, which are often difficult to locate. We investigated the utility of selective venous sampling in tumor localization. The primary endpoint was identification of the FGF-23 concentration ratio between the venous drainage of the tumor bed and the general circulation that was diagnostic of the location of an FGF-23-secreting tumor. Fourteen subjects underwent 15 sampling procedures after functional and anatomic imaging studies. Subjects fit into three imaging categories: no suspicious site, multiple sites, and single site (positive controls). FGF-23 levels were measured by ELISA. Suspicious tumors were resected for diagnosis, confirmation, and cure. In subjects with a positive venous sampling study and subsequent cure, a minimum ratio of 1.6 was diagnostic. In 7 of 14 subjects there was suggestive imaging, a diagnostic ratio, and an associated TIO tumor (true positive). Four of these required complicated resection procedures. In 4 of 14 subjects with no suspicious site on imaging studies, an FGF-23 diagnostic ratio was not detected (true negative). Biopsy or resection of a single lesion in 2 of 14 subjects with a diagnostic ratio failed to identify a TIO tumor (false positive). A diagnostic FGF-23 ratio was absent in 1 of 14 subjects whose tumor was a single highly suspicious lesion on imaging studies (false negative). These data yield a sensitivity of 0.87 [95% confidence interval (CI) 0.47-0.99] and a specificity of 0.71 (95% CI 0.29-0.96). Selective venous sampling for FGF-23 was particularly useful in subjects with multiple suspicious sites or an anatomically challenging planned resection but not in the absence of a suspicious lesion on imaging studies. (C) 2011 American Society for Bone and Mineral Research. C1 [Andreopoulou, Panagiota; Dumitrescu, Claudia E.; Kelly, Marilyn H.; Brillante, Beth A.; Peck, Carolee M. Cutler; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Chang, Richard] NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Wodajo, Felasfa M.] Inova Fairfax Hosp, Fairfax, VA USA. RP Collins, MT (reprint author), Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 228,30 Convent Dr,MSC 4320, Bethesda, MD 20892 USA. EM mc247k@nih.gov FU Division of Intramural Research, National Institute of Dental and Craniofacial Research (NIDCR); National Institutes of Health, Department of Health and Human Services FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research (NIDCR) at the Intramural Research Program, National Institutes of Health, Department of Health and Human Services. NR 20 TC 31 Z9 31 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUN PY 2011 VL 26 IS 6 BP 1295 EP 1302 DI 10.1002/jbmr.316 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 770SP UT WOS:000291109100015 PM 21611969 ER PT J AU Wang, XQ Hawkins, BT Miller, DS AF Wang, Xueqian Hawkins, Brian T. Miller, David S. TI Activating PKC-beta 1 at the blood-brain barrier reverses induction of P-glycoprotein activity by dioxin and restores drug delivery to the CNS SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE blood-brain barrier; capillaries; confocal microscopy; pharmacology; receptors ID XENOBIOTIC EFFLUX TRANSPORTERS; MEDIATED UP-REGULATION; MODULATION AB Upregulation of blood-brain barrier (BBB) P-glycoprotein expression causes central nervous system (CNS) pharmacoresistance. However, activation of BBB protein kinase C-beta 1 (PKC-beta 1) rapidly reduces basal P-glycoprotein transport activity. We tested whether PKC-beta 1 activation would reverse CNS drug resistance caused by dioxin acting through aryl hydrocarbon receptor. A selective PKC-beta 1 agonist abolished the increase in P-glycoprotein activity induced by dioxin in isolated rat brain capillaries and reversed the effect of dioxin on brain uptake of verapamil in dioxin-dosed rats. Thus, targeting BBB PKC-beta 1 may be an effective strategy to improve drug delivery to the brain, even in drug-resistant individuals. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1371-1375; doi:10.1038/jcbfm.2011.44; published online 13 April 2011 C1 [Wang, Xueqian; Hawkins, Brian T.; Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Miller, DS (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. FU National Institutes of Health, National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 15 TC 9 Z9 9 U1 0 U2 1 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 JUN PY 2011 VL 31 IS 6 BP 1371 EP 1375 DI 10.1038/jcbfm.2011.44 PG 5 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 771HY UT WOS:000291149000005 PM 21487415 ER PT J AU Godel, M Hartleben, B Herbach, N Liu, SY Zschiedrich, S Lu, S Debreczeni-Mor, A Lindenmeyer, MT Rastaldi, MP Hartleben, G Wiech, T Fornoni, A Nelson, RG Kretzler, M Wanke, R Pavenstadt, H Kerjaschki, D Cohen, CD Hall, MN Ruegg, MA Inoki, K Walz, G Huber, TB AF Goedel, Markus Hartleben, Bjoern Herbach, Nadja Liu, Shuya Zschiedrich, Stefan Lu, Shun Debreczeni-Mor, Andrea Lindenmeyer, Maja T. Rastaldi, Maria-Pia Hartleben, Goetz Wiech, Thorsten Fornoni, Alessia Nelson, Robert G. Kretzler, Matthias Wanke, Ruediger Pavenstaedt, Hermann Kerjaschki, Dontscho Cohen, Clemens D. Hall, Michael N. Rueegg, Markus A. Inoki, Ken Walz, Gerd Huber, Tobias B. TI Role of mTOR in podocyte function and diabetic nephropathy in humans and mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; DE-NOVO; GLOMERULAR-FILTRATION; RENAL HYPERTROPHY; TRANSGENIC MICE; KIDNEY-DISEASE; GROWTH-HORMONE; IN-VIVO; RAPAMYCIN; PATHWAY AB Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy. C1 [Goedel, Markus; Hartleben, Bjoern; Liu, Shuya; Zschiedrich, Stefan; Lu, Shun; Debreczeni-Mor, Andrea; Walz, Gerd; Huber, Tobias B.] Univ Hosp Freiburg, Div Renal, D-79106 Freiburg, Germany. [Herbach, Nadja; Wanke, Ruediger] Univ Munich, Ctr Clin Vet Med, Inst Vet Pathol, Munich, Germany. [Liu, Shuya; Huber, Tobias B.] Univ Freiburg, Spemann Grad Sch Biol & Med, Freiburg, Germany. [Lindenmeyer, Maja T.; Cohen, Clemens D.] Univ Zurich Hosp, Div Nephrol, CH-8091 Zurich, Switzerland. [Lindenmeyer, Maja T.; Cohen, Clemens D.] Univ Zurich Hosp, Inst Physiol, CH-8091 Zurich, Switzerland. [Lindenmeyer, Maja T.; Cohen, Clemens D.] Univ Zurich, Zurich, Switzerland. [Rastaldi, Maria-Pia] Fdn IRCCS Osped Maggiore Policlin, Renal Res Lab, Milan, Italy. [Rastaldi, Maria-Pia] Fdn Amico, Milan, Italy. [Hartleben, Goetz] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany. [Wiech, Thorsten] Univ Hosp Freiburg, Dept Pathol, Freiburg, Germany. [Fornoni, Alessia] Univ Miami, L Miller Sch Med, Diabet Res Inst, Miami, FL USA. [Nelson, Robert G.] NIDDK, NIH, Phoenix, AZ USA. [Kretzler, Matthias] Univ Michigan, Div Nephrol, Ann Arbor, MI 48109 USA. [Pavenstaedt, Hermann] Univ Hosp Munster, Dept Med D, Munster, Germany. [Kerjaschki, Dontscho] Med Univ Vienna, Dept Pathol, Vienna, Austria. [Hall, Michael N.; Rueegg, Markus A.] Univ Basel, Biozentrum, Basel, Switzerland. [Inoki, Ken] Univ Michigan, Inst Life Sci, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Inoki, Ken] Univ Michigan, Div Nephol, Ann Arbor, MI 48109 USA. [Huber, Tobias B.] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, Freiburg, Germany. RP Huber, TB (reprint author), Univ Hosp Freiburg, Div Renal, Breisacher Str 66, D-79106 Freiburg, Germany. EM tobias.huber@uniklinik-freiburg.de RI Nelson, Robert/B-1470-2012; Fornoni, Alessia/F-8350-2013; OI Herbach, Nadja/0000-0001-5893-0356; Wanke, Rudiger/0000-0002-0153-224X FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [NIDDK P30 DK081943]; Swiss National Science Foundation [32-122439/1]; Else Kroner-Fresenius-Stiftung [A62/04]; NIH [DK083491]; Deutsche Forschungsgemeinschaft (DFG) [HU 1016/2-1, SFB 592 B10, P7-KFO 201]; Excellence Initiative of the German Federal and State Governments [EXC 294]; BMBF Gerontosys FX We thank Dorte Thiel, Charlotte Meyer, (Renal Division, University Hospital Freiburg), Elisabeth Wieser, Brigitte Langer (Pathology, Medical University Vienna), Angela Siebert, Heike Sperling (Veterinary Pathology, Munich), and Evelyn Watzig (Pathology, University Hospital Freiburg) for excellent technical assistance. We thank Michael Kottgen and Sebastian Arnold for carefully reading the manuscript. We thank all participating centers of the European Renal cDNA Bank - Kroner-Fresenius biopsy bank and their patients for their cooperation. Active members at the time of the study are listed in ref. 58 and at http://www.forschungsportal.ch/unizh/p9291.htm. This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (to A.G. Nelson; NIDDK P30 DK081943 to M. Kretzler), the Swiss National Science Foundation (32-122439/1 to C.D. Cohen) and the Else Kroner-Fresenius-Stiftung (A62/04 to C.D. Cohen), the NIH (DK083491 to K. Inoki), Deutsche Forschungsgemeinschaft (DFG) grants (HU 1016/2-1, SFB 592 B10, and P7-KFO 201 to T.B. Huber), the Excellence Initiative of the German Federal and State Governments (EXC 294), and BMBF Gerontosys-Project NephAge. NR 58 TC 178 Z9 185 U1 2 U2 28 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 JUN PY 2011 VL 121 IS 6 BP 2197 EP 2209 DI 10.1172/JCI44774 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 772LB UT WOS:000291234300021 PM 21606591 ER PT J AU Rotger, M Dalmau, J Rauch, A McLaren, P Bosinger, SE Martinez, R Sandler, NG Roque, A Liebner, J Battegay, M Bernasconi, E Descombes, P Erkizia, I Fellay, J Hirschel, B Miro, JM Palou, E Hoffmann, M Massanella, M Blanco, J Woods, M Gunthard, HF de Bakker, P Douek, DC Silvestri, G Martinez-Picado, J Telenti, A AF Rotger, Margalida Dalmau, Judith Rauch, Andri McLaren, Paul Bosinger, Steven E. Martinez, Raquel Sandler, Netanya G. Roque, Annelys Liebner, Julia Battegay, Manuel Bernasconi, Enos Descombes, Patrick Erkizia, Itziar Fellay, Jacques Hirschel, Bernard Miro, Jose M. Palou, Eduard Hoffmann, Matthias Massanella, Marta Blanco, Julia Woods, Matthew Guenthard, Huldrych F. de Bakker, Paul Douek, Daniel C. Silvestri, Guido Martinez-Picado, Javier Telenti, Amalio TI Comparative transcriptomics of extreme phenotypes of human HIV-1 infection and SIV infection in sooty mangabey and rhesus macaque SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID VIRUS TYPE-1 INFECTION; ANTIRETROVIRAL THERAPY; LYMPHOCYTE-ACTIVATION; IMMUNE ACTIVATION; LYMPHATIC TISSUE; EXPRESSION; DISEASE; MECHANISMS; SIGNATURES; DISCOVERY AB High levels of HIV-1 replication during the chronic phase of infection usually correlate with rapid progression to severe immunodeficiency. However, a minority of highly viremic individuals remains asymptomatic and maintains high CD4(+) T cell counts. This tolerant profile is poorly understood and reminiscent of the widely studied nonprogressive disease model of SIV infection in natural hosts. Here, we identify transcriptome differences between rapid progressors (RPs) and viremic nonprogressors (VNPs) and highlight several genes relevant for the understanding of HIV-1-induced immunosuppression. RPs were characterized by a specific transcriptome profile of CD4(+) and CD8(+) T cells similar to that observed in pathogenic SIV-infected rhesus macaques. In contrast, VNPs exhibited lower expression of interferon-stimulated genes and shared a common gene regulation profile with nonpathogenic SIV-infected sooty mangabeys. A short list of genes associated with VNP, including CASP1, CD38, LAG3, TNFSF13B, SOCS1, and EEF1D, showed significant correlation with time to disease progression when evaluated in an independent set of CD4(+) T cell expression data. This work characterizes 2 minimally studied clinical patterns of progression to AIDS, whose analysis may inform our understanding of HIV pathogenesis. C1 [Dalmau, Judith; Erkizia, Itziar; Massanella, Marta; Blanco, Julia; Martinez-Picado, Javier] Hosp Badalona Germans Trias & Pujol, AIDS Res Inst IrsiCaixa, Barcelona, Spain. [Rotger, Margalida; Martinez, Raquel; Fellay, Jacques; Telenti, Amalio] Univ Lausanne, Lausanne, Switzerland. [Rotger, Margalida; Martinez, Raquel; Fellay, Jacques; Telenti, Amalio] Univ Hosp, Inst Microbiol, Lausanne, Switzerland. [Rauch, Andri] Univ Hosp Bern, Div Infect Dis, CH-3010 Bern, Switzerland. [McLaren, Paul; de Bakker, Paul] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Bosinger, Steven E.; Silvestri, Guido] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Bosinger, Steven E.; Silvestri, Guido] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Sandler, Netanya G.; Roque, Annelys; Liebner, Julia; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Battegay, Manuel] Univ Basel Hosp, Div Infect Dis & Hosp Epidemiol, CH-4031 Basel, Switzerland. [Bernasconi, Enos] Osped Reg, Lugano, Switzerland. [Descombes, Patrick] Univ Geneva, Geneva, Switzerland. [Hirschel, Bernard] Univ Hosp Geneva, Div Infect Dis, Geneva, Switzerland. [Miro, Jose M.] Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain. [Palou, Eduard] Banc de Sang & Teixits, Barcelona, Spain. [Hoffmann, Matthias] Kantonsspital St Gall, St Gallen, Switzerland. [Woods, Matthew] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Guenthard, Huldrych F.] Univ Zurich, Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, Zurich, Switzerland. [Telenti, Amalio] SHCS, Lausanne, Switzerland. [Martinez-Picado, Javier] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain. RP Martinez-Picado, J (reprint author), Hosp Badalona Germans Trias & Pujol, AIDS Res Inst IrsiCaixa, Badalona 08916, Spain. EM jmpicado@irsicaixa.es; Amalio.telenti@chuv.ch RI gunthard, huldrych/F-1724-2011; Blanco, Julia/A-5347-2008; Martinez-Picado, Javier/G-5507-2012; de Bakker, Paul/B-8730-2009; Infektiologie, USZ/A-6921-2011; SHCS, all/G-4072-2011; Fellay, Jacques/A-6681-2009; Erkizia, Itziar/G-3376-2016; Massanella, Marta/P-8619-2016; SHCS, ch/G-4077-2011; SHCS, only/G-4080-2011 OI Utay, Netanya/0000-0002-6407-8670; gunthard, huldrych/0000-0002-1142-6723; Blanco, Julia/0000-0002-2225-0217; Martinez-Picado, Javier/0000-0002-4916-2129; de Bakker, Paul/0000-0001-7735-7858; Fellay, Jacques/0000-0002-8240-939X; Massanella, Marta/0000-0002-3326-151X; FU SHCS; Swiss National Science Foundation (SNF) [33CSC0-108787, 587, 310000-110012]; HIVACAT; Ragon Institute; Spanish AIDS network [RD06/0006]; Canadian Institutes of Health Research HIV/AIDS Research Initiative [HFE-85139] FX This work has been financed in the framework of the SHCS and supported by the Swiss National Science Foundation (SNF) (grant no. 33CSC0-108787, project no. 587), by SNF grant (310000-110012, to A. Telenti), by the HIVACAT, and, in part, by the Ragon Institute and the Spanish AIDS network (RD06/0006). S.E. Bosinger is a recipient of a Canadian Institutes of Health Research HIV/AIDS Research Initiative Fellowship (HFE-85139). We thank S. Colombo, M. Rickenbach, I. Fernandez, and J. Puig for study coordination; Y. Vallet for software support; John Wherry for the IA gene set; and E. Grau, R. Ayen, and T. Gonzalez for technical assistance. The members of the SHCS are M. Battegay, E. Bernasconi, J. Boni, H.C. Bucher, Ph. Burgisser, A. Calmy, S. Cattacin, M. Cavassini, R. Dubs, M. Egger, L. Elzi, P. Erb, M. Fischer, M. Flepp, A. Fontana, P. Francioli (President of the SHCS, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne), H. Furrer (Chairman of the Clinical and Laboratory Committee), C. Fux, M. Gorgievski, H. Gunthard (Chairman of the Scientific Board), H. Hirsch, B. Hirschel, I. Wish, Ch. Kahlert, L. Kaiser, U. Karrer, C. Kind, Th. Klimkait, B. Ledergerber, G. Martinetti, B. Martinez, N. Muller, D. Nadal, M. Opravil, F. Paccaud, G. Pantaleo, A. Rauch, S. Regenass, M. Rickenbach (Head of Data Center), C. Rudin (Chairman of the Mother and Child Substudy), P. Schmid, D. Schultze, J. Schupbach, R. Speck, P. Taffe, P. Tarr, A. Telenti, A. Trkola, P. Vernazza, R. Weber, and S. Yerly. The members of the HIVACAT involved in this study are B. Clotet, J. Dalmau, I. Erkizia, J.M. Gatell, C. Ligero, M. Lopez-Dieguez, C. Manzardo, J. Martinez-Picado, and J.M. Miro. NR 36 TC 84 Z9 86 U1 2 U2 15 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 JUN PY 2011 VL 121 IS 6 BP 2391 EP 2400 DI 10.1172/JCI45235 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 772LB UT WOS:000291234300037 PM 21555857 ER PT J AU Wu, YJ Liu, CY Sun, H Vijayakumar, A Giglou, PR Qiao, RF Oppenheimer, J Yakar, S LeRoith, D AF Wu, Yingjie Liu, Chengyu Sun, Hui Vijayakumar, Archana Giglou, Pejman Raeisi Qiao, Ruifang Oppenheimer, Joshua Yakar, Shoshana LeRoith, Derek TI Growth hormone receptor regulates beta cell hyperplasia and glucose-stimulated insulin secretion in obese mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ISLET DEVELOPMENT; RESISTANCE; DISRUPTION; DELETION; IRS-2; SIZE; MASS AB Insulin, growth hormone (GH), and insulin-like growth factor-1 (IGF-1) play key roles in the regulation of beta cell growth and function. Although beta cells express the GH receptor, the direct effects of GH on beta cells remain largely unknown. Here we have employed a rat insulin II promoter-driven (RIP-driven) Cre recombinase to disrupt the GH receptor in beta cells (beta GHRKO). beta GHRKO mice fed a standard chow diet exhibited impaired glucose-stimulated insulin secretion but had no changes in beta cell mass. When challenged with a high-fat diet, beta GHRKO mice showed evidence of a beta cell secretory defect, with further deterioration of glucose homeostasis indicated by their altered glucose tolerance and blunted glucose-stimulated insulin secretion. Interestingly, beta GHRKO mice were impaired in beta cell hyperplasia in response to a high-fat diet, with decreased P cell proliferation and overall reduced beta cell mass. Therefore, GH receptor plays critical roles in glucose-stimulated insulin secretion and beta cell compensation in response to a high-fat diet. C1 [Wu, Yingjie; Sun, Hui; Vijayakumar, Archana; Giglou, Pejman Raeisi; Qiao, Ruifang; Oppenheimer, Joshua; Yakar, Shoshana; LeRoith, Derek] Mt Sinai Sch Med, Dept Med, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Wu, Yingjie; Sun, Hui; Vijayakumar, Archana; Giglou, Pejman Raeisi; Qiao, Ruifang; Oppenheimer, Joshua; Yakar, Shoshana; LeRoith, Derek] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY 10029 USA. [Liu, Chengyu] NHLBI, Transgen Core Facil, NIH, Bethesda, MD 20892 USA. RP LeRoith, D (reprint author), Mt Sinai Sch Med, Dept Med, Div Endocrinol Diabet & Bone Dis, 1 Gustave L Levy Pl,Box 1055,Annenberg Bldg Room, New York, NY 10029 USA. EM shoshana.yakar@mssm.edu; derek.leroith@mssm.edu NR 21 TC 36 Z9 36 U1 0 U2 0 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 JUN PY 2011 VL 121 IS 6 BP 2422 EP 2426 DI 10.1172/JCI45027 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 772LB UT WOS:000291234300040 PM 21555853 ER PT J AU Rubin, JE Bacak, BJ Molkov, YI Shevtsova, NA Smith, JC Rybak, IA AF Rubin, Jonathan E. Bacak, Bartholomew J. Molkov, Yaroslav I. Shevtsova, Natalia A. Smith, Jeffrey C. Rybak, Ilya A. TI Interacting oscillations in neural control of breathing: modeling and qualitative analysis SO JOURNAL OF COMPUTATIONAL NEUROSCIENCE LA English DT Article DE Neural oscillations; Respiratory central pattern generator; Pre-Botzinger Complex; Parafacial respiratory group; Coupled oscillators; Phase plane analysis ID RESPIRATORY RHYTHM GENERATION; PRE-BOTZINGER COMPLEX; STEM-SPINAL-CORD; UPPER AIRWAY-RESISTANCE; MAMMALIAN BRAIN-STEM; RETROTRAPEZOID NUCLEUS; NEWBORN RATS; FUNCTIONAL ARCHITECTURE; INSPIRATORY ACTIVITY; EXPIRATORY ACTIVITY AB In mammalian respiration, late-expiratory (late-E, or pre-inspiratory) oscillations emerge in abdominal motor output with increasing metabolic demands (e.g., during hypercapnia, hypoxia, etc.). These oscillations originate in the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) and couple with the respiratory oscillations generated by the interacting neural populations of the Botzinger (BotC) and pre-Botzinger (pre-BotC) complexes, representing the kernel of the respiratory central pattern generator. Recently, we analyzed experimental data on the generation of late-E oscillations and proposed a large-scale computational model that simulates the possible interactions between the BotC/pre-BotC and RTN/pFRG oscillations under different conditions. Here we describe a reduced model that maintains the essential features and architecture of the large-scale model, but relies on simplified activity-based descriptions of neural populations. This simplification allowed us to use methods of dynamical systems theory, such as fast-slow decomposition, bifurcation analysis, and phase plane analysis, to elucidate the mechanisms and dynamics of synchronization between the RTN/pFRG and BotC/pre-BotC oscillations. Three physiologically relevant behaviors have been analyzed: emergence and quantal acceleration of late-E oscillations during hypercapnia, transformation of the late-E activity into a biphasic-E activity during hypercapnic hypoxia, and quantal slowing of BotC/pre-BotC oscillations with the reduction of pre-BotC excitability. Each behavior is elicited by gradual changes in excitatory drives or other model parameters, reflecting specific changes in metabolic and/or physiological conditions. Our results provide important theoretical insights into interactions between RTN/pFRG and BotC/pre-BotC oscillations and the role of these interactions in the control of breathing under different metabolic conditions. C1 [Rubin, Jonathan E.] Univ Pittsburgh, Dept Math, Pittsburgh, PA 15260 USA. [Bacak, Bartholomew J.; Molkov, Yaroslav I.; Shevtsova, Natalia A.; Rybak, Ilya A.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. [Smith, Jeffrey C.] NINDS, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Rubin, JE (reprint author), Univ Pittsburgh, Dept Math, 301 Thackeray Hall, Pittsburgh, PA 15260 USA. EM rubin@math.pitt.edu OI Molkov, Yaroslav/0000-0002-0862-1974 FU National Institute of Neurological Disorders and Stroke (NINDS), NIH [R01 NS057815]; NSF [DMS 0716936]; NIH, NINDS FX This study was supported by National Institute of Neurological Disorders and Stroke (NINDS), NIH grant R01 NS057815 (I.A. Rybak), NSF grant DMS 0716936 (J. E. Rubin) and in part by the Intramural Research Program of the NIH, NINDS (J.C. Smith). NR 64 TC 16 Z9 17 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5313 J9 J COMPUT NEUROSCI JI J. Comput. Neurosci. PD JUN PY 2011 VL 30 IS 3 BP 607 EP 632 DI 10.1007/s10827-010-0281-0 PG 26 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 772RU UT WOS:000291253400007 PM 20927576 ER PT J AU Bosch, RJ Pollard, RB Landay, A Aga, E Fox, L Mitsuyasu, R AF Bosch, Ronald J. Pollard, Richard B. Landay, Alan Aga, Evgenia Fox, Lawrence Mitsuyasu, Ronald CA AIDS Clinical Trials Grp A5132 Tea TI A Randomized Trial of Interleukin-2 During Withdrawal of Antiretroviral Treatment SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID STRUCTURED TREATMENT INTERRUPTION; HIV-INFECTION; THERAPY; REPLICATION; IMMUNIZATIONS AB In HIV-infected individuals on antiretroviral treatment with viral suppression, structured treatment interruptions are designed to allow exposure to endogenous HIV antigens and to thereby boost HIV-specific immunity. AIDS Clinical Trials Group A5132 was an exploratory 2-arm randomized trial that evaluated two 4-week treatment interruptions in combination with 2 strategies for administering interleukin-2 (IL-2): 2.0 million international units of IL-2 subcutaneously daily during the final 2 weeks of treatment interruption and the first week of treatment reinitiation (arm A), or 4.5 million international units of IL-2 subcutaneously twice a day during the first 5 days of treatment reinitiation (arm B). Twenty-one subjects with HIV-1 RNA <50 copies/mL and CD4+ T cell counts >= 300 (median 615) cells/mm(3) were randomized. The primary endpoint was the viral setpoint measured 11-12 weeks after a third treatment interruption (observed for 7 Arm A and 9 Arm B). The median HIV-1 RNA setpoints were 4.3 and 4.5 log(10) copies/mL for Arm A and Arm B, respectively; there was no evidence of a difference between arms (P - 0.50, rank-sum test, worst rank for unobserved viral setpoint). The current study, the first to evaluate IL-2 during repeated short-term treatment interruptions, revealed no evidence for augmentation of HIV immunity. Viral setpoints were similar to historical controls, emphasizing the need for new strategies to enhance HIV-specific immunity. C1 [Bosch, Ronald J.; Aga, Evgenia] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Pollard, Richard B.] Univ Calif, Davis Med Ctr, Sacramento, CA USA. [Landay, Alan] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Fox, Lawrence] NIAID, Bethesda, MD 20892 USA. [Mitsuyasu, Ronald] Univ Calif Los Angeles, Los Angeles, CA USA. RP Bosch, RJ (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, 651 Huntington Ave,FXB-603, Boston, MA 02115 USA. EM rbosch@hsph.harvard.edu FU National Institute of Allergy and Infectious Diseases [AI 38858, AI 68636, AI 38855, AI 68634]; Chiron; Novartis FX The authors thank Anne Sevin (deceased), Peter Bohlin, the participating ACTG sites, and especially the study participants. This study was supported in part by the AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases (AI 38858, AI 68636, AI 38855, and AI 68634). The authors also thank and acknowledge the support of Chiron and Novartis, and the following institutions who participated in the study: Stanford University (AI 69556), University of Miami (AI 69477), University of California, Davis Medical Center, and University of Texas Medical Branch at Galveston (AI 32782). NR 10 TC 2 Z9 2 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD JUN PY 2011 VL 31 IS 6 BP 481 EP 483 DI 10.1089/jir.2010.0119 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 771YY UT WOS:000291197800003 PM 21291323 ER PT J AU Gujer, C Sandgren, KJ Douagi, I Adams, WC Sundling, C Smed-Sorensen, A Seder, RA Hedestam, GBK Lore, K AF Gujer, Cornelia Sandgren, Kerrie J. Douagi, Iyadh Adams, William C. Sundling, Christopher Smed-Sorensen, Anna Seder, Robert A. Hedestam, Gunilla B. Karlsson Lore, Karin TI IFN-alpha produced by human plasmacytoid dendritic cells enhances T cell-dependent naive B cell differentiation SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE CD27; CD86; type I IFN; IgM ID TOXIC-SHOCK-SYNDROME; I INTERFERON; ANTIBODY-RESPONSES; HUMORAL RESPONSES; ADAPTIVE IMMUNITY; HUMAN BLOOD; CD86 B7-2; CPG DNA; ANTIGEN; LYMPHOCYTES AB The development and quality of a humoral immune response are largely influenced by the environment that supports the activation of naive B cells. Human PDCs, through their unique capacity to produce high levels of IFN-alpha, have been shown earlier to enhance B cell responses stimulated by selected TLR ligands. In this study, we investigated whether PDCs also promote B cell activation induced by Th cell interactions and BCR ligation. Sorted human naive CD19(+) CD27(-) B cells were activated in vitro with anti-Ig and irradiated CD4(+) T cells. Under these conditions, the presence of supernatants from TLR-stimulated PDCs increased B cell proliferation, the frequency of B cells that differentiated to CD27(high) CD38(high) cells, and secretion of IgM. Similar results were observed when the B cells were activated in the presence of purified IFN-alpha. In contrast, supernatants from stimulated MDCs did not augment these functions. Also, IFN-alpha treatment of B cells up-regulated the expression of costimulatory molecule CD86 but not CD40, CD80, MHC class II, or CD25. Although direct IFN-alpha exposure of T cells suppressed their proliferative capacity, IFN-alpha treatment of B cells led to a small increase in their capacity to induce superantigen-driven activation of autologous CD4(+) T cells. In summary, PDCs, via their production of IFN-alpha, may render B cells more responsive to T cell contact, which in turn, facilitates B cell proliferation and differentiation to antibody-producing cells. J. Leukoc. Biol. 89: 811-821; 2011. C1 [Lore, Karin] Karolinska Inst, Dept Med, Ctr Infect Med, Stockholm, Sweden. [Douagi, Iyadh; Sundling, Christopher; Smed-Sorensen, Anna; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Adams, William C.; Seder, Robert A.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Lore, K (reprint author), Karolinska Inst, Dept Med, Ctr Infect Med, F59, Stockholm, Sweden. EM karin.lore@ki.se OI Sundling, Christopher/0000-0002-6138-690X FU Swedish Council for Research (Vetenskapsradet); Swedish International Development Agency (Sida); Jeansson's Foundation; Swedish Society for Medicine; Sven Gard Foundation; Karolinska Institutet FX This study was supported by the Swedish Council for Research (Vetenskapsradet), the Swedish International Development Agency (Sida) (G. B. K. H and K. L. funding recipients), the Jeansson's Foundation, the Swedish Society for Medicine (K. L. funding recipient), and the Sven Gard Foundation (C. G., K.J.S., and W. C. A. funding recipients). W. C. A. and C. S. are recipients of graduate student scholarships from Karolinska Institutet. The authors are grateful to technical help by Andrea Hildebrandt and the Department of Transfusion Medicine, Karolinska University Hospital, for assistance with leukapheresis and elutriations. NR 57 TC 14 Z9 14 U1 0 U2 4 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 JUN PY 2011 VL 89 IS 6 BP 811 EP 821 DI 10.1189/jlb.0810460 PG 11 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 770SI UT WOS:000291108400003 PM 21233412 ER PT J AU Wink, DA Hines, HB Cheng, RYS Switzer, CH Flores-Santana, W Vitek, MP Ridnour, LA Colton, CA AF Wink, David A. Hines, Harry B. Cheng, Robert Y. S. Switzer, Christopher H. Flores-Santana, Wilmarie Vitek, Michael P. Ridnour, Lisa A. Colton, Carol A. TI Nitric oxide and redox mechanisms in the immune response SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE oxidative nitrosative stress; signaling cascade ID FACTOR-KAPPA-B; HUMAN-IMMUNODEFICIENCY-VIRUS; CELL-MEDIATED IMMUNOSUPPRESSION; CYTOSOLIC PHOSPHOLIPASE A(2); SYNTHASE TYPE-2 EXPRESSION; RAT ALVEOLAR MACROPHAGES; NECROSIS-FACTOR-ALPHA; HUMAN MONOCYTIC CELLS; GROWTH-FACTOR BETA-1; REGULATORY T-CELLS AB The role of redox molecules, such as NO and ROS, as key mediators of immunity has recently garnered renewed interest and appreciation. To regulate immune responses, these species trigger the eradication of pathogens on the one hand and modulate immunosuppression during tissue-restoration and wound-healing processes on the other. In the acidic environment of the phagosome, a variety of RNS and ROS is produced, thereby providing a cauldron of redox chemistry, which is the first line in fighting infection. Interestingly, fluctuations in the levels of these same reactive intermediates orchestrate other phases of the immune response. NO activates specific signal transduction pathways in tumor cells, endothelial cells, and monocytes in a concentration-dependent manner. As ROS can react directly with NO-forming RNS, NO bioavailability and therefore, NO response(s) are changed. The NO/ROS balance is also important during Th1 to Th2 transition. In this review, we discuss the chemistry of NO and ROS in the context of antipathogen activity and immune regulation and also discuss similarities and differences between murine and human production of these intermediates. J. Leukoc. Biol. 89: 873-891; 2011. C1 [Wink, David A.; Cheng, Robert Y. S.; Switzer, Christopher H.; Flores-Santana, Wilmarie; Ridnour, Lisa A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Hines, Harry B.] USA, Integrated Toxicol Div, Med Res Inst Infect Dis, Frederick, MD USA. [Vitek, Michael P.; Colton, Carol A.] Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B35, Bethesda, MD 20892 USA. EM wink@mail.nih.gov; glia01@aol.com RI Switzer, Christopher/D-9203-2013; OI Cheng, Robert/0000-0003-0287-6439 FU NIA NIH HHS [R01 AG031845, R01 AG031124] NR 251 TC 189 Z9 194 U1 7 U2 44 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 JUN PY 2011 VL 89 IS 6 BP 873 EP 891 DI 10.1189/jlb.1010550 PG 19 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 770SI UT WOS:000291108400008 PM 21233414 ER PT J AU Uyttenhove, C Marillier, RG Tacchini-Cottier, F Charmoy, M Caspi, RR Damsker, JM Goriely, S Su, D Van Damme, J Struyf, S Opdenakker, G Van Snick, J AF Uyttenhove, Catherine Marillier, Reece G. Tacchini-Cottier, Fabienne Charmoy, Melanie Caspi, Rachel R. Damsker, Jesse M. Goriely, Stanislas Su, Dan Van Damme, Jo Struyf, Sofie Opdenakker, Ghislain Van Snick, Jacques TI Technical Advance: Amine-reactive OVA multimers for auto-vaccination against cytokines and other mediators: perspectives illustrated for GCP-2 in L. major infection SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE vaccine; interleukin; chemokine; cross-linking; antigen ID GROWTH-FACTOR-BETA; GRANULOCYTE CHEMOTACTIC PROTEIN-2; AUTOIMMUNE ENCEPHALOMYELITIS; MONOCLONAL-ANTIBODIES; ACTIVE IMMUNIZATION; TUMOR ANGIOGENESIS; KINOID VACCINE; GELATINASE-B; T-CELLS; MICE AB Anticytokine auto-vaccination is a powerful tool for the study of cytokine functions in vivo but has remained rather esoteric as a result of numerous technical difficulties. We here describe a two-step procedure based on the use of OVA multimers purified by size exclusion chromatography after incubation with glutaraldehyde at pH 6. When such polymers are incubated with a target protein at pH 8.5 to deprotonate reactive amines, complexes are formed that confer immunogenicity to self-antigens. The chemokine GCP-2/CXCL6, the cytokines GM-CSF, IL-17F, IL-17E/IL-25, IL-27, and TGF-beta 1, and the MMP-9/gelatinase B are discussed as examples. mAb, derived from such immunized mice, have obvious advantages for in vivo studies of the target proteins. Using a mAb against GCP-2, obtained by the method described here, we provide the first demonstration of the major role played by this chemokine in rapid neutrophil mobilization after Leishmania major infection. Pre-activated OVA multimers reactive with amine residues thus provide an efficient carrier for auto-vaccination against 9-90 kDa autologous proteins. J. Leukoc. Biol. 89: 1001-1007; 2011. C1 [Uyttenhove, Catherine; Marillier, Reece G.; Van Snick, Jacques] Ludwig Inst Canc Res, Brussels Branch, B-1200 Brussels, Belgium. [Uyttenhove, Catherine; Goriely, Stanislas] Catholic Univ Louvain, Cellular Genet Unit, de Duve Inst, B-1200 Brussels, Belgium. [Marillier, Reece G.; Su, Dan; Van Snick, Jacques] Catholic Univ Louvain, Expt Med Unit, de Duve Inst, B-1200 Brussels, Belgium. [Tacchini-Cottier, Fabienne; Charmoy, Melanie] Univ Lausanne, WHO Immunol Res & Training Ctr, Dept Biochem, CH-1066 Epalinges, Switzerland. [Caspi, Rachel R.; Damsker, Jesse M.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Van Damme, Jo; Struyf, Sofie] Katholieke Univ Leuven, Rega Inst Med Res, Lab Mol Immunol, Leuven, Belgium. [Opdenakker, Ghislain] Katholieke Univ Leuven, Rega Inst Med Res, Lab Immunobiol, Leuven, Belgium. RP Van Snick, J (reprint author), Ludwig Inst Canc Res, Brussels Branch, Ave Hippocrate 74, B-1200 Brussels, Belgium. EM jacques.vansnick@bru.licr.org RI Tacchini-Cottier, Fabienne/H-2925-2012 FU Fonds National de la Recherche Scientifique Medicale (FRSM, Belgique); Concerted Research Actions (G.O.A.) of the Regional Government of Flanders; Belgian Federal Science Policy; Swiss National Foundation [310030-129852/1] FX This study was supported by the Fonds National de la Recherche Scientifique Medicale (FRSM, Belgique), the Concerted Research Actions (G.O.A.) of the Regional Government of Flanders, and an Interuniversity Attraction Pole of the Belgian Federal Science Policy. Part of this work was supported by the Swiss National Foundation (310030-129852/1 to F.T-C.). NR 35 TC 13 Z9 13 U1 0 U2 1 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 JUN PY 2011 VL 89 IS 6 BP 1001 EP 1007 DI 10.1189/jlb.1210699 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 770SI UT WOS:000291108400020 PM 21385949 ER PT J AU Dickerson, F Stallings, C Vaughan, C Origoni, A Khushalani, S Dickinson, D Medoff, D AF Dickerson, Faith Stallings, Cassie Vaughan, Crystal Origoni, Andrea Khushalani, Sunil Dickinson, Dwight Medoff, Deborah TI Cognitive Functioning in Recent Onset Psychosis SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE Cognitive functioning; recent onset psychosis; schizophrenia; bipolar disorder ID BIPOLAR DISORDER; NEUROPSYCHOLOGICAL DEFICITS; REPEATABLE BATTERY; SCHIZOPHRENIA; METAANALYSIS; DYSFUNCTION; DEPRESSION AB The purpose of the study was to compare the cognitive functioning of persons with a recent onset of psychosis with schizophrenia-spectrum disorders and bipolar disorder and nonpsychiatric controls. A total of 56 persons with a schizophrenia-spectrum disorder and 60 with bipolar disorder, all with a recent onset psychosis, and 312 nonpsychiatric controls were evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Wisconsin Card Sorting Test (WCST). Comparison of the three groups through analysis of covariance indicated a significant difference among the groups for all of the cognitive variables. Pairwise contrasts of the two recent onset groups showed a significant difference favoring the bipolar disorder group on RBANS Language (p = 0.020) and Total (p = 0.050) and a marginally significant difference on RBANS Immediate Memory (p = 0.053) but not on the other RBANS variables or on the WCST. Cognitive performance is broadly impaired in recent onset psychosis, with a cognitive advantage to bipolar disorder patients compared with schizophrenia-spectrum patients. C1 [Dickerson, Faith; Stallings, Cassie; Vaughan, Crystal; Origoni, Andrea; Khushalani, Sunil] Sheppard Pratt, Baltimore, MD 21204 USA. [Dickinson, Dwight] NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Medoff, Deborah] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Dickerson, F (reprint author), Sheppard Pratt, 6501 N Charles St, Baltimore, MD 21204 USA. EM fdickerson@sheppardpratt.org FU Stanley Medical Research Institute FX This study was funded by the Stanley Medical Research Institute. NR 24 TC 8 Z9 9 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD JUN PY 2011 VL 199 IS 6 BP 367 EP 371 DI 10.1097/NMD.0b013e31821cd0ff PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 771GH UT WOS:000291144700002 PM 21629013 ER PT J AU Buttermore, ED Dupree, JL Cheng, J An, XL Tessarollo, L Bhat, MA AF Buttermore, Elizabeth D. Dupree, Jeffrey L. Cheng, JrGang An, Xiuli Tessarollo, Lino Bhat, Manzoor A. TI The Cytoskeletal Adaptor Protein Band 4.1B Is Required for the Maintenance of Paranodal Axoglial Septate Junctions in Myelinated Axons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GLIAL JUNCTIONS; MOLECULAR-ORGANIZATION; DROSOPHILA-CORACLE; MEMBRANE; DOMAINS; FAMILY; CASPR2; MEMBER; NEUREXIN; BRAIN AB Precise targeting and maintenance of axonal domains in myelinated axons is essential for saltatory conduction. Caspr and Caspr2, which localize at paranodal and juxtaparanodal domains, contain binding sites for the cytoskeletal adaptor protein 4.1B. The exact role of 4.1B in the organization and maintenance of axonal domains is still not clear. Here, we report the generation and characterization of 4.1B-null mice. We show that loss of 4.1B in the PNS results in mislocalization of Caspr at paranodes and destabilization of paranodal axoglial septate junctions (AGSJs) as early as postnatal day 30. In the CNS, Caspr localization is progressively disrupted and ultrastructural analysis showed paranodal regions that were completely devoid of AGSJs, with axolemma separated from the myelin loops, and loops coming off the axolemma. Most importantly, our phenotypic analysis of previously generated 4.1B mutants, used in the study by Horresh et al. (2010), showed that Caspr localization was not affected in the PNS, even after 1 year; and 4.1R was neither expressed, nor enriched at the paranodes. Furthermore, ultrastructural analysis of these 4.1B mutants showed destabilization of CNS AGSJs at similar to 1 year. We also discovered that the 4.1B locus is differentially expressed in the PNS and CNS, and generates multiple splice isoforms in the PNS, suggesting 4.1B may function differently in the PNS versus CNS. Together, our studies provide direct evidence that 4.1B plays a pivotal role in interactions between the paranodal AGSJs and axonal cytoskeleton, and that 4.1B is critically required for long-term maintenance of axonal domains in myelinated axons. C1 [Buttermore, Elizabeth D.; Bhat, Manzoor A.] Univ N Carolina, Sch Med, Curriculum Neurobiol, Chapel Hill, NC 27599 USA. [Buttermore, Elizabeth D.; Bhat, Manzoor A.] Univ N Carolina, Sch Med, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. [Buttermore, Elizabeth D.; Cheng, JrGang; Bhat, Manzoor A.] Univ N Carolina, Sch Med, Ctr Neurosci, Chapel Hill, NC 27599 USA. [Bhat, Manzoor A.] Univ N Carolina, Sch Med, Carolina Ctr Dev Disabil, Chapel Hill, NC 27599 USA. [Dupree, Jeffrey L.] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA 23298 USA. [An, Xiuli] New York Blood Ctr, Red Cell Physiol Lab, New York, NY 10065 USA. [Tessarollo, Lino] NCI, Neural Dev Grp, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Bhat, MA (reprint author), Univ N Carolina, Sch Med, Curriculum Neurobiol, Neurosci Res Bldg, Chapel Hill, NC 27599 USA. EM manzoor_bhat@med.unc.edu FU NIH [GM063074, NS050356]; National Multiple Sclerosis Society; State of North Carolina FX This work was supported by NIH Grants GM063074 and NS050356, the National Multiple Sclerosis Society, and the State of North Carolina (M.A.B.). We thank Alan Fanning and members of the Bhat Laboratory for helpful discussions, and Victoria Madden of University of North Carolina Microscopy Facility for assistance with electron microscopy. NR 40 TC 29 Z9 30 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 1 PY 2011 VL 31 IS 22 BP 8013 EP 8024 DI 10.1523/JNEUROSCI.1015-11.2011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 772CJ UT WOS:000291208100008 PM 21632923 ER PT J AU Tanabe, S Haefner, RM Cumming, BG AF Tanabe, Seiji Haefner, Ralf M. Cumming, Bruce G. TI Suppressive Mechanisms in Monkey V1 Help to Solve the Stereo Correspondence Problem SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PRIMARY VISUAL-CORTEX; BINOCULAR DISPARITY; COMPLEX CELLS; MACAQUE V1; NEURONS; MODELS; DEPTH; SELECTIVITY; CONNECTIVITY; RESPONSES AB Neurons encode the depth in stereoscopic images by combining the signals from the receptive fields in the two eyes. Local variations in single images can activate neurons that do not signal the correct disparity (false matches), giving rise to the stereo correspondence problem. We used binocular white-noise stimuli to decompose the responses of monkey primary visual cortex V1 neurons into the elements of a linear-nonlinear model (via spike-triggered covariance analysis). In our population of disparity-selective neurons, we find both excitatory and suppressive elements in many of the neurons. Their binocular receptive fields were aligned in a specific push-pull manner for disparity. We demonstrate that this arrangement reduces the responses to false matches but preserves the responses to true matches. The responses of the cells to the noise stimuli were well explained by a linear summation of the elements, followed by a nonlinearity. This model also explained the shape of independently measured disparity-tuning curves, although it overestimated the response magnitude. This study constitutes the first direct physiological evidence for the contribution of suppressive mechanisms to disparity selectivity. This new mechanism contributes to solving the stereo correspondence problem. C1 [Tanabe, Seiji; Haefner, Ralf M.; Cumming, Bruce G.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Tanabe, S (reprint author), 1410 Pelham Pkwy S,Room 822, Bronx, NY 10461 USA. EM seiji.tanabe@gmail.com OI Haefner, Ralf M/0000-0002-5031-0379 FU National Eye Institute/National Institutes of Health FX This work was supported by the Intramural Program of the National Eye Institute/National Institutes of Health. We thank H. Nienborg for comments on this manuscript and D. Parker and B. Nagy for excellent animal care. NR 30 TC 19 Z9 19 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 1 PY 2011 VL 31 IS 22 BP 8295 EP 8305 DI 10.1523/JNEUROSCI.5000-10.2011 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 772CJ UT WOS:000291208100035 PM 21632950 ER PT J AU Kirk, M Calzone, K Arimori, N Tonkin, E AF Kirk, Maggie Calzone, Kathleen Arimori, Naoko Tonkin, Emma TI Genetics-Genomics Competencies and Nursing Regulation SO JOURNAL OF NURSING SCHOLARSHIP LA English DT Article DE Genetics; genomics; competence; regulation; nexus; nursing education; nursing licensure ID TRANSLATION; EDUCATION; KNOWLEDGE AB Purpose: The aim of this article is to explore the interaction between the integration of genetics-genomics competencies into nursing curricula and regulatory standards. By taking a global perspective of activity in this field, we aim to develop a framework that can inform strategic planning in relation to international genetics-genomics and nursing education. Methods: We focus our exploration around a small-scale international survey on the progress, achievements, and critical success factors of 10 countries in relation to the integration of genetics-genomics into nursing education, with exemplars from three of those countries. Findings: Analysis of the data generated 10 themes, each with several subthemes that play a critical role in the development of genetics-genomics in nursing education and practice. The themes were organized into three overarching themes: nursing in genetics, genetics in nursing, and recognition and support. Genetics-genomics competence is not fully integrated into nursing education at an appropriate level in any country, nor was it reflected robustly in current standards for registration and licensure. Conclusion: Strong leadership from the specialist genetics community plays a critical role in defining genetics-genomics competence but the engagement of nursing professionals at senior levels in both government and regulatory institutions is essential if nurses are to be active participants in the innovations offered by genomic healthcare. Clinical Relevance: Safe and effective nursing practice must incorporate the needs of those with, at risk for, or susceptible to genetic-genomic conditions, as well as those who might benefit from the application of genomic technologies in the diagnosis and management of common conditions such as cancer and heart disease. The scope of such practice can be articulated though competence statements. Professional regulation defines the standard of competence that practicing nurses should demonstrate at initial registration and licensure. C1 [Kirk, Maggie] Univ Glamorgan, Fac Hlth Sport & Sci, NHS Natl Genet Educ & Dev Ctr, Pontypridd CF37 1DL, M Glam, Wales. [Calzone, Kathleen] NCI CCR Genet Branch, Bethesda, MD USA. [Arimori, Naoko] St Lukes Coll Nursing, Tokyo, Japan. RP Kirk, M (reprint author), Univ Glamorgan, Fac Hlth Sport & Sci, NHS Natl Genet Educ & Dev Ctr, Pontypridd CF37 1DL, M Glam, Wales. EM mkirk@glam.ac.uk RI Kirk, Maggie/G-9333-2012; Tonkin, Emma/L-8370-2016 OI Kirk, Maggie/0000-0003-1745-7106; FU Department of Health; Japan Society for the Promotion of Science [12307059]; National Institutes of Health; National Human Genome Research Institute; The Office of Policy, Communications and Education (OPCE); Genomic Healthcare Branch; National Cancer Institute, Center for Cancer Research, Genetics Branch; Office of Rare Disease FX The NHS National Genetics Education & Development Centre is funded by the Department of Health. Naoko Arimori is supported by a Grant-in-Aid for Scientific Research (A) No. 12307059 from the Japan Society for the Promotion of Science. The U.S. Genetic-Genomic Nursing Competency Initiative is supported by the National Institutes of Health, National Human Genome Research Institute, The Office of Policy, Communications and Education (OPCE), Genomic Healthcare Branch; National Cancer Institute, Center for Cancer Research, Genetics Branch; and the Office of Rare Disease; as well as in-kind support from the American Nurses Association and the American Association of Colleges of Nursing. Thanks to Dr. Juping Yu for her help in compiling Table 2 and to those who participated in the survey. NR 27 TC 24 Z9 24 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6546 J9 J NURS SCHOLARSHIP JI J. Nurs. Scholarsh. PD JUN PY 2011 VL 43 IS 2 BP 107 EP 116 DI 10.1111/j.1547-5069.2011.01388.x PG 10 WC Nursing SC Nursing GA 767PH UT WOS:000290868000002 PM 21605314 ER PT J AU Shrader, JA Joe, GO AF Shrader, Joseph A. Joe, Galen O. TI Posttransplant Distal Limb Syndrome SO JOURNAL OF ORTHOPAEDIC & SPORTS PHYSICAL THERAPY LA English DT Editorial Material C1 [Shrader, Joseph A.] NIH, Ctr Clin, Dept Rehabil Med, Phys Therapy Sect, Bethesda, MD 20892 USA. RP Shrader, JA (reprint author), NIH, Ctr Clin, Dept Rehabil Med, Phys Therapy Sect, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU J O S P T, PI ALEXANDRIA PA 1111 NORTH FAIRFAX ST, STE 100, ALEXANDRIA, VA 22314-1436 USA SN 0190-6011 J9 J ORTHOP SPORT PHYS JI J. Orthop. Sports Phys. Ther. PD JUN PY 2011 VL 41 IS 6 BP 458 EP 458 DI 10.2519/jospt.2011.0412 PG 1 WC Orthopedics; Rehabilitation; Sport Sciences SC Orthopedics; Rehabilitation; Sport Sciences GA 772NY UT WOS:000291241800011 PM 21628828 ER PT J AU Covington, SN Hillard, PJ Sterling, EW Nelson, LM AF Covington, Sharon N. Hillard, Paula J. Sterling, Evelina W. Nelson, Lawrence M. CA Primary Ovarian Insufficiency TI A Family Systems Approach to Primary Ovarian Insufficiency SO JOURNAL OF PEDIATRIC AND ADOLESCENT GYNECOLOGY LA English DT Article DE Primary ovarian insufficiency; POI; Premature ovarian failure; POF; Premature menopause; Adoloscence; Family systems; Emotional; Psychological; Parenting ID STIGMA; FAILURE; WOMEN AB Receiving the diagnosis of Primary Ovarian Insufficiency (POI) can be emotionally difficult and confusing for young girls and their families. Parents need assistance in knowing how to help their daughters understand and live with the diagnosis in a way that allows for healthy growth and development. This paper provides a starting point for parents and clinicians with "Tips and Tools for Talking: Helping Your Daughter Understand Primary Ovarian Insufficiency". C1 [Covington, Sharon N.; Nelson, Lawrence M.] NICHHD, Integrat Reprod Med Grp, Intramural Res Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Hillard, Paula J.] Stanford Univ, Sch Med, Dept Obstet & Gynecol, Div Gynecol Specialties Pediat & Adolescent Gynec, Stanford, CA 94305 USA. [Sterling, Evelina W.; Primary Ovarian Insufficiency] Rachels Well Inc, Marietta, GA USA. RP Covington, SN (reprint author), 15001 Shady Grove Rd,Suite 220, Rockville, MD 20850 USA. EM sharon.covington@integramed.com FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National institutes of Health, Bethesda, Maryland FX This work was supported in part by the Intramural Research Program on Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National institutes of Health, Bethesda, Maryland. LMN is a Commissioned Officer in the United States Public Health Service NR 11 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-3188 J9 J PEDIATR ADOL GYNEC JI J. Pediatr Adolesc. Gynecol. PD JUN PY 2011 VL 24 IS 3 BP 137 EP 141 DI 10.1016/j.jpag.2010.12.004 PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 773TN UT WOS:000291333800008 PM 21269850 ER PT J AU Fox, SD Falk, RT Veenstra, TD Issaq, HJ AF Fox, Stephen D. Falk, Roni T. Veenstra, Timothy D. Issaq, Haleem J. TI Quantitation of free and total bisphenol A in human urine using liquid chromatography-tandem mass spectrometry SO JOURNAL OF SEPARATION SCIENCE LA English DT Article DE Biofluids; Bisphenol A; HPLC/MS/MS; Selected reaction monitoring; Urine/BPA ID IN-SITU DERIVATIZATION; HPLC-MS/MS METHOD; HUMAN EXPOSURE; PHASE MICROEXTRACTION; ENVIRONMENTAL PHENOLS; NORMAL WOMEN; SERUM; QUANTIFICATION; METABOLITES; EXTRACTION AB Bisphenol A (BPA) is employed in the synthesis of polycarbonate plastics and epoxy resins and is widely used in consumer products including as a coating for the inside of almost all food and beverage containers and thermal-imaging paper. Bisphenol A is considered to have important health implications because it possesses weak estrogenic activity and can leach from storage containers resulting in its consumption by both humans and animals. It is metabolized in the body and excreted into urine as a glucuronide derivative. In this report, we present an accurate, selective, sensitive, and reproducible high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) method for the quantitation of BPA in human urine, which is not prone to exogenous contamination. BPA-glucuronide is hydrolyzed enzymatically, extracted with toluene, derivatized with dansyl chloride, and the BPA-(dansyl)(2) derivative is analyzed using reversed-phase HPLC/MS/MS. Calibration was linear to 50 ng/mL with a limit of quantitation of 50 pg/mL and a limit of detection of 5 pg/mL. C1 [Fox, Stephen D.; Veenstra, Timothy D.; Issaq, Haleem J.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Falk, Roni T.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Issaq, HJ (reprint author), NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM issaqh@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors thank Dow Chemical Company (Midland, MI) for graciously donating a sample of BPA-monoglucuronide sodium salt. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contracts 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 United States Government. NR 37 TC 19 Z9 19 U1 1 U2 32 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1615-9306 J9 J SEP SCI JI J. Sep. Sci. PD JUN PY 2011 VL 34 IS 11 BP 1268 EP 1274 DI 10.1002/jssc.201100087 PG 7 WC Chemistry, Analytical SC Chemistry GA 773XY UT WOS:000291346400007 PM 21506272 ER PT J AU Shad, MU Bidesi, AP Chen, LA Ernst, M Rao, U AF Shad, Mujeeb U. Bidesi, Anup P. Chen, Li-Ann Ernst, Monique Rao, Uma TI Neurobiology of Decision Making in Depressed Adolescents: A Functional Magnetic Resonance Imaging Study SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE neurobiology; decision making; depressed; fMRI ID VENTROMEDIAL PREFRONTAL CORTEX; FAMILY HISTORY METHOD; RISK-TAKING; GAMBLING TASK; DEVELOPMENTAL-CHANGES; ORBITOFRONTAL CORTEX; CHOICE SELECTION; PUBERTAL CHANGES; PERSPECTIVE; PERFORMANCE AB Objective: Despite evidence that impaired reward- and risk-related behavior during adolescence can have potentially serious short- and long-term consequences, few studies have investigated the impact of depression on reward-related selection in adolescents. This study examined the relationship between reward-related behavior and prefrontal activations in depressed and healthy adolescents during a decision-making task. Method: A total of 22 adolescents with no personal or family history of psychiatric illness and 22 adolescents with major depressive disorder were administered a monetary, two-option decision-making task, the Wheel of Fortune, using a functional magnetic resonance imaging protocol. The analysis was focused on the selection phase, i.e., the first phase of the decision-making process, which typically includes two more phases, the anticipation of outcome and the feedback. Results: Similar prefrontal regions were activated in healthy and depressed adolescents during reward-related selection. However, in a contrast involving the selection of high-risk (low-probability/high-magnitude reward) versus equal-risk (50% chance of reward) options, healthy adolescents showed greater activation than patients in the right lateral orbitofrontal cortex (OFC), whereas participants with depression showed greater activation than healthy subjects in the left dorsal OFC and right caudal anterior cingulate cortex. In addition, healthy adolescents, but not participants with depression, showed a negative correlation between high-risk behavior and neuronal activation in prespecified prefrontal regions. Conclusions: These results suggest subtle changes in the neural responses to reward selection in depressed adolescents. These findings should be replicated in larger samples, and the association of these neuronal changes with treatment response and prognosis should be examined. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(6):612-621. C1 [Shad, Mujeeb U.] Univ Texas Hlth Sci Ctr, Houston, TX USA. [Bidesi, Anup P.; Chen, Li-Ann] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Ernst, Monique] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Rao, Uma] Meharry Med Coll, Nashville, TN 37208 USA. RP Shad, MU (reprint author), 1941 East Rd, BBSB 3118, Houston, TX 77054 USA. EM mujeeb.u.shad@uth.tmc.edu FU National Institutes of Health [DA14037, DA15131, DA17804, DA17805, MH62464, MH68391]; University of Texas Southwestern Medical Center; Meharry Medical College; Eli Lilly and Co. FX This work was supported in part by grants from the National Institutes of Health (DA14037, DA15131, DA17804, DA17805, MH62464, and MH68391), the Sarah M. and Charles E. Seay Endowed Chair in Child Psychiatry at University of Texas Southwestern Medical Center, and the Endowed Chair in Brain and Behavior Research at Meharry Medical College (U.R.).; Dr. Shad has received funding from Eli Lilly and Co. Drs. Ernst and Rao, Mr. Bidesi, and Ms. Chen report no biomedical financial interests or potential conflicts of interest. NR 47 TC 13 Z9 13 U1 2 U2 15 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 JUN PY 2011 VL 50 IS 6 BP 612 EP 621 DI 10.1016/j.jaac.2011.03.011 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 773DZ UT WOS:000291288500012 PM 21621145 ER PT J AU Cruz, MLS Hance, LF Korelitz, J Aguilar, A Byrne, J Serchuck, LK Hazra, R Worrell, C AF Santos Cruz, Maria Leticia Hance, Laura Freimanis Korelitz, James Aguilar, Adriana Byrne, Julianne Serchuck, Leslie K. Hazra, Rohan Worrell, Carol CA NISDI Pediat Study Grp 2010 TI Characteristics of HIV Infected Adolescents in Latin America: Results from the NISDI Pediatric Study SO JOURNAL OF TROPICAL PEDIATRICS LA English DT Article DE HIV-infected adolescents; Latin America; Cohort study ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; OLDER CHILDREN; FOLLOW-UP; COHORT; PROGRESSION; MORTALITY; ADHERENCE; SURVIVAL; DISEASE AB Methods: The NISDI pediatric protocol is an ongoing prospective cohort study that collects demographic, clinical, immunologic, virologic and medication data. Youth were enrolled at 15 sites in Brazil, Argentina and Mexico between 2002 and 2006. HIV-infected subjects aged 12-21 years at the time of enrollment were analyzed. Results: Data from 120 HIV-infected youth were analyzed. Sixty-nine (58%) had acquired HIV through vertical transmission (VT); 51(42%) via horizontal transmission (HT). Twenty-eight percent of the VT group were not diagnosed until they were epsilon 10 years of age. Ninety-one percent of the VT group and 46% of the HT were receiving ARV at enrollment. Modes of HT included sexual (ST), blood product transfusion (BPT) and unknown (U). Severe immunodeficiency was frequent (21%) in the ST group. Low BMI was frequent in the VT and BPT sub-groups. Utilization of HAART increased over the course of the study, but viral suppression was present in only 38% of the VT group and 37% of the HT group at study end. Conclusions: This cohort of HIV-infected adolescents in Latin America displayed a diverse epidemiologic pattern. Care providers must be prepared to address the diverse needs and challenges of this population. The levels of virologic suppression achieved were inadequate. Further research into appropriate interventions for this population is urgently needed. C1 [Santos Cruz, Maria Leticia] Hosp Servidores Estado RJ, Serv Doencas Infecciosas & Parasitarias, Rio De Janeiro, Brazil. [Hance, Laura Freimanis; Korelitz, James; Byrne, Julianne] WESTAT Corp, Rockville, MD 20850 USA. [Aguilar, Adriana] Hosp Diego Paroissien, Buenos Aires, DF, Argentina. [Serchuck, Leslie K.; Hazra, Rohan; Worrell, Carol] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD USA. RP Cruz, MLS (reprint author), Hosp Servidores Estado, SaudeServ Doencas Infecciosas & Parasitarias, Rua Sacadura Cabral 178,Anexo 4, BR-20221903 Rio De Janeiro, Brazil. EM mleticia@diphse.com.br RI Mussi-Pinhata, Marisa/G-6568-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3345, N01-DK-8-0001] FX Eunice Kennedy Shriver National Institute of Child Health and Human Development Contracts #N01-HD-3-3345 and #N01-DK-8-0001. NR 28 TC 9 Z9 10 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0142-6338 EI 1465-3664 J9 J TROP PEDIATRICS JI J. Trop. Pediatr. PD JUN PY 2011 VL 57 IS 3 BP 165 EP 172 DI 10.1093/tropej/fmq068 PG 8 WC Pediatrics; Tropical Medicine SC Pediatrics; Tropical Medicine GA 770DQ UT WOS:000291067600003 ER PT J AU Shukan, E Hitt, N AF Shukan, Evan Hitt, Nancy TI Perhaps a pilot study RESPONSE SO LAB ANIMAL LA English DT Editorial Material C1 [Shukan, Evan; Hitt, Nancy] Natl Inst Neurol Disorders & Stroke, Anim Hlth Care Sect, NIH, Bethesda, MD 20824 USA. RP Shukan, E (reprint author), Natl Inst Neurol Disorders & Stroke, Anim Hlth Care Sect, NIH, Bethesda, MD 20824 USA. NR 2 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 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD JUN PY 2011 VL 40 IS 6 BP 173 EP 173 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 771UX UT WOS:000291187300013 PM 21597495 ER PT J AU Pai, VM Rapacchi, S Kellman, P Croisille, P Wen, H AF Pai, V. M. Rapacchi, S. Kellman, P. Croisille, P. Wen, H. TI PCATMIP: Enhancing Signal Intensity in Diffusion-Weighted Magnetic Resonance Imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE principal component analysis; diffusion; temporal MIP; low SNR ID PRINCIPAL COMPONENT ANALYSIS; MRI; MOTION; FMRI; REGISTRATION; FRAMEWORK; IMAGES; FLOWS; MODEL AB Diffusion-weighted MRI studies generally lose signal intensity to physiological motion, which can adversely affect quantification/diagnosis. Averaging over multiple repetitions, often used to improve image quality, does not eliminate the signal loss. In this article, PCATMIP, a combined principal component analysis and temporal maximum intensity projection approach, is developed to address this problem. Data are first acquired for a fixed number of repetitions. Assuming that physiological fluctuations of image intensities locally are likely temporally correlated unlike random noise, a local moving boxcar in the spatial domain is used to reconstruct low-noise images by considering the most relevant principal components in the temporal domain. Subsequently, a temporal maximum intensity projection yields a high signal-intensity image. Numerical and experimental studies were performed for validation and to determine optimal parameters for increasing signal intensity and minimizing noise. Subsequently, a combined principal component analysis and temporal maximum intensity projection approach was used to analyze diffusion-weighted porcine liver MRI scans. In these scans, the variability of apparent diffusion coefficient values among repeated measurements was reduced by 59% relative to averaging, and there was an increase in the signal intensity with higher intensity differences observed at higher b-values. In summary, a combined principal component analysis and temporal maximum intensity projection approach is a postprocessing approach that corrects for bulk motion-induced signal loss and improves apparent diffusion coefficient measurement reproducibility. Magn Reson Med 65:1611-1619, 2011. (C)2010 Wiley-Liss, Inc. C1 [Pai, V. M.; Kellman, P.; Wen, H.] NHLBI, LCE, NIH, Bethesda, MD 20892 USA. [Rapacchi, S.; Croisille, P.] Inst Natl Sci Appl Lyon, CREATIS LRMN, Lyon, France. RP Pai, VM (reprint author), NHLBI, LCE, NIH, Room B1D-416,MSC 1061,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM paiv@mail.nih.gov RI Croisille, Pierre/H-4928-2014; Wen, Han/G-3081-2010 OI Croisille, Pierre/0000-0003-4019-3460; Wen, Han/0000-0001-6844-2997 NR 23 TC 10 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2011 VL 65 IS 6 BP 1611 EP 1619 DI 10.1002/mrm.22748 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 770VB UT WOS:000291115500011 PM 21590803 ER PT J AU Morton, RA Luo, GX Davis, MI Hales, TG Lovinger, DM AF Morton, Russell A. Luo, Guoxiang Davis, Margaret I. Hales, Tim G. Lovinger, David M. TI Fluorophore assisted light inactivation (FALI) of recombinant 5-HT(3)A receptor constitutive internalization and function SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article DE 5-Hydroxytryptamine type 3 (5-HT3) receptors; Fluorophore assisted light inactivation; Constitutive internalization; Electrophysiology ID GREEN FLUORESCENT PROTEIN; EGFP-FUSION PROTEINS; LASER INACTIVATION; SINGLET-OXYGEN; 5-HT3 RECEPTORS; MODULATION; SUBUNIT; CALI; ENDOCYTOSIS; ANTAGONIST AB Fluorescent proteins and molecules are now widely used to tag and visualize proteins resulting in an improved understanding of protein trafficking, localization, and function. In addition, fluorescent tags have also been used to inactivate protein function in a spatially and temporally-defined manner, using a technique known as fluorophore-assisted light inactivation (FALI) or chromophore-assisted light inactivation (CALI). In this study we tagged the serotonin(3) A subunit with the alpha-bungarotoxin binding sequence (BBS) and subsequently labeled 5-HT(3)A/BBS receptors with fluorescently conjugated alpha-bungarotoxin in live cells. We show that 5-HT(3)A/BBS receptors are constitutively internalized in the absence of an agonist and internalization as well as receptor function are inhibited by fluorescence. The fluorescence-induced disruption of function and internalization was reduced with oxygen radical scavengers suggesting the involvement of reactive oxygen species, implicating the FALI process. Furthermore, these data suggest that intense illumination during live-cell microscopy may result in inadvertent FALI and inhibition of protein trafficking. (C) 2011 Published by Elsevier Inc. C1 [Morton, Russell A.; Luo, Guoxiang; Davis, Margaret I.; Lovinger, David M.] NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. [Morton, Russell A.; Hales, Tim G.; Lovinger, David M.] George Washington Univ, Dept Physiol & Pharmacol, Washington, WA USA. [Hales, Tim G.] Univ Dundee, Ninewells Hosp & Med Sch, Ctr Neurosci, Inst Acad Anaesthesia, Dundee DD1 9SY, Scotland. RP Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, NIH, 5625 Fishers Lane Rm Ts 13A, Rockville, MD 20852 USA. EM lovindav@mail.nih.gov OI Davis, Margaret/0000-0002-0489-8351 FU Intramural NIH HHS [ZIA AA000407-09] NR 44 TC 3 Z9 3 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 EI 1095-9327 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD JUN PY 2011 VL 47 IS 2 BP 79 EP 92 DI 10.1016/j.mcn.2011.02.007 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 771YK UT WOS:000291196400002 PM 21338684 ER PT J AU Richardson, RM Kells, AP Rosenbluth, KH Salegio, EA Fiandaca, MS Larson, PS Starr, PA Martin, AJ Lonser, RR Federoff, HJ Forsayeth, JR Bankiewicz, KS AF Richardson, R. Mark Kells, Adrian P. Rosenbluth, Kathryn H. Salegio, Ernesto Aguilar Fiandaca, Massimo S. Larson, Paul S. Starr, Philip A. Martin, Alastair J. Lonser, Russell R. Federoff, Howard J. Forsayeth, John R. Bankiewicz, Krystof S. TI Interventional MRI-guided Putaminal Delivery of AAV2-GDNF for a Planned Clinical Trial in Parkinson's Disease SO MOLECULAR THERAPY LA English DT Article ID CONVECTION-ENHANCED DELIVERY; DOPAMINERGIC NIGROSTRIATAL PATHWAY; DECARBOXYLASE GENE-THERAPY; AGED RHESUS-MONKEYS; NEUROTROPHIC FACTOR; ADENOASSOCIATED VIRUS; PHASE-I; INTRAPUTAMENAL INFUSION; PRIMATE BRAIN; BASAL GANGLIA AB Clinical trials involving direct infusion of neurotrophic therapies for Parkinson's disease (PD) have suffered from poor coverage of the putamen. The planned use of a novel interventional-magnetic resonance imaging (iMRI) targeting system for achieving precise, real-time convection-enhanced delivery in a planned clinical trial of adeno-associated virus serotype 2 (AAV2)-glial-derived neurotrophic factor (GDNF) in PD patients was modeled in nonhuman primates (NHP). NHP received bilateral coinfusions of gadoteridol (Gd)/AAV2-GDNF into two sites in each putamen, and three NHP received larger infusion volumes in the thalamus. The average targeting error for cannula tip placement in the putamen was <1 mm, and adjacent putamenal infusions were distributed in a uniform manner. GDNF expression patterns in the putamen were highly correlated with areas of Gd distribution seen on MRI. The distribution volume to infusion volume ratio in the putamen was similar to that in the thalamus, where larger infusions were achieved. Modeling the placement of adjacent 150 and 300 mu l thalamic infusions into the three-dimensional space of the human putamen demonstrated coverage of the postcommissural putamen, containment within the striatum and expected anterograde transport to globus pallidus and substantia nigra pars reticulata. The results elucidate the necessary parameters for achieving widespread GDNF expression in the putamenal motor area and afferent substantia nigra of PD patients. C1 [Richardson, R. Mark; Kells, Adrian P.; Rosenbluth, Kathryn H.; Salegio, Ernesto Aguilar; Fiandaca, Massimo S.; Larson, Paul S.; Starr, Philip A.; Forsayeth, John R.; Bankiewicz, Krystof S.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Martin, Alastair J.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, Bethesda, MD USA. [Federoff, Howard J.] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. [Federoff, Howard J.] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20007 USA. RP Richardson, RM (reprint author), Univ Calif San Francisco, Dept Neurol Surg, 505 Parnassus Ave,Room M779, San Francisco, CA 94143 USA. EM richardsonma@neuosurg.usf.edu RI Richardson, Robert/C-6819-2016 OI Richardson, Robert/0000-0003-2620-7387 FU NIH [F32 NS064692]; Michael J. Fox Foundation FX This work was supported in part by an NIH award F32 NS064692 (R.M.R.), and the Michael J. Fox Foundation (K.S.B.). NR 44 TC 49 Z9 49 U1 3 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD JUN PY 2011 VL 19 IS 6 BP 1048 EP 1057 DI 10.1038/mt.2011.11 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 772PA UT WOS:000291244900008 PM 21343917 ER PT J AU Magtanong, L Ho, CH Barker, SL Jiao, W Baryshnikova, A Bahr, S Smith, AM Heisler, LE Choy, JS Kuzmin, E Andrusiak, K Kobylianski, A Li, ZJ Costanzo, M Basrai, MA Giaever, G Nislow, C Andrews, B Boone, C AF Magtanong, Leslie Ho, Cheuk Hei Barker, Sarah L. Jiao, Wei Baryshnikova, Anastasia Bahr, Sondra Smith, Andrew M. Heisler, Lawrence E. Choy, John S. Kuzmin, Elena Andrusiak, Kerry Kobylianski, Anna Li, Zhijian Costanzo, Michael Basrai, Munira A. Giaever, Guri Nislow, Corey Andrews, Brenda Boone, Charles TI Dosage suppression genetic interaction networks enhance functional wiring diagrams of the cell SO NATURE BIOTECHNOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; PROTEIN-KINASE; RIBOSOMAL-PROTEINS; GENOMIC DATA; YEAST; COMPLEX; OVEREXPRESSION; KINETOCHORE; EXPRESSION; CYCLE AB Dosage suppression is a genetic interaction in which overproduction of one gene rescues a mutant phenotype of another gene. Although dosage suppression is known to map functional connections among genes, the extent to which it might illuminate global cellular functions is unclear. Here we analyze a network of interactions linking dosage suppressors to 437 essential genes in yeast. For 424 genes, we curated interactions from the literature. Analyses revealed that many dosage suppression interactions occur between functionally related genes and that the majority do not overlap with other types of genetic or physical interactions. To confirm the generality of these network properties, we experimentally identified dosage suppressors for 29 genes from pooled populations of temperature-sensitive mutant cells transformed with a high-copy molecular-barcoded open reading frame library, MoBY-ORF 2.0. We classified 87% of the 1,640 total interactions into four general types of suppression mechanisms, which provided insight into their relative frequencies. This work suggests that integrating the results of dosage suppression studies with other interaction networks could generate insights into the functional wiring diagram of a cell. C1 [Magtanong, Leslie; Ho, Cheuk Hei; Barker, Sarah L.; Jiao, Wei; Baryshnikova, Anastasia; Bahr, Sondra; Smith, Andrew M.; Heisler, Lawrence E.; Kuzmin, Elena; Andrusiak, Kerry; Kobylianski, Anna; Li, Zhijian; Costanzo, Michael; Giaever, Guri; Nislow, Corey; Andrews, Brenda; Boone, Charles] Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Banting & Best Dept Med Genet, Toronto, ON, Canada. [Choy, John S.; Basrai, Munira A.] NCI, Genet Branch Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Giaever, Guri] Univ Toronto, Dept Pharmaceut Sci, Toronto, ON, Canada. [Magtanong, Leslie; Ho, Cheuk Hei; Barker, Sarah L.; Jiao, Wei; Baryshnikova, Anastasia; Bahr, Sondra; Smith, Andrew M.; Kuzmin, Elena; Andrusiak, Kerry; Li, Zhijian; Costanzo, Michael; Giaever, Guri; Nislow, Corey; Andrews, Brenda; Boone, Charles] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. RP Boone, C (reprint author), Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. EM brenda.andrews@utoronto.ca; charlie.boone@utoronto.ca RI Smith, Andrew/C-1253-2009; Giaever, Guri/D-3930-2009; OI Baryshnikova, Anastasia/0000-0002-0123-2052; Nislow, Corey/0000-0002-4016-8874 FU Canadian Institutes of Health Research (CIHR) [020380, MOP-81340, MOP-84305, MOP-57830]; University of Toronto; US National Cancer Institute; US National Institutes of Health; Canadian Cancer Society; Genome Canada through the Ontario Genomics Institute [2004-OGI-3-01]; Natural Sciences and Engineering Research Council of Canada [RGPIN 204899-06] FX We thank S. Dixon for critical comments on the manuscript, M. Gebbia for microarray technical support, and C. Myers and J. Bellay for advice and data analysis support. L.M. was supported by a Canadian Institutes of Health Research (CIHR) doctoral research award. A.M.S. was supported by a University of Toronto open fellowship. J.S.C. and M.A.B. were supported by the Intramural Research Program of the US National Cancer Institute, US National Institutes of Health. G.G. was supported by the Canadian Cancer Society and the CIHR (research agreements 020380 and MOP-81340, respectively). C.N. was supported by the CIHR (MOP-84305). C.B. and B. A. were supported by Genome Canada through the Ontario Genomics Institute (2004-OGI-3-01). C.B. was supported by the CIHR (MOP-57830) and the Natural Sciences and Engineering Research Council of Canada (RGPIN 204899-06). NR 51 TC 43 Z9 43 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 2011 VL 29 IS 6 BP 505 EP U66 DI 10.1038/nbt.1855 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 773WL UT WOS:000291342100016 PM 21572441 ER PT J AU Collins, FS AF Collins, Francis S. TI Mining for therapeutic gold SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM collinsf@mail.nih.gov NR 2 TC 45 Z9 45 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD JUN PY 2011 VL 10 IS 6 BP 397 EP 397 DI 10.1038/nrd3461 PG 1 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 771NE UT WOS:000291165000001 PM 21629277 ER PT J AU Billington, N Sellers, JR AF Billington, Neil Sellers, James R. TI Dynein struts its stuff SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID MICROTUBULE-BINDING DOMAIN; CYTOPLASMIC DYNEIN; MOTOR DOMAIN; INTRACELLULAR-TRANSPORT; COILED-COIL; MECHANISM; ATPASE; STALK; PROTEIN; RING AB The mechanisms of dynein activity have remained a mystery because of dynein's size and complexity, but two papers now shed light on how dynein functions at the molecular level. C1 [Billington, Neil; Sellers, James R.] NHLBI, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Billington, N (reprint author), NHLBI, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov OI Billington, Neil/0000-0003-2306-0228 NR 21 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUN PY 2011 VL 18 IS 6 BP 635 EP 636 DI 10.1038/nsmb.2082 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 773LE UT WOS:000291308000001 PM 21642959 ER PT J AU Martin, D Pantoja, C Fernandez-Minan, A Valdes-Quezada, C Molto, E Matesanz, F Bogdanovic, O de la Calle-Mustienes, E Dominguez, O Taher, L Furlan-Magaril, M Alcina, A Canon, S Fedetz, M Blasco, MA Pereira, PS Ovcharenko, I Recillas-Targa, F Montoliu, L Manzanares, M Guigo, R Serrano, M Casares, F Gomez-Skarmeta, JL AF Martin, David Pantoja, Cristina Fernandez-Minan, Ana Valdes-Quezada, Christian Molto, Eduardo Matesanz, Fuencisla Bogdanovic, Ozren de la Calle-Mustienes, Elisa Dominguez, Orlando Taher, Leila Furlan-Magaril, Mayra Alcina, Antonio Canon, Susana Fedetz, Maria Blasco, Maria A. Pereira, Paulo S. Ovcharenko, Ivan Recillas-Targa, Felix Montoliu, Lluis Manzanares, Miguel Guigo, Roderic Serrano, Manuel Casares, Fernando Luis Gomez-Skarmeta, Jose TI Genome-wide CTCF distribution in vertebrates defines equivalent sites that aid the identification of disease-associated genes SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID BETA-GLOBIN INSULATOR; MULTIPLE-SCLEROSIS; TRANSCRIPTIONAL INSULATION; FUNCTIONAL-ANALYSIS; REGULATORY REGIONS; ENHANCER-BLOCKING; RISK; CHROMATIN; CELLS; ORGANIZATION AB Many genomic alterations associated with human diseases localize in noncoding regulatory elements located far from the promoters they regulate, making it challenging to link noncoding mutations or risk-associated variants with target genes. The range of action of a given set of enhancers is thought to be defined by insulator elements bound by the 11 zinc-finger nuclear factor CCCTC-binding protein (CTCF). Here we analyzed the genomic distribution of CTCF in various human, mouse and chicken cell types, demonstrating the existence of evolutionarily conserved CTCF-bound sites beyond mammals. These sites preferentially flank transcription factor-encoding genes, often associated with human diseases, and function as enhancer blockers in vivo, suggesting that they act as evolutionarily invariant gene boundaries. We then applied this concept to predict and functionally demonstrate that the polymorphic variants associated with multiple sclerosis located within the EVI5 gene impinge on the adjacent gene GFI1. C1 [Fernandez-Minan, Ana; Bogdanovic, Ozren; de la Calle-Mustienes, Elisa; Casares, Fernando; Luis Gomez-Skarmeta, Jose] UPO, CSIC, Ctr Andaluz Biol Desarrollo, Seville, Spain. [Martin, David; Guigo, Roderic] Univ Pompeu Fabra, Ctr Genom Regulat, Barcelona, Spain. [Pantoja, Cristina; Dominguez, Orlando; Blasco, Maria A.; Serrano, Manuel] Ctr Nacl Invest Oncol, Madrid, Spain. [Valdes-Quezada, Christian; Furlan-Magaril, Mayra; Recillas-Targa, Felix] Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Mol Genet, Mexico City 04510, DF, Mexico. [Molto, Eduardo; Montoliu, Lluis] CSIC, Ctr Nacl Biotecnol, Dept Mol & Cellular Biol, Madrid, Spain. [Molto, Eduardo; Montoliu, Lluis] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras, Madrid, Spain. [Matesanz, Fuencisla; Alcina, Antonio; Fedetz, Maria] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain. [Taher, Leila; Ovcharenko, Ivan] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Canon, Susana; Manzanares, Miguel] CNIC, Madrid, Spain. [Pereira, Paulo S.] Univ Porto, IBMC, P-4150180 Oporto, Portugal. RP Casares, F (reprint author), UPO, CSIC, Ctr Andaluz Biol Desarrollo, Seville, Spain. EM fcasfer@upo.es; jlgomska@upo.es RI Pereira, Paulo/C-2184-2008; Gomez-Skarmeta, Jose Luis/B-5268-2014; Guigo, Roderic/D-1303-2010; Montoliu, Lluis/I-2039-2015; Serrano, Manuel/H-2634-2015; Matesanz, Fuencisla/F-3715-2016; Manzanares, Miguel/E-1702-2015; Blasco , Maria A./M-1694-2014; Casares, Fernando/L-1272-2014 OI Gomez-Skarmeta, Jose Luis/0000-0001-5125-4332; Guigo, Roderic/0000-0002-5738-4477; Montoliu, Lluis/0000-0003-3941-1176; Serrano, Manuel/0000-0001-7177-9312; Matesanz, Fuencisla/0000-0002-9429-1819; Manzanares, Miguel/0000-0003-4849-2836; Blasco , Maria A./0000-0002-4211-233X; Bogdanovic, Ozren/0000-0001-5680-0056; Casares, Fernando/0000-0002-2181-3858 FU Spanish Ministerio de Ciencia e Innovacion (MICINN) [BFU2007-60042/BMC, BFU2010-14839, Petri PET2007_0158, CONSOLIDER CSD2007-00008, BFU2009-07044, PN-SAF2009-11491, BFU2008-00838, BFU2006-12185, BIO2009-12697, BIO2006-03380, CONSOLIDER CSD2007-00050]; Proyecto de Excelencia (Junta de Andalucia) [CVI-3488, CVI 2658, P07-CVI-02551]; FIS (ISCIII) [PI081636]; Regional Government of Madrid [CAM S-SAL-0190-2006]; Pro-CNIC Foundation; Direccion General de Asuntos del Personal Academico, Universidad Nacional Autonoma de Mexico [IN209403, IN214407, IN203811]; Consejo Nacional de Ciencia y Tecnologia, Mexico (CONACyT) [42653-Q, 58767, 128464]; US NCBI (NIH); Spanish MICINN [RETICS RD07/0067/0012] FX This research was supported by the following grants: BFU2007-60042/BMC, BFU2010-14839, Petri PET2007_0158, CONSOLIDER CSD2007-00008 (Spanish Ministerio de Ciencia e Innovacion (MICINN)) and Proyecto de Excelencia CVI-3488 (Junta de Andalucia) to J.L.G.-S.; BFU2009-07044 (MICINN) and Proyecto de Excelencia CVI 2658 (Junta de Andalucia) to F.C.; FIS PI081636 (ISCIII) to F.M.; PN-SAF2009-11491 (MICINN) and Proyecto de Excelencia P07-CVI-02551 (Junta de Andalucia) to A.A.; BFU2008-00838, CONSOLIDER CSD2007-00008 (MICINN), Regional Government of Madrid (CAM S-SAL-0190-2006) and the Pro-CNIC Foundation to M. M.; BFU2006-12185 and BIO2009-12697 (MICINN) to L.M.; Direccion General de Asuntos del Personal Academico, Universidad Nacional Autonoma de Mexico (IN209403, IN214407 and IN203811) and Consejo Nacional de Ciencia y Tecnologia, Mexico (CONACyT: 42653-Q, 58767 and 128464) to F.R.-T.; Intramural Research Program of the US NCBI (NIH) to I.O. and BIO2006-03380, CONSOLIDER CSD2007-00050 (MICINN) and RETICS RD07/0067/0012 (Spanish MICINN) to R.G.L.M. thanks A. Fernandez for technical assistance and L. Barrios for statistical analysis. F.R.-T. thanks G. G. Avendano for technical assistance. NR 54 TC 49 Z9 49 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUN PY 2011 VL 18 IS 6 BP 708 EP U108 DI 10.1038/nsmb.2059 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 773LE UT WOS:000291308000012 PM 21602820 ER PT J AU Snyder, JS Ramchand, P Rabbett, S Radik, R Wojtowicz, JM Cameron, HA AF Snyder, Jason S. Ramchand, Preethi Rabbett, Sarah Radik, Ruvim Wojtowicz, J. Martin Cameron, Heather A. TI Septo-temporal gradients of neurogenesis and activity in 13-month-old rats SO NEUROBIOLOGY OF AGING LA English DT Article DE Adult neurogenesis; Dentate gyrus; Septal; Temporal; Dorsal; Ventral; Fos; Immediate-early gene; Aging; Spatial; Water maze; Stress; Anxiety ID GENERATED GRANULE CELLS; ADULT HIPPOCAMPAL NEUROGENESIS; ENHANCED SYNAPTIC PLASTICITY; DENTATE GYRUS; WATER-MAZE; VENTRAL HIPPOCAMPUS; CRITICAL PERIOD; NEURONS; DORSAL; MEMORY AB Recent studies suggest that hippocampal function is partially dissociable along its septo-temporal axis: the septal hippocampus is more critical for spatial processing, while the temporal hippocampus may be more important for non-spatial-related behavior. In young adults, water maze training specifically activates new neurons in the temporal hippocampus, but it is unknown whether subregional differences are maintained in older animals, which have reduced neurogenesis levels. We therefore examined gradients of activity-related Fos expression and neurogenesis in 13-month-old rats and found that neurogenesis occurs relatively evenly throughout the dentate gyrus. Water maze experience significantly increased Fos expression in the suprapyramidal blade and Foswas highest in the septal pole of the dentate gyrus whether the animal learned a platform location, swam in the absence of a platform or remained in their cage. No Fos+ young neurons were found using typical markers of immature neurons. However, Fos expression in the subgranular zone, where adult-born neurons predominate, was disproportionally high in the temporal dentate gyrus. These findings indicate that adult-born neurons in the temporal hippocampus are preferentially activated compared with older neurons. Published by Elsevier Inc. C1 [Snyder, Jason S.; Ramchand, Preethi; Rabbett, Sarah; Cameron, Heather A.] NIMH, Unit Neuroplast, NIH, Bethesda, MD 20892 USA. [Snyder, Jason S.; Radik, Ruvim; Wojtowicz, J. Martin] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8, Canada. RP Snyder, JS (reprint author), NIMH, Unit Neuroplast, NIH, Bldg 35-3C911,MSC3718, Bethesda, MD 20892 USA. EM snyderjason@mail.nih.gov RI Snyder, Jason/F-3435-2011; Cameron, Heather/E-6221-2011; OI Cameron, Heather/0000-0002-3245-5777; Snyder, Jason/0000-0002-5509-0272 FU Ontario Graduate Scholarship; Canadian Institutes of Health Research; National Institute of Mental Health [Z01-MH002784] FX This work was funded by an Ontario Graduate Scholarship (JSS), the Canadian Institutes of Health Research (JMW) and the Intramural Program of the National Institute of Mental Health, Z01-MH002784 (HAC). NR 46 TC 20 Z9 21 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUN PY 2011 VL 32 IS 6 BP 1149 EP 1156 DI 10.1016/j.neurobiolaging.2009.05.022 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 771LS UT WOS:000291160000015 PM 19632743 ER PT J AU Del Bo, R Corti, S Santoro, D Ghione, I Fenoglio, C Ghezzi, S Ranieri, M Galimberti, D Mancuso, M Siciliano, G Briani, C Murri, L Scarpini, E Schymick, JC Traynor, BJ Bresolin, N Comi, GP AF Del Bo, Roberto Corti, Stefania Santoro, Domenico Ghione, Isabella Fenoglio, Chiara Ghezzi, Serena Ranieri, Michela Galimberti, Daniela Mancuso, Michelangelo Siciliano, Gabriele Briani, Chiara Murri, Luigi Scarpini, Elio Schymick, Jennifer C. Traynor, Bryan J. Bresolin, Nereo Comi, Giacomo P. TI No major progranulin genetic variability contribution to disease etiopathogenesis in an ALS Italian cohort SO NEUROBIOLOGY OF AGING LA English DT Article DE Amyotrophic lateral sclerosis; Progranulin; Genetic risk factor; Susceptibility ID FRONTOTEMPORAL LOBAR DEGENERATION; AMYOTROPHIC-LATERAL-SCLEROSIS; MUTATION CARRIERS; EXPRESSION; ALZHEIMER AB To analyze the contribution of progranulin (PGRN) to the etiopathogenesis of amyotrophic lateral sclerosis (ALS), we performed a PGRN gene screening in 146 Italian patients (12 familial cases) and evaluated the association of two common variants with risk of developing ALS in 239 sporadic cases (SALS). Progranulin mRNA and protein levels were measured in peripheral blood mononuclear cells and serum of a subset of these patients and controls. PGRN sequence analysis revealed a heterozygous change (p.S120Y), previously observed in an independent sporadic ALS-FTD patient. Haplotype analysis showed a conserved PGRN region among these two subjects consistent with possible common ancestor allele. Two non-coding polymorphisms were not associated to increased risk to develop ALS; mRNA and serum levels were not significantly different between cases and controls. Overall, our data argue against the hypothesis of progranulin as a major risk factor for motor neuron dysfunction, at least in Italian population. The p.S120Y variant may characterize rare patients with SALS, although its pathogenetic mechanism remains to be elucidated. (C) 2009 Elsevier Inc. All rights reserved. C1 [Del Bo, Roberto; Corti, Stefania; Santoro, Domenico; Ghione, Isabella; Fenoglio, Chiara; Ghezzi, Serena; Ranieri, Michela; Galimberti, Daniela; Scarpini, Elio; Bresolin, Nereo; Comi, Giacomo P.] Univ Milan, Dept Neurol Sci, Dino Ferrari Ctr,IRCCS Fdn, Osped Maggiore Policlin Mangiagalli & Regina Elen, I-20122 Milan, Italy. [Mancuso, Michelangelo; Siciliano, Gabriele; Murri, Luigi] Univ Pisa, Neurol Inst, Dept Neurosci, Pisa, Italy. [Briani, Chiara] Univ Padua, Dept Neurosci, Padua, Italy. [Schymick, Jennifer C.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Grp, Neurogenet Lab, Bethesda, MD 20892 USA. RP Del Bo, R (reprint author), Univ Milan, Dept Neurol Sci, Osped Maggiore Policlin, Via F Sforza 35, I-20122 Milan, Italy. EM roberto.delbo@unimi.it RI Traynor, Bryan/G-5690-2010; Comi, Giacomo /K-5702-2016; Corti, Stefania/K-6034-2016; Siciliano, Gabriele/K-7259-2016; OI Comi, Giacomo /0000-0002-1383-5248; Corti, Stefania/0000-0001-5425-969X; Siciliano, Gabriele/0000-0002-6142-2384; galimberti, daniela/0000-0002-9284-5953; scarpini, elio/0000-0002-6395-2119 FU Italian Ministry; National Institute on Aging [Z01 AG000949-02] FX The financial support of the following research grant to NB and SC is gratefully acknowledged: Italian Ministry PRIN 2007-"Molecular pathogenesis of motor neuron disorders as a tool for the identification of novel biomolecular and cellular therapeutic agents".; This research was supported (in part) by the Intramural Research Program of the National Institute on Aging (project Z01 AG000949-02). NR 22 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUN PY 2011 VL 32 IS 6 BP 1157 EP 1158 DI 10.1016/j.neurobiolaging.2009.06.006 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 771LS UT WOS:000291160000016 PM 19632744 ER PT J AU Liu, R Gao, X Lu, Y Chen, HL AF Liu, Rui Gao, Xiang Lu, Yi Chen, Honglei TI Meta-analysis of the relationship between Parkinson disease and melanoma SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; MALIGNANT-MELANOMA; CANCER INCIDENCE; SKIN-CANCER; RISK; DIAGNOSIS; SMOKING; TRIAL; LEVODOPA; GENDER AB Objective: To assess the epidemiologic evidence on melanoma in relation to Parkinson disease (PD) via systematic review and meta-analysis. Methods: Epidemiologic studies on melanoma and PD were searched using PubMed, Web of Science, Scoups, and Embase (1965 through June 2010). Eligible studies were those that reported risk estimates of melanoma among patients with PD or vice versa. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects models. Results: We identified 12 eligible publications on melanoma and PD: 8 had fewer than 10 cases with both PD and melanoma, and 7 provided gender-specific results. The pooled OR was 2.11 (95% CI 1.26-3.54) overall, 2.04 (1.55-2.69) for men, and 1.52 (0.85-2.75) for women. Analyses by temporal relationship found that melanoma occurrence was significantly higher after the diagnosis of PD (OR 3.61, 95% CI 1.49-8.77), but not before PD diagnosis (OR 1.07, 95% CI 0.62-1.84). Further analyses revealed that the lack of significance in the latter analysis was due to one study, which when excluded resulted in a significant association (OR 1.44, 95% CI 1.06-1.96). We also analyzed nonmelanoma skin cancers in relation to PD and found no significant relationship (OR 1.11, 95% CI 0.94-1.30). Conclusions: Collective epidemiologic evidence supports an association of PD with melanoma. Further research is needed to examine the nature and mechanisms of this relationship. Neurology (R) 2011;76:2002-2009 C1 [Liu, Rui; Chen, Honglei] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Gao, Xiang] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Lu, Yi] Social & Sci Syst, Durham, NC USA. RP Chen, HL (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM chenh2@niehs.nih.gov OI Chen, Honglei/0000-0003-3446-7779 FU National Institute of Environmental Health Sciences [Z01-ES-101986] FX Supported by the intramural research program of the National Institute of Environmental Health Sciences (Z01-ES-101986). NR 40 TC 73 Z9 73 U1 1 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 JUN PY 2011 VL 76 IS 23 BP 2002 EP 2009 DI 10.1212/WNL.0b013e31821e554e PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 773WZ UT WOS:000291343500013 PM 21646627 ER PT J AU Mattson, MP AF Mattson, Mark P. TI Commentary: Proteooxidotoxic Process of Aggregation SO NEUROMOLECULAR MEDICINE LA English DT Review DE Alzheimer's disease; Amyloid beta-peptide; Huntington's disease; Membrane lipid peroxidation; Oxidative stress; Parkinson's disease ID LIPID-PEROXIDATION; BETA-PEPTIDE; NEUROTOXICITY; DISEASE AB A recent editorial entitled "State of Aggregation" (Nat. Neurosci. 2011; 14:399) described the importance of establishing the structural state of pathogenic protein aggregates (A beta, alpha-synuclein, huntingtin, etc.) in studies of neurodegenerative disorders. While this is a laudable goal, it is based on the assumption that the neurotoxicity depends upon a specific tertiary structure of the protein aggregates. Here, I describe evidence (not mentioned in the editorial) that suggests that it is not the protein oligomers, per se, that damage neurons. Instead, neurons are damaged by an unseen sequence(s) of chemical reactions that generate reactive oxygen species (ROS), and it is the ROS that cause both protein aggregation and neurotoxicity. The latter "proteooxidotoxicity" mechanism provides an explanation for numerous findings in the field of neurodegenerative disorders, including the inability to identify specific receptors for the pathogenic proteins. 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 FU National Institute on Aging FX Supported by the Intramural Research Program of the National Institute on Aging. NR 10 TC 2 Z9 2 U1 0 U2 0 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 JUN PY 2011 VL 13 IS 2 BP 91 EP 92 DI 10.1007/s12017-011-8146-x PG 2 WC Neurosciences SC Neurosciences & Neurology GA 772TB UT WOS:000291258000001 PM 21594669 ER PT J AU Kim, LJ Nalls, MA Eiriksdottir, G Sigurdsson, S Launer, LJ Koster, A Chaves, PHM Jonsdottir, B Garcia, M Gudnason, V Harris, TB AF Kim, Lauren J. Nalls, Michael A. Eiriksdottir, Gudny Sigurdsson, Sigurdur Launer, Lenore J. Koster, Annemarie Chaves, Paulo H. M. Jonsdottir, Birna Garcia, Melissa Gudnason, Vilmundur Harris, Tamara B. CA AGES-Reykjavik Study Investigators TI Associations of Visceral and Liver Fat With the Metabolic Syndrome Across the Spectrum of Obesity: The AGES-Reykjavik Study SO OBESITY LA English DT Article ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; IMPAIRED GLUCOSE-TOLERANCE; CARDIOVASCULAR-DISEASE; ABDOMINAL FAT; FETUIN-A; TISSUE DISTRIBUTION; JAPANESE-AMERICANS; INSULIN-RESISTANCE; DIABETES-MELLITUS AB Visceral adipose tissue (VAT) is a key pathogenic fat depot in the metabolic syndrome (MetS), but liver fat (LF) may also play an important role. We evaluated associations of VAT and LF with MetS in normal weight, overweight, and obese men and women (BMI <25, 25-29.9, and >= 30 kg/m(2), respectively). This analysis included 2,495 participants from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study with computed tomography measurements for VAT and LF. MetS was defined by >= 3 of the following: larger abdominal circumference, hypertension, elevated triglyceride (TG), low high-density lipoprotein (HDL), impaired fasting glucose (IFG), and microalbuminuria. We estimated the odds of MetS per 1-s.d. increase in VAT and LF, adjusting for key covariates. VAT was associated with an increased odds of MetS in normal weight, overweight, and obese women (odds ratios (OR) = 2.78, 1.63, and 1.43, respectively; all P < 0.01) that diminished in magnitude with increasing BMI (VAT x BMI class interaction P < 0.001). In men, VAT was related to MetS only among the overweight (OR = 1.69, P < 0.01). LF was associated with MetS in the overweight and obese groups in women (OR = 1.38 and 1.45; both P < 0.001) and in men (OR = 1.38, P = 0.01; and OR = 1.27, P = 0.10), but not in the normal weight groups. These BMI-specific relationships persisted when both fat depots were included in the model. VAT and LF were associated with MetS independently of each other, and these relationships were modified by BMI class such that, VAT was the more important depot at lower levels of obesity and LF at higher levels. Importantly, fatty liver may be a novel metabolic risk factor in overweight and obese individuals. C1 [Kim, Lauren J.; Launer, Lenore J.; Koster, Annemarie; Garcia, Melissa; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Koster, Annemarie] Maastricht Univ, Dept Internal Med, Sch Publ Hlth & Primary Care CAPHRI, Maastricht, Netherlands. [Eiriksdottir, Gudny; Sigurdsson, Sigurdur; Jonsdottir, Birna; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Chaves, Paulo H. M.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Chaves, Paulo H. M.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. RP Kim, LJ (reprint author), NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. EM KimLJ@mail.nih.gov RI Koster, Annemarie/E-7438-2010; Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 FU National Institutes of Health [N01-AG-12100]; Hjartavernd (the Icelandic Heart Association); Althingi (Icelandic Parliament); National Institutes of Health, National Institute on Aging FX This study was funded by the National Institutes of Health contract N01-AG-12100, Hjartavernd (the Icelandic Heart Association), and the Althingi (Icelandic Parliament). This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Lastly, we are indebted to the study participants for their willingness to take part in this study. NR 40 TC 26 Z9 26 U1 0 U2 2 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 JUN PY 2011 VL 19 IS 6 BP 1265 EP 1271 DI 10.1038/oby.2010.291 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 769NG UT WOS:000291021600023 PM 21183935 ER PT J AU Foster, MC Hwang, SJ Massaro, JM Hoffmann, U DeBoer, IH Robins, SJ Vasan, RS Fox, CS AF Foster, Meredith C. Hwang, Shih-Jen Massaro, Joseph M. Hoffmann, Udo DeBoer, Ian H. Robins, Sander J. Vasan, Ramachandran S. Fox, Caroline S. TI Association of Subcutaneous and Visceral Adiposity With Albuminuria: The Framingham Heart Study SO OBESITY LA English DT Article ID BODY-FAT DISTRIBUTION; CHRONIC KIDNEY-DISEASE; METABOLIC RISK-FACTORS; INSULIN SENSITIVITY; DIABETES-MELLITUS; CENTRAL OBESITY; SEX-DIFFERENCES; TISSUE VOLUMES; RENAL-DISEASE; ALL-CAUSE AB Microalbuminuria is a common condition associated with increased incidence of cardiovascular events and mortality. Abdominal obesity is associated with microalbuminuria, but studies linking visceral adipose tissue (VAT) and microalbuminuria are limited. Our objective was to determine the associations of albuminuria with VAT and subcutaneous adipose tissue (SAT). We performed a cross-sectional study in the Framingham Multi-Detector Computed Tomography (MDCT) cohort (n = 3,099, 48.2% women, mean age 53 years). VAT and SAT volumes were measured using computed tomography. Urinary albumin-to-creatinine ratio (UACR) was calculated from spot urine samples. Microalbuminuria was defined as a UACR >25 mg/g in women or >17 mg/g in men. Overall, 7.9% (n = 244) of the sample had microalbuminuria. Among men, VAT (odds ratio (OR) 1.48 per s.d., P < 0.0001) and SAT (OR 1.37 per s.d., P = 0.0002) were associated with microalbuminuria in minimally adjusted models, which remained significant after multivariable adjustment (VAT OR 1.34 per s.d., P = 0.001; SAT OR 1.28 per s.d., P = 0.005). Additionally, when considered jointly, VAT (P = 0.002) but not SAT (P = 0.2) was associated with microalbuminuria. In women, VAT was associated with microalbuminuria after minimal adjustment (OR 1.28, P = 0.01), but not after multivariable adjustment (OR 1.03, P = 0.8). In multivariable models in women, SAT was associated with a decreased odds of having microalbuminuria (OR 0.75 per s.d., P = 0.03). In conclusion, VAT is associated with microalbuminuria in men but not women. Albuminuria may be a manifestation of visceral adiposity. C1 [Foster, Meredith C.; Hwang, Shih-Jen; Robins, Sander J.; Vasan, Ramachandran S.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [DeBoer, Ian H.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Robins, Sander J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Robins, Sander J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol & Metab, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute [N01-HC-25195] FX The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute (N01-HC-25195). NR 40 TC 30 Z9 32 U1 1 U2 3 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 JUN PY 2011 VL 19 IS 6 BP 1284 EP 1289 DI 10.1038/oby.2010.308 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 769NG UT WOS:000291021600026 PM 21183930 ER PT J AU Switzer, CH Cheng, RYS Vitek, TM Christensen, DJ Wink, DA Vitek, MP AF Switzer, C. H. Cheng, R. Y. S. Vitek, T. M. Christensen, D. J. Wink, D. A. Vitek, M. P. TI Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy SO ONCOGENE LA English DT Article DE SET/I(2)PP2A; PP2A; Akt; nm23-H1; Rac1 ID PROTEIN PHOSPHATASE 2A; CHRONIC MYELOGENOUS LEUKEMIA; ACUTE UNDIFFERENTIATED LEUKEMIA; TUMOR-SUPPRESSOR; APOLIPOPROTEIN-E; GENE-EXPRESSION; CARCINOMA CELLS; BLAST CRISIS; HUMAN BREAST; C-MYC AB The SET oncoprotein participates in cancer progression by affecting multiple cellular processes, inhibiting the tumor suppressor protein phosphatase 2A (PP2A), and inhibiting the metastasis suppressor nm23-H1. On the basis of these multiple activities, we hypothesized that targeted inhibition of SET would have multiple discrete and measurable effects on cancer cells. Here, the effects of inhibiting SET oncoprotein function on intracellular signaling and proliferation of human cancer cell lines was investigated. We observed the effects of COG112, a novel SET interacting peptide, on PP2A activity, Akt signaling, nm23-H1 activity and cellular migration/invasion in human U87 glioblastoma and MDA-MB-231 breast adenocarcinoma cancer cell lines. We found that COG112 interacted with SET protein and inhibited the association between SET and PP2A catalytic subunit (PP2A-c) and nm23-H1. The interaction between COG112 and SET caused PP2A phosphatase and nm23-H1 exonuclease activities to increase. COG112-mediated increases in PP2A activity resulted in the inhibition of Akt signaling and cellular proliferation. Additionally, COG112 inhibited SET association with Ras-related C-3 botulinum toxin substrate 1 (Rac1), leading to decreased cellular migration and invasion. COG112 treatment releases the SET-mediated inhibition of the tumor suppressor PP2A, as well as the metastasis suppressor nm23-H1. These results establish SET as a novel molecular target and that the inhibition of SET may have beneficial effects in cancer chemotherapy. Oncogene (2011) 30, 2504-2513; doi: 10.1038/onc.2010.622; published online 7 February 2011 C1 [Switzer, C. H.; Cheng, R. Y. S.; Vitek, T. M.; Wink, D. A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Christensen, D. J.; Vitek, M. P.] Cognosci Inc, Res Triangle Pk, NC 27709 USA. [Vitek, M. P.] Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B35, Bethesda, MD 20892 USA. EM wink@mail.nih.gov; mikevitek@cognosci.com RI Switzer, Christopher/D-9203-2013; OI Cheng, Robert/0000-0003-0287-6439 FU Intramural NIH HHS [ZIA BC010899-03, ZIA SC007281-17] NR 49 TC 66 Z9 69 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN PY 2011 VL 30 IS 22 BP 2504 EP 2513 DI 10.1038/onc.2010.622 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 771ZE UT WOS:000291198400002 PM 21297667 ER PT J AU He, MG Congdon, N MacKenzie, G Zeng, YF Silver, JD Ellwein, L AF He, Mingguang Congdon, Nathan MacKenzie, Graeme Zeng, Yangfa Silver, Joshua D. Ellwein, Leon TI The Child Self-Refraction Study Results from Urban Chinese Children in Guangzhou SO OPHTHALMOLOGY LA English DT Article ID HAND-HELD AUTOREFRACTOR; PRIMARY-SCHOOL CHILDREN; VISUAL IMPAIRMENT; CLINICAL-EVALUATION; SOUTHERN CHINA; UNITED-STATES; AGE-CHILDREN; X-PRES; ERROR; MYOPIA AB Objective: To compare visual and refractive outcomes between self-refracting spectacles (Adaptive Eyecare, Ltd, Oxford, UK), noncycloplegic autorefraction, and cycloplegic subjective refraction. Design: Cross-sectional study. Participants: Chinese school-children aged 12 to 17 years. Methods: Children with uncorrected visual acuity <= 6/12 in either eye underwent measurement of the logarithm of the minimum angle of resolution visual acuity, habitual correction, self-refraction without cycloplegia, autorefraction with and without cycloplegia, and subjective refraction with cycloplegia. Main Outcome Measures: Proportion of children achieving corrected visual acuity >= 6/7.5 with each modality; difference in spherical equivalent refractive error between each of the modalities and cycloplegic subjective refractive error. Results: Among 556 eligible children of consenting parents, 554 (99.6%) completed self-refraction (mean age, 13.8 years; 59.7% girls; 54.0% currently wearing glasses). The proportion of children with visual acuity >= 6/7.5 in the better eye with habitual correction, self-refraction, noncycloplegic autorefraction, and cycloplegic subjective refraction were 34.8%, 92.4%, 99.5% and 99.8%, respectively (self-refraction versus cycloplegic subjective refraction, P<0.001). The mean difference between cycloplegic subjective refraction and noncycloplegic autorefraction (which was more myopic) was significant (-0.328 diopter [ D]; Wilcoxon signed-rank test P<0.001), whereas cycloplegic subjective refraction and self-refraction did not differ significantly (-0.009 D; Wilcoxon signed-rank test P = 0.33). Spherical equivalent differed by >= 1.0 D in either direction from cycloplegic subjective refraction more frequently among right eyes for self-refraction (11.2%) than noncycloplegic autorefraction (6.0%; P = 0.002). Self-refraction power that differed by >= 1.0 D from cycloplegic subjective refractive error (11.2%) was significantly associated with presenting without spectacles (P = 0.011) and with greater absolute power of both spherical (P = 0.025) and cylindrical (P = 0.022) refractive error. Conclusions: Self-refraction seems to be less prone to accommodative inaccuracy than noncycloplegic autorefraction, another modality appropriate for use in areas where access to eye care providers is limited. Visual results seem to be comparable. Greater cylindrical power is associated with less accurate results; the adjustable glasses used in this study cannot correct astigmatism. Further studies of the practical applications of this modality are warranted. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2011; 118: 1162-1169 (C) 2011 by the American Academy of Ophthalmology. C1 [He, Mingguang; Congdon, Nathan; Zeng, Yangfa] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China. [MacKenzie, Graeme] Adlens Ltd, Oxford, England. [MacKenzie, Graeme] John Radcliffe Hosp, Nuffield Lab Ophthalmol, Oxford OX3 9DU, England. [Silver, Joshua D.] St Catherines Coll, Ctr Vis Developing World, Oxford, England. [Ellwein, Leon] NEI, Bethesda, MD 20892 USA. RP He, MG (reprint author), Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, 54 Xianlie S Rd, Guangzhou 510060, Guangdong, Peoples R China. EM mingguang_he@yahoo.com OI He, Mingguang/0000-0002-6912-2810 FU Partnership for Child Development, (Imperial College of Science, Technology and Medicine) under the World Bank [FY2009] FX Funded by a subgrant to the Nuffield Laboratory of Ophthalmology (University of Oxford) from the Partnership for Child Development, (Imperial College of Science, Technology and Medicine) under the World Bank's FY2009 Development Grant Facility (DGF) Window 1. The self-refracting spectacles used in this study were provided free of charge by Adaptive Eyecare, Ltd. NR 46 TC 9 Z9 11 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD JUN PY 2011 VL 118 IS 6 BP 1162 EP 1169 DI 10.1016/j.ophtha.2010.10.003 PG 8 WC Ophthalmology SC Ophthalmology GA 771JJ UT WOS:000291152700023 PM 21232802 ER PT J AU Vendruscolo, LF Schlosburg, JE Misra, KK Chen, SA Greenwell, TN Koob, GF AF Vendruscolo, Leandro F. Schlosburg, Joel E. Misra, Kaushik K. Chen, Scott A. Greenwell, Thomas N. Koob, George F. TI Escalation patterns of varying periods of heroin access SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Heroin self-administration; Opioid dependence; Drug addiction; Escalation; Naloxone-precipitated withdrawal ID OPIATE DEPENDENCE; WITHDRAWAL; RATS; CONSUMPTION; CLONIDINE; METHADONE; REWARD; FOOD AB The prevalence of opioid abuse and dependence has been on the rise in just the past few years. Animal studies indicate that extended access to heroin produces escalation of intake over time, whereas stable intake is observed under limited-access conditions. Escalation of drug intake has been suggested to model the transition from controlled drug use to compulsive drug seeking and taking. Here, we directly compared the pattern of heroin intake in animals with varying periods of heroin access. Food intake was also monitored over the course of escalation. Rats were allowed to lever press on a fixed-ratio 1 schedule of reinforcement to receive intravenous infusions of heroin for 1, 6, 12, or 23 h per day for 14 sessions. The results showed that heroin intake in the 12 and 23 h groups markedly increased over time, whereas heroin intake in the 1 h group was stable. The 6 h group showed a significant but modest escalation of intake. Total heroin intake was similar in the 12 and 23 h groups, but the rate of heroin self-administration was two-fold higher in the 12 h group compared with the 23 h group. Food intake decreased over sessions only in the 12 h group. The 12 and 23 h groups showed marked physical signs of naloxone-precipitated withdrawal. These findings suggest that 12 h heroin access per day may be the optimal access time for producing escalation of heroin intake. The advantages of this model and the potential relevance for studying drug addiction are discussed. (C) 2011 Elsevier Inc. All rights reserved. C1 [Vendruscolo, Leandro F.; Schlosburg, Joel E.; Misra, Kaushik K.; Koob, George F.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Chen, Scott A.] Natl Inst Drug Abuse, Off Extramural Affairs, Bethesda, MD USA. [Greenwell, Thomas N.] NEI, Div Extramural Res, Bethesda, MD 20892 USA. RP Vendruscolo, LF (reprint author), Scripps Res Inst, Comm Neurobiol Addict Disorders, 10550 N Torrey Pines Rd,SP30-2400, La Jolla, CA 92037 USA. EM leandro@scripps.edu RI koob, george/P-8791-2016; OI Greenwell, Thomas/0000-0001-6069-0064 FU National Institutes of Health, National Institute on Drug Abuse [DA004043]; Pearson Center for Alcoholism and Addiction Research; National Institute on Alcohol Abuse and Alcoholism [T32AA007456] FX This is publication number 21017 from The Scripps Research Institute. Research was financially supported by National Institutes of Health grant DA004043 from the National Institute on Drug Abuse and the Pearson Center for Alcoholism and Addiction Research. Training for author JES was provided by National Institute on Alcohol Abuse and Alcoholism grant T32AA007456. The authors would like to thank Michael Arends for proofreading the manuscript. NR 22 TC 24 Z9 24 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JUN PY 2011 VL 98 IS 4 BP 570 EP 574 DI 10.1016/j.pbb.2011.03.004 PG 5 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 773GP UT WOS:000291295300011 PM 21406200 ER PT J AU De Mukhopadhyay, K Bandyopadhyay, A Chang, TTA Elkahloun, AG Cornell, JE Yang, JH Goins, BA Yeh, IT Sun, LZ AF De Mukhopadhyay, Keya Bandyopadhyay, Abhik Chang, Ting-Tung A. Elkahloun, Abdel G. Cornell, John E. Yang, Junhua Goins, Beth A. Yeh, I-Tien Sun, Lu-Zhe TI Isolation and Characterization of a Metastatic Hybrid Cell Line Generated by ER Negative and ER Positive Breast Cancer Cells in Mouse Bone Marrow SO PLOS ONE LA English DT Article ID ALDEHYDE DEHYDROGENASE-ACTIVITY; STEM-CELLS; PROSPECTIVE IDENTIFICATION; SPONTANEOUS FUSION; IN-VITRO; EXPRESSION; HYPOTHESIS; VARIANT AB Background: The origin and the contribution of breast tumor heterogeneity to its progression are not clear. We investigated the effect of a growing orthotopic tumor formed by an aggressive estrogen receptor (ER)-negative breast cancer cell line on the metastatic potential of a less aggressive ER-positive breast cancer cell line for the elucidation of how the presence of heterogeneous cancer cells might affect each other's metastatic behavior. Methods: ER positive ZR-75-1/GFP/puro cells, resistant to puromycin and non-tumorigenic/non-metastatic without exogenous estrogen supplementation, were injected intracardiacally into mice bearing growing orthotopic tumors, formed by ER negative MDA-MB-231/GFP/Neo cells resistant to G418. A variant cell line B6, containing both estrogen-dependent and -independent cells, were isolated from GFP expressing cells in the bone marrow and re-inoculated in nude mice to generate an estrogen-independent cell line B6TC. Results: The presence of ER negative orthotopic tumors resulted in bone metastasis of ZR-75-1 without estrogen supplementation. The newly established B6TC cell line was tumorigenic without estrogen supplementation and resistant to both puromycin and G418 suggesting its origin from the fusion of MDA-MB-231/GFP/Neo and ZR-75-1/GFP/puro in the mouse bone marrow. Compared to parental cells, B6TC cells were more metastatic to lung and bone after intracardiac inoculation. More significantly, B6TC mice also developed brain metastasis, which was not observed in the MDA-MB-231/GFP/Neo cell-inoculated mice. Low expression of ER alpha and CD24, and high expression of EMT-related markers such as Vimentin, CXCR4, and Integrin-beta 1 along with high CD44 and ALDH expression indicated stem cell-like characteristics of B6TC. Gene microarray analysis demonstrated a significantly different gene expression profile of B6TC in comparison to those of parental cell lines. Conclusions: Spontaneous generation of the novel hybrid cell line B6TC, in a metastatic site with stem cell-like properties and propensity to metastasize to brain, suggest that cell fusion can contribute to tumor heterogeneity. C1 [De Mukhopadhyay, Keya; Bandyopadhyay, Abhik; Yang, Junhua; Sun, Lu-Zhe] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Chang, Ting-Tung A.; Goins, Beth A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Elkahloun, Abdel G.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Cornell, John E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Yeh, I-Tien] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. RP De Mukhopadhyay, K (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. EM SUNL@uthscsa.edu FU National Institutes of Health (NIH) [R01CA079683, R01CA075253, P01CA040035]; Department of Defense Breast Cancer Research [W81XWH-06-1-0616]; Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio through National Cancer Institute Cancer Center [P30CA054174] FX This work was supported in part by National Institutes of Health (NIH) grants R01CA079683, R01CA075253, P01CA040035; Department of Defense Breast Cancer Research Program Concept Award W81XWH-06-1-0616; and the Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio through the National Cancer Institute Cancer Center Support Grant P30CA054174. Additional support was provided by the Intramural Program of the National Human Genome Research Institute, NIH. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 48 TC 0 Z9 0 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 1 PY 2011 VL 6 IS 6 AR e20473 DI 10.1371/journal.pone.0020473 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773LX UT WOS:000291309900022 ER PT J AU Bevans, M Wehrlen, L Prachenko, O Soeken, K Zabora, J Wallen, GR AF Bevans, Margaret Wehrlen, Leslie Prachenko, Olena Soeken, Karen Zabora, James Wallen, Gwenyth R. TI Distress screening in allogeneic hematopoietic stem cell (HSCT) caregivers and patients SO PSYCHO-ONCOLOGY LA English DT Article DE cancer; oncology; distress thermometer; distress screening; validity; accuracy ID QUALITY-OF-LIFE; BONE-MARROW-TRANSPLANTATION; CANCER-RELATED FATIGUE; PSYCHOLOGICAL DISTRESS; THERMOMETER; SYMPTOMS; VALIDATION; DEPRESSION; INTERVENTIONS; SPOUSES AB Family caregivers of allogeneic hematopoietic stem cell transplant (HSCT) patients are at risk for experiencing significant psychological distress yet screening caregivers has not been well studied. Objective: This analysis explored the psychometric characteristics of the Distress Thermometer (DT) by examining its relationship, sensitivity, and specificity relative to the Brief Symptom Inventory 18 (BSI-18) and the Multidimensional Fatigue Symptom Inventory (MFSI) in a sample of allogeneic HSCT caregivers and patients. Methods: Longitudinal data were drawn from an ongoing intervention study for HSCT caregivers and patients. Data from one hundred and fifty-six English-speaking adults where patients (n=65) were receiving their first allogeneic HSCT with at least one adult caregiver (n=91) were eligible for this analysis. Study questionnaires were administered at baseline, initial discharge, and 6 weeks following discharge. Results: Construct validity was supported by significant relationships (p<0.001) between the DT and the BSI-18 GSI and the MFSI-Emotional subscales for caregivers and patients. The diagnostic utility of the DT for patients was good (AUC=0.85 +/- 0.05, p=0.001), while for caregivers it was poor (AUC=0.61 +/- 0.08, p=0.28). A DT cut point of 5 was supported for patients (sensitivity=1.0, specificity=0.68), while for caregivers there was less confidence (sensitivity=0.70, specificity=0.52). Caregivers and patients reporting a higher number of problems had a greater level of distress (p<0.001). Conclusions: These findings support the validity of the DT in screening for distress in HSCT caregivers and patients. Although the diagnostic utility of the DT for HSCT caregivers may be limited, understanding factors associated with distress can guide practice for this understudied population. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Bevans, Margaret; Wehrlen, Leslie; Prachenko, Olena; Wallen, Gwenyth R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Soeken, Karen] Univ Maryland, Sch Nursing, Baltimore, MD 21201 USA. [Zabora, James] Catholic Univ Amer, Natl Catholic Sch Social Serv, Washington, DC 20064 USA. RP Bevans, M (reprint author), 5061 Durham Rd W, Columbia, MD 21044 USA. EM mbevans@cc.nih.gov FU NIH, Clinical Center FX The authors thank the following individuals for their assistance in recruitment of subjects: Laura Musse, Bazetta (Zetta) Blacklock-Schuver, Caroline Stewart, Wynona (Nona) Coles, Beth Link, and Rose Goodwin. The authors are grateful to the following physicians for supporting this study: Drs. John Barrett, Richard Childs, Daniel Fowler, Michael Bishop, John Tisdale, Elizabeth Kang, Matthew Hsieh, and Courtney Fitzhugh. In addition, the authors are appreciative to the nursing and support staff members of 3NE Nursing Unit, 3SE Day Hospital, and OP 7 & OP12 clinics. We also acknowledge funding by the Intramural Research Program of the NIH, Clinical Center. NR 53 TC 25 Z9 27 U1 6 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1057-9249 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD JUN PY 2011 VL 20 IS 6 SI SI BP 615 EP 622 DI 10.1002/pon.1906 PG 8 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 770UH UT WOS:000291113500007 PM 21626610 ER PT J AU Shearer, GM Boasso, A AF Shearer, Gene M. Boasso, Adriano TI Recognizing the HUMAN POTENTIAL SO SCIENTIST LA English DT Article ID IMMUNODEFICIENCY-VIRUS; ALLOIMMUNIZATION; TRANSMISSION; CHEMOKINES; VACCINES; MACAQUES; HIV-1; WOMEN C1 [Shearer, Gene M.] NIH, Ctr Canc Res, Bethesda, MD USA. [Boasso, Adriano] Univ London Imperial Coll Sci Technol & Med, Dept Med, London SW7 2AZ, England. RP Shearer, GM (reprint author), NIH, Ctr Canc Res, Bethesda, MD USA. NR 13 TC 0 Z9 0 U1 0 U2 1 PU SCIENTIST INC PI PHILADELPHIA PA 400 MARKET ST, STE 1250, PHILADELPHIA, PA 19106 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD JUN PY 2011 VL 25 IS 6 SI SI BP 44 EP 49 PG 6 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 770YS UT WOS:000291125000010 ER PT J AU Anwar-Mohamed, A Degenhardt, OS El Gendy, MAM Seubert, JM Kleeberger, SR El-Kadi, AOS AF Anwar-Mohamed, Anwar Degenhardt, Owen S. El Gendy, Mohamed A. M. Seubert, John M. Kleeberger, Steven R. El-Kadi, Ayman O. S. TI The effect of Nrf2 knockout on the constitutive expression of drug metabolizing enzymes and transporters in C57Bl/6 mice livers SO TOXICOLOGY IN VITRO LA English DT Article DE Nrf2; Phase I metabolizing enzymes; Phase II metabolizing enzymes; Cytochrome P450 ID ARYL-HYDROCARBON RECEPTOR; TRANSCRIPTION FACTOR NRF2; GLUTATHIONE S-TRANSFERASES; NAD(P)H-QUINONE OXIDOREDUCTASE-1; INDUCIBLE EXPRESSION; CONSENSUS SEQUENCE; NUCLEAR RECEPTORS; OXIDATIVE STRESS; RESPONSE ELEMENT; GENE-EXPRESSION AB Previous reports have proposed a cross-talk between the nuclear factor erythroid-2 p45-related factor-2 (Nrf2)/antioxidant response element (ARE) and the aryl hydrocarbon receptor (AhR)/xenobiotic response element (XRE) signaling pathways. Therefore, the aim of the current study was to examine the level of phase I, phase II drug metabolizing enzymes (DMEs), and phase III transporters and their related transcription factors in the Nrf2 knockout model. Our results showed that phase II DMEs that are under the control of Nrf2 typified by NAD(P)H: quinone oxidoreductase 1 (Nqo1), and glutathione S-transferase (Gst) were significantly lower at the mRNA, protein, and catalytic activity levels in the livers of Nrf2 knockout mice compared to wild type. Furthermore, phase I cytochrome P450s (CYF's), Cyp1, and Cyp2b10 at mRNA, protein, and catalytic activity levels were significantly lower in the livers of Nrf2 knockout mice. Interestingly, our results showed that the transcription factors AhR, constitutive androstane receptor (CAR), and pregnane X receptor (PXR) at mRNA, and protein expression levels were significantly lower in the livers of Nrf2 knockout mice compared to wild type. Importantly, phase III drug transporters mRNA levels of the multiple drug resistance associated proteins (Mrp2 and Mrp3), and solute carrier organic anion transporters (Slco1a6 and Slco2b1) were significantly lower in the liver of Nrf2 knockout mice. Co-activators, Ncoa1, Ncoa2, and Ncoa3 mRNA levels were not altered while co-repressors, Ncor1 and Ncor2 were significantly lower in the livers of Nrf2 knockout mice. In conclusion, knockout of Nrf2 causes disruption to the coordination of phase I, phase II drug DMEs, and phase III drug transporters through altering the transcription factors controlling them. (C) 2011 Elsevier Ltd. All rights reserved. C1 [El-Kadi, Ayman O. S.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Dent Pharm Ctr 3126, Edmonton, AB T6G 2N8, Canada. [Kleeberger, Steven R.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. RP El-Kadi, AOS (reprint author), Univ Alberta, Fac Pharm & Pharmaceut Sci, Dent Pharm Ctr 3126, Edmonton, AB T6G 2N8, Canada. EM aelkadi@pharmacy.ualberta.ca OI Anwar-Mohamed, Anwar/0000-0001-9214-7859; El Gendy, Mohamed/0000-0003-0706-2792 FU Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN 250139-07]; Alberta Ingenuity Scholarship award; AHFMR; Egyptian Government FX This work was supported by Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant RGPIN 250139-07 to A.O.S. A.A-M. is recipient of Alberta Ingenuity Scholarship award. O.S.D. is the recipient of AHFMR summer studentship. M.A.M.E. is the recipient of the Egyptian Government Scholarship. NR 42 TC 25 Z9 25 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD JUN PY 2011 VL 25 IS 4 BP 785 EP 795 DI 10.1016/j.tiv.2011.01.014 PG 11 WC Toxicology SC Toxicology GA 771ET UT WOS:000291140700004 PM 21281708 ER PT J AU Zimmermann, LJ Ferrucci, L Liu, K Tian, L Guralnik, JM Criqui, MH Liao, YH McDermott, MM AF Zimmermann, Laura J. Ferrucci, Luigi Liu, Kiang Tian, Lu Guralnik, Jack M. Criqui, Michael H. Liao, Yihua McDermott, Mary M. TI Poorer clock draw test scores are associated with greater functional impairment in peripheral artery disease: The Walking and Leg Circulation Study II SO VASCULAR MEDICINE LA English DT Article DE ankle-brachial index; clock draw test; cognitive impairment; functional performance; peripheral artery disease; walking ID LOWER-EXTREMITY ISCHEMIA; ANKLE-BRACHIAL INDEX; VASCULAR COGNITIVE IMPAIRMENT; PHYSICAL-ACTIVITY; EDINBURGH ARTERY; DAILY-LIFE; CARDIOVASCULAR-DISEASES; INFLAMMATORY MARKERS; MEDICATION ADHERENCE; GENERAL-POPULATION AB We hypothesized that, in the absence of clinically recognized dementia, cognitive dysfunction measured by the clock draw test (CDT) is associated with greater functional impairment in men and women with peripheral artery disease (PAD). Participants were men and women aged 60 years and older with Mini-Mental Status Examination scores >= 24 with PAD (n = 335) and without PAD (n = 234). We evaluated the 6-minute walk test, 4-meter walking velocity at usual and fastest pace, the Short Physical Performance Battery (SPPB), and accelerometer-measured physical activity. CDTs were scored using the Shulman system as follows: Category 1 (worst): CDT score 0-2; Category 2: CDT score 3; Category 3 (best): CDT score 4-5. Results were adjusted for age, sex, race, education, ankle-brachial index (ABI), and comorbidities. In individuals with PAD, lower CDT scores were associated with slower 4-meter usual-paced walking velocity (Category 1: 0.78 meters/second; Category 2: 0.83 meters/second; Category 3: 0.86 meters/second; p-trend = 0.025) and lower physical activity (Category 1: 420 activity units; Category 2: 677 activity units; Category 3: 701 activity units; p-trend = 0.045). Poorer CDT scores were also associated with worse functional performance in individuals without PAD (usual and fast-paced walking velocity and SPPB, p-trend = 0.022, 0.043, and 0.031, respectively). In conclusion, cognitive impairment identified with CDT is independently associated with greater functional impairment in older, dementia-free individuals with and without PAD. Longitudinal studies are necessary to explore whether baseline CDT scores and changes in CDT scores over time can predict long-term decline in functional performance in individuals with and without PAD. C1 [Zimmermann, Laura J.; Liu, Kiang; Liao, Yihua; McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. [Tian, Lu] Stanford Sch Med, Palo Alto, CA USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Criqui, Michael H.] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. RP Zimmermann, LJ (reprint author), 750 N Lake Shore Dr,10th Floor 157B, Chicago, IL 60611 USA. EM lzimmermann007@md.northwestern.edu; mdm608@northwestern.edu FU National Heart, Lung and Blood Institute [R01-HL58099, R01-HL64739, R01-HL071223, R01-HL083064, R01-HL076298]; National Center for Research Resources, NIH [RR-00048]; National Institute on Aging, NIH; Agency for Healthcare Research and Quality [5T32HS000078-13] FX ySupported by grants #R01-HL58099, R01-HL64739, R01-HL071223, R01-HL083064, and R01-HL076298 from the National Heart, Lung and Blood Institute and by grant #RR-00048 from the National Center for Research Resources, NIH. Supported in part by the Intramural Research Program, National Institute on Aging, NIH. Dr Zimmermann was supported by the Institutional National Research Service Award 5T32HS000078-13 from the Agency for Healthcare Research and Quality. NR 49 TC 4 Z9 4 U1 2 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD JUN PY 2011 VL 16 IS 3 BP 173 EP 181 DI 10.1177/1358863X11407109 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 772FB UT WOS:000291218600002 PM 21636676 ER PT J AU McDermott, MM Liu, K Guralnik, JM Tian, L Ferrucci, L Pearce, WH Liao, YH Criqui, MH AF McDermott, Mary M. Liu, Kiang Guralnik, Jack M. Tian, Lu Ferrucci, Luigi Pearce, William H. Liao, Yihua Criqui, Michael H. TI Lower calf muscle density is associated with mobility loss and mortality in peripheral arterial disease SO VASCULAR MEDICINE LA English DT Meeting Abstract C1 [McDermott, Mary M.; Liu, Kiang; Pearce, William H.; Liao, Yihua] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Guralnik, Jack M.; Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. [Tian, Lu] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD JUN PY 2011 VL 16 IS 3 MA 30 BP 232 EP 233 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 772FB UT WOS:000291218600038 ER PT J AU Reagan, WJ Irizarry-Rovira, A Poitout-Belissent, F Bolliger, AP Ramaiah, SK Travlos, G Walker, D Bounous, D Walter, G AF Reagan, William J. Irizarry-Rovira, Armando Poitout-Belissent, Florence Bolliger, Anne Provencher Ramaiah, Shashi K. Travlos, Greg Walker, Dana Bounous, Denise Walter, Gail CA Bone Marrow Working Grp ASVCP STP TI Best practices for evaluation of bone marrow in nonclinical toxicity studies SO VETERINARY CLINICAL PATHOLOGY LA English DT Article DE Bone marrow; best practice; cytology; histopathology; flow cytometry ID FLOW-CYTOMETRIC EVALUATION; CYNOMOLGUS MONKEYS; CELL COUNTS; WISTAR RATS; ULTRASTRUCTURAL TECHNIQUES; MYELODYSPLASTIC SYNDROMES; PERIPHERAL-BLOOD; FEED RESTRICTION; BIOPSY SPECIMENS; IN-VITRO AB This manuscript is intended to provide a best practice approach to accurately and consistently assess toxicant-induced bone marrow effects of test articles. In nonclinical toxicity studies, complete blood count data in conjunction with the histological examination of the bone marrow are recommended as the foundation for assessing the effect of test articles on the hematopoietic system. This approach alone can be used successfully in many studies. However, in some situations it may be necessary to further characterize effects on the different hematopoietic lineages, either by cytological or flow cytometric evaluation of the bone marrow. Both modalities can be used successfully, and which one is selected will depend on the expertise, preference of the facility, and the nature of the change in the bone marrow. Other specialized techniques such as clonogenic assays or electron microscopy are used rarely to further characterize hematotoxicity. The indications and techniques to successfully employ histological, cytological, or flow cytometric evaluation as well as clonogenic assays and electron microscopy are reviewed. William J. Reagan, Armando Irizarry-Rovira, Florence Poitout-Belissent, Anne Provencher Bolliger, Shashi K. Ramaiah, Greg Travlos, Dana Walker, Denise Bounous, and Gail Walter. "Best Practices for Evaluation of Bone Marrow in Nonclinical Toxicity Studies." Toxicologic Pathology (39.2) pp. 435-448, copyright 2011 by The Author(s), Reprinted by Permission of SAGE Publications Inc. C1 [Reagan, William J.] Pfizer Inc, Groton, CT 06340 USA. [Irizarry-Rovira, Armando] Eli Lilly & Co Inc, Indianapolis, IN USA. [Poitout-Belissent, Florence] Charles River Labs, Senneville, PQ, Canada. [Bolliger, Anne Provencher] Charles River Labs, Sherbrooke, PQ, Canada. [Ramaiah, Shashi K.] Pfizer Inc, Cambridge, MA USA. [Travlos, Greg] NIEHS, Res Triangle Pk, NC 27709 USA. [Walker, Dana] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Bounous, Denise] Bristol Myers Squibb Co, Princeton, NJ USA. [Walter, Gail] PLC, DVM, Kalamazoo, MI USA. RP Reagan, WJ (reprint author), Pfizer Global Res & Dev, Drug Safety Res & Dev, 8274-1203 Eastern Point Rd, Groton, CT 06340 USA. EM william.j.reagan@pfizer.com NR 88 TC 13 Z9 13 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0275-6382 J9 VET CLIN PATH JI Vet. Clin. Pathol. PD JUN PY 2011 VL 40 IS 2 BP 119 EP 135 DI 10.1111/j.1939-165X.2011.00323.x PG 17 WC Veterinary Sciences SC Veterinary Sciences GA 772SV UT WOS:000291257200002 PM 21631562 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Commentary: Will Academia Embrace Comparative Effectiveness Research? SO ACADEMIC MEDICINE LA English DT Editorial Material ID HEALTH CENTERS; TRANSLATIONAL SCIENCE AB In recent medical history, a number of therapies that were widely adopted based on observational data or pathophysiological constructs turned out to be useless or even harmful when tested in randomized comparative effectiveness trials. These therapies not only harmed patients but also did a disservice to the practical education of medical students, residents, and fellows. These trainees effectively learned that it is acceptable to implement practices even in the absence of high-quality evidence, and so they may not have learned how to analyze the quality of evidence. In this issue of Academic Medicine, seven groups address critical aspects of the intersection between comparative effectiveness research (CER) and academic medicine. Their topics include the need at academic health centers for cultural shifts, for addressing conflicts of interest, for exploiting academic talent and electronic information resources, for interacting well with policy makers, for incorporating economic evaluations, for incorporating tests of educational methods, for developing multidisciplinary models, and for integrating CER into "predictive health." This commentary argues that academia must embrace CER by insisting on the highest levels of evidence, by viewing all clinical interactions as opportunities for scientific advancement, by setting an example for policy makers and colleagues working in nonacademic settings, and by engaging all physicians in the clinical research enterprise. C1 NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI liu, jing/D-9482-2012; Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 12 TC 5 Z9 5 U1 0 U2 3 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 JUN PY 2011 VL 86 IS 6 BP 671 EP 673 DI 10.1097/ACM.0b013e318217d6e6 PG 3 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 769IM UT WOS:000291006100010 PM 21613887 ER PT J AU Pohlhaus, JR Jiang, H Wagner, RM Schaffer, WT Pinn, VW AF Pohlhaus, Jennifer Reineke Jiang, Hong Wagner, Robin M. Schaffer, Walter T. Pinn, Vivian W. TI Sex Differences in Application, Success, and Funding Rates for NIH Extramural Programs SO ACADEMIC MEDICINE LA English DT Article ID WOMEN AB Purpose The authors provide an analysis of sex differences in National Institutes of Health (NIH) award programs to inform potential initiatives for promoting diversity in the research workforce. Method In 2010, the authors retrieved data for NIH extramural grants in the electronic Research Administration Information for Management, Planning, and Coordination II database and used statistical analysis to determine any sex differences in securing NIH funding, as well as subsequent success of researchers who had already received independent NIH support. Results Success and funding rates for men and women were not significantly different in most award programs. Furthermore, in programs where participation was lower for women than men, the disparity was primarily related to a lower percentage of women applicants compared with men, rather than decreased success rates or funding rates. However, for subsequent grants, both application and funding rates were generally higher for men than for women. Conclusions Cross-sectional analysis showed that women and men were generally equally successful at all career stages, but longitudinal analysis showed that men with previous experience as NIH grantees had higher application and funding rates than women at similar career points. On average, although women received larger R01 awards than men, men had more R01 awards than women at all points in their careers. Therefore, while greater participation of women in NIH programs is under way, further action will be required to eradicate remaining sex differences. C1 [Pohlhaus, Jennifer Reineke; Pinn, Vivian W.] NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. [Wagner, Robin M.] NIH, Off Extramural Res, Div Informat Serv, Bethesda, MD 20892 USA. RP Pohlhaus, JR (reprint author), 6705 Rockledge Dr,Suite 350H,MSC 7963, Bethesda, MD 20892 USA. EM pohlhausj@mail.nih.gov RI Schaffer, Walter/E-5982-2010 OI Schaffer, Walter/0000-0002-2276-4656 FU NIH FX All authors are employees or contractors for the NIH; in this way, this work was supported by the NIH. NR 31 TC 43 Z9 43 U1 3 U2 14 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 JUN PY 2011 VL 86 IS 6 BP 759 EP 767 DI 10.1097/ACM.0b013e31821836ff PG 9 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 769IM UT WOS:000291006100029 PM 21512358 ER PT J AU Qiu, G Wan, RQ Hu, JP Mattson, MP Spangler, E Liu, S Yau, SY Lee, TMC Gleichmann, M Ingram, DK So, KF Zou, S AF Qiu, Guang Wan, Ruiqian Hu, Jingping Mattson, Mark P. Spangler, Edward Liu, Shan Yau, Suk-Yu Lee, Tatia M. C. Gleichmann, Marc Ingram, Donald K. So, Kwok-Fai Zou, Sige TI Adiponectin protects rat hippocampal neurons against excitotoxicity SO AGE LA English DT Article DE Adiponectin; Neuroprotection; Hippocampus; Kainic acid; AMPK ID HUMAN CEREBROSPINAL-FLUID; INSULIN SENSITIVITY; ALZHEIMERS-DISEASE; ENDOTHELIAL-CELLS; NITRIC-OXIDE; KINASE; RECEPTORS; GLUCOSE; BRAIN; HYPOTHALAMUS AB Adiponectin exerts multiple regulatory functions in the body and in the hypothalamus primarily through activation of its two receptors, adiponectin receptor1 and adiponectin receptor 2. Recent studies have shown that adiponectin receptors are widely expressed in other areas of the brain including the hippocampus. However, the functions of adiponectin in brain regions other than the hypothalamus are not clear. Here, we report that adiponectin can protect cultured hippocampal neurons against kainic acid-induced (KA) cytotoxicity. Adiponectin reduced the level of reactive oxygen species, attenuated apoptotic cell death, and also suppressed activation of caspase-3 induced by KA. Pretreatment of hippocampal primary neurons with an AMPK inhibitor, compound C, abolished adiponectin-induced neuronal protection. The AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, attenuated KA-induced caspase-3 activity. These findings suggest that the AMPK pathway is critically involved in adiponectin-induced neuroprotection and may mediate the antioxidative and anti-apoptotic properties of adiponectin. C1 [Qiu, Guang; Yau, Suk-Yu; So, Kwok-Fai] Univ Hong Kong, Li Ka Shing Fac Med, Dept Anat, Pokfulam, Hong Kong, Peoples R China. [Qiu, Guang] Nanfang Med Univ, Nanfang Hosp, Dept Neurol, Guangzhou, Guangdong, Peoples R China. [Wan, Ruiqian; Mattson, Mark P.; Gleichmann, Marc] NIA, Neurosci Lab, Baltimore, MD 21224 USA. [Qiu, Guang; Hu, Jingping; Spangler, Edward; Zou, Sige] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. [Liu, Shan] JiNan Univ, Dept Nursing, Fac Med, Guangzhou, Guangdong, Peoples R China. [Lee, Tatia M. C.] Univ Hong Kong, Neuropsychol Lab, Pokfulam, Hong Kong, Peoples R China. [Lee, Tatia M. C.] Univ Hong Kong, Lab Cognit Affect Neurosci, HKU Alzheimers Dis Res Network, Pokfulam, Hong Kong, Peoples R China. [Ingram, Donald K.] Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA USA. RP So, KF (reprint author), Univ Hong Kong, Li Ka Shing Fac Med, Dept Anat, Pokfulam, Hong Kong, Peoples R China. EM hrmaskf@hkucc.hku.hk; zous@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institute on Aging, National Institutes of Health, USA FX The authors would like to thank Drs. Min Zhu and Haiyang Jiang for technical assistance, Dr. Peter Rapp for suggestions and thoughtful review of the manuscript and Kris Rozankowski for editing the manuscript. This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, USA NR 45 TC 25 Z9 28 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 J9 AGE JI Age PD JUN PY 2011 VL 33 IS 2 BP 155 EP 165 DI 10.1007/s11357-010-9173-5 PG 11 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 769ZG UT WOS:000291056200005 PM 20842535 ER PT J AU Glancy, B Balaban, RS AF Glancy, Brian Balaban, Robert S. TI Protein composition and function of red and white skeletal muscle mitochondria SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE proteomics; fast and slow-twitch muscle; iTRAQ; energetics; oxidative phosphorylation ID OXYGEN-CONSUMPTION; SLOW-TWITCH; INTERMYOFIBRILLAR MITOCHONDRIA; OXIDATIVE CAPACITY; PROTEOMIC ANALYSIS; STATISTICAL-MODEL; ENERGY METABOLISM; RESPIRATION RATE; SOLEUS MUSCLES; CYTOCHROME-C AB Glancy B, Balaban RS. Protein composition and function of red and white skeletal muscle mitochondria. Am J Physiol Cell Physiol 300: C1280-C1290, 2011. First published February 2, 2011; doi: 10.1152/ajpcell.00496.2010.-Red and white muscles are faced with very different energetic demands. However, it is unclear whether relative mitochondrial protein expression is different between muscle types. Mitochondria from red and white porcine skeletal muscle were isolated with a Percoll gradient. Differences in protein composition were determined using blue native (BN)-PAGE, two-dimensional differential in gel electrophoresis (2D DIGE), optical spectroscopy, and isobaric tag for relative and absolute quantitation (iTRAQ). Complex IV and V activities were compared using BN-PAGE in-gel activity assays, and maximal mitochondrial respiration rates were assessed using pyruvate (P) + malate (M), glutamate (G) + M, and palmitoyl-carnitine (PC) + M. Without the Percoll step, major cytosolic protein contamination was noted for white mitochondria. Upon removal of contamination, very few protein differences were observed between red and white mitochondria. BN-PAGE showed no differences in the subunit composition of Complexes I-V or the activities of Complexes IV and V. iTRAQ analysis detected 358 mitochondrial proteins, 69 statistically different. Physiological significance may be lower: at a 25% difference, 48 proteins were detected; at 50%, 14 proteins were detected; and 3 proteins were detected at a 100%. Thus any changes could be argued to be physiologically modest. One area of difference was fat metabolism where four beta-oxidation enzymes were similar to 25% higher in red mitochondria. This was correlated with a 40% higher rate of PC + M oxidation in red mitochondria compared with white mitochondria with no differences in P + M and G + M oxidation. These data suggest that metabolic demand differences between red and white muscle fibers are primarily matched by the number of mitochondria and not by significant alterations in the mitochondria themselves. C1 [Glancy, Brian; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Glancy, B (reprint author), NHLBI, Cardiac Energet Lab, NIH, 10 Ctr Dr,Rm B1D416, Bethesda, MD 20892 USA. EM glancybp@nhlbi.nih.gov RI Glancy, Brian/P-3163-2016 OI Glancy, Brian/0000-0002-8571-244X FU Division of Intramural Research, National Heart, Lung, and Blood Institute FX This study was supported by Intramural Funding of the Division of Intramural Research, National Heart, Lung, and Blood Institute. NR 55 TC 17 Z9 17 U1 0 U2 27 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JUN PY 2011 VL 300 IS 6 BP C1280 EP C1290 DI 10.1152/ajpcell.00496.2010 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 769LY UT WOS:000291016400009 PM 21289287 ER PT J AU Frattarelli, JL Krsmanovic, LZ Catt, KJ AF Frattarelli, John L. Krsmanovic, Lazar Z. Catt, Kevin J. TI The relationship between pulsatile GnRH secretion and cAMP production in immortalized GnRH neurons SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE gonadotropin-releasing hormone; adenosine 3 ', 5 '-cyclic monophosphate ID GONADOTROPIN-RELEASING-HORMONE; PROTEIN-KINASE-C; INOSITOL PHOSPHATE PRODUCTION; HYPOTHALAMIC NEURONS; GT1 CELLS; DICTYOSTELIUM-DISCOIDEUM; ADENYLYL-CYCLASE; COUPLED-RECEPTOR; CALCIUM; EXPRESSION AB In perifused immortalized GnRH neurons (GT1-7), simultaneous measurements of GnRH and cAMP revealed that the secretory profiles for both GnRH and cAMP are pulsatile. An analysis of GnRH and cAMP pulses in 16 independent experiments revealed that 25% of pulses coincide. Inversion of the peak and nadir levels was found in 33% and random relationship between GnRH and cAMP found in 42% of analyzed pulses. The random relation between GnRH and cAMP pulse resets to synchronous after an inverse relation between pulses occurred during the major GnRH release, indicating that GnRH acts as a switching mechanism to synchronize cAMP and GnRH release in perifused GT1-7 neurons. Activation of GnRH receptors with increasing agonist concentrations caused a biphasic change in cAMP levels. Low nanomolar concentrations increased cAMP production, but at high concentrations the initial increase was followed by a rapid decline to below the basal level. Blockade of the GnRH receptors by peptide and nonpeptide antagonists generated monotonic nonpulsatile increases in both GnRH and cAMP production. These findings indicate that cAMP positively regulates GnRH secretion but does not participate in the mechanism of pulsatile GnRH release. C1 [Frattarelli, John L.; Krsmanovic, Lazar Z.; Catt, Kevin J.] NICHHD, Sect Hormonal Regulat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Krsmanovic, LZ (reprint author), NICHD, Sect Hormonal Regulat, PDEGEN, NIH, Bldg 49,Rm 6A-36, Bethesda, MD 20892 USA. EM lazar@mail.nih.gov NR 35 TC 1 Z9 1 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUN PY 2011 VL 300 IS 6 BP E1022 EP E1030 DI 10.1152/ajpendo.00081.2011 PG 9 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 768SP UT WOS:000290959000009 PM 21447787 ER PT J AU Ruggiero, C Ehrenshaft, M Cleland, E Stadler, K AF Ruggiero, Christine Ehrenshaft, Marilyn Cleland, Ellen Stadler, Krisztian TI High-fat diet induces an initial adaptation of mitochondrial bioenergetics in the kidney despite evident oxidative stress and mitochondrial ROS production SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE reactive oxygen species; chronic kidney diseases; obesity; mitochondria ID PROGRESSIVE RENAL-DISEASE; INSULIN-RESISTANCE; LIPID-METABOLISM; SKELETAL-MUSCLE; ACID OXIDATION; US ADULTS; OBESITY; MICE; TISSUE; IMMUNOLOCALIZATION AB Obesity and metabolic syndrome are associated with an increased risk for several diabetic complications, including diabetic nephropathy and chronic kidney diseases. Oxidative stress and mitochondrial dysfunction are often proposed mechanisms in various organs in obesity models, but limited data are available on the kidney. Here, we fed a lard-based high-fat diet to mice to investigate structural changes, cellular and subcellular oxidative stress and redox status, and mitochondrial biogenesis and function in the kidney. The diet induced characteristic changes, including glomerular hypertrophy, fibrosis, and interstitial scarring, which were accompanied by a proinflammatory transition. We demonstrate evidence for oxidative stress in the kidney through 3-nitrotyrosine and protein radical formation on high-fat diet with a contribution from iNOS and NOX-4 as well as increased generation of mitochondrial oxidants on carbohydrate-and lipid-based substrates. The increased H(2)O(2) emission in the mitochondria suggests altered redox balance and mitochondrial ROS generation, contributing to the overall oxidative stress. No major derailments were observed in respiratory function or biogenesis, indicating preserved and initially improved bioenergetic parameters and energy production. We suggest that, regardless of the oxidative stress events, the kidney developed an adaptation to maintain normal respiratory function as a possible response to an increased lipid overload. These findings provide new insights into the complex role of oxidative stress and mitochondrial redox status in the pathogenesis of the kidney in obesity and indicate that early oxidative stress-related changes, but not mitochondrial bioenergetic dysfunction, may contribute to the pathogenesis and development of obesity-linked chronic kidney diseases. C1 [Ruggiero, Christine; Cleland, Ellen; Stadler, Krisztian] Pennington Biomed Res Ctr, Oxidat Stress & Dis Lab, Baton Rouge, LA 70808 USA. [Ehrenshaft, Marilyn] NIEHS, Free Rad Metabolite Sect, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Stadler, K (reprint author), Pennington Biomed Res Ctr, Oxidat Stress & Dis Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM krisztian.stadler@pbrc.edu FU NIH [DK-083615, P20 RR-021945]; Pennington Foundation; NORC P F [2P30DK072476]; CNRU [NIH 1P30 DK-072476] FX Research in this laboratory is supported partially by NIH (DK-083615) to K. Stadler and the Pennington Foundation and by a NORC P & F grant (2P30DK072476). The work utilized the facilities of the Cell Biology and Bioimaging Core, which are supported in part by COBRE (NIH P20 RR-021945) and CNRU (NIH 1P30 DK-072476) center grants from the NIH. NR 45 TC 44 Z9 46 U1 1 U2 12 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUN PY 2011 VL 300 IS 6 BP E1047 EP E1058 DI 10.1152/ajpendo.00666.2010 PG 12 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 768SP UT WOS:000290959000012 PM 21386058 ER PT J AU Fee, E Garofalo, ME AF Fee, Elizabeth Garofalo, Mary E. TI Red Emma (1869-1940): Idealistic Revolutionary SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 [Fee, Elizabeth] NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20894 USA. [Garofalo, Mary E.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Fee, E (reprint author), NIH, Hist Med Div, Natl Lib Med, 8600 Rockville Pile, Bethesda, MD 20894 USA. EM eliza-beth_fee@nlm.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 2 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 JUN PY 2011 VL 101 IS 6 BP 1044 EP 1045 DI 10.2105/AJPH.2010.300038 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 767VQ UT WOS:000290887000016 ER PT J AU Fee, E AF Fee, Elizabeth TI George Huntington Williams (1892-1992): Baltimore's Commissioner of Health SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20894 USA. RP Fee, E (reprint author), NIH, Hist Med Div, Natl Lib Med, 8600 Rockville Pike,MSC-3819, Bethesda, MD 20894 USA. EM elizabeth_fee@nlm.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 4 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 JUN PY 2011 VL 101 IS 6 BP 1049 EP 1049 DI 10.2105/AJPH.2009.190835 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 767VQ UT WOS:000290887000018 PM 21493936 ER PT J AU Reznick, JS Fee, E AF Reznick, Jeffrey S. Fee, Elizabeth TI Walt Whitman: "A Feather in My Wings" SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Reznick, Jeffrey S.; Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20894 USA. RP Reznick, JS (reprint author), NIH, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM jeffrey.reznick@nih.gov NR 4 TC 0 Z9 0 U1 0 U2 2 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 JUN PY 2011 VL 101 IS 6 BP 1053 EP 1053 DI 10.2105/AJPH.2010.300022 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 767VQ UT WOS:000290887000022 PM 21493946 ER PT J AU Omsland, A Beare, PA Hill, J Cockrell, DC Howe, D Hansen, B Samuel, JE Heinzen, RA AF Omsland, Anders Beare, Paul A. Hill, Joshua Cockrell, Diane C. Howe, Dale Hansen, Bryan Samuel, James E. Heinzen, Robert A. TI Isolation from Animal Tissue and Genetic Transformation of Coxiella burnetii Are Facilitated by an Improved Axenic Growth Medium SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID Q-FEVER; HOST-CELL; PHASE-I; BORDETELLA-PERTUSSIS; MACROPHAGES; IDENTIFICATION; CYCLODEXTRINS; TRANSLOCATION; REPLICATE; APOPTOSIS AB We recently described acidified citrate cysteine medium (ACCM), which supports host cell-free (axenic) growth of Coxiella burnetii. After 6 days of incubation, greater than 3 logs of growth was achieved with the avirulent Nine Mile phase II (NMII) strain. Here, we describe modified ACCM and culture conditions that support improved growth of C. burnetii and their use in genetic transformation and pathogen isolation from tissue samples. ACCM was modified by replacing fetal bovine serum with methyl-beta-cyclodextrin to generate ACCM-2. Cultivation of NMII in ACCM-2 with moderate shaking and in 2.5% oxygen yielded 4 to 5 logs of growth over 7 days. Similar growth was achieved with the virulent Nine Mile phase I and G isolates of C. burnetii. Colonies that developed after 6 days of growth in ACCM-2 agarose were approximately 0.5 mm in diameter, roughly 5-fold larger than those formed in ACCM agarose. By electron microscopy, colonies consisted primarily of the C. burnetii small cell variant morphological form. NMII was successfully cultured in ACCM-2 when medium was inoculated with as little as 10 genome equivalents contained in tissue homogenates from infected SCID mice. A completely axenic C. burnetii genetic transformation system was developed using ACCM-2 that allowed isolation of transformants in about 2 1/2 weeks. Transformation experiments demonstrated clonal populations in colonies and a transformation frequency of approximately 5 x 10(-5). Cultivation in ACCM-2 will accelerate development of C. burnetii genetic tools and provide a sensitive means of primary isolation of the pathogen from Q fever patients. C1 [Omsland, Anders; Beare, Paul A.; Hill, Joshua; Cockrell, Diane C.; Howe, Dale; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Hansen, Bryan] NIAID, Electron Microscopy Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Hill, Joshua; Samuel, James E.] Texas A&M Hlth Sci Ctr, Dept Microbial & Mol Pathogenesis, College Stn, TX 77843 USA. RP Heinzen, RA (reprint author), NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov FU National Institutes of Health; National Institute of Allergy and Infectious Diseases [RO1AI037744, R21AI088430, R56AI090142-01] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (to R. A. H.), and by Public Health Service grants RO1AI037744, R21AI088430, and R56AI090142-01 from the National Institute of Allergy and Infectious Diseases (to J.E.S.). NR 28 TC 62 Z9 63 U1 0 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JUN PY 2011 VL 77 IS 11 BP 3720 EP 3725 DI 10.1128/AEM.02826-10 PG 6 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 767HY UT WOS:000290847800021 PM 21478315 ER PT J AU Kim, JH Deschamps, JR Rothman, RB Dersch, CM Folk, JE Cheng, KJ Jacobson, AE Rice, KC AF Kim, Jin-Hee Deschamps, Jeffrey R. Rothman, Richard B. Dersch, Christina M. Folk, John E. Cheng, Kejun Jacobson, Arthur E. Rice, Kenner C. TI Probes for narcotic receptor mediated phenomena. Part 42: Synthesis and in vitro pharmacological characterization of the N-methyl and N-phenethyl analogues of the racemic ortho-c and para-c oxide-bridged phenylmorphans SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Racemates; Ortho-c and para-c oxide bridged phenylmorphans; N-Phenethyl substituent; Opioid receptor affinity; Functional assays; Molecular shape; Opioid antagonist activity ID ISOMERS; 5-(META-HYDROXYPHENYL)MORPHAN; AFFINITY; MORPHINE AB A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmorphans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacological properties of these compounds were determined. The N-phenethyl substituted ortho-c oxide-bridged phenylmorphan(rac-(3R, 6aS, 11aS)-2-phenethyl-2,3,4,5,6,11a-hexahydro-1H-3,6a-methanobenzofuro-[2,3-c]azocin-10-ol (12)) was found to have the highest l-opioid receptor affinity (K(i) = 1.1 nM) of all of the a- through f-oxide-bridged phenylmorphans. Functional data ([(35)S]GTP-gamma-S) showed that the racemate 12 was more than three times more potent than naloxone as an l-opioid antagonist. Published by Elsevier Ltd. C1 [Kim, Jin-Hee; Folk, John E.; Cheng, Kejun; Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Kim, Jin-Hee; Folk, John E.; Cheng, Kejun; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Deschamps, Jeffrey R.] USN, Ctr Biomol Sci & Engn, Res Lab, Washington, DC 20375 USA. [Rothman, Richard B.; Dersch, Christina M.] NIDA, Clin Psychopharmacol Sect, Chem Biol Res Branch, Addict Res Ctr,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Rice, KC (reprint author), NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, 5625 Fishers Lane,Room 4N03, Bethesda, MD 20892 USA. EM jheeeee@gmail.com; kr21f@nih.gov OI Deschamps, Jeffrey/0000-0001-5845-0010 FU NIH, National Institute on Drug Abuse (NIDA); National Institute of Alcohol Abuse and Alcoholism NIAAA; NIDA with the Naval Research Laboratory (NRL) [Y1-DA1101] FX The work of the Drug Design and Synthesis Section, CBRB, NIDA, & NIAAA, was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism NIAAA). The Clinical Psychopharmacology Section, CBRB, NIDA, was supported by the NIH Intramural Research Program of NIDA. The X-ray crystallographic work was supported by NIDA through an Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL). We thank Dr. Klaus Gawrisch and Dr. Walter Teague (Laboratory of Membrane Biochemistry and Biophysics, NIAAA, for NMR spectral data. The authors also thank Noel Whittaker and Wesley White, Laboratory of Analytical Chemistry, NIDDK, for mass spectral data. NR 16 TC 5 Z9 5 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUN 1 PY 2011 VL 19 IS 11 BP 3434 EP 3443 DI 10.1016/j.bmc.2011.04.028 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 768RQ UT WOS:000290955400017 PM 21570305 ER PT J AU Keyak, JH Sigurdsson, S Karlsdottir, G Oskarsdottir, D Sigmarsdottir, A Zhao, S Kornak, J Harris, TB Sigurdsson, G Jonsson, BY Siggeirsdottir, K Eiriksdottir, G Gudnason, V Lang, TF AF Keyak, J. H. Sigurdsson, S. Karlsdottir, G. Oskarsdottir, D. Sigmarsdottir, A. Zhao, S. Kornak, J. Harris, T. B. Sigurdsson, G. Jonsson, B. Y. Siggeirsdottir, K. Eiriksdottir, G. Gudnason, V. Lang, T. F. TI Male-female differences in the association between incident hip fracture and proximal femoral strength: A finite element analysis study SO BONE LA English DT Article DE Hip fracture; Femur; Bone strength; Finite element analysis; Osteoporosis; Quantitative computed tomography ID QUANTITATIVE COMPUTED-TOMOGRAPHY; CT-SCAN DATA; IN-VITRO; BODY-COMPOSITION; TRABECULAR BONE; FEMUR; PREDICTION; MODELS; OSTEOPOROSIS; DENSITY AB Hip fracture risk is usually evaluated using dual energy X-ray absorptiometry (DXA) or quantitative computed tomography (QCT) which provide surrogate measures for proximal femoral strength. However, proximal femoral strength can best be estimated explicitly by combining QCT with finite element (FE) analysis. To evaluate this technique for predicting hip fracture in older men and women, we performed a nested age- and sex-matched case-control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Baseline (pre-fracture) QCT scans of 5500 subjects were obtained. During 4-7 years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as age- and sex-matched controls. FE-strength of the left hip of each subject for stance (F(Stance)) and posterolateral fall (F(Fall)) loading, and total femur areal bone mineral density (aBMD) were computed from the QCT data. F(Stance) and F(Fall) in incident hip fracture subjects were 13%-25% less than in control subjects (p <= 0.006) after controlling for demographic parameters. The difference between FE strengths of fracture and control subjects was disproportionately greater ill men (stance, 22%; fall, 25%) than in women (stance, 13%; fall, 18%) (p <= 0.033), considering that Fstar,ce and FFall in fracture subjects were greater in men than in women ( p < 0.001). For men, F(Stance) was associated with hip fracture after accounting for aBMD (p = 0.013). These data indicate that F(Stance) provides information about fracture risk that is beyond that provided by aBMD (p = 0.013). These findings support further exploration of possible sex differences in the predictors of hip fracture and of sex-specific strategies for using FE analysis to manage osteoporosis. (C) 2011 Elsevier Inc. All rights reserved. C1 [Keyak, J. H.] Univ Calif Irvine, Dept Radiol Sci, Irvine, CA 92697 USA. [Keyak, J. H.] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92697 USA. [Keyak, J. H.] Univ Calif Irvine, Dept Mech & Aerosp Engn, Irvine, CA 92697 USA. [Sigurdsson, S.; Karlsdottir, G.; Oskarsdottir, D.; Sigmarsdottir, A.; Sigurdsson, G.; Siggeirsdottir, K.; Eiriksdottir, G.; Gudnason, V.] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Jonsson, B. Y.] Malmo Univ Hosp, Malmo, Sweden. [Zhao, S.; Kornak, J.; Lang, T. F.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Kornak, J.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Harris, T. B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Sigurdsson, G.] Landspitalinn Univ Hosp, Reykjavik, Iceland. [Sigurdsson, G.; Gudnason, V.] Univ Iceland, Reykjavik, Iceland. RP Keyak, JH (reprint author), Univ Calif Irvine, Dept Radiol Sci, Irvine, CA 92697 USA. EM jhkeyak@uci.edu RI Lang, Thomas/B-2685-2012; Gudnason, Vilmundur/K-6885-2015 OI Lang, Thomas/0000-0002-3720-8038; Gudnason, Vilmundur/0000-0001-5696-0084 FU NIH/NIA [R01AG028832]; NIH/NIAMS [R01AR46197]; NIH [N01-AG-12100]; NIA; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX This study was supported by NIH/NIA R01AG028832 and NIH/NIAMS R01AR46197. The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study was approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. NR 27 TC 63 Z9 63 U1 3 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD JUN PY 2011 VL 48 IS 6 BP 1239 EP 1245 DI 10.1016/j.bone.2011.03.682 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 768XX UT WOS:000290974200003 PM 21419886 ER PT J AU Johannesdottir, F Poole, KES Reeve, J Siggeirsdottir, K Aspelund, T Mogensen, B Jonsson, BY Sigurdsson, S Harris, TB Gudnason, VG Sigurdsson, G AF Johannesdottir, Fjola Poole, Kenneth E. S. Reeve, Jonathan Siggeirsdottir, Kristin Aspelund, Thor Mogensen, Brynjolfur Jonsson, Brynjolfur Y. Sigurdsson, Sigurdur Harris, Tamara B. Gudnason, Vilmundur G. Sigurdsson, Gunnar TI Distribution of cortical bone in the femoral neck and hip fracture: A prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study SO BONE LA English DT Article DE Cortical thickness; Hip fracture; Quantitative computed tomography; Proximal femur; BMD ID GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; QUANTITATIVE COMPUTED-TOMOGRAPHY; PROXIMAL FEMUR; MINERAL DENSITY; OSTEOPOROTIC FRACTURES; TRABECULAR BONE; FAILURE LOAD; AXIS LENGTH; STRENGTH; RISK AB In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm(2), DXA-like), (p = 0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n = 143) from controls (n = 298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture. (C) 2011 Elsevier Inc. All rights reserved. C1 [Mogensen, Brynjolfur; Sigurdsson, Gunnar] Landspitali Univ Hosp, IS-108 Reykjavik, Iceland. [Johannesdottir, Fjola; Aspelund, Thor; Mogensen, Brynjolfur; Gudnason, Vilmundur G.; Sigurdsson, Gunnar] Univ Iceland, Reykjavik, Iceland. [Poole, Kenneth E. S.; Reeve, Jonathan] Univ Cambridge, Cambridge, England. [Siggeirsdottir, Kristin; Aspelund, Thor; Sigurdsson, Sigurdur; Gudnason, Vilmundur G.; Sigurdsson, Gunnar] Iceland Heart Assoc, Kopavogur, Iceland. [Jonsson, Brynjolfur Y.] Malmo Univ Hosp, Malmo, Sweden. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. RP Sigurdsson, G (reprint author), Landspitali Univ Hosp, IS-108 Reykjavik, Iceland. EM fjolajo@hi.is; kenpoole@doctors.org.uk; jonathan@srl.cam.ac.uk; kristin@hjarta.is; aspelund@hjarta.is; brynjolf@landspitali.is; Brynjolfur.Jonsson@skane.se; sigurdur@hjarta.is; harris99@nia.nih.gov; v.gudnason@hjarta.is; gunnars@landspitali.is RI Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Reeve, Jonathan/C-7551-2012; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Reeve, Jonathan/0000-0002-4364-2682; Gudnason, Vilmundur/0000-0001-5696-0084 FU NIH [N01-AG-1-2100]; NIA; Icelandic Heart association; Icelandic Parliament; Icelandic Centre of Research; University of Iceland; Arthritis Research UK; Cambridge NIHR Biomedical Research Centre FX The following institutes provided support: the NIH, contract N01-AG-1-2100; the NIA Intramural Research Program; the Icelandic Heart association; the Icelandic Parliament and the Icelandic Centre of Research. Dr Sigurdsson acknowledges support from the University of Iceland Research Fund. Dr Poole acknowledges the support of the Arthritis Research UK and the Cambridge NIHR Biomedical Research Centre. The authors would like to thank Keenan Brown (Mindways software, Texas, USA) for his assistance. NR 47 TC 40 Z9 42 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD JUN PY 2011 VL 48 IS 6 BP 1268 EP 1276 DI 10.1016/j.bone.2011.03.776 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 768XX UT WOS:000290974200007 PM 21473947 ER PT J AU Uckun, FM Qazi, S Ozer, Z Garner, AL Pitt, J Ma, H Janda, KD AF Uckun, Fatih M. Qazi, Sanjive Ozer, Zahide Garner, Amanda L. Pitt, Jason Ma, Hong Janda, Kim D. TI Inducing apoptosis in chemotherapy-resistant B-lineage acute lymphoblastic leukaemia cells by targeting HSPA5, a master regulator of the anti-apoptotic unfolded protein response signalling network SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE Unfolded protein response; endoplasmic reticulum; acute lymphoblastic leukaemia; biotherapy; apoptosis ID ENDOPLASMIC-RETICULUM STRESS; CHILDRENS ONCOLOGY GROUP; PEPTIDIC GRP78 LIGAND; CANCER-CELLS; MOLECULAR TARGET; TYROSINE KINASE; PRECURSOR LEUKEMIA; OXIDATIVE STRESS; PROSTATE-CANCER; TERMINAL DOMAIN AB P>We present previously unknown evidence that the immunoglobulin heavy chain binding protein BIP/HSPA5, also known as glucose regulated protein (GRP)78, serving as a pivotal component of the pro-survival axis of the unfolded protein response (UPR) signalling network, is abundantly expressed in relapsed B-lineage acute lymphoblastic leukaemia (ALL) and contributes to chemotherapy resistance of leukaemic B-cell precursors. The resistance of B-lineage ALL cells to the standard anti-leukaemic drug vincristine was overcome by the HSPA5 inhibitor epigallocatechin gallate, which inhibits the anti-apoptotic function of HSPA5 by targeting its ATP-binding domain. Notably, chemotherapy-resistant B-lineage ALL cells underwent apoptosis within 48 h of exposure to a doxorubicin-conjugated cell-penetrating cyclic anti-HSPA5 peptide targeting surface-expressed HSPA5 molecules on leukaemia cells. The identification of the HSPA5 as a chemoresistance biomarker and molecular target for B-lineage ALL may lead to new anti-leukaemic treatment strategies that are much needed. C1 [Uckun, Fatih M.] Univ So Calif, Keck Sch Med, Dept Pediat, Div Hematol Oncol, Los Angeles, CA 90033 USA. [Uckun, Fatih M.; Ozer, Zahide; Ma, Hong] Childrens Hosp Los Angeles, Childrens Ctr Canc & Blood Dis, Dev Therapeut Program, Los Angeles, CA 90027 USA. [Uckun, Fatih M.; Ozer, Zahide; Ma, Hong] Childrens Hosp Los Angeles, Childrens Ctr Canc & Blood Dis, Syst Immunobiol Lab, Los Angeles, CA 90027 USA. [Uckun, Fatih M.; Qazi, Sanjive] Gustavus Adolphus Coll, Dept Biol, St Peter, MN 56082 USA. [Uckun, Fatih M.; Qazi, Sanjive] Gustavus Adolphus Coll, Bioinformat Program, St Peter, MN 56082 USA. [Garner, Amanda L.; Janda, Kim D.] Scripps Res Inst, Dept Chem, Skaggs Inst Chem Biol, Worm Inst Med Res WIRM, La Jolla, CA 92037 USA. [Garner, Amanda L.; Janda, Kim D.] Scripps Res Inst, Dept Immunol, Skaggs Inst Chem Biol, Worm Inst Med Res WIRM, La Jolla, CA 92037 USA. [Pitt, Jason] NCI, NIH, Bethesda, MD 20892 USA. RP Uckun, FM (reprint author), Childrens Hosp Los Angeles, Childrens Ctr Canc & Blood Dis, Dev Therapeut Program, MS 57, Los Angeles, CA 90027 USA. EM fmuckun@chla.usc.edu NR 53 TC 26 Z9 27 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2011 VL 153 IS 6 BP 741 EP 752 DI 10.1111/j.1365-2141.2011.08671.x PG 12 WC Hematology SC Hematology GA 769UR UT WOS:000291044300006 PM 21517817 ER PT J AU Fracasso, PM Williams, KJ Chen, RC Picus, J Ma, CX Ellis, MJ Tan, BR Pluard, TJ Adkins, DR Naughton, MJ Rader, JS Arquette, MA Fleshman, JW Creekmore, AN Goodner, SA Wright, LP Guo, ZF Ryan, CE Tao, Y Soares, EM Cai, SR Lin, L Dancey, J Rudek, MA McLeod, HL Piwnica-Worms, H AF Fracasso, Paula M. Williams, Kerry J. Chen, Ronald C. Picus, Joel Ma, Cynthia X. Ellis, Matthew J. Tan, Benjamin R. Pluard, Timothy J. Adkins, Douglas R. Naughton, Michael J. Rader, Janet S. Arquette, Matthew A. Fleshman, James W. Creekmore, Allison N. Goodner, Sherry A. Wright, Lisa P. Guo, Zhanfang Ryan, Christine E. Tao, Yu Soares, Eliane M. Cai, Shi-rong Lin, Li Dancey, Janet Rudek, Michelle A. McLeod, Howard L. Piwnica-Worms, Helen TI A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Phase 1; Irinotecan; UCN-01; Chk1; Ribosomal protein S6 ID PROTEIN-KINASE-C; CELL-CYCLE CHECKPOINTS; HUMAN BREAST-CARCINOMA; 7-HYDROXYSTAUROSPORINE UCN-01; DNA-DAMAGE; ALPHA(1)-ACID GLYCOPROTEIN; INHIBITOR UCN-01; CANCER-CELLS; I TRIAL; CLINICAL-PHARMACOLOGY AB UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors. Patients received irinotecan (75-125 mg/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50-90 mg/m(2) IV on day 2 and 25-45 mg/m(2) on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained. Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 mg/m(2) on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C-max and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks). UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway. C1 [Fracasso, Paula M.] Univ Virginia, Dept Med, Charlottesville, VA 22908 USA. [Dancey, Janet] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Rudek, Michelle A.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Fracasso, Paula M.; Williams, Kerry J.; Chen, Ronald C.; Picus, Joel; Ma, Cynthia X.; Ellis, Matthew J.; Tan, Benjamin R.; Pluard, Timothy J.; Adkins, Douglas R.; Naughton, Michael J.; Arquette, Matthew A.; Creekmore, Allison N.; Goodner, Sherry A.; Wright, Lisa P.; Guo, Zhanfang; Tao, Yu; Soares, Eliane M.; Cai, Shi-rong; Lin, Li; McLeod, Howard L.; Piwnica-Worms, Helen] Alvin J Siteman Canc Ctr, Dept Internal Med, St Louis, MO USA. [Fracasso, Paula M.; Williams, Kerry J.; Chen, Ronald C.; Picus, Joel; Ma, Cynthia X.; Ellis, Matthew J.; Tan, Benjamin R.; Pluard, Timothy J.; Adkins, Douglas R.; Naughton, Michael J.; Rader, Janet S.; Arquette, Matthew A.; Fleshman, James W.; Creekmore, Allison N.; Goodner, Sherry A.; Wright, Lisa P.; Guo, Zhanfang; Ryan, Christine E.; Tao, Yu; Soares, Eliane M.; Cai, Shi-rong; Lin, Li; McLeod, Howard L.; Piwnica-Worms, Helen] Washington Univ, Sch Med, St Louis, MO USA. [Rader, Janet S.] Alvin J Siteman Canc Ctr, Dept Obstet & Gynecol, St Louis, MO USA. [Fleshman, James W.] Alvin J Siteman Canc Ctr, Dept Surg, St Louis, MO USA. [Ryan, Christine E.; Cai, Shi-rong; Piwnica-Worms, Helen] Alvin J Siteman Canc Ctr, Dept Cell Biol & Physiol, St Louis, MO USA. [Ryan, Christine E.; Cai, Shi-rong; Piwnica-Worms, Helen] Howard Hughes Med Inst, Bethesda, MD 20817 USA. RP Fracasso, PM (reprint author), Univ Virginia, Dept Med, POB 800716, Charlottesville, VA 22908 USA. EM fracasso@virginia.edu RI Piwnica-Worms, Helen/C-5214-2012 FU St. Louis Men's Group Against Cancer; NCI Translational Research Initiative (Pharmacology Core, Alvin J. Siteman Cancer Center) [22XS046, P30 CA091842]; Doris Duke Charitable Foundation (Analytical Pharmacology Core, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins) [P30 CA069773]; Howard Hughes Medical Institute; Komen Foundation [UL1 RR024992] FX We wish to thank the patients and their families for participation in this study. We also thank the nurses, clinical research and regulatory coordinators at the Siteman Cancer Center for their care of the patients on this study. Dr. Mark A. Watson, Director, Tissue Procurement Core, Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital is thanked for tissue acquisition, storage, and processing, and Dr. Katherine Deschryver is thanked for IHC scoring. Grant support: St. Louis Men's Group Against Cancer and NCI Translational Research Initiative Subcontract 22XS046 (P. M. Fracasso), P30 CA091842 (Pharmacology Core, Alvin J. Siteman Cancer Center), Doris Duke Charitable Foundation (R. C. Chen), P30 CA069773 (Analytical Pharmacology Core, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins), Howard Hughes Medical Institute, Komen Foundation, UL1 RR024992. NR 68 TC 27 Z9 27 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUN PY 2011 VL 67 IS 6 BP 1225 EP 1237 DI 10.1007/s00280-010-1410-1 PG 13 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 769RR UT WOS:000291036500002 PM 20694727 ER PT J AU Chuk, MK Cole, DE McCully, C Loktionova, NA Pegg, AE Parker, RJ Pauly, G Widemann, BC Balis, FM Fox, E AF Chuk, Meredith K. Cole, Diane E. McCully, Cynthia Loktionova, Natalia A. Pegg, Anthony E. Parker, Robert J. Pauly, Gary Widemann, Brigitte C. Balis, Frank M. Fox, Elizabeth TI Plasma and CNS pharmacokinetics of O(4)-benzylfolic acid (O(4)BF) and metabolite in a non-human primate model SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE O(6)-alkylguanine-DNA alkyltransferase (AGT); O(4)-benzylfolic acid; Pharmacokinetics; CSF pharmacokinetics ID PROGRESSIVE MALIGNANT GLIOMA; PHASE-I TRIAL; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; PLUS O-6-BENZYLGUANINE; CEREBROSPINAL-FLUID; FOLATE RECEPTOR; CELL-LINES; CARMUSTINE; O(6)-BENZYLGUANINE; RECURRENT AB O(6)-alkylguanine-DNA alkyltransferase (AGT) repairs DNA damage from alkylating agents by transferring the alkyl adducts from the O(6)-position of guanine in DNA to AGT. The folate analog O(4)-benzylfolic acid (O(4)BF) is an inhibitor of AGT with reported selectivity of the alpha-folate receptor in tumors. We studied plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of O(4)BF in a non-human primate model. Rhesus monkeys (Macaca mulatta) received O(4)BF (10-50 mg/kg) intravenously, and serial blood and CSF samples were obtained. Analyte concentrations in plasma were measured by HPLC/photo diode array, and an HPLC/MS/MS assay was used for CSF samples. A putative metabolite of O(4)BF was detected in plasma and CSF. O(4)BF and the metabolite inactivated purified AGT with ED(50) of 0.04 mcM. The median clearance of O(4)BF was 8 ml/min/kg and half-life was 1.1 h. The metabolite had a substantially longer half-life (> 20 h) and greater AUC than O(4)BF. The AUC of the metabolite increased disproportionately to the dose of O(4)BF, suggesting saturable elimination. CSF penetration of O(4)BF and its metabolite was < 1%. At the 50 mg/kg dose level, the C(max) in CSF for O(4)BF was less than 0.09 mcM and for the metabolite the C(max) ranged from 0.02 to 0.04 mcM (O(4)BF equivalents). Concentrations of O(4)BF and the metabolite in CSF exceeded the ED(50) of AGT; however, recently reported lack of receptor specificity and pharmacokinetic data suggesting saturable elimination of both O(4)BF and its metabolite may limit dose-escalation and future clinical development of this agent. C1 [Chuk, Meredith K.; Cole, Diane E.; McCully, Cynthia; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Loktionova, Natalia A.; Pegg, Anthony E.] Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. [Parker, Robert J.] US FDA, Lab Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Pauly, Gary] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Balis, Frank M.; Fox, Elizabeth] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Chuk, MK (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr,Bldg 10,Rm 1W-5750, Bethesda, MD 20892 USA. EM chukmk@gmail.com FU NIH [R01 CA-071976]; NIH, National Cancer Institute, Center for Cancer Research FX We would like to recognize Robert Moschel and John Strong for their contribution to this project and their enduring contributions to the advancement of pharmacology. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The work of NAL and AEP was supported in part by NIH grant R01 CA-071976. NR 18 TC 0 Z9 0 U1 1 U2 5 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 JUN PY 2011 VL 67 IS 6 BP 1291 EP 1297 DI 10.1007/s00280-010-1407-9 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 769RR UT WOS:000291036500009 PM 20725726 ER PT J AU Rausch, L Green, C Steinmetz, K LeValley, S Catz, P Zaveri, N Schweikart, K Tomaszewski, J Mirsalis, J AF Rausch, Linda Green, Carol Steinmetz, Karen LeValley, Sue Catz, Paul Zaveri, Nurulain Schweikart, Karen Tomaszewski, Joseph Mirsalis, Jon TI Preclinical pharmacokinetic, toxicological and biomarker evaluation of SR16157, a novel dual-acting steroid sulfatase inhibitor and selective estrogen receptor modulator SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Estrone sulfatase; Steroid sulfatase; Biomarker; SERM; Breast cancer ID BREAST-CANCER-CELLS; PROLIFERATION AB SR16157 is a novel dual-acting inhibitor of estrogen action that irreversibly inhibits the estrogen biosynthetic enzyme steroid sulfatase (STS) and releases the selective estrogen receptor modulator SR16137, which blocks the estrogen receptor. SR16157 is a promising agent for the endocrine therapy of breast cancer. We conducted preclinical in vivo toxicity evaluations to determine the maximum-tolerated dose (MTD), target organ(s) of toxicity, reversibility, dose-limiting toxicity, no observable adverse effect level (NOAEL), and toxicokinetics (TK) and to investigate a potential biomarker for use in SR16157 clinical trials. SR16157 was administered to female Fischer 344 rats or beagle dogs by oral gavage (po) or capsule. Intravenous (iv) groups were included for the determination of bioavailability. Endpoints evaluated included clinical observations, body weights, hematology, serum chemistry, pharmacokinetics, TK, pathology of tissues, and STS activity in liver, or peripheral blood mononuclear cells (PBMCs). For rats, the MTD (i.e., the highest dose that did not cause lethality but produced toxicity) was 33 mg/kg/day (198 mg/m(2)/day), and the NOAEL was < 10 mg/kg/day (60 mg/m(2)/day). For dogs, the MTD was estimated to exceed 10 mg/kg/day (200 mg/m(2)/day), and the NOAEL was estimated to be at or above 2.5 mg/kg/day (50 mg/m(2)/day). Our studies demonstrate that SR16157 has excellent pharmacokinetic properties and an acceptable toxicological profile. Modulation of STS activity in PBMCs appeared to be a possible biomarker for use in future clinical trials of SR16157. C1 [Rausch, Linda; Green, Carol; Steinmetz, Karen; LeValley, Sue; Catz, Paul; Zaveri, Nurulain; Mirsalis, Jon] SRI Int, Menlo Pk, CA 94025 USA. [Schweikart, Karen; Tomaszewski, Joseph] NCI, Bethesda, MD 20892 USA. RP Rausch, L (reprint author), SRI Int, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM linda.rausch@sri.com FU Division of Cancer Treatment and Diagnosis, NCI [N01-CM-42203]; NCI [SR16157] FX This work was supported under Contract N01-CM-42203 issued by the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI. The preclinical development of SR16157 was sponsored by NCI's Rapid Access to Intervention Development Program, Cycles 9 and 13, PI: Zaveri; the authors would also like to thank Wan-Ru Chao and Mas Tanabe for their MCF-7 xenograft efficacy work in nude mice. NR 12 TC 8 Z9 9 U1 0 U2 5 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 JUN PY 2011 VL 67 IS 6 BP 1341 EP 1352 DI 10.1007/s00280-010-1430-x PG 12 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 769RR UT WOS:000291036500014 PM 20737149 ER PT J AU Sacks, DB Arnold, M Bakris, GL Bruns, DE Horvath, AR Kirkman, MS Lernmark, A Metzger, BE Nathan, DM AF Sacks, David B. Arnold, Mark Bakris, George L. Bruns, David E. Horvath, Andrea Rita Kirkman, M. Sue Lernmark, Ake Metzger, Boyd E. Nathan, David M. TI Executive Summary: Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus SO CLINICAL CHEMISTRY LA English DT Editorial Material ID US AB BACKGROUND: Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. APPROACH: An expert committee compiled evidence-based recommendations for the use of laboratory analysis in patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. A draft of the guidelines was posted on the Internet, and the document was modified in response to comments. The guidelines were reviewed by the joint Evidence-Based Laboratory Medicine Committee of the AACC and the National Academy of Clinical Biochemistry and were accepted after revisions by the Professional Practice Committee and subsequent approval by the Executive Committee of the American Diabetes Association. CONTENT: In addition to the long-standing criteria based on measurement of venous plasma glucose, diabetes can be diagnosed by demonstrating increased hemoglobin A(1c) (Hb A(1c)) concentrations in the blood. Monitoring of glycemic control is performed by the patients measuring their own plasma or blood glucose with meters and by laboratory analysis of Hb A(1c). The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended. (C) 2011 American Association for Clinical Chemistry and American Diabetes Association C1 [Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Arnold, Mark] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. [Bakris, George L.] Univ Chicago, Dept Med, Hypertens Dis Unit, Sect Endocrinol Diabet & Metab, Chicago, IL 60637 USA. [Bruns, David E.] Univ Virginia, Sch Med, Dept Pathol, Charlottesville, VA 22908 USA. [Horvath, Andrea Rita] Univ Sydney, Screening & Test Evaluat Program, Sch Publ Hlth, SEALS Dept Clin Chem,Prince Wales Hosp, Sydney, NSW 2006, Australia. [Kirkman, M. Sue] Amer Diabet Assoc, Alexandria, VA USA. [Lernmark, Ake] Lund Univ, Dept Clin Sci, CRC, Skane Univ Hosp Malmo, Malmo, Sweden. [Metzger, Boyd E.] Northwestern Univ, Div Endocrinol, Feinberg Sch Med, Chicago, IL 60611 USA. [Nathan, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nathan, David M.] Harvard Univ, Sch Med, Ctr Diabet, Boston, MA USA. RP Sacks, DB (reprint author), NIH, Dept Lab Med, 10 Ctr Dr,Bldg 10,Rm 2C306, Bethesda, MD 20892 USA. EM sacksdb@mail.nih.gov OI Sacks, David/0000-0003-3100-0735 NR 8 TC 43 Z9 44 U1 1 U2 6 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2011 VL 57 IS 6 BP 793 EP 798 DI 10.1373/clinchem.2011.163634 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 769PF UT WOS:000291028600002 PM 21617153 ER PT J AU Huestis, MA Verstraete, A Kwong, TC Morland, J Vincent, MJ de la Torre, R AF Huestis, Marilyn A. Verstraete, Alain Kwong, Tai C. Morland, Jorg Vincent, Michael J. de la Torre, Raphael TI Oral Fluid Testing: Promises and Pitfalls SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Verstraete, Alain] Univ Ghent, Dept Clin Chem Microbiol & Immunol, B-9000 Ghent, Belgium. [Kwong, Tai C.] Univ Rochester, Med Ctr, Dept Pathol & Lab Med, Rochester, NY 14642 USA. [Morland, Jorg] Norwegian Inst Publ Hlth, Div Forens Toxicol & Drug Abuse, Oslo, Norway. [Vincent, Michael J.] Immunalysis Corp, Pomona, CA USA. [de la Torre, Raphael] IMIM Hosp Mar Res Inst, Human Pharmacol & Clin Neurosci Res Grp, Barcelona, Spain. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, Biomed Res Ctr, 251 Bayview Blvd,Rm 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov RI Verstraete, Alain/B-4150-2013 OI Verstraete, Alain/0000-0002-0956-3315 FU Intramural NIH HHS [Z01 DA000412-11, ZIA DA000412-12] NR 0 TC 20 Z9 21 U1 0 U2 15 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2011 VL 57 IS 6 BP 805 EP 810 DI 10.1373/clinchem.2010.152124 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 769PF UT WOS:000291028600005 PM 21350039 ER PT J AU Sacks, DB Arnold, M Bakris, GL Bruns, DE Horvath, AR Kirkman, MS Lernmark, A Metzger, BE Nathan, DM AF Sacks, David B. Arnold, Mark Bakris, George L. Bruns, David E. Horvath, Andrea Rita Kirkman, M. Sue Lernmark, Ake Metzger, Boyd E. Nathan, David M. TI Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus SO CLINICAL CHEMISTRY LA English DT Article ID GLUTAMIC-ACID DECARBOXYLASE; POINT-OF-CARE; NUTRITION EXAMINATION SURVEY; RANDOMIZED CONTROLLED-TRIAL; IMPAIRED FASTING GLUCOSE; GENOME-WIDE ASSOCIATION; ANTIBODY STANDARDIZATION PROGRAM; PROTEIN-TYROSINE-PHOSPHATASE; HEMOGLOBIN A(1C) MEASUREMENT; COST-EFFECTIVENESS ANALYSIS AB BACKGROUND: Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. APPROACH: An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence Based Laboratory Medicine Committee of the AACC jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. CONTENT: In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A(1c) (Hb A(1c)) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of Hb A(1c). The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY: The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended. (C) 2011 American Association for Clinical Chemistry and American Diabetes Association C1 [Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Arnold, Mark] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. [Bakris, George L.] Univ Chicago, Dept Med, Hypertens Dis Unit, Sect Endocrinol Diabet & Metab, Chicago, IL 60637 USA. [Bruns, David E.] Univ Virginia, Sch Med, Dept Pathol, Charlottesville, VA 22908 USA. [Horvath, Andrea Rita] Univ Sydney, Sch Publ Hlth, Screening & Test Evaluat Program, SEALS Dept Clin Chem,Prince Wales Hosp, Sydney, NSW 2006, Australia. [Kirkman, M. Sue] Amer Diabet Assoc, Alexandria, VA USA. [Lernmark, Ake] Lund Univ, CRC, Skane Univ Hosp Malmo, Dept Clin Sci, Malmo, Sweden. [Metzger, Boyd E.] Northwestern Univ, Feinberg Sch Med, Div Endocrinol, Chicago, IL 60611 USA. [Nathan, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nathan, David M.] Harvard Univ, Sch Med, Ctr Diabet, Boston, MA USA. RP Sacks, DB (reprint author), NIH, Dept Lab Med, 10 Ctr Dr,Bldg 10,Rm 2C306, Bethesda, MD 20892 USA. EM sacksdb@mail.nih.gov OI Sacks, David/0000-0003-3100-0735 FU GlaxoSmithKline; Forest Laboratories; Novartis; PepsiCo; Abbott Diagnostics; Siemens; NIH; Partnership for Clean Competition FX G.L. Bakris, GlaxoSmithKline, Forest Laboratories, Novartis, and PepsiCo; D.E. Bruns, Abbott Diagnostics, Siemens, NIH, and Partnership for Clean Competition. NR 381 TC 140 Z9 148 U1 3 U2 36 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2011 VL 57 IS 6 BP E1 EP E47 DI 10.1373/clinchem.2010.161596 PG 47 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 769PF UT WOS:000291028600001 PM 21617152 ER PT J AU Yang, MH Kwon, S Kostov, Y Rasooly, A Rao, G Ghosh, U AF Yang, Minghui Kwon, Seokjoon Kostov, Yordan Rasooly, Avraham Rao, Govind Ghosh, Upal TI Study of the biouptake of labeled single-walled carbon nanotubes using fluorescence-based method SO ENVIRONMENTAL CHEMISTRY LETTERS LA English DT Article DE Carbon nanotubes; Biouptake; Fluorescence ID PULMONARY TOXICITY; BIOACCUMULATION; VISUALIZATION; MICROSCOPY; CHEMISTRY; SEDIMENT; CELLS AB Single-wall carbon nanotubes (CNT) are one of the most attractive engineered nanomaterials due to their unique electrical, mechanical and thermal properties, and potential use in a variety of commercial products. Due to their small size, CNT could become easily airborne and reach the various environmental compartments and eventually the food chain and humans. However, the environmental fate processes and health impacts of CNT are not clear. This study investigated a method for the quantitative measurement of carbon nanotube (CNT) in natural media such soil and benthic organism tissues. Fluorescence dye Nile blue was used for noncovalent labeling of CNT to enable their fluorescence detection. Labeled nanotubes were successfully detected in soil samples as well as in worm tissue. We were also able to detect the presence of labeled carbon nanotubes in worms exposed for 1 week to CNT-laden soil, which indicates CNT may transfer through environmental food web. The method allows for laboratory measurements of CNT mass transfer and partitioning into various environmental systems. C1 [Yang, Minghui; Kostov, Yordan; Rao, Govind] Univ Maryland, Ctr Adv Sensor Technol, Baltimore, MD 21227 USA. [Yang, Minghui; Kostov, Yordan; Rao, Govind] Univ Maryland, Dept Chem & Biochem Engn, Baltimore, MD 21227 USA. [Kwon, Seokjoon; Ghosh, Upal] Univ Maryland, Dept Civil & Environm Engn, Baltimore, MD 21227 USA. [Rasooly, Avraham] FDA, Off Sci & Engn, Div Biol, Silver Spring, MD 20993 USA. [Rasooly, Avraham] NCI, Bethesda, MD 20892 USA. RP Kostov, Y (reprint author), Univ Maryland, Ctr Adv Sensor Technol, 5200 Westland Blvd, Baltimore, MD 21227 USA. EM kostov@umbc.edu FU Department of Health and Human Services [HHSF223200610765P] FX This work was partially supported by a subcontract to Dr Kostov from grant HHSF223200610765P, Department of Health and Human Services. NR 23 TC 7 Z9 7 U1 0 U2 17 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1610-3653 J9 ENVIRON CHEM LETT JI Environ. Chem. Lett. PD JUN PY 2011 VL 9 IS 2 BP 235 EP 241 DI 10.1007/s10311-009-0271-5 PG 7 WC Chemistry, Multidisciplinary; Engineering, Environmental; Environmental Sciences SC Chemistry; Engineering; Environmental Sciences & Ecology GA 769TJ UT WOS:000291040900013 ER PT J AU Eksi, S Williamson, KC AF Eksi, Saliha Williamson, Kim C. TI Protein Targeting to the Parasitophorous Vacuole Membrane of Plasmodium falciparum SO EUKARYOTIC CELL LA English DT Article ID MALARIA PARASITES; HOST ERYTHROCYTE; SEXUAL DEVELOPMENT; GENE FAMILY; EXPRESSION; GAMETOCYTES; CYTOPLASM; INVASION; CELLS; GAMETOCYTOGENESIS AB Red blood cell (RBC) invasion and parasitophorous vacuole (PV) formation by Plasmodium falciparum are critical for the development and pathogenesis of malaria, a continuing global health problem. Expansion of the PV membrane (PVM) during growth is orchestrated by the parasite. This is particularly important in mature RBCs, which lack internal organelles and no longer actively synthesize membranes. Pfs16, a 16-kDa integral PVM protein expressed by gametocytes, was chosen as a model for studying the trafficking of material from the parasite across the PV space to the PVM. The locations of Pfs16-green fluorescent protein (GFP) reporter proteins containing distinct regions of Pfs16 were tracked from RBC invasion to emergence. Inclusion of the 53 C-terminal amino acids (aa) of Pfs16 to a GFP reporter construct already containing the N-terminal secretory signal sequence was sufficient for targeting to and retention on the PVM. An amino acid motif identified in this region was also found in seven other known PVM proteins. Removal of the 11 C-terminal aa did not affect PVM targeting, but membrane retention was decreased. Additionally, during emergence from the PVM and RBC, native Pfs16 and the full-length Pfs16-GFP reporter protein were found to concentrate on the ends of the gametocyte. Capping was not observed in constructs lacking the amino acids between the N-terminal secretory signal sequence and the transmembrane domain, suggesting that this region, which is not required for PVM targeting, is involved in capping. This is the first report to define the amino acid domains required for targeting to the P. falciparum PVM. C1 [Williamson, Kim C.] NIAID, LMVR, NIH, Rockville, MD 20892 USA. [Eksi, Saliha; Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60626 USA. RP Williamson, KC (reprint author), NIAID, LMVR, NIH, TBIII Rm3E28C,12735 Twinbrook Pkwy, Rockville, MD 20892 USA. EM williamsonk2@mail.nih.gov FU National Institute of Allergy and Infectious Disease [AI069314, AI48826]; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This investigation received financial support from Public Health Service grants AI069314 and AI48826 from the National Institute of Allergy and Infectious Disease and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 40 TC 10 Z9 10 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD JUN PY 2011 VL 10 IS 6 BP 744 EP 752 DI 10.1128/EC.00008-11 PG 9 WC Microbiology; Mycology SC Microbiology; Mycology GA 770MP UT WOS:000291091100004 PM 21498641 ER PT J AU Nandagopal, R Sinaii, N Avila, NA Van Ryzin, C Chen, WY Finkielstain, GP Mehta, SP McDonnell, NB Merke, DP AF Nandagopal, Radha Sinaii, Ninet Avila, Nilo A. Van Ryzin, Carol Chen, Wuyan Finkielstain, Gabriela P. Mehta, Sneha P. McDonnell, Nazli B. Merke, Deborah P. TI Phenotypic profiling of parents with cryptic nonclassic congenital adrenal hyperplasia: findings in 145 unrelated families SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID STEROID 21-HYDROXYLASE DEFICIENCY; WOMEN; MYELOLIPOMA; INCIDENTALOMAS; PREVALENCE; EXPERIENCE; GENOTYPE; CARRIERS; DISEASE; SERUM AB Objective: To comprehensively phenotype parents identified with nonclassic congenital adrenal hyperplasia (NCCAH) by family genetic studies, termed here as cryptic NCCAH and to define the incidence of cryptic NCCAH in the parents of a large cohort of patients with 21-hydroxylase deficiency. Design: Genotyping was performed on 249 parents of 145 unrelated congenital adrenal hyperplasia (CAH) patients. Parents with two CYP21A2 mutations underwent extensive evaluation. Results: Of the 249 parents, ten (4%; seven females and three males) were identified as having cryptic NCCAH. The majority was of ethnicities previously reported to have a higher incidence of NCCAH. Cosyntropin stimulation performed in eight parents provided biochemical confirmation (17-hydroxy-progesterone range 56-364 nmol/l) and cortisol response was < 500 nmol/l in three parents (38%). Of the seven women (27-54 years) with cryptic NCCAH, four had prior infertility, two reported irregular menses, two had treatment for hirsutism, one had androgenic alopecia. Men were asymptomatic. All cryptic NCCAH parents reported normal puberty and had normal height. Adrenal hypertrophy and a small adrenal myelolipoma were observed in two parents; testicular adrenal rest tissue was not found. Conclusions: Parents diagnosed with NCCAH by genetic testing are mostly asymptomatic. Temporary female infertility and suboptimal cortisol response were commonly observed. Ongoing glucocorticoid therapy is not indicated in adults with CAH identified by family genotype studies unless symptomatic, but glucocorticoid stress coverage should be considered in select cases. Parents of a child with CAH have a 1:25 risk of having NCCAH; if the mother of a child with CAH has infertility, evaluation for NCCAH is indicated. C1 [Nandagopal, Radha; Finkielstain, Gabriela P.; Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Div Endocrinol, Bethesda, MD 20892 USA. [Nandagopal, Radha; Van Ryzin, Carol] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Sinaii, Ninet; Mehta, Sneha P.; Merke, Deborah P.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Avila, Nilo A.] Vet Affairs Med Ctr, Serv Radiol, Washington, DC 20422 USA. [Avila, Nilo A.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Chen, Wuyan] NIA, Clin Invest Lab, Baltimore, MD 21224 USA. [McDonnell, Nazli B.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Nandagopal, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Div Endocrinol, Bethesda, MD 20892 USA. EM rnandago@childrensnational.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health Clinical Center; Congenital Adrenal Hyperplasia Research, Education and Support (CARES) Foundation; National Institute of Child Health and Human Development FX This work was supported (in part) by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institutes of Health Clinical Center, and (in part) by The Congenital Adrenal Hyperplasia Research, Education and Support (CARES) Foundation. Dr Nandagopal received fellowship support from the Inter-Institute Pediatric Endocrinology Training Program, National Institute of Child Health and Human Development; both Dr Nandagopal and Dr Merke are Commissioned Officers in the United States Public Health Service. NR 39 TC 19 Z9 20 U1 0 U2 4 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD JUN PY 2011 VL 164 IS 6 BP 977 EP 984 DI 10.1530/EJE-11-0019 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 769MZ UT WOS:000291020500016 PM 21444649 ER PT J AU Larson, T Nussenblatt, RB Sen, HN AF Larson, Theresa Nussenblatt, Robert B. Sen, H. Nida TI Emerging drugs for uveitis SO EXPERT OPINION ON EMERGING DRUGS LA English DT Review DE autoimmune; biologics; immunosuppression; inflammation; uveitis ID OCULAR-INFLAMMATORY-DISEASE; SIGHT-THREATENING UVEITIS; CYSTOID MACULAR EDEMA; TRIAMCINOLONE ACETONIDE INJECTION; JUVENILE IDIOPATHIC ARTHRITIS; CHRONIC NONINFECTIOUS UVEITIS; INTERFERON-ALPHA TREATMENT; NECROSIS-FACTOR-ALPHA; LONG-TERM EFFICACY; OF-THE-LITERATURE AB Areas covered: This review describes the current and future treatments of uveitis. A literature search was performed in PUBMED from 1965 to 2010 on drugs treating ocular inflammation with emphasis placed on more recent, larger studies. Readers should gain a basic understanding of current treatment strategies beginning with corticosteroids and transitioning to steroid sparing agents. Steroid sparing agents include antimetabolites such as methotrexate, azathioprine and mycophenolate mofetil; calcineurin inhibitors which include cyclosporine, tacrolimus; alkylating agents which include cyclophosphamide and chlorambucil; and biologics which include the TNF-alpha alpha inhibitors infliximab, adalimumab and etanercept and daclizumab, IFN-alpha alpha(2a) and rituximab. Expert opinion: Newer agents are typically formulated from existing drugs or developed based on new advances in immunology. Future treatment will require a better understanding of the mechanisms involved in autoimmune diseases and better delivery systems in order to provide targeted treatment with minimal side effects. C1 [Larson, Theresa; Nussenblatt, Robert B.; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. RP Larson, T (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM larsonta@nei.nih.gov FU NEI FX None of the authors have any conflict of interest in the materials mentioned in the manuscript. This research is supported by the NEI Intramural Research Program. NR 127 TC 39 Z9 43 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8214 J9 EXPERT OPIN EMERG DR JI Expert Opin Emerg. Drugs PD JUN PY 2011 VL 16 IS 2 BP 309 EP 322 DI 10.1517/14728214.2011.537824 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 768UY UT WOS:000290965100007 PM 21210752 ER PT J AU Dodick, DW Silberstein, SD Lindblad, AS Holroyd, K Mathew, N Cordell, J Hirtz, D AF Dodick, D. W. Silberstein, S. D. Lindblad, A. S. Holroyd, K. Mathew, N. Cordell, J. Hirtz, D. TI Clinical Trial Design in Chronic Migraine: Lessons Learned from the NINDS CRC Chronic Migraine Treatment Trial (CMTT) SO HEADACHE LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting on American-Headache-Society CY JUN 02-05, 2011 CL Washington, DC SP Amer Headache Soc C1 [Dodick, D. W.] Mayo Clin, Dept Neurol, Scottsdale, AZ USA. [Silberstein, S. D.] Thomas Jefferson Univ, Jefferson Headache Ctr, Philadelphia, PA 19107 USA. [Lindblad, A. S.] EMMES Corp, Rockville, MD USA. [Holroyd, K.] Ohio Univ, Dept Psychol, Athens, OH 45701 USA. [Mathew, N.] Houston Headache Clin, Houston, TX USA. [Cordell, J.; Hirtz, D.] NINDS, 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 0017-8748 J9 HEADACHE JI Headache PD JUN PY 2011 VL 51 SU 1 BP 2 EP 3 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 768WJ UT WOS:000290969100006 ER PT J AU Silberstein, S Dodick, DW Lindblad, AS Holroyd, K Mathew, N Cordell, J Hirtz, D AF Silberstein, S. Dodick, D. W. Lindblad, A. S. Holroyd, K. Mathew, N. Cordell, J. Hirtz, D. TI A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Adding Propranolol to Topiramate in Subjects with Suboptimal Response to Topiramate Alone: Results from the NINDS CRC Chronic Migraine Treatment Trial (CMTT) SO HEADACHE LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting on American-Headache-Society CY JUN 02-05, 2011 CL Washington, DC SP Amer Headache Soc C1 [Silberstein, S.] Thomas Jefferson Univ, Jefferson Headache Ctr, Philadelphia, PA 19107 USA. [Dodick, D. W.] Mayo Clin, Dept Neurol, Scottsdale, AZ USA. [Lindblad, A. S.] EMMES Corp, Rockville, MD USA. [Holroyd, K.] Ohio Univ, Dept Psychol, Athens, OH 45701 USA. [Mathew, N.] Houston Headache Clin, Houston, TX USA. [Cordell, J.; Hirtz, D.] NINDS, 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 0017-8748 J9 HEADACHE JI Headache PD JUN PY 2011 VL 51 SU 1 BP 5 EP 6 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 768WJ UT WOS:000290969100013 ER PT J AU Cantor, FK AF Cantor, F. K. TI Neck Muscles and Migraine SO HEADACHE LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting on American-Headache-Society CY JUN 02-05, 2011 CL Washington, DC SP Amer Headache Soc C1 [Cantor, F. K.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0017-8748 J9 HEADACHE JI Headache PD JUN PY 2011 VL 51 SU 1 BP 12 EP 13 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 768WJ UT WOS:000290969100031 ER PT J AU Cantor, FK AF Cantor, F. K. TI Migraine Intensification by Interferon-Beta SO HEADACHE LA English DT Meeting Abstract CT 53rd Annual Scientific Meeting on American-Headache-Society CY JUN 02-05, 2011 CL Washington, DC SP Amer Headache Soc C1 [Cantor, F. K.] NINDS, Neuroimmunol Branch, 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 0017-8748 J9 HEADACHE JI Headache PD JUN PY 2011 VL 51 SU 1 BP 21 EP 21 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 768WJ UT WOS:000290969100053 ER PT J AU Patrone, D Resnik, D AF Patrone, Daniel Resnik, David TI Pandemic Ventilator Rationing and Appeals Processes SO HEALTH CARE ANALYSIS LA English DT Article DE Appeals processes; Ethics; Justice; Pandemic influenza; Ventilator rationing ID CRITICALLY-ILL; PUBLIC-HEALTH; ALLOCATION; PRINCIPLES; TRIAGE; CARE AB In a severe influenza pandemic, hospitals will likely experience serious and widespread shortages of patient pulmonary ventilators and of staff qualified to operate them. Deciding who will receive access to mechanical ventilation will often determine who lives and who dies. This prospect raises an important question whether pandemic preparedness plans should include some process by which individuals affected by ventilator rationing would have the opportunity to appeal adverse decisions. However, the issue of appeals processes to ventilator rationing decisions has been largely neglected in state pandemic planning efforts. If we are to devise just and effective plans for coping with a severe influenza pandemic, more attention to the issue of appeals processes for pandemic ventilator rationing decisions is needed. Arguments for and against appeals processes are considered, and some suggestions are offered to help efforts at devising more rational pandemic preparedness plans. C1 [Patrone, Daniel] Union Grad Coll, Mt Sinai Sch Med, Schenectady, NY 12038 USA. [Resnik, David] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. RP Patrone, D (reprint author), Union Grad Coll, Mt Sinai Sch Med, 807 Union St,Humanities Bldg 020, Schenectady, NY 12038 USA. EM dpatrone@gmail.com FU Intramural NIH HHS [ZIA ES102646-03, ZIA ES102646-04] NR 33 TC 2 Z9 2 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1065-3058 J9 HEALTH CARE ANAL JI Health Care Anal. PD JUN PY 2011 VL 19 IS 2 BP 165 EP 179 DI 10.1007/s10728-010-0148-6 PG 15 WC Ethics; Health Policy & Services; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Biomedical Social Sciences GA 763QX UT WOS:000290575900006 PM 20354793 ER PT J AU Schwartz, AV Vittinghoff, E Bauer, DC Hillier, TA Strotmeyer, ES Ensrud, KE Donaldson, MG Cauley, JA Harris, TB Koster, A Womack, CR Palermo, L Black, DM AF Schwartz, Ann V. Vittinghoff, Eric Bauer, Douglas C. Hillier, Teresa A. Strotmeyer, Elsa S. Ensrud, Kristine E. Donaldson, Meghan G. Cauley, Jane A. Harris, Tamara B. Koster, Annemarie Womack, Catherine R. Palermo, Lisa Black, Dennis M. CA SOF Res Grp Osteoporotic Fractures Men MrOS Re Hlth ABC Res Grp TI Association of BMD and FRAX Score With Risk of Fracture in Older Adults With Type 2 Diabetes SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BONE-MINERAL DENSITY; OSTEOPOROTIC FRACTURES; BODY-COMPOSITION; WOMEN; MEN; PREDICTION; HEALTH; HIP; THIAZOLIDINEDIONES; METAANALYSIS AB Context Type 2 diabetes mellitus (DM) is associated with higher bone mineral density (BMD) and paradoxically with increased fracture risk. It is not known if low BMD, central to fracture prediction in older adults, identifies fracture risk in patients with DM. Objective To determine if femoral neck BMD T score and the World Health Organization Fracture Risk Algorithm (FRAX) score are associated with hip and nonspine fracture risk in older adults with type 2 DM. Design, Setting, and Participants Data from 3 prospective observational studies with adjudicated fracture outcomes (Study of Osteoporotic Fractures [December 1998-July 2008]; Osteoporotic Fractures in Men Study [March 2000-March 2009]; and Health, Aging, and Body Composition study [April 1997-June 2007]) were analyzed in older community-dwelling adults (9449 women and 7436 men) in the United States. Main Outcome Measure Self-reported incident fractures, which were verified by radiology reports. Results Of 770 women with DM, 84 experienced a hip fracture and 262 a nonspine fracture during a mean (SD) follow-up of 12.6 (5.3) years. Of 1199 men with DM, 32 experienced a hip fracture and 133 a nonspine fracture during a mean (SD) follow-up of 7.5 (2.0) years. Age-adjusted hazard ratios (HRs) for 1-unit decrease in femoral neck BMD T score in women with DM were 1.88 (95% confidence interval [CI], 1.43-2.48) for hip fracture and 1.52 (95% CI, 1.31-1.75) for nonspine fracture, and in men with DM were 5.71 (95% CI, 3.42-9.53) for hip fracture and 2.17 (95% CI, 1.75-2.69) for nonspine fracture. The FRAX score was also associated with fracture risk in participants with DM (HRs for 1-unit increase in FRAX hip fracture score, 1.05; 95% CI, 1.03-1.07, for women with DM and 1.16; 95% CI, 1.07-1.27, for men with DM; HRs for 1-unit increase in FRAX osteoporotic fracture score, 1.04; 95% CI, 1.02-1.05, for women with DM and 1.09; 95% CI, 1.04-1.14, for men with DM). However, for a given T score and age or for a given FRAX score, participants with DM had a higher fracture risk than those without DM. For a similar fracture risk, participants with DM had a higher T score than participants without DM. For hip fracture, the estimated mean difference in T score for women was 0.59 (95% CI, 0.31-0.87) and for men was 0.38 (95% CI, 0.09-0.66). Conclusions Among older adults with type 2 DM, femoral neck BMD T score and FRAX score were associated with hip and nonspine fracture risk; however, in these patients compared with participants without DM, the fracture risk was higher for a given T score and age or for a given FRAX score. JAMA. 2011;305(21):2184-2192 www.jama.com C1 [Schwartz, Ann V.; Vittinghoff, Eric; Bauer, Douglas C.; Palermo, Lisa; Black, Dennis M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94107 USA. [Hillier, Teresa A.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Strotmeyer, Elsa S.; Cauley, Jane A.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Ensrud, Kristine E.] Univ Minnesota, VA Med Ctr, Minneapolis, MN 55455 USA. [Ensrud, Kristine E.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Donaldson, Meghan G.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Harris, Tamara B.; Koster, Annemarie] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Koster, Annemarie] Maastricht Univ, Dept Hlth Care Studies, Maastricht, Netherlands. [Womack, Catherine R.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. RP Schwartz, AV (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, 185 Berry St,Lobby 5,Ste 5700, San Francisco, CA 94107 USA. EM aschwartz@psg.ucsf.edu RI Koster, Annemarie/E-7438-2010; Strotmeyer, Elsa/F-3015-2014; Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Strotmeyer, Elsa/0000-0002-4093-6036; Cauley, Jane A/0000-0003-0752-4408 FU Amgen; Novartis; Roche; Merck; National Institutes of Health; National Institute on Aging [R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; American Diabetes Association [1-04-JF-46]; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institutes of Health Roadmap for Medical Research [U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810, UL1 RR024140]; National Institute of Nursing Research [R01-NR012459]; National Institutes of Health, National Institute on Aging FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Schwartz reported receiving honorarium from Amgen. Dr Bauer reported receiving research support from Amgen and Novartis. Dr Ensrud reported receiving travel support from Merck and Pfizer. Ms Palermo reported that she is a consultant for Nycomed. Dr Black reported receiving research support from Novartis, Roche, Merck, and Amgen. No other authors reported any disclosures.; This study was funded by an investigator-initiated grant from Amgen (Dr Schwartz). The Study of Osteoporotic Fractures is supported by National Institutes of Health funding. The National Institute on Aging provides support under the following grants: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The Osteoporotic Fractures in Men study is supported by National Institutes of Health funding and by grant 1-04-JF-46 from the American Diabetes Association (Dr Strotmeyer). The National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, the National Center for Research Resources, and the National Institutes of Health Roadmap for Medical Research provided support under the following grants: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810, and UL1 RR024140. The Health, Aging, and Body Composition study is supported by contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 from the National Institute on Aging; grant R01-AG028050 from the National Institute on Aging; grant R01-NR012459 from the National Institute of Nursing Research; and by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 26 TC 157 Z9 163 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 1 PY 2011 VL 305 IS 21 BP 2184 EP 2192 DI 10.1001/jama.2011.715 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 770RN UT WOS:000291106300021 PM 21632482 ER PT J AU Kang, EM Marciano, BE DeRavin, S Zarember, KA Holland, SM Malech, HL AF Kang, Elizabeth M. Marciano, Betty E. DeRavin, SukSee Zarember, Kol A. Holland, Steven M. Malech, Harry L. TI Chronic granulomatous disease: Overview and hematopoietic stem cell transplantation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review DE Chronic granulomatous disease; infection; inflammation; autoimmune; allogeneic hematopoietic transplantation ID BONE-MARROW-TRANSPLANTATION; UMBILICAL-CORD BLOOD; OF-THE-LITERATURE; FULMINANT MULCH PNEUMONITIS; VERSUS-HOST-DISEASE; UNRELATED-DONOR; NADPH OXIDASE; GENE-THERAPY; CLINICAL-FEATURES; MCLEOD PHENOTYPE AB Chronic granulomatous disease (CGD) still causes significant morbidity and mortality. The difficulty in considering high-risk yet curative treatments, such as allogeneic bone marrow transplantation, lies in the unpredictable courses of both CGD and bone marrow transplantation in different patients. Some patients with CGD can have frequent infections, granulomatous or autoimmune disorders necessitating immunosuppressive therapy, or both but also experience long periods of relative good health. However, the risk of death is clearly higher in patients with CGD of all types, and the complications of CGD short of death can still cause significant morbidity. Therefore, with recent developments and improvements, bone marrow transplantation, previously considered an experimental or high-risk procedure, has emerged as an important option for patients with CGD. We will discuss the complications of CGD that result in significant morbidity and mortality, particularly the most common infections and autoimmune/inflammatory complications, as well as their typical management. We will then discuss the status of bone marrow transplantation. (J Allergy Clin Immunol 2011;127:1319-26.) C1 [Kang, Elizabeth M.; DeRavin, SukSee; Zarember, Kol A.; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Marciano, Betty E.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Kang, EM (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 6-3752,10 Ctr Dr, Bethesda, MD 20892 USA. EM ekang@niaid.nih.gov OI Malech, Harry/0000-0001-5874-5775 FU NIH; National Institute of Allergy and Infectious Diseases FX Supported by the Intramural Research Program of the NIH, the National Institute of Allergy and Infectious Diseases. NR 91 TC 72 Z9 75 U1 0 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2011 VL 127 IS 6 BP 1319 EP 1326 DI 10.1016/j.jaci.2011.03.028 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 769WH UT WOS:000291048500001 PM 21497887 ER PT J AU Zielinska, AK Beenken, KE Joo, HS Mrak, LN Griffin, LM Luong, TT Lee, CY Otto, M Shaw, LN Smeltzer, MS AF Zielinska, Agnieszka K. Beenken, Karen E. Joo, Hwang-Soo Mrak, Lara N. Griffin, Linda M. Luong, Thanh T. Lee, Chia Y. Otto, Michael Shaw, Lindsey N. Smeltzer, Mark S. TI Defining the Strain-Dependent Impact of the Staphylococcal Accessory Regulator (sarA) on the Alpha-Toxin Phenotype of Staphylococcus aureus SO JOURNAL OF BACTERIOLOGY LA English DT Article ID VIRULENCE DETERMINANTS; IN-VITRO; BIOFILM FORMATION; RAT MODEL; AGR; EXPRESSION; TRANSCRIPTION; USA300; IDENTIFICATION; ACTIVATION AB We demonstrate that mutation of the staphylococcal accessory regulator (sarA) limits the accumulation of alpha-toxin and phenol-soluble modulins (PSMs) in Staphylococcus aureus isolates of the USA300 clonal lineage. Degradation assays and experiments done with protease inhibitors suggested that this was due to the increased production of extracellular proteases rather than differences associated with the impact of sarA on transcription of the target gene (hla) or the accessory gene regulator (agr). This was confirmed by demonstrating that concomitant mutation of the gene encoding aureolysin (aur) reversed the alpha-toxin and PSM-deficient phenotypes of a USA300 sarA mutant. Mutation of sarA had little impact on the alpha-toxin or PSM phenotypes of the commonly studied strain Newman, which is known to have a mutation in saeS that results in constitutive activation of the saeRS regulatory system, and we also demonstrate that repair of this defect resulted in the increased production of extracellular proteases and reversed both the alpha-toxin and PSM-positive phenotypes of a Newman sarA mutant. C1 [Zielinska, Agnieszka K.; Beenken, Karen E.; Mrak, Lara N.; Griffin, Linda M.; Luong, Thanh T.; Lee, Chia Y.; Smeltzer, Mark S.] Univ Arkansas Med Sci, Dept Microbiol & Immunol, Little Rock, AR 72205 USA. [Joo, Hwang-Soo; Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Shaw, Lindsey N.] Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL 33620 USA. RP Smeltzer, MS (reprint author), Univ Arkansas Med Sci, Dept Microbiol & Immunol, Mail Slot 511,4301 W Markham, Little Rock, AR 72205 USA. EM smeltzermarks@uams.edu OI JOO, HWANG-SOO/0000-0003-4668-3225; Otto, Michael/0000-0002-2222-4115; Shaw, Lindsey/0000-0002-0629-8990 FU National Institute of Allergy and Infectious Diseases; Clinical and Translational Sciences Award [RR0298884]; [AI074935]; [AI090250]; [AI37027] FX This work was supported by grants AI074935 (M. S. S.), AI090250 (L.N.S.), and AI37027 (C.Y.L. and T. T. L.) and by The Intramural Research Program of the National Institute of Allergy and Infectious Diseases (M.O.). Support was also obtained from resources provided through the Clinical and Translational Sciences Award (RR0298884) to the University of Arkansas for Medical Sciences. Bacterial isolates were obtained from the NIAID-Supported Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA). NR 46 TC 42 Z9 42 U1 0 U2 4 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 JUN PY 2011 VL 193 IS 12 BP 2948 EP 2958 DI 10.1128/JB.01517-10 PG 11 WC Microbiology SC Microbiology GA 769KH UT WOS:000291011000006 PM 21478342 ER PT J AU Molitch, ME Clemmons, DR Malozowski, S Merriam, GR Vance, ML AF Molitch, Mark E. Clemmons, David R. Malozowski, Saul Merriam, George R. Vance, Mary Lee TI Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GH-REPLACEMENT THERAPY; BONE-MINERAL DENSITY; QUALITY-OF-LIFE; INTIMA-MEDIA THICKNESS; TRAUMATIC BRAIN-INJURY; CARDIOVASCULAR RISK-FACTORS; BASE-LINE CHARACTERISTICS; RECOMBINANT HUMAN GH; BODY-MASS INDEX; BENIGN INTRACRANIAL HYPERTENSION AB Objective: The aim was to update The Endocrine Society Clinical Practice Guideline on Evaluation and Treatment of Adult Growth Hormone Deficiency (GHD) previously published in 2006. Consensus Process: Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes. Conclusions: GHD can persist from childhood or be newly acquired. Confirmation through stimulation testing is usually required unless there is a proven genetic/structural lesion persistent from childhood. GH therapy offers benefits in body composition, exercise capacity, skeletal integrity, and quality of life measures and is most likely to benefit those patients who have more severe GHD. The risks associated with GH treatment are low. GH dosing regimens should be individualized. The final decision to treat adults with GHD requires thoughtful clinical judgment with a careful evaluation of the benefits and risks specific to the individual. (J Clin Endocrinol Metab 96: 1587-1609, 2011) C1 [Molitch, Mark E.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Clemmons, David R.] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Malozowski, Saul] Natl Inst Diabet Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. [Merriam, George R.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98493 USA. [Merriam, George R.] Univ Washington, Sch Med, Tacoma, WA USA. [Vance, Mary Lee] Univ Virginia, Hlth Sci Ctr, Charlottesville, VA 22908 USA. RP Molitch, ME (reprint author), Endocrine Soc, 8401 Connecticut Ave,Suite 900, Chevy Chase, MD 20815 USA. EM govt-prof@endo-society.org FU Eli Lilly, Co.; American Diabetes Association; American College of Physicians; Pituitary Society; Sanofi Aventis; Ipsen; Corcept; Pfizer, Inc.; Genentech, Inc.; Lilly Inc.; Ipsen Inc.; America Neuroendocrine Society; National Institutes of Health; Washington State Health Department; Novo Nordisk, Inc.; Novartis Pharmaceuticals FX Financial Disclosures of the Task Force: Mark E. Molitch, M. D. (chair)-Financial or Business/Organizational Interests: Eli Lilly, Co., American Diabetes Association, American College of Physicians, Pituitary Society, Sanofi Aventis, Ipsen, Corcept; Significant Financial Interest or Leadership Position: none declared. David R. Clemmons, M. D.-Financial or Business/Organizational Interests: Pfizer, Inc., Genentech, Inc., Lilly Inc., Ipsen Inc.; Significant Financial Interest or Leadership Position: none declared. Saul Malozowski, M. D.-Financial or Business/Organizational Interests: none declared; Significant Financial Interest or Leadership Position: none declared. George R. Merriam, M. D.-Financial or Business/Organizational Interests: America Neuroendocrine Society, National Institutes of Health, Washington State Health Department; Significant Financial Interest or Leadership Position: Novo Nordisk, Inc., Eli Lilly, Co., American Neuroendocrine Society. Mary Lee Vance, M. D.-Financial or Business/Organizational Interests: Novartis Pharmaceuticals, Ipsen; Significant Financial Interest or Leadership Position: none declared. NR 215 TC 198 Z9 211 U1 1 U2 15 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2011 VL 96 IS 6 BP 1587 EP 1609 DI 10.1210/jc.2011-0179 PG 23 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 766TU UT WOS:000290810200029 PM 21602453 ER PT J AU Rother, KI Brown, RJ AF Rother, Kristina I. Brown, Rebecca J. TI Selecting Weight Loss Surgery Based on HDL Genotype-Are We There Yet? At the Brink of "Personalized Surgery" SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID DENSITY-LIPOPROTEIN-CHOLESTEROL; SWEDISH OBESE SUBJECTS; BARIATRIC SURGERY; REDUCTION; MORTALITY; DISEASE; RISK; LOCI; SOS C1 [Rother, Kristina I.; Brown, Rebecca J.] NIDDK, Diabet Obes & Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Rother, KI (reprint author), Bldg 10,Room 8C-432A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kristina.rother@nih.gov NR 19 TC 1 Z9 1 U1 0 U2 0 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 JUN PY 2011 VL 96 IS 6 BP 1664 EP 1667 DI 10.1210/jc.2011-0686 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 766TU UT WOS:000290810200037 PM 21602458 ER PT J AU Chen, LW Zhang, CL Yeung, E Ye, AJ Mumford, SL Wactawski-Wende, J Schisterman, EF AF Chen, Liwei Zhang, Cuilin Yeung, Edwina Ye, Aijun Mumford, Sunni L. Wactawski-Wende, Jean Schisterman, Enrique F. TI Age at Menarche and Metabolic Markers for Type 2 Diabetes in Premenopausal Women: The BioCycle Study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RISK-FACTORS; INSULIN-RESISTANCE; MENSTRUAL-CYCLE; ADULTHOOD; ASSOCIATION; GIRLS; ADOLESCENCE; MATURATION; CHILDHOOD; COHORT AB Context: Early age at menarche has been linked to an elevated risk of type 2 diabetes. However, the underlying mechanism is unclear. Objective: Our objective was to examine associations between age at menarche and type 2 diabetes risk factors. Design, Participants, and Setting: The BioCycle Study followed 253 healthy premenopausal women from the general population (Buffalo, NY) for one to two menstrual cycles. Main Outcome Measures: Age at menarche was self-reported. Body mass index and waist circumference were measured by trained personnel. Total body and trunk fat were measured by dual-energy x-ray absorptiometry. Fasting glucose, insulin, highly sensitive C-reactive protein, and SHBG levels were measured up to eight times per cycle. Insulin resistance (IR) and beta-cell function were evaluated using the homeostasis model assessment (HOMA)-IR and HOMA-beta. Results: The mean age at menarche was 12.5 +/- 1.2 yr. After adjustment for age, race, education, and physical activity, early menarche (<= 12 yr) was significantly associated with an increase of 1.35 kg/m(2) in body mass index (P = 0.01), 2.52% in percent total body fat (P = 0.004), 3.02% in percent trunk fat (P = 0.004), 0.15 mu IU/ml in (log) insulin (P = 0.02), 0.15 U in (log) HOMA-IR (P = 0.03), and 0.16 U in (log) HOMA-beta (P = 0.01) compared with average menarche (12-14 yr). No associations were found for SHBG or highly sensitive C-reactive protein. Conclusions: Early onset of menarche is associated with unfavorable metabolic phenotypes compared with average onset of menarche in healthy premenopausal women, including reduced insulin sensitivity and beta-cell function and greater total and trunk fat. (J Clin Endocrinol Metab 96: E1007-E1012, 2011) C1 [Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Chen, Liwei] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, Dept Epidemiol, New Orleans, LA 70112 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03,MSC 7510, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov RI Perez , Claudio Alejandro/F-8310-2010; Yeung, Edwina/F-5992-2015; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Yeung, Edwina/0000-0002-3851-2613; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 20 TC 29 Z9 30 U1 0 U2 4 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 JUN PY 2011 VL 96 IS 6 BP E1007 EP E1012 DI 10.1210/jc.2010-2526 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 766TU UT WOS:000290810200025 PM 21470999 ER PT J AU Gravenstein, KS Napora, JK Short, RG Ramachandran, R Carlson, OD Metter, EJ Ferrucci, L Egan, JM Chia, CW AF Gravenstein, Kristofer S. Napora, Joshua K. Short, Ryan G. Ramachandran, Ramona Carlson, Olga D. Metter, E. Jeffrey Ferrucci, Luigi Egan, Josephine M. Chia, Chee W. TI Cross-Sectional Evidence of a Signaling Pathway from Bone Homeostasis to Glucose Metabolism SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID INSULIN-RESISTANCE; SERUM OSTEOCALCIN; BETA-CELL; POSTMENOPAUSAL WOMEN; BODY-FAT; ADIPONECTIN; LEPTIN; PLASMA; ASSOCIATION; SECRETION AB Context: Preclinical studies suggested the existence of a signaling pathway connecting bone and glucose metabolisms. Supposedly leptin modulates osteocalcin bioactivity, which in turn stimulates insulin and adiponectin secretion, and beta-cell proliferation. Objective: The objective of the investigation was to study the reciprocal relationships of adiponectin, leptin, osteocalcin, insulin resistance, and insulin secretion to verify whether such relationships are consistent with a signaling pathway connecting bone homeostasis and glucose metabolism. Design: This was a cross-sectional analysis. Setting: The study was conducted with community-dwelling volunteers participating in the Baltimore Longitudinal Study of Aging. Participants: Two hundred eighty women and 300 men with complete data on fasting plasma adiponectin, leptin, and osteocalcin, oral glucose tolerance test (plasma glucose and insulin values available at t = 0, 20, and 120 min), and anthropometric measures participated in the study. Main Outcome Measures: Linear regression models were used to test independent associations of adiponectin, osteocalcin, and leptin with the indices of insulin resistance and secretion. The expected reciprocal relationship between different biomarkers was verified by structural equation modeling. Results: In linear regression models, leptin was strongly associated with indices of both insulin resistance and secretion. Both adiponectin and osteocalcin were negatively associated with insulin resistance. Structural equation modeling revealed a direct inverse association of leptin with osteocalcin; a direct positive association of osteocalcin with adiponectin; and an inverse relationship of osteocalcin with insulin resistance and adiponectin with insulin resistance and secretion, which is cumulatively consistent with the hypothesized model. Conclusions: Bone and glucose metabolisms are probably connected through a complex pathway that involves leptin, osteocalcin, and adiponectin. The clinical relevance of such a pathway for bone pathology in diabetes should be further investigated. (J Clin Endocrinol Metab 96: E884-E890, 2011) C1 [Gravenstein, Kristofer S.; Ramachandran, Ramona; Metter, E. Jeffrey; Ferrucci, Luigi; Egan, Josephine M.; Chia, Chee W.] NIA, Clin Res Branch, NIH, Baltimore, MD 21225 USA. [Napora, Joshua K.; Short, Ryan G.; Carlson, Olga D.; Egan, Josephine M.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. RP Chia, CW (reprint author), NIA, Clin Res Branch, NIH, 3001 S Hanover St,NM-533, Baltimore, MD 21225 USA. EM chiac@mail.nih.gov FU National Institutes of Health, National Institute on Aging FX This work was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 35 TC 28 Z9 30 U1 0 U2 2 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 JUN PY 2011 VL 96 IS 6 BP E884 EP E890 DI 10.1210/jc.2010-2589 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 766TU UT WOS:000290810200002 PM 21389141 ER PT J AU Jumpertz, R Hanson, RL Sievers, ML Bennett, PH Nelson, RG Krakoff, J AF Jumpertz, Reiner Hanson, Robert L. Sievers, Maurice L. Bennett, Peter H. Nelson, Robert G. Krakoff, Jonathan TI Higher Energy Expenditure in Humans Predicts Natural Mortality SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DISEASE; RISK AB Context: Higher metabolic rates increase free radical formation, which may accelerate aging and lead to early mortality. Objective: Our objective was to determine whether higher metabolic rates measured by two different methods predict early natural mortality in humans. Design: Nondiabetic healthy Pima Indian volunteers (n = 652) were admitted to an inpatient unit for approximately 7 d as part of a longitudinal study of obesity and diabetes risk factors. Vital status of study participants was determined through December 31, 2006. Twenty-four-hour energy expenditure (24EE) was measured in 508 individuals, resting metabolic rate (RMR) was measured in 384 individuals, and 240 underwent both measurements on separate days. Data for 24EE were collected in a respiratory chamber between 1985 and 2006 with a mean (SD) follow-up time of 11.1 (6.5) yr and for RMR using an open-circuit respiratory hood system between 1982 and 2006 with a mean follow-up time of 15.4 (6.3) yr. Cox regression models were used to test the effect of EE on natural mortality, controlled for age, sex, and body weight. Results: In both groups, 27 natural deaths occurred during the study period. For each 100-kcal/24 h increase in EE, the risk of natural mortality increased by 1.29 (95% confidence interval = 1.00-1.66; P < 0.05) in the 24EE group and by 1.25 (95% confidence interval = 1.01-1.55; P < 0.05) in the RMR group, after adjustment for age, sex, and body weight in proportional hazard analyses. Conclusions: Higher metabolic rates as reflected by 24EE or RMR predict early natural mortality, indicating that higher energy turnover may accelerate aging in humans. (J Clin Endocrinol Metab 96: E972-E976, 2011) C1 [Jumpertz, Reiner] NIDDKD, Obes & Diabet Clin Res Sect, NIH, Dept Hlth & Human Serv, Phoenix, AZ 85016 USA. [Hanson, Robert L.; Sievers, Maurice L.; Bennett, Peter H.; Nelson, Robert G.] NIDDKD, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ 85014 USA. RP Jumpertz, R (reprint author), NIDDKD, Obes & Diabet Clin Res Sect, NIH, Dept Hlth & Human Serv, 4212 N 16th St, Phoenix, AZ 85016 USA. EM jumpertzr@mail.nih.gov RI Nelson, Robert/B-1470-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Institute of Diabetes and Digestive and Kidney Diseases FX This study was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 19 TC 13 Z9 13 U1 0 U2 2 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 JUN PY 2011 VL 96 IS 6 BP E972 EP E976 DI 10.1210/jc.2010-2944 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 766TU UT WOS:000290810200018 PM 21450984 ER PT J AU Kawate, T Robertson, JL Li, MF Silberberg, SD Swartz, KJ AF Kawate, Toshimitsu Robertson, Janice L. Li, Mufeng Silberberg, Shai D. Swartz, Kenton J. TI Ion access pathway to the transmembrane pore in P2X receptor channels SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; K+ CHANNEL; ACETYLCHOLINE-RECEPTOR; INWARD RECTIFICATION; POTASSIUM CHANNELS; ATP; ELECTROSTATICS; PAIN; CONDUCTANCE AB P2X receptors are trimeric cation channels that open in response to the binding of adenosine triphosphate (ATP) to a large extracellular domain. The x-ray structure of the P2X4 receptor from zebrafish (zfP2X4) receptor reveals that the extracellular vestibule above the gate opens to the outside through lateral fenestrations, providing a potential pathway for ions to enter and exit the pore. The extracellular region also contains a void at the central axis, providing a second potential pathway. To investigate the energetics of each potential ion permeation pathway, we calculated the electrostatic free energy by solving the Poisson-Boltzmann equation along each of these pathways in the zfP2X4 crystal structure and a homology model of rat P2X2 (rP2X2). We found that the lateral fenestrations are energetically favorable for monovalent cations even in the closed-state structure, whereas the central pathway presents strong electrostatic barriers that would require structural rearrangements to allow for ion accessibility. To probe ion accessibility along these pathways in the rP2X2 receptor, we investigated the modification of introduced Cys residues by methanethiosulfonate (MTS) reagents and constrained structural changes by introducing disulfide bridges. Our results show that MTS reagents can permeate the lateral fenestrations, and that these become larger after ATP binding. Although relatively small MTS reagents can access residues in one of the vestibules within the central pathway, no reactive positions were identified in the upper region of this pathway, and disulfide bridges that constrain movements in that region do not prevent ion conduction. Collectively, these results suggest that ions access the pore using the lateral fenestrations, and that these breathe as the channel opens. The accessibility of ions to one of the chambers in the central pathway likely serves a regulatory function. C1 [Kawate, Toshimitsu; Li, Mufeng; Silberberg, Shai D.; Swartz, Kenton J.] Natl Inst Neurol Disorders & Stroke, Porter Neurosci Res Ctr, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. [Robertson, Janice L.] Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02454 USA. RP Kawate, T (reprint author), Natl Inst Neurol Disorders & Stroke, Porter Neurosci Res Ctr, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. EM kawatet@ninds.nih.gov; swartzk@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH); NIH [NS 072869, NS 070954]; Howard Hughes Medical Institute FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH; to K.J. Swartz), and NIH Pathway to Independence awards to T. Kawate (NS 072869) and M. Li (NS 070954). J.L. Robertson was supported by funding from the Howard Hughes Medical Institute. NR 40 TC 45 Z9 46 U1 1 U2 5 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 JUN PY 2011 VL 137 IS 6 BP 579 EP 590 DI 10.1085/jgp.201010593 PG 12 WC Physiology SC Physiology GA 769VT UT WOS:000291047100009 PM 21624948 ER PT J AU Donley, G Danis, M AF Donley, Greer Danis, Marion TI Making the Case for Talking to Patients about the Costs of End-of-Life Care SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID SURROGATE DECISION-MAKING; ILL HOSPITALIZED ADULTS; DRUG COSTS; LAST YEAR; CANCER; COMMUNICATION; MORTALITY; DEATH; PREFERENCES; CAREGIVERS AB Costs at the end of life disproportionately contribute to health care costs in the United States. Addressing these costs will therefore be an important component in making the U. S. health care system more financially sustainable. In this paper, we explore the moral justifications for having discussions of end-of-life costs in the doctor-patient encounter as part of an effort to control costs. As health care costs are partly shared through pooled resources, such as insurance and taxation, and partly borne by individuals through out-of-pocket expenses, we separate our defense for, and approach to, discussing both pooled and individual aspects of cost. We argue that there needs to be a shift away from formulating the options as a dichotomous choice of paying attention to end-of-life costs versus ignoring such costs. The question should be how personal costs will be managed and how societal expenditures should be allocated. These are issues that we believe patients care about and need to have addressed in a manner with which they are comfortable. Conversations about how money will be spent at the end of life should begin before the end is near. We propose discussing costs from the onset of chronic illness and incorporating financial issues in advance care planning. Through these approaches one can avoid abruptly and insensitively introducing financial issues at the very conclusion of a person's life when one would prefer to address the painful and important issues of spiritual and existential loss that are appropriately the focus when a person is dying. C1 [Danis, Marion] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. RP Donley, G (reprint author), NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 45 TC 8 Z9 8 U1 0 U2 6 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 SUM PY 2011 VL 39 IS 2 BP 183 EP 193 PG 11 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 762PQ UT WOS:000290492300008 PM 21561513 ER PT J AU Magin, RL Li, WG Velasco, MP Trujillo, J Reiter, DA Morgenstern, A Spencer, RG AF Magin, Richard L. Li, Weiguo Pilar Velasco, M. Trujillo, Juan Reiter, David A. Morgenstern, Ashley Spencer, Richard G. TI Anomalous NMR relaxation in cartilage matrix components and native cartilage: Fractional-order models SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE T-1 relaxation; T-2 relaxation; Fractional calculus; Cartilage; Extracellular matrix; Magnetic resonance imaging ID FIELD-GRADIENT SPECTROSCOPY; FRACTAL NETWORKS; DIFFUSION; CALCULUS; EQUATION; T-2; DYNAMICS; KINETICS; SYSTEMS; MEDIA AB We present a fractional-order extension of the Bloch equations to describe anomalous NMR relaxation phenomena (T-1 and T-2). The model has solutions in the form of Mittag-Leffler and stretched exponential functions that generalize conventional exponential relaxation. Such functions have been shown by others to be useful for describing dielectric and viscoelastic relaxation in complex, heterogeneous materials. Here, we apply these fractional-order T-1 and T-2 relaxation models to experiments performed at 9.4 and 11.7 Tesla on type I collagen gels, chondroitin sulfate mixtures, and to bovine nasal cartilage (BNC), a largely isotropic and homogeneous form of cartilage. The results show that the fractional-order analysis captures important features of NMR relaxation that are typically described by multi-exponential decay models. We find that the T-2 relaxation of BNC can be described in a unique way by a single fractional-order parameter (alpha), in contrast to the lack of uniqueness of multi-exponential fits in the realistic setting of a finite signal-to-noise ratio. No anomalous behavior of T-1 was observed in BNC. In the single-component gels, for T-2 measurements, increasing the concentration of the largest components of cartilage matrix, collagen and chondroitin sulfate, results in a decrease in alpha, reflecting a more restricted aqueous environment. The quality of the curve fits obtained using Mittag-Leffler and stretched exponential functions are in some cases superior to those obtained using mono- and bi-exponential models. In both gels and BNC, alpha appears to account for micro-structural complexity in the setting of an altered distribution of relaxation times. This work suggests the utility of fractional-order models to describe T-2 NMR relaxation processes in biological tissues. (C) 2011 Elsevier Inc. All rights reserved. C1 [Magin, Richard L.; Li, Weiguo] Univ Illinois, Dept Bioengn, Chicago, IL 60607 USA. [Pilar Velasco, M.] Univ Complutense Madrid, Fac Matemat, Dept Matemat Aplicada, E-28040 Madrid, Spain. [Trujillo, Juan] Univ La Laguna, Dept Anal Matemat, Tenerife 38271, Spain. [Reiter, David A.; Morgenstern, Ashley; Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. RP Magin, RL (reprint author), Univ Illinois, Dept Bioengn, MC 063,Room 210,Sci & Engn Off Bldg,851 S Morgan, Chicago, IL 60607 USA. RI Trujillo, Juan/A-1195-2008; Velasco, M. Pilar/G-6747-2015 OI Trujillo, Juan/0000-0001-8700-6410; Velasco, M. Pilar/0000-0002-0988-2527 FU National Institute of Bioengineering and Biomedical Imaging, National Institutes of Health (NIH) [R01EB 007537]; NIH, Institute on Aging; NIH [R01 EB007537]; MICINN of Spain [MTM2007-60246, MTM2010-16499] FX Grant Sponsors: National Institute of Bioengineering and Biomedical Imaging, National Institutes of Health (NIH), Grant Number R01EB 007537, and the Intramural Research Program of the NIH, Institute on Aging.; R.L. Magin would like to acknowledge the support of NIH Grant R01 EB007537 for partial support of this work. D.A. Reiter and R.G. Spencer would like to acknowledge the support of the Intramural Research Program of the NIH, National Institute on Aging. J. Trujillo and M.P. Velasco would like to acknowledge support for this work, in part, from the MICINN of Spain (Grants MTM2007-60246 and MTM2010-16499). NR 48 TC 15 Z9 19 U1 2 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD JUN PY 2011 VL 210 IS 2 BP 184 EP 191 DI 10.1016/j.jmr.2011.03.006 PG 8 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 768GM UT WOS:000290921900004 PM 21498095 ER PT J AU Schumacher, J Kristensen, AS Wendland, JR Nothen, MM Mors, O McMahon, FJ AF Schumacher, Johannes Kristensen, Ann Suhl Wendland, Jens R. Noethen, Markus M. Mors, Ole McMahon, Francis J. TI The genetics of panic disorder SO JOURNAL OF MEDICAL GENETICS LA English DT Review ID NATIONAL-COMORBIDITY-SURVEY; GENOME-WIDE ASSOCIATION; 5-YEAR FOLLOW-UP; ANXIETY DISORDERS; MAJOR DEPRESSION; BEHAVIORAL-INHIBITION; PSYCHIATRIC-DISORDERS; FAMILIAL TRANSMISSION; HIGH-RISK; JAPANESE POPULATION AB Panic disorder (PD) is one of the most common anxiety disorders, with a prevalence of 3.4-4.7%. Although PD seems to have no known cause, and its underlying aetiology is not well understood, studies have consistently shown that genetic factors explain about half of the variance. It is likely that most cases of PD have a complex genetic basis. Existing data suggest, however, that the genetic architecture underlying PD is heterogeneous and differs between cases. For example, the degree of genetic complexity, and the pattern of genes involved might differ in familial versus non-familial cases, in early-versus late-onset cases, or when different comorbid conditions, gender and potential intermediate or sub-phenotypes are considered. At the molecular genetic level, linkage and association studies-the latter including traditional candidate gene and recent genome-wide studies-have been used to study PD. Although no robust molecular genetic findings have emerged so far, it is conceivable that the first PD susceptibility genes will be identified in the coming years via the application of modern molecular genetic methods and through multicentre collaborations to bring together combined, large datasets. Such findings could have a major impact on our understanding of the pathophysiology of this disorder, and would provide important opportunities to investigate genotype-phenotype correlations, as well as the interaction between genetic and environmental factors involved in the pathogenesis of PD. Here, the authors summarise the latest genetics findings about PD, and give an overview of anticipated future developments. C1 [Schumacher, Johannes; Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany. [Schumacher, Johannes; Wendland, Jens R.; McMahon, Francis J.] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kristensen, Ann Suhl; Mors, Ole] Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark. RP Schumacher, J (reprint author), Univ Bonn, Inst Human Genet, Sigmund Freud St 25, D-53127 Bonn, Germany. EM johannes.schumacherj@uni-bonn.de RI Wendland, Jens/A-1809-2012; Schumacher, Johannes/F-4970-2015; OI Schumacher, Johannes/0000-0001-9217-6457; McMahon, Francis/0000-0002-9469-305X; Nothen, Markus/0000-0002-8770-2464 FU National Genomic Network of the 'Bundesministerium fur Bildung und Forschung' (BMBF); NIH/DFG; Alfried Krupp von Bohlen und Halbach-Stiftung; National Institute of Mental Health, National Institutes of Health (NIMH-NIH) FX This study was supported by the National Genomic Network of the 'Bundesministerium fur Bildung und Forschung' (BMBF), by an NIH/DFG Research Career Transition Award to JS, by the Alfried Krupp von Bohlen und Halbach-Stiftung to MMN, and by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) to FJM and JRW. NR 86 TC 17 Z9 17 U1 11 U2 23 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 JUN PY 2011 VL 48 IS 6 BP 361 EP 368 DI 10.1136/jmg.2010.086876 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 768SL UT WOS:000290958600001 PM 21493958 ER PT J AU Matsuda, K Chung, JY Ylaya, K Fukunaga, M Li, TQ Rushing, E Hewitt, S AF Matsuda, Kant Chung, Joon-Yong Ylaya, Kris Fukunaga, Masaki Li, Tie-Qiang Rushing, Elisabeth Hewitt, Stephen TI Radiologic-Pathologic-Proteomics Correlation. High Field 7T MRI and Multiplex Tissue Immunoblotting of Autopsy Brains SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 87th Annual Meeting of the American-Association-of-Neuropathologists CY JUN 23-26, 2011 CL Seattle, WA SP Amer Assoc Neuropathologists C1 [Matsuda, Kant] NYU, Div Neuropathol, Dept Pathol, New York, NY 10003 USA. [Chung, Joon-Yong] NCI, Appl Mol Pathol Lab, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Ylaya, Kris; Hewitt, Stephen] NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Fukunaga, Masaki; Li, Tie-Qiang] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Rushing, Elisabeth] Univ Spital Zurich, Inst Neuropathol, Zurich, Switzerland. RI Fukunaga, Masaki/F-6441-2013 OI Fukunaga, Masaki/0000-0003-1010-2644 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2011 VL 70 IS 6 MA 88 BP 521 EP 521 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 766AV UT WOS:000290751700097 ER PT J AU Bilbao, J Goldfarb, L Young, B Kong, K Cohen, S AF Bilbao, Juan Goldfarb, Lev Young, Beverley Kong, Kester Cohen, Sandra TI Clinical and Myopathological Manifestations of Filaminopathy in a Newly Identified Pedigree SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 87th Annual Meeting of the American-Association-of-Neuropathologists CY JUN 23-26, 2011 CL Seattle, WA SP Amer Assoc Neuropathologists C1 [Bilbao, Juan] Univ Toronto, Sunnybrook Hosp, Toronto, ON M5S 1A1, Canada. [Goldfarb, Lev] Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2011 VL 70 IS 6 MA 104 BP 525 EP 526 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 766AV UT WOS:000290751700113 ER PT J AU Blair, EM Nelson, KB AF Blair, E. M. Nelson, K. B. TI Migraine and preterm birth SO JOURNAL OF PERINATOLOGY LA English DT Article DE migraine; preterm birth; growth retardation; cerebral palsy ID NEWBORN ENCEPHALOPATHY; INCREASED RISK; PREGNANCY; WOMEN; PREECLAMPSIA; HEADACHE; DELIVERY; STROKE; COMORBIDITY; SUMATRIPTAN AB Objective: To investigate whether maternal migraine was associated with preterm birth. Study Design: Case-control sample within a population-based study of risk factors for cerebral palsy (CP). Infants without CP were matched for gestational age with those with CP. Maternal migraine was self-identified at first prenatal visit, most in the first trimester. Result: Infants without CP born to women with migraine had a higher rate of preterm birth (odds ratio (OR) = 3.5, 95% confidence interval (CI) 1.5, 8.5), as did infants who died in the perinatal period (OR = 7.3, 95% CI 0.98, 54), the difference marginal for nominal statistical significance. In all outcome groups, infants of women with migraine had a higher observed rate of suboptimal intrauterine growth. In term infants, the rate of maternal migraine was higher in those with CP than in controls (OR = 2.18, 95% CI 0.92, 5.25). Pre-eclampsia was reported more frequently in women with migraine who gave birth to a child with CP or a perinatal death, particularly in those born preterm; OR = 5.1 (1.3, 20) and OR = 2.9 (1.1, 7.6), respectively, but not in women giving birth to a control whether term or preterm. Conclusion: Maternal migraine, as self-reported early in pregnancy, was associated with preterm birth in survivors without CP and in infants who died in the perinatal period. The combination of maternal migraine and pre-eclampsia was associated with CP and perinatal death. The association of maternal migraine with outcomes of pregnancy warrants further study. Journal of Perinatology (2011) 31, 434-439; doi:10.1038/jp.2010.148; published online 23 December 2010 C1 [Nelson, K. B.] NINDS, Bethesda, MD 20892 USA. [Blair, E. M.] Univ Western Australia, Telethon Inst Child Hlth Res, Ctr Child Hlth Res, Nedlands, WA 6009, Australia. [Nelson, K. B.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. RP Nelson, KB (reprint author), NINDS, Bldg 10,Room 5C438, Bethesda, MD 20892 USA. EM nelsonk@ninds.nih.gov FU National Health and Medical Research Council of Australia [353514] FX The authors are grateful to the National Health and Medical Research Council of Australia for support, and to Linda Watson and Jan de Groot for their valuable contributions to data extraction and management. This study was supported by the National Health and Medical Research Council of Australia under Program grant no. 353514, approved by the Princess Margaret Hospital/King Edward Memorial Hospital Ethics Committee, the Confidentiality of Health Information Committee of the WA Department of Health and by individual hospital and regional ethics committees where required. NR 37 TC 6 Z9 6 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0743-8346 J9 J PERINATOL JI J. Perinatol. PD JUN PY 2011 VL 31 IS 6 BP 434 EP 439 DI 10.1038/jp.2010.148 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 769NX UT WOS:000291024300010 PM 21183924 ER PT J AU Chawla, LS Amdur, RL Amodeo, S Kimmel, PL Palant, CE AF Chawla, Lakhmir S. Amdur, Richard L. Amodeo, Susan Kimmel, Paul L. Palant, Carlos E. TI The severity of acute kidney injury predicts progression to chronic kidney disease SO KIDNEY INTERNATIONAL LA English DT Article DE acute kidney injury; acute renal failure; albumin; chronic kidney disease; predicts; severity ID ACUTE-RENAL-FAILURE; ACUTE TUBULAR-NECROSIS; HOSPITALIZED-PATIENTS; SERUM CREATININE; CARDIAC-SURGERY; MORTALITY; OUTCOMES; ALBUMIN; EPIDEMIOLOGY; DIAGNOSIS AB Acute kidney injury (AKI) is associated with progression to advanced chronic kidney disease (CKD). We tested whether patients who survive AKI and are at higher risk for CKD progression can be identified during their hospital admission, thus providing opportunities to intervene. This was assessed in patients in the Department of Veterans Affairs Healthcare System hospitalized with a primary diagnosis indicating AKI (ICD9 codes 584.xx). In the exploratory phase, three multivariate prediction models for progression to stage 4 CKD were developed. In the confirmatory phase, the models were validated in 11,589 patients admitted for myocardial infarction or pneumonia during the same time frame that had RIFLE codes R, I, or F and complete data for all predictor variables. Of the 5351 patients in the AKI group, 728 entered stage 4 CKD after hospitalization. Models 1, 2, and 3 were all significant with 'c' statistics of 0.82, 0.81, and 0.77, respectively. In model validation, all three were highly significant when tested in the confirmatory patients, with moderate to large effect sizes and good predictive accuracy ('c' 0.81-0.82). Patients with AKI who required dialysis and then recovered were at especially high risk for progression to CKD. Hence, the severity of AKI is a robust predictor of progression to CKD. Kidney International (2011) 79, 1361-1369; doi:10.1038/ki.2011.42; published online 23 March 2011 C1 [Chawla, Lakhmir S.] George Washington Univ, Med Ctr, Dept Anesthesiol & Crit Care Med, Washington, DC 20037 USA. [Chawla, Lakhmir S.; Kimmel, Paul L.; Palant, Carlos E.] George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, Washington, DC 20037 USA. [Amdur, Richard L.; Amodeo, Susan; Palant, Carlos E.] Vet Affairs Med Ctr, Res & Med Serv, Washington, DC 20422 USA. [Amdur, Richard L.] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. [Amdur, Richard L.] Georgetown Univ, Sch Med, Dept Surg, Washington, DC USA. [Amodeo, Susan] Vet Affairs Med Ctr, Fiscal Serv, Washington, DC 20422 USA. [Kimmel, Paul L.] NIDDK, NIH, Bethesda, MD USA. RP Chawla, LS (reprint author), George Washington Univ, Med Ctr, Dept Anesthesiol & Crit Care Med, 900 23rd St NW,Room G-105, Washington, DC 20037 USA. EM lchawla@mfa.gwu.edu FU Institutional Review Board and Research and Development Committee of the DC VAMC FX This project was approved by the Institutional Review Board and Research and Development Committee of the DC VAMC. The authors express their gratitude to Paul Eggers (NIDDK), David Lyle, and George J Busch (Clinical User Support, Veterans Administration Decision Support System), and to Robert Williamson (Information Resource Management, Washington DC VA Medical Center) for their valuable assistance with data collection. NR 27 TC 217 Z9 223 U1 2 U2 13 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 JUN PY 2011 VL 79 IS 12 BP 1361 EP 1369 DI 10.1038/ki.2011.42 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 770NJ UT WOS:000291093300012 PM 21430640 ER PT J AU Kreitman, RJ Arons, E Stetler-Stevenson, M Miller, KB AF Kreitman, Robert J. Arons, Evgeny Stetler-Stevenson, Maryalice Miller, Kenneth B. TI Response of hairy cell leukemia to bendamustine SO LEUKEMIA & LYMPHOMA LA English DT Letter ID TERM-FOLLOW-UP; CLADRIBINE; PENTOSTATIN; BL22 C1 [Kreitman, Robert J.; Arons, Evgeny] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Miller, Kenneth B.] Tufts Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA USA. RP Kreitman, RJ (reprint author), 9000 Rockville Pike,Room 37-5124B, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU Intramural NIH HHS NR 15 TC 9 Z9 9 U1 0 U2 1 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 JUN PY 2011 VL 52 IS 6 BP 1153 EP 1156 DI 10.3109/10428194.2011.562575 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 767PS UT WOS:000290869100035 PM 21463128 ER PT J AU Dimock, D Thomas, V Cushing, A Purdy, JB Worrell, C Kopp, JB Hazra, R Hadigan, C AF Dimock, David Thomas, Vijaya Cushing, Anna Purdy, Julia B. Worrell, Carol Kopp, Jeffrey B. Hazra, Rohan Hadigan, Colleen TI Longitudinal assessment of metabolic abnormalities in adolescents and young adults with HIV-infection acquired perinatally or in early childhood SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN IMMUNODEFICIENCY VIRUS-1; CARDIOVASCULAR RISK-FACTORS; IMPAIRED GLUCOSE-TOLERANCE; RECOMBINANT HUMAN LEPTIN; INSULIN-RESISTANCE; PROTEASE INHIBITORS; FAT REDISTRIBUTION; OBESE CHILDREN; LONG-TERM AB Metabolic complications of HIV pose challenges for health maintenance among young adults who acquired HIV in early childhood. Between July 2004 and July 2009, we evaluated 47 HIV-infected subjects who acquired HIV in early life. Participants completed glucose tolerance testing; insulin, lipid, urine albumin, and creatinine determinations; and dual-energy x-ray absorptiometry scans. Longitudinal data were available for 39 subjects; duration of follow-up was 26.4 +/- 16.8 months. At baseline, participants were 17.1 +/- 3.9 years old; and duration of antiretroviral therapy was 12.7 +/- 3.4 years. CD4 count was 658 +/- 374 cells per cubic millimeter, and 55% had undetectable viral load. Impaired glucose tolerance was present in 15%; 33% had insulin resistance (homeostasis model assessment of insulin resistance >4.0). Furthermore, 52% had triglycerides of at least 150 mg/dL, 36% had high-density lipoprotein cholesterol less than 40 mg/dL, 18% had low-density lipoprotein cholesterol of at least 130 mg/dL, and 25% had total cholesterol of at least 200 mg/dL. Microalbuminuria was present in 15% of participants and was inversely correlated with CD4% (P = .001). During follow-up, more than one third remained insulin resistant; lipid parameters tended to improve. There were significant increases in body mass index (P = .0002), percentage leg fat (P = .008), and percentage trunk fat (P = .002). Impaired glucose tolerance, insulin resistance, dyslipidemia, and microalbuminuria are common among young adults with HIV. Long-term exposure to therapy may translate into substantial persistent metabolic risk. Published by Elsevier Inc. C1 [Dimock, David; Thomas, Vijaya; Cushing, Anna; Hadigan, Colleen] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. [Purdy, Julia B.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Purdy, Julia B.; Hazra, Rohan] NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Worrell, Carol; Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Branch, NIH, Bethesda, MD USA. RP Hadigan, C (reprint author), NIAID, Immunoregulat Lab, Bldg 10, Bethesda, MD 20892 USA. EM hadiganc@niaid.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU Divisions of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, and National Cancer Institute, National Institutes of Health, Bethesda, MD FX The authors would like to thank Seshagiri Vakkalanka, Jennifer Graf, and Dr Jim Reynolds for their assistance with data collection and management. This study was funded by Divisions of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, and National Cancer Institute, National Institutes of Health, Bethesda, MD. NR 40 TC 19 Z9 19 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 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD JUN PY 2011 VL 60 IS 6 BP 874 EP 880 DI 10.1016/j.metabol.2010.08.007 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 770GX UT WOS:000291076100019 PM 20947103 ER PT J AU Yang, J Manolio, TA Pasquale, LR Boerwinkle, E Caporaso, N Cunningham, JM de Andrade, M Feenstra, B Feingold, E Hayes, MG Hill, WG Landi, MT Alonso, A Lettre, G Lin, P Ling, H Lowe, W Mathias, RA Melbye, M Pugh, E Cornelis, MC Weir, BS Goddard, ME Visscher, PM AF Yang, Jian Manolio, Teri A. Pasquale, Louis R. Boerwinkle, Eric Caporaso, Neil Cunningham, Julie M. de Andrade, Mariza Feenstra, Bjarke Feingold, Eleanor Hayes, M. Geoffrey Hill, William G. Landi, Maria Teresa Alonso, Alvaro Lettre, Guillaume Lin, Peng Ling, Hua Lowe, William Mathias, Rasika A. Melbye, Mads Pugh, Elizabeth Cornelis, Marilyn C. Weir, Bruce S. Goddard, Michael E. Visscher, Peter M. TI Genome partitioning of genetic variation for complex traits using common SNPs SO NATURE GENETICS LA English DT Article ID BODY-MASS INDEX; VON-WILLEBRAND-FACTOR; WIDE ASSOCIATION; HUMAN HEIGHT; LARGE PROPORTION; AGING RESEARCH; BLOOD-GROUP; FACTOR-VIII; HERITABILITY; POPULATION AB We estimate and partition genetic variation for height, body mass index (BMI), von Willebrand factor and QT interval (QTi) using 586,898 SNPs genotyped on 11,586 unrelated individuals. We estimate that similar to 45%, similar to 17%, similar to 25% and similar to 21% of the variance in height, BMI, von Willebrand factor and QTi, respectively, can be explained by all autosomal SNPs and a further similar to 0.5-1% can be explained by X chromosome SNPs. We show that the variance explained by each chromosome is proportional to its length, and that SNPs in or near genes explain more variation than SNPs between genes. We propose a new approach to estimate variation due to cryptic relatedness and population stratification. Our results provide further evidence that a substantial proportion of heritability is captured by common SNPs, that height, BMI and QTi are highly polygenic traits, and that the additive variation explained by a part of the genome is approximately proportional to the total length of DNA contained within genes therein. C1 [Yang, Jian; Visscher, Peter M.] Queensland Inst Med Res, Queensland Stat Genet Lab, Brisbane, Qld 4006, Australia. [Manolio, Teri A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Pasquale, Louis R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Div Epidemiol, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Caporaso, Neil; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Cunningham, Julie M.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [de Andrade, Mariza] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Feenstra, Bjarke; Melbye, Mads] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Feingold, Eleanor] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Hayes, M. Geoffrey] Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Hill, William G.] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Alonso, Alvaro] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Lettre, Guillaume] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Lin, Peng] Washington Univ, Sch Med, Human & Stat Genet Program, St Louis, MO USA. [Ling, Hua; Pugh, Elizabeth] Johns Hopkins Univ, Sch Med, Ctr Inherited Dis Res, Baltimore, MD USA. [Mathias, Rasika A.] Johns Hopkins Univ, Sch Med, Dept Gen Internal Med, Baltimore, MD USA. [Cornelis, Marilyn C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Weir, Bruce S.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Goddard, Michael E.] Univ Melbourne, Dept Food & Agr Syst, Melbourne, Vic 3010, Australia. [Goddard, Michael E.] Dept Primary Ind, Biosci Res Div, Bundoora, Vic, Australia. RP Visscher, PM (reprint author), Queensland Inst Med Res, Queensland Stat Genet Lab, Brisbane, Qld 4006, Australia. EM peter.visscher@qimr.edu.au RI Alonso, Alvaro/A-4917-2010; Hill, William/B-3198-2012; Weir, Bruce/A-2894-2013; Lin, P/G-7702-2014; Yang, Jian/A-5852-2010; OI Alonso, Alvaro/0000-0002-2225-8323; Yang, Jian/0000-0003-2001-2474; Feenstra, Bjarke/0000-0003-1478-649X; Goddard, Michael/0000-0001-9917-7946; Feingold, Eleanor/0000-0003-2898-6484; Visscher, Peter/0000-0002-2143-8760; de Andrade, Mariza/0000-0003-2329-2686 FU US National Institutes of Health Genes, Environment and Health Initiative; Research to Prevent Blindness in New York City; Canadian Institutes of Health Research; Australian National Health and Medical Research Council (NHMRC) [389892, 613672]; Australian Research Council (ARC) [DP0770096, DP1093900]; [U01 HG 004402]; [U01 HG 004399]; [U01 HG 004728]; [U01 HG04424]; [U01 HG 004446] FX Funding support for the Gene, Environment Association Studies (GENEVA) project has been provided through the US National Institutes of Health Genes, Environment and Health Initiative. For the ARIC project, support was from U01 HG 004402 (PI: E. A. Boerwinkle). For the NHS and HPFS support is from U01 HG 004399 and U01 HG 004728 (PIs: F. B. Hu and L. R. Pasquale). The genotyping for the ARIC, NHS and HPFS studies was performed at the Broad Institute of MIT and Harvard with funding support from U01 HG04424 (PI: S. Gabriel). The GENEVA Coordinating Center receives support from U01 HG 004446 (PI: B. S. Weir). Assistance with GENEVA data cleaning was provided by the National Center for Biotechnology Information. D. Crosslin and C. Laurie of the GENEVA project assisted in making the data available for analysis. A Physician Scientist Award from Research to Prevent Blindness in New York City also supports L. R. P. M. C. C. is a recipient of a Canadian Institutes of Health Research Fellowship. We acknowledge funding from the Australian National Health and Medical Research Council (NHMRC grants 389892 and 613672) and the Australian Research Council (ARC grants DP0770096 and DP1093900). We thank D. Posthuma for discussions and the referees for constructive comments. NR 43 TC 341 Z9 345 U1 8 U2 74 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 JUN PY 2011 VL 43 IS 6 BP 519 EP U44 DI 10.1038/ng.823 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 769ME UT WOS:000291017000007 PM 21552263 ER PT J AU Kato, N Takeuchi, F Tabara, Y Kelly, TN Go, MJ Sim, XL Tay, WT Chen, CH Zhang, Y Yamamoto, K Katsuya, T Yokota, M Kim, YJ Ong, RTH Nabika, T Gu, DF Chang, LC Kokubo, Y Huang, W Ohnaka, K Yamori, Y Nakashima, E Jaquish, CE Lee, JY Seielstad, M Isono, M Hixson, JE Chen, YT Miki, T Zhou, XY Sugiyama, T Jeon, JP Liu, JJ Takayanagi, R Kim, SS Aung, T Sung, YJ Zhang, XG Wong, TY Han, BG Kobayashi, S Ogihara, T Zhu, DL Iwai, N Wu, JY Teo, YY Tai, ES Cho, YS He, J AF Kato, Norihiro Takeuchi, Fumihiko Tabara, Yasuharu Kelly, Tanika N. Go, Min Jin Sim, Xueling Tay, Wan Ting Chen, Chien-Hsiun Zhang, Yi Yamamoto, Ken Katsuya, Tomohiro Yokota, Mitsuhiro Kim, Young Jin Ong, Rick Twee Hee Nabika, Toru Gu, Dongfeng Chang, Li-Ching Kokubo, Yoshihiro Huang, Wei Ohnaka, Keizo Yamori, Yukio Nakashima, Eitaro Jaquish, Cashell E. Lee, Jong-Young Seielstad, Mark Isono, Masato Hixson, James E. Chen, Yuan-Tsong Miki, Tetsuro Zhou, Xueya Sugiyama, Takao Jeon, Jae-Pil Liu, Jian Jun Takayanagi, Ryoichi Kim, Sung Soo Aung, Tin Sung, Yun Ju Zhang, Xuegong Wong, Tien Yin Han, Bok-Ghee Kobayashi, Shotai Ogihara, Toshio Zhu, Dingliang Iwai, Naoharu Wu, Jer-Yuarn Teo, Yik Ying Tai, E. Shyong Cho, Yoon Shin He, Jiang TI Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians SO NATURE GENETICS LA English DT Article ID GENETIC-BASIS; ESSENTIAL-HYPERTENSION; JAPANESE POPULATION; POSITIVE SELECTION; REGIONAL BURDEN; GLOBAL BURDEN; RISK-FACTORS; WILL UNLOCK; LOCI; DISEASE AB We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 x 10(-8)) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 x 10(-31) and P = 1.3 x 10(-35) for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention. C1 [Tabara, Yasuharu] Ehime Univ, Grad Sch Med, Dept Basic Med Res & Educ, Toon, Japan. [Kelly, Tanika N.; He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Go, Min Jin; Kim, Young Jin; Lee, Jong-Young; Jeon, Jae-Pil; Kim, Sung Soo; Han, Bok-Ghee; Cho, Yoon Shin] Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea. [Sim, Xueling; Teo, Yik Ying] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore. [Tay, Wan Ting; Aung, Tin; Wong, Tien Yin] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Chen, Chien-Hsiun; Chang, Li-Ching; Chen, Yuan-Tsong; Wu, Jer-Yuarn] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Chen, Chien-Hsiun; Wu, Jer-Yuarn] China Med Univ, Sch Chinese Med, Taichung, Taiwan. [Zhang, Yi; Zhu, Dingliang] Shanghai Jiao Tong Univ, Sch Med, Shanghai Rui Jin Hosp, State Key Lab Med Genet, Shanghai 200030, Peoples R China. [Zhang, Yi; Zhu, Dingliang] Shanghai Res Inst Hypertens, Shanghai, Peoples R China. [Yamamoto, Ken] Kyushu Univ, Med Inst Bioregulat, Div Genome Anal, Fukuoka 812, Japan. [Katsuya, Tomohiro] Osaka Univ, Grad Sch Med, Dept Clin Gene Therapy, Suita, Osaka, Japan. [Yokota, Mitsuhiro] Aichi Gakuin Univ, Sch Dent, Dept Genome Sci, Nagoya, Aichi 464, Japan. [Ong, Rick Twee Hee; Teo, Yik Ying] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore. [Nabika, Toru] Shimane Univ, Sch Med, Dept Funct Pathol, Izumo, Shimane, Japan. [Gu, Dongfeng] Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100037, Peoples R China. [Gu, Dongfeng] Chinese Acad Med Sci, Fuwai Hosp, Beijing 100037, Peoples R China. [Gu, Dongfeng] Peking Union Med Coll, Beijing 100021, Peoples R China. [Gu, Dongfeng] Chinese Natl Ctr Cardiovasc Dis, Beijing, Peoples R China. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Huang, Wei] Chinese Natl Human Genom Ctr, Dept Genet, Shanghai, Peoples R China. [Ohnaka, Keizo] Kyushu Univ, Grad Sch Med Sci, Dept Geriatr Med, Fukuoka 812, Japan. [Yamori, Yukio] Mukogawa Womens Univ, Inst World Hlth Dev, Nishinomiya, Hyogo, Japan. [Nakashima, Eitaro] Nagoya Univ, Grad Sch Med, Dept Internal Med, Div Endocrinol & Diabet, Nagoya, Aichi 4648601, Japan. [Nakashima, Eitaro] Chubu Rosai Hosp, Dept Endocrinol & Diabet, Nagoya, Aichi, Japan. [Jaquish, Cashell E.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Seielstad, Mark] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Hixson, James E.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol, Houston, TX USA. [Miki, Tetsuro] Ehime Univ, Grad Sch Med, Dept Geriatr Med, Toon, Japan. [Zhou, Xueya; Zhang, Xuegong] Tsinghua Univ, Dept Automat, Key Lab Bioinformat, Beijing 100084, Peoples R China. [Sugiyama, Takao; Teo, Yik Ying] Asahi Life Fdn, Inst Adult Dis, Tokyo, Japan. [Liu, Jian Jun] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore. [Takayanagi, Ryoichi] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Fukuoka 812, Japan. [Aung, Tin; Wong, Tien Yin] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Sung, Yun Ju] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Wong, Tien Yin] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Kobayashi, Shotai] Shimane Univ Hosp, Izumo, Shimane, Japan. [Ogihara, Toshio] Osaka Univ, Grad Sch Med, Dept Geriatr Med & Nephrol, Suita, Osaka, Japan. [Iwai, Naoharu] Natl Cerebral & Cardiovasc Ctr, Dept Genom Med, Suita, Osaka, Japan. [Teo, Yik Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore. [Teo, Yik Ying; Tai, E. Shyong] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117548, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore. [He, Jiang] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Kato, Norihiro; Takeuchi, Fumihiko; Isono, Masato] Natl Ctr Global Hlth & Med, Dept Gene Diagnost & Therapeut, Res Inst, Tokyo, Japan. RP Kato, N (reprint author), Natl Ctr Global Hlth & Med, Dept Gene Diagnost & Therapeut, Res Inst, Tokyo, Japan. EM nokato@ri.ncgm.go.jp OI Seielstad, Mark/0000-0001-5783-1401; Tai, E Shyong/0000-0003-2929-8966 FU Japan Science Technology Agency; National Institute of Biomedical Innovation Organization (NIBIO); Ministry of Education, Culture, Sports, Science and Technology of Japan; National Center for Global Health and Medicine (NCGM); National Heart, Lung, and Blood Institute, National Institutes of Health (Bethesda, Maryland, USA) [U01HL072507, R01HL087263, R01HL090682]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Bethesda, Maryland, USA) [K12HD043451]; Korea Centers for Disease Control & Prevention, Republic of Korea [4845-301, 4851-302, 4851-307]; Chinese National Key Program for Basic Research [2004CB518603, 2006CB503804, 2009CB521905]; Chinese National High Tech Program [2009AA022703, 2006AA02Z179]; Ministry of Science and Technology, National Natural Science Foundation [30871361]; National Medical Research Council [NMRC 0796/2003, NMRC/STaR/0003/2008, NMRC/CSA/008/2009]; Biomedical Research Council (BMRC) [09/1/35/19/616]; Biomedical Research Council of Singapore [BMRC 05/1/36/19/413, 03/1/27/18/216]; National Medical Research Council of Singapore [NMRC/1174/2008]; Singapore National Research Foundation [NRF-RF-2010-05]; Ministry of Education, Culture, Sports, Science and Technology, Japan; Ministry of Health, Labor and Welfare, Health and Labor Sciences Research Grants, Japan [H15-longevity-005, H17-longevity-003, H16-kenko-001, H18-longevity (kokusai)]; Japan Atherosclerosis Prevention Fund; Academia Sinica Genomic Medicine Multicenter Study; National Science Council, Taiwan (National Clinical Core) [NSC97-3112-B-001-014]; National Science Council, Taiwan (National Genotyping Center) [NSC97-3112-B-001-015] FX CAGE: The CAGE Network Studies were supported by grants for the Core Research for Evolutional Science and Technology (CREST) from the Japan Science Technology Agency; the Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); KAKENHI (Grant-in-Aid for Scientific Research) on Priority Areas 'Applied Genomics' from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and the Grant of National Center for Global Health and Medicine (NCGM).; GenSalt: The Genetic Epidemiology Network of Salt Sensitivity is supported by research grants (U01HL072507, R01HL087263 and R01HL090682) from the National Heart, Lung, and Blood Institute, National Institutes of Health (Bethesda, Maryland, USA). T.N.K. is supported partially by Award Number K12HD043451 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Bethesda, Maryland, USA).; KARE: KARE and HEXA-shared control studies were supported by grants from Korea Centers for Disease Control & Prevention, Republic of Korea (4845-301, 4851-302, 4851-307).; Shanghai: This work was supported by the Chinese National Key Program for Basic Research (grants 973: 2004CB518603, 2006CB503804 and 2009CB521905) and Chinese National High Tech Program (grants 863: 2009AA022703 and 2006AA02Z179) and the Ministry of Science and Technology, National Natural Science Foundation (30871361).; SiMES: The Singapore Malay Eye Study (SiMES) was funded by the National Medical Research Council (NMRC 0796/2003 and NMRC/STaR/0003/2008) and the Biomedical Research Council (BMRC, 09/1/35/19/616).; SP2: The Singapore Prospective Study Program (SP2) was funded through grants from the Biomedical Research Council of Singapore (BMRC 05/1/36/19/413 and 03/1/27/18/216) and the National Medical Research Council of Singapore (NMRC/1174/2008). Y.Y.T. acknowledges support from the Singapore National Research Foundation (NRF-RF-2010-05). E. S. T. also receives additional support from the National Medical Research Council through a clinician scientist award (NMRC/CSA/008/2009).; Suita/Ehime Study: The Ehime Study was supported by Grants for Scientific Research (Priority Areas 'Medical Genome Science (Millennium Genome Project)' and 'Applied Genomics') from the Ministry of Education, Culture, Sports, Science and Technology, Japan; a Grants-in-Aid (H15-longevity-005, H17-longevity-003, H16-kenko-001, H18-longevity (kokusai)) from the Ministry of Health, Labor and Welfare, Health and Labor Sciences Research Grants, Japan; a Science and Technology Incubation Program in Advanced Regions, Japan Science and Technology Agency; and the Japan Atherosclerosis Prevention Fund.; Taiwan Super Control Study: This study was supported by Academia Sinica Genomic Medicine Multicenter Study; National Research Program for Genomic Medicine, National Science Council, Taiwan (National Clinical Core, NSC97-3112-B-001-014; and National Genotyping Center, NSC97-3112-B-001-015). NR 43 TC 235 Z9 247 U1 5 U2 46 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 JUN PY 2011 VL 43 IS 6 BP 530 EP U57 DI 10.1038/ng.834 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 769ME UT WOS:000291017000009 PM 21572416 ER PT J AU Haiman, CA Chen, GK Blot, WJ Strom, SS Berndt, SI Kittles, RA Rybicki, BA Isaacs, WB Ingles, SA Stanford, JL Diver, WR Witte, JS Hsing, AW Nemesure, B Rebbeck, TR Cooney, KA Xu, JF Kibel, AS Hu, JJ John, EM Gueye, SM Watya, S Signorello, LB Hayes, RB Wang, ZM Yeboah, E Tettey, Y Cai, QY Kolb, S Ostrander, EA Zeigler-Johnson, C Yamamura, Y Neslund-Dudas, C Haslag-Minoff, J Wu, W Thomas, V Allen, GO Murphy, A Chang, BL Zheng, SL Leske, MC Wu, SY Ray, AM Hennis, AJM Thun, MJ Carpten, J Casey, G Carter, EN Duarte, ER Xia, LY Sheng, X Wan, P Pooler, LC Cheng, I Monroe, KR Schumacher, F Le Marchand, L Kolonel, LN Chanock, SJ Van Den Berg, D Stram, DO Henderson, BE AF Haiman, Christopher A. Chen, Gary K. Blot, William J. Strom, Sara S. Berndt, Sonja I. Kittles, Rick A. Rybicki, Benjamin A. Isaacs, William B. Ingles, Sue A. Stanford, Janet L. Diver, W. Ryan Witte, John S. Hsing, Ann W. Nemesure, Barbara Rebbeck, Timothy R. Cooney, Kathleen A. Xu, Jianfeng Kibel, Adam S. Hu, Jennifer J. John, Esther M. Gueye, Serigne M. Watya, Stephen Signorello, Lisa B. Hayes, Richard B. Wang, Zhaoming Yeboah, Edward Tettey, Yao Cai, Qiuyin Kolb, Suzanne Ostrander, Elaine A. Zeigler-Johnson, Charnita Yamamura, Yuko Neslund-Dudas, Christine Haslag-Minoff, Jennifer Wu, William Thomas, Venetta Allen, Glenn O. Murphy, Adam Chang, Bao-Li Zheng, S. Lilly Leske, M. Cristina Wu, Suh-Yuh Ray, Anna M. Hennis, Anselm J. M. Thun, Michael J. Carpten, John Casey, Graham Carter, Erin N. Duarte, Edder R. Xia, Lucy Y. Sheng, Xin Wan, Peggy Pooler, Loreall C. Cheng, Iona Monroe, Kristine R. Schumacher, Fredrick Le Marchand, Loic Kolonel, Laurence N. Chanock, Stephen J. Van Den Berg, David Stram, Daniel O. Henderson, Brian E. TI Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21 SO NATURE GENETICS LA English DT Article ID MULTIPLE LOCI; RISK LOCUS; 8Q24; VARIANTS AB In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 x 10(-13)). The frequency of the risk allele is similar to 5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations. C1 [Haiman, Christopher A.; Chen, Gary K.; Ingles, Sue A.; Casey, Graham; Carter, Erin N.; Duarte, Edder R.; Xia, Lucy Y.; Sheng, Xin; Wan, Peggy; Pooler, Loreall C.; Monroe, Kristine R.; Schumacher, Fredrick; Van Den Berg, David; Stram, Daniel O.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Blot, William J.; Signorello, Lisa B.] Int Epidemiol Inst, Rockville, MD USA. [Blot, William J.; Signorello, Lisa B.; Cai, Qiuyin] Vanderbilt Univ, Dept Med, Div Epidemiol, Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Blot, William J.; Signorello, Lisa B.; Cai, Qiuyin] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Strom, Sara S.; Yamamura, Yuko] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Berndt, Sonja I.; Hsing, Ann W.; Wang, Zhaoming; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kittles, Rick A.] Univ Illinois, Dept Med, Chicago, IL USA. [Rybicki, Benjamin A.; Neslund-Dudas, Christine] Henry Ford Hosp, Dept Biostat & Res Epidemiol, Detroit, MI 48202 USA. [Isaacs, William B.] Johns Hopkins Hosp & Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD USA. [Stanford, Janet L.; Kolb, Suzanne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Diver, W. Ryan; Thun, Michael J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Witte, John S.] Univ Calif San Francisco, Inst Human Genet, Dept Epidemiol, San Francisco, CA 94143 USA. [Witte, John S.] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [Nemesure, Barbara; Zheng, S. Lilly; Leske, M. Cristina; Wu, Suh-Yuh; Hennis, Anselm J. M.] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Rebbeck, Timothy R.; Zeigler-Johnson, Charnita; Chang, Bao-Li] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.; Zeigler-Johnson, Charnita; Chang, Bao-Li] Abramson Canc Ctr, Philadelphia, PA USA. [Cooney, Kathleen A.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Xu, Jianfeng] Wake Forest Univ, Sch Med, Ctr Canc Genom, Winston Salem, NC 27109 USA. [Kibel, Adam S.; Haslag-Minoff, Jennifer; Wu, William] Washington Univ, Dept Surg, Div Urol, St Louis, MO USA. [Hu, Jennifer J.; Thomas, Venetta; Allen, Glenn O.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Hu, Jennifer J.; Thomas, Venetta; Allen, Glenn O.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Gueye, Serigne M.] Hop Gen Grand Yoff, Dakar, Senegal. [Watya, Stephen] Makerere Univ, Dept Surg, Urol Unit, Mulago Hosp, Kampala, Uganda. [Hayes, Richard B.] NYU, Dept Environm Med, Langone Med Ctr, Div Epidemiol, New York, NY 10016 USA. [Yeboah, Edward; Tettey, Yao] Univ Ghana, Sch Med, Legon, Ghana. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Murphy, Adam] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Hennis, Anselm J. M.] Univ W Indies, Fac Med Sci, Bridgetown, Barbados. [Hennis, Anselm J. M.] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Hennis, Anselm J. M.] Minist Hlth, Bridgetown, Barbados. [Carpten, John] Translat Genom Res Inst, Phoenix, AZ USA. [Cheng, Iona; Le Marchand, Loic; Kolonel, Laurence N.] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. RP Haiman, CA (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. EM haiman@usc.edu OI Zeigler-Johnson, Charnita/0000-0003-2641-7755; Hayes, Richard/0000-0002-0918-661X; Ostrander, Elaine/0000-0001-6075-9738 FU US National Institutes of Health (NIH) [CA63464, CA54281, CA1326792, CA148085, HG004726]; Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), NIH; Cancer Research Fund [99-00524V-10258, 97-12013]; University of California [98-00924V]; Department of Health Services; NCI [CA114379]; NIH [CA056678, CA082664, CA092579, ES011126, S06GM08016, CA092447]; Department of Health and Human Services [N01-PC-35139]; California Department of Health Services [103885]; Centers for Disease Control and Prevention (CDC) [1U58DP000807-3]; Department of Defense (DOD) [W81XWH-07-1-0122, DAMD W81XWH-07-1-0203, DAMD W81XWH-06-1-0066]; Vanderbilt-Ingram Cancer Center [CA68485]; St. Louis Men's Group Against Cancer; David H. Nickerson Foundation; California Cancer Research Program [99-00527V-10182]; Commonwealth of Pennsylvania; American Cancer Society; National Health Genome Research Institute [N01-HG-25487]; Office of Minority Health [N01-HG-25487]; [CA68578]; [ES007784]; [DAMD W81XWH-07-1-0645]; [CA140388]; [CA88164]; [CA127298]; [CA112028]; [CA085074]; [CA105641] FX The Multiethnic Cohort (MEC) and the genotyping in this study were supported by US National Institutes of Health (NIH) grants CA63464, CA54281, CA1326792, CA148085 and HG004726. Genotyping of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) and Ghana samples was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), NIH. The Los Angeles Study of Aggressive Prostate Cancer (LAAPC) was funded by grant 99-00524V-10258 from the Cancer Research Fund under Interagency Agreement #97-12013 (University of California contract #98-00924V) with the Department of Health Services Cancer Research Program. Cancer incidence data for the MEC and LAAPC studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with Federal funds from the NCI, NIH, Department of Health and Human Services under Contract No. N01-PC-35139 and the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885 and grant number 1U58DP000807-3 from the Centers for Disease Control and Prevention (CDC). The King County (Washington) Prostate Cancer Study (KCPCS) was supported by NIH grants CA056678, CA082664 and CA092579 with additional support from the Fred Hutchinson Cancer Research Center and the Intramural Program of the National Human Genome Research Institute. Prostate Cancer Case-Control Studies at MD Anderson (MDA) was support by grants CA68578, ES007784, DAMD W81XWH-07-1-0645 and CA140388. The Gene-Environment Interaction in Prostate Cancer Study (GECAP) was supported by NIH grant ES011126. Prostate Cancer Genetics Study (CaP Genes) was supported by CA88164 and CA127298. Identifying Prostate Cancer Genes (IPCG) was supported by Department of Defense (DOD) grant W81XWH-07-1-0122. Case-Control Study of Prostate Cancer among African Americans in Washington, DC (DCPC) was supported by NIH grant S06GM08016 and DOD grants DAMD W81XWH-07-1-0203 and DAMD W81XWH-06-1-0066. The Southern Community Cohort Study (SCCS) is funded by NIH grant CA092447. SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab, which is supported in part by the Vanderbilt-Ingram Cancer Center (CA68485). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; and Arkansas Department of Health, Cancer Registry. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, CDC. Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry, which participates in the National Program of Cancer Registries (NPCR) of the CDC. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. We thank C. Edlund from the University of Southern California (USC) Genomics Core for his technical and informatics assistance. The authors thank C. Berg and P.; Prorok, Division of Cancer Prevention, NCI, the screening center investigators and staffof the PLCO Cancer Screening Trial, T. Riley and staff at Information Management Services, Inc. and B. O'Brien and staff at Westat, Inc. for their contributions to the PLCO Cancer Screening Trial. We also acknowledge the technical support of M. Gielzak and G. Yan. The authors would like to thank E. Tay and V. Okyne for their expert help in coordinating the Ghana study; A. DeMarzo and G. Netto of Johns Hopkins University for pathology review; V. Devairakkam, N. Kim and J. Heinrich of Research Triangle Institute (RTI) for their expert study management; and S. Niwa and A. Truelove of Westat for study support and data management. The Washington University Prostate Cancer Study (WUPCS) was supported by CA112028, the St. Louis Men's Group Against Cancer and the David H. Nickerson Foundation. The San Francisco Bay Area Prostate Cancer Study (SFPCS) was funded by grant 99-00527V-10182 from the California Cancer Research Program. The Study of Clinical Outcomes, Risk and Ethnicity (SCORE) was supported by CA085074 and CA105641, as well as a grant from the Commonwealth of Pennsylvania. The Cancer Prevention Study II Nutrition Cohort (CPS-II) is supported by the American Cancer Society. Prostate Cancer in a Black Population (PCBP) was supported by grant CA114379 (NCI) and contract N01-HG-25487 (National Health Genome Research Institute and the Office of Minority Health). NR 21 TC 100 Z9 100 U1 0 U2 6 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 JUN PY 2011 VL 43 IS 6 BP 570 EP U103 DI 10.1038/ng.839 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 769ME UT WOS:000291017000015 PM 21602798 ER PT J AU Talley, EM Newman, D Mimno, D Herr, BW Wallach, HM Burns, GAPC Leenders, AGM McCallum, A AF Talley, Edmund M. Newman, David Mimno, David Herr, Bruce W., II Wallach, Hanna M. Burns, Gully A. P. C. Leenders, A. G. Miriam McCallum, Andrew TI Database of NIH grants using machine-learned categories and graphical clustering SO NATURE METHODS LA English DT Letter C1 [Talley, Edmund M.; Leenders, A. G. Miriam] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Newman, David] Univ Calif Irvine, Irvine, CA USA. [Mimno, David; Wallach, Hanna M.; McCallum, Andrew] Univ Massachusetts, Amherst, MA 01003 USA. [Herr, Bruce W., II] ChalkLabs, Bloomington, IN USA. [Burns, Gully A. P. C.] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. RP Talley, EM (reprint author), Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. EM talleye@ninds.nih.gov OI Mimno, David/0000-0001-7510-9404; Burns, Gully/0000-0003-1493-865X FU NINDS NIH HHS [HHSN271200900637P, HHSN271200900639P, HHSN271200900640P, HHSN271200900244P, HHSN271201000620P, HHSN271201000701P, HHSN271201000704P, HHSN271201000758P]; PHS HHS [271200900244P, 271200900426P, 271200900637P, 271200900639P, 271200900640P, 271200900695P, 271201000620P, 271201000701P, 271201000704P, 271201000758P] NR 0 TC 12 Z9 12 U1 1 U2 10 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 JUN PY 2011 VL 8 IS 6 BP 443 EP 444 DI 10.1038/nmeth.1619 PG 2 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 769QB UT WOS:000291031800003 PM 21623347 ER PT J AU Shipman, SL Schnell, E Hirai, T Chen, BS Roche, KW Nicoll, RA AF Shipman, Seth L. Schnell, Eric Hirai, Takaaki Chen, Bo-Shiun Roche, Katherine W. Nicoll, Roger A. TI Functional dependence of neuroligin on a new non-PDZ intracellular domain SO NATURE NEUROSCIENCE LA English DT Article ID INHIBITORY SYNAPSE FORMATION; CELL-ADHESION MOLECULE; EXCITATORY SYNAPSES; RECEPTOR TRAFFICKING; SILENT SYNAPSES; AMPA RECEPTORS; AUTISM; NEUREXIN; MUTATION; PROTEIN AB Neuroligins, a family of postsynaptic adhesion molecules, are important in synaptogenesis through a well-characterized transsynaptic interaction with neurexin. In addition, neuroligins are thought to drive postsynaptic assembly through binding of their intracellular domain to PSD-95. However, there is little direct evidence to support the functional necessity of the neuroligin intracellular domain in postsynaptic development. We found that presence of endogenous neuroligin obscured the study of exogenous mutated neuroligin. We therefore used chained microRNAs in rat organotypic hippocampal slices to generate a reduced background of endogenous neuroligin. On this reduced background, we found that neuroligin function was critically dependent on the cytoplasmic tail. However, this function required neither the PDZ ligand nor any other previously described cytoplasmic binding domain, but rather required a previously unknown conserved region. Mutation of a single critical residue in this region inhibited neuroligin-mediated excitatory synaptic potentiation. Finally, we found a functional distinction between neuroligins 1 and 3. C1 [Shipman, Seth L.; Nicoll, Roger A.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Shipman, Seth L.; Nicoll, Roger A.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. [Shipman, Seth L.] Univ Calif San Francisco, Neurosci Grad Program, San Francisco, CA 94143 USA. [Schnell, Eric] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Hirai, Takaaki; Chen, Bo-Shiun; Roche, Katherine W.] NINDS, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Nicoll, RA (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. EM nicoll@cmp.ucsf.edu RI Shipman, Seth/G-2562-2011; Chen, Bo-Shiun/H-4633-2012; OI Schnell, Eric/0000-0002-5623-5015; Roche, Katherine/0000-0001-7282-6539 FU US National Institute of Mental Health FX We thank A.M. Craig, T. Sudhof and F. Varoqueaux for neuroligin constructs. We are grateful to K. Bjorgan for technical assistance and all members of the Nicoll laboratory and E. Dreyfuss for discussion of and comments on the manuscript. This work was supported by grants from the US National Institute of Mental Health. NR 50 TC 43 Z9 43 U1 0 U2 6 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 JUN PY 2011 VL 14 IS 6 BP 718 EP U388 DI 10.1038/nn.2825 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 768SH UT WOS:000290958000014 PM 21532576 ER PT J AU Jensen, RT AF Jensen, Robert T. TI CANCER A roadmap for the land of small tumors SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Editorial Material ID GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS; PANCREATIC ENDOCRINE TUMORS AB Advances in the diagnosis, treatment and management of neuroendocrine tumors have led to a consensus meeting of the National Cancer Institute, the new directions of which are now reported by Kulke and colleagues. Many thoughtful proposals are presented that should be of interest to the increasing number of physicians who see patients with these unique tumors. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDKD, Digest Dis Branch, NIH, Bldg 10,Room 9C-103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov NR 10 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 1759-5029 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD JUN PY 2011 VL 7 IS 6 BP 319 EP 321 DI 10.1038/nrendo.2011.73 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 769JH UT WOS:000291008200003 PM 21556022 ER PT J AU Riley, EP Infante, MA Warren, KR AF Riley, Edward P. Infante, M. Alejandra Warren, Kenneth R. TI Fetal Alcohol Spectrum Disorders: An Overview SO NEUROPSYCHOLOGY REVIEW LA English DT Review DE Fetal alcohol syndrome (FAS); Fetal alcohol spectrum disorders (FASD); Prenatal alcohol exposure; Brain-behavior ID MECONIUM ANALYSIS; ETHYL-ESTERS; FATTY-ACID; PREVALENCE; EXPOSURE; PREGNANCY; DIAGNOSIS; CHILDREN; SAMPLE; FASD AB When fetal alcohol syndrome (FAS) was initially described, diagnosis was based upon physical parameters including facial anomalies and growth retardation, with evidence of developmental delay or mental deficiency. Forty years of research has shown that FAS lies towards the extreme end of what are now termed fetal alcohol spectrum disorders (FASD). The most profound effects of prenatal alcohol exposure are on the developing brain and the cognitive and behavioral effects that ensue. Alcohol exposure affects brain development via numerous pathways at all stages from neurogenesis to myelination. For example, the same processes that give rise to the facial characteristics of FAS also cause abnormal brain development. Behaviors as diverse as executive functioning to motor control are affected. This special issue of Neuropsychology Review addresses these changes in brain and behavior highlighting the relationship between the two. A diagnostic goal is to recognize FAS as a disorder of brain rather than one of physical characteristics. C1 [Riley, Edward P.; Infante, M. Alejandra] San Diego State Univ, Ctr Behav Teratol, Dept Psychol, San Diego, CA 92120 USA. [Infante, M. Alejandra] San Diego State Univ Univ Calif San Diego, Joint Doctoral Program Clin Psychol, San Diego, CA USA. [Warren, Kenneth R.] NIAAA, Bethesda, MD USA. RP Riley, EP (reprint author), San Diego State Univ, Ctr Behav Teratol, Dept Psychol, 6330 Alvarado Court,Suite 100, San Diego, CA 92120 USA. EM eriley@mail.sdsu.edu RI Riley, Edward/E-6369-2013 OI Riley, Edward/0000-0001-8747-891X FU National Institute of Health NIAAA [R01 AA010417, U24 AA014811, T32 AA013525] FX The authors greatly acknowledge the help of Jason Dudley and Kristen Breit in preparing the figure for this manuscript. Preparation of this paper was supported by National Institute of Health NIAAA Grants R01 AA010417, U24 AA014811, and T32 AA013525 to epr. and was conducted in conjunction with the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD). More information about the CIFASD can be found at www.cifasd.org NR 45 TC 173 Z9 177 U1 6 U2 113 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1040-7308 EI 1573-6660 J9 NEUROPSYCHOL REV JI Neuropsychol. Rev. PD JUN PY 2011 VL 21 IS 2 BP 73 EP 80 DI 10.1007/s11065-011-9166-x PG 8 WC Psychology, Clinical; Neurosciences SC Psychology; Neurosciences & Neurology GA 766RR UT WOS:000290804700001 PM 21499711 ER PT J AU Sathian, K Buxbaum, LJ Cohen, LG Krakauer, JW Lang, CE Corbetta, M Fitzpatrick, SM AF Sathian, K. Buxbaum, Laurel J. Cohen, Leonardo G. Krakauer, John W. Lang, Catherine E. Corbetta, Maurizio Fitzpatrick, Susan M. TI Neurological Principles and Rehabilitation of Action Disorders: Common Clinical Deficits SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article ID NATURALISTIC ACTION; MOVEMENT CONTROL; STROKE; RECOVERY; APRAXIA; CEREBELLUM; LESIONS; HAND AB In this chapter, the authors use the computation, anatomy, and physiology (CAP) principles to consider the impact of common clinical problems on action. They focus on 3 major syndromes: paresis, apraxia, and ataxia. They also review mechanisms that could account for spontaneous recovery, using what is known about the best-studied clinical dysfunction-paresis-and also ataxia. Together, this and the previous chapter lay the groundwork for the third chapter in this series, which reviews the relevant rehabilitative interventions. C1 [Sathian, K.] Emory Univ, Atlanta, GA 30322 USA. [Sathian, K.] Atlanta VAMC, Rehabil R&D Ctr Excellence, Atlanta, GA USA. [Buxbaum, Laurel J.] Moss Rehabil Res Inst, Philadelphia, PA USA. [Cohen, Leonardo G.] NINDS, NIH, Bethesda, MD 20892 USA. [Krakauer, John W.] Johns Hopkins Univ, Baltimore, MD USA. [Lang, Catherine E.] Washington Univ, Sch Med, St Louis, MO USA. [Fitzpatrick, Susan M.] James S McDonnell Fdn, St Louis, MO USA. RP Sathian, K (reprint author), Emory Univ, Atlanta, GA 30322 USA. FU NICHD NIH HHS [R01 HD061117] NR 21 TC 13 Z9 13 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD JUN PY 2011 VL 25 SU 5 BP 21S EP 32S DI 10.1177/1545968311410941 PG 12 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 769SO UT WOS:000291038800003 PM 21613535 ER PT J AU Simmons, HE Holmes, EC Gildow, FE Bothe-Goralczyk, MA Stephenson, AG AF Simmons, H. E. Holmes, E. C. Gildow, F. E. Bothe-Goralczyk, M. A. Stephenson, A. G. TI Experimental Verification of Seed Transmission of Zucchini yellow mosaic virus SO PLANT DISEASE LA English DT Article ID POTYVIRUSES; STYRIACA; SQUASH; YIELD; MELON; ZYMV AB Within two decades of its discovery, Zucchini yellow mosaic virus (ZYMV) achieved a global distribution. However, whether or not seed transmission occurs in this economically significant crop pathogen is controversial, and the relative impact of seed transmission on the epidemiology of ZYMV remains unclear. Using reverse transcription polymerase chain reaction, we observed a seed transmission rate of 1.6% in Cucurbita pepo subsp. texana and show that seed-infected C. pepo plants are capable of initiating horizontal ZYMV infections, both mechanically and via an aphid vector (Myzus persicae). We also provide evidence that ZYMV-infected seeds may act as effective viral reservoirs, partially accounting for the current geographic distribution of ZYMV. Finally, the observation that ZYMV infection of C. pepo seeds results in virtually symptomless infection, coupled with our finding that an antibody test failed to detect vertically transmitted ZYMV in infected seed, highlights the urgent need to standardize current detection methods for seed infection. C1 [Simmons, H. E.; Holmes, E. C.; Bothe-Goralczyk, M. A.; Stephenson, A. G.] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. Fogarty Int Ctr, NIH, Bethesda, MD 20892 USA. [Gildow, F. E.] Penn State Univ, Dept Plant Pathol, University Pk, PA 16802 USA. RP Simmons, HE (reprint author), Penn State Univ, Dept Biol, University Pk, PA 16802 USA. EM hes142@psu.edu OI Holmes, Edward/0000-0001-9596-3552 FU NSF [DEB02-35217]; USDA National Institute of Food and Agriculture [2008-35302-04577, 2009-33120-20093] FX We thank William Sackett for his invaluable advice and assistance with the aphid transmission tests. Sarah Scanlon and Kelly Wall for field, greenhouse, and lab assistance, Tony Omeis for greenhouse assistance as well as the use of the Biology Greenhouse, and R. Oberheim and his staff for use of the Horticulture Farm at the PSU Agriculture Experiment Station at Rock Springs, PA. This work was supported by NSF Grant DEB02-35217 and by grants 2008-35302-04577 and 2009-33120-20093 from the USDA National Institute of Food and Agriculture. NR 24 TC 19 Z9 19 U1 2 U2 14 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0191-2917 J9 PLANT DIS JI PLANT DIS. PD JUN PY 2011 VL 95 IS 6 BP 751 EP 754 DI 10.1094/PDIS-11-10-0843 PG 4 WC Plant Sciences SC Plant Sciences GA 767TN UT WOS:000290879700018 ER PT J AU Srivastava, M Eidelman, O Torosyan, Y Jozwik, C Mannon, RB Pollard, HB AF Srivastava, Meera Eidelman, Ofer Torosyan, Yelizaveta Jozwik, Catherine Mannon, Roslyn B. Pollard, Harvey B. TI Elevated expression levels of ANXA11, integrins beta 3 and alpha 3, and TNF-alpha contribute to a candidate proteomic signature in urine for kidney allograft rejection SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Graft rejection; Protein arrays; Urine ID LUNG EPITHELIAL-CELLS; ACUTE-RENAL-FAILURE; TRANSPLANT REJECTION; CYTOPLASMIC DOMAIN; IFN-GAMMA; DYSFUNCTION; PROTEINS; BINDING; CANCER; PHASE AB Purpose: Kidney transplantation is the treatment of choice for end stage renal disease, with long-term allograft loss being the major obstacle, and for which potential treatments are based on a histological diagnosis. The problem is that markers for predicting graft rejection are limited in number, are invasive, and are quite non-specific. We have hypothesized that protein biomarkers might be discovered in the urine of patients when acute or chronic rejection might be occurring. Experimental design: We have established a workflow in which initial screening for candidate biomarkers is first performed using urine samples on large-scale antibody microarrays. This approach generated several dozen candidates. The next step is to qualify some of the strongest signals using the high-throughput Reverse Capture Protein Microarray platform. Results: Four top candidates including ANXA11, Integrin alpha 3, Integrin beta 3 and TNF-alpha, initially identified by the antibody microarray platform, were all qualified using Reverse Capture Protein Microarrays. We also used receiver operating condition (ROC) curves to independently quantify the specificity and sensitivity of these four analytes. Conclusions and clinical relevance: The present data suggest that these novel four analytes in the urine, together or independently, may contribute to a robust and quantitative urine proteomic signature for diagnosing acute or chronic rejection of renal allografts. C1 [Srivastava, Meera; Eidelman, Ofer; Torosyan, Yelizaveta; Jozwik, Catherine; Pollard, Harvey B.] Uniformed Serv Univ Sch Med USUHS, Dept Anat Physiol & Genet, Bethesda, MD USA. [Srivastava, Meera; Eidelman, Ofer; Torosyan, Yelizaveta; Jozwik, Catherine; Pollard, Harvey B.] Uniformed Serv Univ Sch Med USUHS, USU Ctr Med Prote, Bethesda, MD USA. [Mannon, Roslyn B.] NIDDK, Transplantat Branch, NIH, Bethesda, MD USA. [Mannon, Roslyn B.] Univ Alabama, Div Nephrol, Birmingham, AL USA. RP Srivastava, M (reprint author), USU Sch Med, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM msrivastava@usuhs.mil FU NIH [RO1DK053051, NO1HV28187]; Cystic Fibrosis Foundation FX The authors express appreciation to Ms. Wei Huang for outstanding technical support for this project, and gratefully acknowledge financial support from the NIH [RO1DK053051 (H.B.P.); NO1HV28187 (H.B.P.)], and the Cystic Fibrosis Foundation (H.B.P.). NR 41 TC 12 Z9 14 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD JUN PY 2011 VL 5 IS 5-6 BP 311 EP 321 DI 10.1002/prca.201000109 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 770LK UT WOS:000291087800012 PM 21591265 ER PT J AU Soto, PL Grandy, DK Hursh, SR Katz, JL AF Soto, Paul L. Grandy, David K. Hursh, Steven R. Katz, Jonathan L. TI Behavioral economics of food reinforcement and the effects of prefeeding, extinction, and eticlopride in dopamine D-2 receptor mutant mice SO PSYCHOPHARMACOLOGY LA English DT Article DE Behavioral economics; Dopamine D-2 receptors; Knockout mice; Eticlopride; Fixed-ratio schedule of reinforcement ID NUCLEUS-ACCUMBENS DOPAMINE; DEFICIENT MICE; ANHEDONIA HYPOTHESIS; COCAINE; REWARD; GENE; RATS; MICRODIALYSIS; STRIATUM; RELEASE AB Several studies have investigated the reinforcing effects of food in genetically engineered mice lacking dopamine D-2 receptors (DA D(2)Rs); however, behavioral economic analyses quantifying reinforcement have not been conducted. The role of DA D(2)Rs in food reinforcement was examined by comparing responding under various fixed-ratio (FR) schedules of reinforcement, and effects of extinction, satiation, and the DA D2R antagonist eticlopride, in mice with and without genetic deletions of the receptor. Response rates of DA D2R knockout (KO) mice were generally lower than those of littermate wild-type (WT) and heterozygous (HET) mice. The demand curve (consumption vs. FR value) for KO mice decreased more steeply than that of HET or WT mice, suggesting that reinforcing effectiveness is decreased with DA D2R deletion. Prefeeding decreased, whereas extinction increased overall response rates as a proportion of baseline, with no significant genotype differences. Both (+)- and (-)-eticlopride dose-dependently decreased responding in all genotypes with (-)-eticlopride more potent than (+)-eticlopride in all but KO mice. The enantiomers were equipotent in KO mice, and similar in potency to (+)-eticlopride in WT and HET mice. That prefeeding and extinction did not vary across genotypes indicates a lack of involvement of DA D(2)Rs in these processes. Differences between (-)-eticlopride effects and extinction indicate that DA D2R blockade does not mimic extinction. The maintenance of responding in KO mice indicates that the DA D2R is not necessary for reinforcement. However, the economic analysis indicates that the DA D2R contributes substantially to the effectiveness of food reinforcement. C1 [Soto, Paul L.; Hursh, Steven R.] Johns Hopkins Med Inst, Dept Psychiat & Behav Sci, Div Behav Biol, Baltimore, MD 21205 USA. [Grandy, David K.] Oregon Hlth & Sci Univ, Portland, OR USA. [Katz, Jonathan L.] NIDA, Baltimore, MD USA. RP Soto, PL (reprint author), Johns Hopkins Med Inst, Dept Psychiat & Behav Sci, Div Behav Biol, Ross 469,720 Rutland Ave, Baltimore, MD 21205 USA. EM psoto@jhmi.edu FU Department of Health and Human Services, National Institutes of Health; National Institute on Drug Abuse FX These studies were supported by the Intramural Research Program of the Department of Health and Human Services, National Institutes of Health, and National Institute on Drug Abuse and were conducted in accordance with the NIH principles of animal care and use. The authors would like to thank Dawn French-Evans for her expert technical assistance in collecting and preparing the data for analysis. NR 42 TC 7 Z9 7 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 2011 VL 215 IS 4 BP 775 EP 784 DI 10.1007/s00213-011-2173-z PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 769SC UT WOS:000291037600016 PM 21287342 ER PT J AU Mohan, R Beydoun, HA Beydoun, MA Barnes-Eley, M Davis, J Lance, R Schellhammer, P AF Mohan, Ravinder Beydoun, Hind A. Beydoun, May A. Barnes-Eley, Myra Davis, John Lance, Raymond Schellhammer, Paul TI Self-rated health as a tool for estimating health-adjusted life expectancy among patients newly diagnosed with localized prostate cancer: a preliminary study SO QUALITY OF LIFE RESEARCH LA English DT Article DE Localized prostate cancer; Life expectancy; Self-rated Health; Urology ID MEN; MORTALITY; SURVIVAL; ONCOLOGISTS; COMORBIDITY; UROLOGISTS; INDEX AB Localized prostate cancer (LPC) patients are faced with numerous treatment options, including observation or watchful waiting. The choice of treatment largely depends on their baseline health-adjusted life expectancy (HALE). By consensus, physicians recommend treatment if the patient's HALE is ten or more years. However, the estimation of HALE is difficult. Although subjective by nature, self-rated health (SRH) is a robust predictor of mortality. We studied the usefulness of SRH in estimating HALE in patients who are considering treatment for LPC. A total of 144 LPC patients from a large urology private practice in Norfolk, Virginia, were surveyed before they had chosen a treatment option. HALE determined by SRH correlated well with objective health measures and was higher than age-based life expectancy by an average of 2 years. The observed difference in life expectancy due to SRH adjustment was higher among patients with a better socioeconomic and health profile. SRH is an easy-to-use indicator of HALE in LPC patients. A table for HALE estimation by age and SRH is provided for men aged 70-80 years. Additional research with larger samples and prospective study designs are needed before the SRH method can be used in primary care and urology settings. C1 [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Mohan, Ravinder] Eastern Virginia Med Sch, Dept Family & Community Med, Norfolk, VA 23501 USA. [Beydoun, May A.] NIA, Baltimore, MD 21224 USA. [Barnes-Eley, Myra] Childrens Hosp Kings Daughters, Ctr Pediat Res, Norfolk, VA USA. [Davis, John] MD Anderson Canc Ctr, Dept Urol Oncol, Houston, TX USA. [Lance, Raymond; Schellhammer, Paul] Eastern Virginia Med Sch, Dept Urol, Norfolk, VA 23501 USA. RP Beydoun, HA (reprint author), Eastern Virginia Med Sch, Grad Program Publ Hlth, 700 W Olney Rd,POB 980, Norfolk, VA 23501 USA. EM mohanr@evms.edu; baydouha@evms.edu; baydounm@mail.nih.gov; pediatrics@chkd.org; johndavis@mdanderson.org; lancrs@evms.edu; schellpf@evms.edu FU Norfolk Foundation; US Health Resources Service Administration Department of Health and Human Services; NIH, National Institute on Aging FX Support for this project was provided in part through grants from the Norfolk Foundation, and the US Health Resources Service Administration Department of Health and Human Services. In addition, the project was supported in part by the intramural research program of the NIH, National Institute on Aging. We would like to thank Mr. Brian Main for his help with the patient database. NR 31 TC 8 Z9 8 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD JUN PY 2011 VL 20 IS 5 BP 713 EP 721 DI 10.1007/s11136-010-9805-3 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 769RQ UT WOS:000291036400010 PM 21132389 ER PT J AU Googe, J Brucker, AJ Bressler, NM Qin, HJ Aiello, LP Antoszyk, A Beck, RW Bressler, SB Ferris, FL Glassman, AR Marcus, D Stockdale, CR AF Googe, Joseph Brucker, Alexander J. Bressler, Neil M. Qin, Haijing Aiello, Lloyd P. Antoszyk, Andrew Beck, Roy W. Bressler, Susan B. Ferris, Frederick L., III Glassman, Adam R. Marcus, Dennis Stockdale, Cynthia R. CA Diabetic Retinopathy Writing Comm TI RANDOMIZEDTRIAL EVALUATING SHORT-TERM EFFECTS OF INTRAVITREAL RANIBIZUMAB OR TRIAMCINOLONE ACETONIDE ON MACULAR EDEMA AFTER FOCAL/GRID LASER FOR DIABETIC MACULAR EDEMA IN EYES ALSO RECEIVING PANRETINAL PHOTOCOAGULATION SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE proliferative diabetic retinopathy; diabetic macular edema; panretinal photocoagulation; ranibizumab; triamcinolone; randomized clinical trial; Diabetic Retinopathy Clinical Research Network ID ENDOTHELIAL GROWTH-FACTOR; CLINICAL-TRIAL; RETINOPATHY AB Purpose: To evaluate 14-week effects of intravitreal ranibizumab or triamcinolone in eyes receiving focal/grid laser for diabetic macular edema and panretinal photocoagulation. Methods: Three hundred and forty-five eyes with a visual acuity of 20/320 or better, center-involved diabetic macular edema receiving focal/grid laser, and diabetic retinopathy receiving prompt panretinal photocoagulation were randomly assigned to sham (n = 123), 0.5-mg ranibizumab (n = 113) at baseline and 4 weeks, and 4-mg triamcinolone at baseline and sham at 4 weeks (n = 109). Treatment was at investigator discretion from 14 weeks to 56 weeks. Results: Mean changes (+/-SD) in visual acuity letter score from baseline were significantly better in the ranibizumab (+1 +/- 11; P < 0.001) and triamcinolone (+2 +/- 11; P, 0.001) groups compared with those in the sham group (24 +/- 14) at the 14-week visit, mirroring retinal thickening results. These differences were not maintained when study participants were followed for 56 weeks for safety outcomes. One eye (0.9%; 95% confidence interval, 0.02%-4.7%) developed endophthalmitis after receiving ranibizumab. Cerebrovascular/cardiovascular events occurred in 4%, 7%, and 3% of the sham, ranibizumab, and triamcinolone groups, respectively. Conclusion: The addition of 1 intravitreal triamcinolone injection or 2 intravitreal ranibizumab injections in eyes receiving focal/grid laser for diabetic macular edema and panretinal photocoagulation is associated with better visual acuity and decreased macular edema by 14 weeks. Whether continued long-term intravitreal treatment is beneficial cannot be determined from this study. RETINA 31: 1009-1027, 2011 C1 [Googe, Joseph; Diabetic Retinopathy] SE Retina Associates PC, Knoxville, TN USA. [Brucker, Alexander J.] Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Bressler, Neil M.; Bressler, Susan B.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Qin, Haijing; Beck, Roy W.; Glassman, Adam R.; Stockdale, Cynthia R.] Jaeb Ctr Hlth Res, Tampa, FL USA. [Aiello, Lloyd P.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02115 USA. [Antoszyk, Andrew] Charlotte Eye Ear Nose & Throat Assoc PA, Charlotte, NC USA. [Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. [Marcus, Dennis] SE Retina Ctr PC, Augusta, GA USA. RP Googe, J (reprint author), SE Retina Associates PC, Knoxville, TN USA. FU National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Department of Health and Human Services [EY14231, EY14229, EY018817]; Genentech; Allergan, Inc; Office of Research Administration; Allergan; Bausch Lomb; Carl Zeiss Meditec; EMMES Corporation; Lumenis; Notal Vision; Novartis; QLT; Regeneron; Steba Biotech; Abbott Medical Optics; ForSight Labs, LLC; Genzyme Corporation FX A complete list of the DRCR. net can be found at www.drcr.net. Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and Department of Health and Human Services (EY14231, EY14229, and EY018817).; Genentech provided ranibizumab for the study, and Allergan, Inc, provided triamcinolone for the study. In addition, Genentech and Allergan, Inc, provided funds to DRCR. net to defray the study's clinical site costs.; A. J. Brucker: Genentech (C, G); L. P. Aiello: Genentech (O); A. Antoszyk: Genentech (C, G) and Allergan (G); S. S. Bressler: Genentech (G) and Allergan (G); D. Marcus: Genentech (C, G, T, B); N. Bressler: Grants to investigator at the Johns Hopkins University are negotiated and administered by the institution (such as the School of Medicine) that receives the grants, typically through the Office of Research Administration.; Dr. Neil Bressler is the principal investigator of grants at the Johns Hopkins University sponsored by the following entities (not including the National Institutes of Health): Allergan, Bausch & Lomb, Carl Zeiss Meditec, EMMES Corporation, Genentech, Lumenis, Notal Vision, Novartis, QLT, Regeneron, Steba Biotech, Abbott Medical Optics, ForSight Labs, LLC, and Genzyme Corporation. NR 28 TC 48 Z9 51 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD JUN PY 2011 VL 31 IS 6 BP 1009 EP 1027 DI 10.1097/IAE.0b013e318217d739 PG 19 WC Ophthalmology SC Ophthalmology GA 769JT UT WOS:000291009400002 ER PT J AU Yu, BB Tiwari, RC Feuer, EJ AF Yu, Binbing Tiwari, Ram C. Feuer, Eric J. TI Estimating the personal cure rate of cancer patients using population-based grouped cancer survival data SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article ID PROPORTIONAL HAZARDS MODEL; INTERVAL-CENSORED DATA; REGRESSION-ANALYSIS; ALGORITHM; FAILURE; EM AB Cancer patients are subject to multiple competing risks of death and may die from causes other than the cancer diagnosed. The probability of not dying from the cancer diagnosed, which is one of the patients' main concerns, is sometimes called the 'personal cure' rate. Two approaches of modelling competing-risk survival data, namely the cause-specific hazards approach and the mixture model approach, have been used to model competing-risk survival data. In this article, we first show the connection and differences between crude cause-specific survival in the presence of other causes and net survival in the absence of other causes. The mixture survival model is extended to population-based grouped survival data to estimate the personal cure rate. Using the colorectal cancer survival data from the Surveillance, Epidemiology and End Results Programme, we estimate the probabilities of dying from colorectal cancer, heart disease, and other causes by age at diagnosis, race and American Joint Committee on Cancer stage. C1 [Yu, Binbing] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Tiwari, Ram C.] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Feuer, Eric J.] NCI, Stat Res & Applicat Branch, Bethesda, MD 20892 USA. RP Yu, BB (reprint author), NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. EM yubi@mail.nih.gov FU National Cancer Institute; National Institute on Aging FX The research of Dr Yu was carried out in part at the Information Management Services, Inc. and was supported in part by the contract with the National Cancer Institute and by the Intramural Research Programme of the National Institute on Aging. NR 17 TC 2 Z9 2 U1 1 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD JUN PY 2011 VL 20 IS 3 BP 261 EP 274 DI 10.1177/0962280209347046 PG 14 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA 768TU UT WOS:000290962100006 ER PT J AU Baker, SG AF Baker, Stuart G. TI Modelling the cumulative risk of a false-positive screening test SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Letter C1 NCI, Biometry Res Grp, Canc Prevent Div, EPN 3131, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, EPN 3131, 6130 Execut Blvd MSC 7354, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 4 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD JUN PY 2011 VL 20 IS 3 BP 291 EP 293 DI 10.1177/0962280210392588 PG 3 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA 768TU UT WOS:000290962100008 PM 21609977 ER PT J AU Hill, MD Martin, RH Palesch, YY Tamariz, D Waldman, BD Ryckborst, KJ Moy, CS Barsan, WG Ginsberg, MD AF Hill, Michael D. Martin, Renee H. Palesch, Yuko Y. Tamariz, Diego Waldman, Bonnie D. Ryckborst, Karla J. Moy, Claudia S. Barsan, William G. Ginsberg, Myron D. CA ALIAS Investigators NETT Network TI The Albumin in Acute Stroke Part 1 Trial An Exploratory Efficacy Analysis SO STROKE LA English DT Article DE ischemic stroke albumin; neuroprotection; adjuvant stroke therapy; acute treatment ID ACUTE ISCHEMIC-STROKE; MARKED NEUROPROTECTIVE EFFICACY; LOCAL VASCULAR DYNAMICS; FOCAL CEREBRAL-ISCHEMIA; ALIAS PILOT TRIAL; DOSE-ESCALATION; RAT MODEL; THERAPY; SAFETY; THROMBOLYSIS AB Background and Purpose-The Albumin in Acute Stroke (ALIAS) Part 2 Trial is directly testing whether 2 g/kg of 25% human albumin (ALB) administered intravenously within 5 hours of ischemic stroke onset results in improved clinical outcome. Recruitment into Part 1 of the ALIAS Trial was halted for safety reasons. ALIAS Part 2 is a new, reformulated trial with more-stringent exclusion criteria. Our aim was to explore the efficacy of ALB in the ALIAS Part 1 data and to assess the statistical assumptions underlying the ALIAS Part 2 Trial. Methods-ALIAS is a multicenter, blinded, randomized controlled trial. Data on 434 subjects, comprising the ALIAS Part 1 subjects, were analyzed. We examined both the thrombolysis and nonthrombolysis cohorts combined and separately in a "target population" by excluding subjects who would not have been eligible for the ALIAS Part 2 Trial; the latter comprised patients >83 years of age, those with elevated baseline troponin values, and those with in-hospital stroke. We examined the differences in the primary composite outcome, defined as a modified Rankin Scale score of 0 to 1 and/or a National Institutes of Health Stroke Scale score of 0 to 1 at 90 days after randomization. Results-In the combined thrombolysis plus nonthrombolysis cohorts of the target population, 44.7% of subjects in the ALB group had a favorable outcome compared with 36.0% in the saline group (absolute effect size = 8.7%; 95% CI, -2.2% to 19.5%). Among thrombolyzed subjects of the target population, 46.7% had a favorable outcome in the ALB group compared with 36.6% in the saline group (absolute effect size = 10.1%; 95% CI, -2.0% to 20.0%). Conclusions-Preliminary results from the ALIAS Part 1 suggest a trend toward a favorable primary outcome in subjects treated with ALB and support the validity of the statistical assumptions that underlie the ALIAS Part 2 Trial. The ALIAS Part 2 Trial will confirm or refute these results. C1 [Hill, Michael D.; Ryckborst, Karla J.] Univ Calgary, Fac Med, Dept Clin Neurosci, Calgary, AB T2N 2T9, Canada. [Hill, Michael D.] Univ Calgary, Fac Med, Dept Med, Calgary, AB T2N 2T9, Canada. [Hill, Michael D.] Univ Calgary, Fac Med, Dept Radiol, Calgary, AB T2N 2T9, Canada. [Hill, Michael D.] Univ Calgary, Fac Med, Dept Community Hlth Sci, Calgary, AB T2N 2T9, Canada. [Martin, Renee H.; Palesch, Yuko Y.; Waldman, Bonnie D.] Med Univ S Carolina, Dept Med, Div Biostat & Epidemiol, Charleston, SC 29425 USA. [Tamariz, Diego; Ginsberg, Myron D.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Moy, Claudia S.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Barsan, William G.] Univ Michigan, Sch Med, Dept Emergency Med, Ann Arbor, MI USA. RP Hill, MD (reprint author), Univ Calgary, Dept Clin Neurosci, Calgary Stroke Program, Foothills Hosp, Room 1242A,1403 29th St NW, Calgary, AB T2N 2T9, Canada. EM michael.hill@ucalgary.ca RI Hill, Michael/C-9073-2012 OI Hill, Michael/0000-0002-6269-1543 FU National Institutes of Health [U01 NS040406, U01 NS054630] FX The ALIAS Trial is funded by National Institutes of Health cooperative agreements U01 NS040406 and U01 NS054630. NR 17 TC 33 Z9 35 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2011 VL 42 IS 6 BP 1621 EP 1625 DI 10.1161/STROKEAHA.110.610980 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 769QH UT WOS:000291032700040 PM 21546491 ER PT J AU Wendler, D AF Wendler, David TI What we worry about when we worry about the ethics of clinical research SO THEORETICAL MEDICINE AND BIOETHICS LA English DT Article DE Clinical research; Risks; Informed consent; Exploitation ID PEDIATRIC RESEARCH; INDUCEMENT; SUBJECT; RISKS AB Clinical research is thought to be ethically problematic and is subject to extensive regulation and oversight. Despite frequent endorsement of this view, there has been almost no systematic evaluation of why clinical research might be ethically problematic. As a result, it is difficult to determine whether the regulations to which clinical research is subject address the ethical concerns it raises. Commentators who consider this question at all tend to assume that clinical research is ethically problematic because it exposes some individuals to risks for the benefit of others. Yet, many other activities that expose some individuals to risks for the benefit of others are not subject to extensive regulation and oversight. This difference raises the question of whether clinical research is distinct from these activities in normatively relevant ways and, if so, what implications this difference (or differences) has for how clinical research should be regulated and conducted. The present manuscript attempts to answer this question by comparing clinical research to two other activities that expose some individuals to risks for the benefit of others. This comparison highlights an aspect of clinical research which has received relatively little attention, namely, the active role investigators play in exposing subjects to risks. I argue that this aspect explains much of the ethical concern expressed regarding clinical research. I end by considering the normative significance of this feature and the implications it has for how clinical research should be regulated and conducted. C1 NIH Clin Ctr, Dept Bioeth, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH Clin Ctr, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 30 TC 2 Z9 2 U1 1 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-7415 EI 1573-1200 J9 THEOR MED BIOETH JI Theor. Med. Bioeth. PD JUN PY 2011 VL 32 IS 3 BP 161 EP 180 DI 10.1007/s11017-011-9176-y PG 20 WC Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Social Issues; Biomedical Social Sciences GA 762BH UT WOS:000290446800002 PM 21400219 ER PT J AU Boverhof, DR Chamberlain, MP Elcombe, CR Gonzalez, FJ Heflich, RH Hernandez, LG Jacobs, AC Jacobson-Kram, D Luijten, M Maggi, A Manjanatha, MG van Benthem, J Gollapudi, BB AF Boverhof, Darrell R. Chamberlain, Mark P. Elcombe, Clifford R. Gonzalez, Frank J. Heflich, Robert H. Hernandez, Lya G. Jacobs, Abigail C. Jacobson-Kram, David Luijten, Mirjam Maggi, Adriana Manjanatha, Mugimane G. van Benthem, Jan Gollapudi, B. Bhaskar TI Transgenic Animal Models in Toxicology: Historical Perspectives and Future Outlook SO TOXICOLOGICAL SCIENCES LA English DT Article DE transgenic models; knock-out models; humanized models; risk assessment ID PREGNANE-X-RECEPTOR; ARYL-HYDROCARBON RECEPTOR; CONSTITUTIVE ANDROSTANE RECEPTOR; CYP1B1 DETERMINES SUSCEPTIBILITY; ZINC-FINGER NUCLEASES; EMBRYONIC STEM-CELLS; DNA-POLYMERASE ETA; IN-VIVO; DRUG-METABOLISM; TARGETED DISRUPTION AB Transgenic animal models are powerful tools for developing a more detailed understanding on the roles of specific genes in biological pathways and systems. Applications of these models have been made within the field of toxicology, most notably for the screening of mutagenic and carcinogenic potential and for the characterization of toxic mechanisms of action. It has long been a goal of research toxicologists to use the data from these models to refine hazard identification and characterization to better inform human health risk assessments. This review provides an overview on the applications of transgenic animal models in the assessment of mutagenicity and carcinogenicity, their use as reporter systems, and as tools for understanding the roles of xenobiotic-metabolizing enzymes and biological receptors in the etiology of chemical toxicity. Perspectives are also shared on the future outlook for these models in toxicology and risk assessment and how transgenic technologies are likely to be an integral tool for toxicity testing in the 21st century. C1 [Boverhof, Darrell R.; Gollapudi, B. Bhaskar] Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. [Chamberlain, Mark P.; Elcombe, Clifford R.] CXR Biosci Ltd, Dundee DD1 5JJ, Scotland. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Heflich, Robert H.; Manjanatha, Mugimane G.] US FDA, Natl Ctr Toxicol Research, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Hernandez, Lya G.; Luijten, Mirjam; van Benthem, Jan] Natl Inst Publ Hlth & Environm RIVM, Lab Hlth Protect Res, NL-3720 BA Bilthoven, Netherlands. [Jacobs, Abigail C.; Jacobson-Kram, David; Maggi, Adriana] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20933 USA. [Maggi, Adriana] Univ Milan, Dept Pharmacol Sci 3, Milan, Italy. [Maggi, Adriana] Univ Milan, Ctr Excellence Neurodegenerat Dis, Milan, Italy. RP Boverhof, DR (reprint author), Dow Chem Co USA, Toxicol & Environm Res & Consulting, 1803 Bldg, Midland, MI 48674 USA. EM RBoverhof@dow.com NR 213 TC 31 Z9 35 U1 1 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 2011 VL 121 IS 2 BP 207 EP 233 DI 10.1093/toxsci/kfr075 PG 27 WC Toxicology SC Toxicology GA 768JS UT WOS:000290931000001 PM 21447610 ER PT J AU Szabo, DT Diliberto, JJ Hakk, H Huwe, JK Birnbaum, LS AF Szabo, David Taylor Diliberto, Janet J. Hakk, Heldur Huwe, Janice K. Birnbaum, Linda S. TI Toxicokinetics of the Flame Retardant Hexabromocyclododecane Alpha: Effect of Dose, Timing, Route, Repeated Exposure, and Metabolism SO TOXICOLOGICAL SCIENCES LA English DT Article DE toxicokinetics; biotransformation; lipophilic; persistent organic pollutants; endocrine disruptors; risk assessment; brominated flame retardant; hexabromocyclododecane; mixture; metabolism ID POLYBROMINATED DIPHENYL ETHERS; CYP1A2-KNOCKOUT; BREAST-MILK; WISTAR RATS; MICE; HBCDS; GAMMA; ACCUMULATION; C57BL/6N; BEHAVIOR AB Alpha-hexabromocyclododecane (alpha-HBCD) is an emerging persistent organic pollutant present in the hexabromocyclododecane (HBCD) commercial mixture. HBCD is used as an additive flame retardant in a wide variety of household consumer products. Three main stereoisomers, alpha (alpha), beta (beta), and gamma (gamma), comprise roughly 10, 10, and 80% of the mixture, respectively. Despite its small contribution to HBCD global production and usage, alpha-HBCD is the major stereoisomer found in wildlife and human tissues including breast milk and blood in North America, European Union, and Asia. No mammalian or human data are currently available regarding the toxicokinetics of alpha-HBCD. This study was conducted in an effort to fully characterize the absorption, distribution, metabolism, and elimination of alpha-HBCD following a single and repeated exposure with respect to dose, time, and route of administration in female C57BL/6 mice. Results indicate that similar to 90% of the administered dose (3 mg/kg) was absorbed after oral exposure. Disposition was (1) dictated by lipophilicity, as adipose, liver, muscle, and skin were major depots and (2) was dose dependent with nonlinear accumulation at higher doses. Elimination, both whole-body and from individual tissues, was biphasic. alpha-HBCD-derived radioactivity was excreted in the feces as parent and metabolites, whereas urine only contained metabolites. Presence of polar metabolites in the blood and urine were a major factor in determining the rapid initial whole-body half-life after a single oral exposure. Initial half-lives were similar to 1-3 days and much longer terminal half-lives of 17 days were observed, suggesting the potential for alpha-HBCD bioaccumulation. A 10-day repeated study supports alpha-HBCD bioaccumulation potential. Stereoisomerization previously observed after exposure to gamma-HBCD was not seen after exposure of alpha-HBCD. The toxicokinetic behavior reported here has important implications for the extrapolation of toxicological studies of the commercial HBCD mixture to the assessment of risk of alpha-HBCD which is the major stereoisomer found in wildlife and people. C1 [Szabo, David Taylor; Diliberto, Janet J.] US EPA, Off Res & Dev, Natl Hlth Effects & Exposure Res Lab, Integrated Syst Toxicol Div, Res Triangle Pk, NC 27711 USA. [Szabo, David Taylor] Univ N Carolina, Curriculum Toxicol, Res Triangle Pk, NC 27711 USA. [Hakk, Heldur; Huwe, Janice K.] Agr Res Serv, USDA, Biosci Res Lab, Fargo, ND 58102 USA. [Birnbaum, Linda S.] NCI, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC 27709 USA. RP Szabo, DT (reprint author), US EPA, Off Res & Dev, Natl Hlth Effects & Exposure Res Lab, Integrated Syst Toxicol Div, Mail Drop B143-01,109 TW Alexander Dr, Res Triangle Pk, NC 27711 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 38 TC 22 Z9 22 U1 3 U2 49 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 2011 VL 121 IS 2 BP 234 EP 244 DI 10.1093/toxsci/kfr059 PG 11 WC Toxicology SC Toxicology GA 768JS UT WOS:000290931000002 PM 21441408 ER PT J AU Hurst, FP Jindal, RM Fletcher, JJ Dharnidharka, V Gorman, G Lechner, B Nee, R Agodoa, LY Abbott, KC AF Hurst, Frank P. Jindal, Rahul M. Fletcher, James J. Dharnidharka, Vikas Gorman, Greg Lechner, Brent Nee, Robert Agodoa, Lawrence Y. Abbott, Kevin C. TI Incidence, Predictors and Associated Outcomes of Renal Cell Carcinoma in Long-term Dialysis Patients SO UROLOGY LA English DT Review ID ACQUIRED CYSTIC-DISEASE; KIDNEY-DISEASE; UNITED-STATES; TRANSPLANTATION; CANCER; CT AB We carried out an analysis of the United States Renal Data System to determine the incidence, risk factors and prognosis of renal cell carcinoma (RCC) in a national population of patients receiving incident long-term dialysis. In Cox regression, male gender, older age, end-stage renal disease caused by obstruction, tuberous sclerosis, focal segmental glomerulosclerosis, as well as acquired renal cysts, were independently associated with RCC. Most cases of RCC in incident long-term dialysis patients occurred in patients without acquired renal cysts. A diagnosis of RCC was associated with increased risk of subsequent mortality overall and in all high-risk groups. UROLOGY 77: 1271-1276, 2011. Published by Elsevier Inc. C1 [Jindal, Rahul M.] Walter Reed Army Med Ctr, Dept Organ Transplantat, Serv Nephrol, Washington, DC 20307 USA. Portsmouth Naval Hosp, Serv Nephrol, Portsmouth, VA USA. Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Gainesville, FL USA. Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. George Washington Univ, Dept Med, Washington, DC USA. Univ Florida, Gainesville, FL USA. NIDDK, NIH, Bethesda, MD USA. RP Jindal, RM (reprint author), Walter Reed Army Med Ctr, Dept Organ Transplantat, Serv Nephrol, 6900 Georgia Ave NW, Washington, DC 20307 USA. EM jindalr@msn.com OI Abbott, Kevin/0000-0003-2111-7112 NR 23 TC 15 Z9 15 U1 1 U2 2 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 JUN PY 2011 VL 77 IS 6 BP 1271 EP 1276 DI 10.1016/j.urology.2011.01.007 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 769VX UT WOS:000291047500003 PM 21459420 ER PT J AU Berg, CD AF Berg, Christine D. TI The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: The prostate cancer screening results in context SO ACTA ONCOLOGICA LA English DT Review ID GENOME-WIDE ASSOCIATION; UNITED-STATES; ANTIGEN; RISK; HISTORY; STAGE; SERUM; MEN AB Background. The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) was conducted in sites around USA during a period of marked secular changes in the use of prostate specific antigen (PSA) screening for prostate cancer. Material and methods. Trends in prostate cancer incidence, stage at presentation and mortality are useful when interpreting the results from a screening trial that commenced in 1993 and enrolled participants through 2001. The last participants completed active screening in 2006. Incidence and mortality data published to date on PLCO need to be placed into the context of the secular trends. Additional data analyses have been conducted on subsets of the participants and these results can also enhance the interpretation of the trial. Additionally, the accompanying biospecimen repository has served as a rich research resource yielding informative findings. Results. The PLCO is best viewed as a trial comparing a regimented active annual screening program of PSA screening for six rounds, four of which had accompanying digital rectal examination (DRE) to patterns of screening that were occurring in the population in many academic and community settings across the USA. The epidemiology and molecular genetics of prostate cancer is becoming better understood and analyses of the PLCO resource have contributed. One approach to risk assessment utilizing genetic markers from selected members of the PLCO prostate cancer cohort has been developed. A modeling effort with CISNET-ERSPC-PLCO is underway to compare and contrast findings such as effects of different PSA thresholds and screening intervals. Conclusions. The information emerging from PLCO is useful to inform the debate around prostate cancer screening. An understanding of the biologic differences underpinning indolent and aggressive prostate cancer will better guide the future development of screening and treatment strategies. C1 NCI, Canc Prevent Div, Early Detect Res Grp, Bethesda, MD 20852 USA. RP Berg, CD (reprint author), NCI, Canc Prevent Div, Early Detect Res Grp, Bethesda, MD 20852 USA. EM bergc@mail.nih.gov RI Berg , Christine/K-1047-2014 FU National Cancer Institute FX The PLCO trial was funded by contracts from the National Cancer Institute. The ClinicalTrials.gov identifier for PLCO is NCT00002540. The author acknowledges the contributions to this work made by the co-authors on the other prostate cancer manuscripts emanating from the PLCO. She thanks the study subjects for their contributions in making this study possible. There are no conflicts of interest to report for this article. NR 25 TC 5 Z9 6 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PD JUN PY 2011 VL 50 SU 1 BP 12 EP 17 DI 10.3109/0284186X.2010.531283 PG 6 WC Oncology SC Oncology GA 767QL UT WOS:000290871000004 PM 21604935 ER PT J AU Dawson, DA AF Dawson, Deborah A. TI THE CHALLENGE OF DISTINGUISHING HIGH-VOLUME AND FREQUENT RISKY DRINKING SO ADDICTION LA English DT Editorial Material DE Binge drinking; hazardous drinking; heavy episodic drinking; risk drinking; volume ID PREVENTIVE PARADOX; ALCOHOL-CONSUMPTION C1 NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Dawson, DA (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Lane Room 3071 MSC9403, Bethesda, MD 20892 USA. EM deborah.anne.dawson@gmail.com NR 9 TC 3 Z9 3 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD JUN PY 2011 VL 106 IS 6 BP 1046 EP 1047 DI 10.1111/j.1360-0443.2010.03302.x PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 763CW UT WOS:000290532600003 PM 21564367 ER PT J AU Heilig, M Warren, KR Kunos, G Silverman, PB Hewitt, BG AF Heilig, Markus Warren, Kenneth R. Kunos, George Silverman, Peter B. Hewitt, Brenda G. TI Addiction Research Centres and the Nurturing of Creativity SO ADDICTION LA English DT Editorial Material DE Alcohol abuse; alcohol dependence; alcohol use disorders; alcohol use problems; alcoholism; alcohol-related history; NIAAA; NIH ID ALCOHOLISM; ACTIVATION; RECEPTOR AB The aim of this paper is to present a concise account of the history, mission, structure and some recent achievements of the US National Institute on Alcohol Abuse and Alcoholism (NIAAA). Created by the US Congress 40 years ago, the NIAAA has evolved from an entity charged mainly with building a national system of alcoholism treatment services to one with responsibility for developing, nurturing and supporting the biomedical and behavioral science foundation necessary to reduce the significant domestic and global public health impact of alcohol use disorders. The NIAAA is unique in that it functions both as a funding agency, supporting research at universities and other external, or 'extramural' research institutions, and is also a research institution itself, where alcohol research is carried out in-house, or 'intramurally'. Of a $450.2 million 2009 Congressional Appropriation, approximately 90% was devoted toward the former and approximately 10% towards the latter objective. The current NIAAA Strategic Plan builds on a new organizing principle for long-range research planning, based on a life-span perspective that recognizes that human biology and behavior continue to change throughout life and changes occurring throughout the life-span affect individuals' drinking patterns as well as the decisions they may make to change their drinking habits or to seek help for alcohol use problems. Within this framework, major efforts are currently being devoted to educating practitioners on clinically useful, science-based assessment and treatment methods that exist today, and development of personalized new treatments for tomorrow. C1 [Heilig, Markus; Warren, Kenneth R.; Kunos, George; Silverman, Peter B.; Hewitt, Brenda G.] NIAAA, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, Intramural Res Program, 10 Ctr Dr,10-1-5334, Bethesda, MD 20892 USA. EM mheilig@mail.nih.gov OI Heilig, Markus/0000-0003-2706-2482 FU Intramural NIH HHS [ZIA AA000351-09, ZIA AA000350-09] NR 12 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 J9 ADDICTION JI Addiction PD JUN PY 2011 VL 106 IS 6 BP 1052 EP 1060 DI 10.1111/j.1360-0443.2010.02995.x PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 763CW UT WOS:000290532600008 PM 20569230 ER PT J AU Metifiot, M Vandegraaff, N Maddali, K Naumova, A Zhang, XM Rhodes, D Marchand, C Pommier, Y AF Metifiot, Mathieu Vandegraaff, Nick Maddali, Kasthuraiah Naumova, Alena Zhang, Xuemin Rhodes, David Marchand, Christophe Pommier, Yves TI Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143 SO AIDS LA English DT Article DE elvitegravir; HIV-1; integrase inhibitor; integrase resistance; raltegravir ID HIV-1 INTEGRASE; EXPERIENCED PATIENTS; INHIBITION; PATTERNS; INTASOME; MUTANTS; VIRUS AB Objective: In this study, we characterized elvitegravir activity in the context of raltegravir resistance mutations. Design: Using site-directed mutagenesis, we generated recombinant integrase proteins and viruses harboring raltegravir resistance mutation to assess the biochemical and cellular activity of elvitegravir in the presence of such mutants. Methods: Recombinant proteins were used in gel-based assays. Antiviral data were obtained with reporter viruses in a single-round infection using a luciferase-based assay. Results: Although main raltegravir resistance pathways involving mutations at integrase position 148 and 155 confer cross-resistance to elvitegravir, elvitegravir remains fully active against the Y143R mutant integrase and virus particles. Conclusion: In addition to favorable pharmacokinetics compared to raltegravir, our findings provide the rationale for using elvitegravir in patients failing raltegravir because of the integrase mutation Y143. (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Metifiot, Mathieu; Maddali, Kasthuraiah; Naumova, Alena; Zhang, Xuemin; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Vandegraaff, Nick; Rhodes, David] Avexa Ltd, Melbourne, Vic, Australia. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM pommier@nih.gov FU NIH, National Cancer Institute (NCI), Center for Cancer Research (CCR) [Z01BC007333-09LMP]; IATAP (Intramural AIDS Target Antiviral Program) FX M.M., D.R., C.M., and Y.P conceived and designed the experiments. M.M., N.V., X.Z., and A.N performed the experiments. M.M., N.V., and Y.P analyzed the data. K. M. contributed to reagents/materials. M.M., C.M., and Y.P. wrote the paper. Our studies are supported by the Intramural Research Program of the NIH, National Cancer Institute (NCI), Center for Cancer Research (CCR) (Z01BC007333-09LMP), and by a grant from IATAP (Intramural AIDS Target Antiviral Program). NR 16 TC 52 Z9 53 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 1 PY 2011 VL 25 IS 9 BP 1175 EP 1178 DI 10.1097/QAD.0b013e3283473599 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 766BN UT WOS:000290753700004 PM 21505303 ER PT J AU Murphy, AA Herrmann, E Osinusi, AO Wu, L Sachau, W Lempicki, RA Yang, J Chung, TL Wood, BJ Haagmans, BL Kottilil, S Polis, MA AF Murphy, Alison A. Herrmann, Eva Osinusi, Anu O. Wu, Lynn Sachau, William Lempicki, Richard A. Yang, Jun Chung, Tei L. Wood, Brad J. Haagmans, Bart L. Kottilil, Shyam Polis, Michael A. TI Twice-weekly pegylated interferon-alpha-2a and ribavirin results in superior viral kinetics in HIV/hepatitis C virus co-infected patients compared to standard therapy SO AIDS LA English DT Article DE hepatitis C virus; HIV; sustained virologic response; twice-weekly interferon; viral kinetics ID CHRONIC HEPATITIS-C; HUMAN-IMMUNODEFICIENCY-VIRUS; ALPHA-2A PLUS RIBAVIRIN; RANDOMIZED CONTROLLED-TRIAL; HIV-COINFECTED PERSONS; PEGINTERFERON ALPHA-2A; VIROLOGICAL RESPONSE; INDUCTION THERAPY; AFRICAN-AMERICAN; LIVER FIBROSIS AB Background: Hepatitis C virus (HCV)/HIV co-infected patients have more rapid progression of liver fibrosis and only modest cure rates (sustained virologic responses, SVRs) when compared to HCV monoinfected patients. Method: We compared the virologic responses of either twice-weekly peginterferon-alpha-2a 180 mu g/week (for 4 weeks, followed by weekly dosing) or weekly peginterferon-alpha-2a 180 mu g/week, and weight-based ribavirin (1-1.2 g/day), among HIV/HCV co-infected genotype-1 individuals. Results: Patients receiving the investigational dosing had lower levels of HCV RNA at all time points after initiation of therapy. More patients on this arm achieved clinically relevant early virological responses at weeks 1, 2, 4, 12, and 24. The enhanced early virologic response observed with the investigational arm was associated with a higher induction of interferon-stimulated genes. This early double dose regimen also resulted in a rapid normalization of liver enzymes. Twice-weekly peginterferon-a-2a was associated with more frequent early virological responses with similar safety profiles when compared with standard therapy. Conclusion: Our results, when confirmed in larger randomized clinical trials, may provide a novel therapeutic approach to improve SVR among HIV/HCV co-infected patients, especially African-American patients. (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Polis, Michael A.] NIAID, Collaborat Clin Res Branch, LIR, NIH,DHHS, Bethesda, MD 20892 USA. [Herrmann, Eva; Chung, Tei L.] Goethe Univ Frankfurt, Dept Med, Inst Biostat & Math Modeling, Frankfurt, Germany. [Wu, Lynn] US FDA, Div Pulm Allergy & Rheumatol Prod, Silver Spring, MD USA. [Osinusi, Anu O.; Lempicki, Richard A.; Yang, Jun] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Wood, Brad J.] NIH, Div Radiol Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Haagmans, Bart L.] Erasmus MC, Rotterdam, Netherlands. RP Polis, MA (reprint author), NIAID, Collaborat Clin Res Branch, LIR, NIH,DHHS, 6700B Rockledge Dr,1118, Bethesda, MD 20892 USA. EM mpolis@niaid.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Polis, Michael/0000-0002-9151-2268 FU NIH, (National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health [HSN261200800001E]; German Research Foundation (DFG) FX The present research was supported in whole or in part by the Intramural Research Program of the NIH, (National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health, under Contract No. HSN261200800001E). It was also supported in part by the German Research Foundation (DFG) as part of the clinical research unit KFO 129. NR 31 TC 13 Z9 14 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 1 PY 2011 VL 25 IS 9 BP 1179 EP 1187 DI 10.1097/QAD.0b013e3283471d53 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 766BN UT WOS:000290753700005 PM 21593619 ER PT J AU Althoff, KN Eichelberger, M Gange, SJ Sharp, GB Gao, J Glesby, MJ Young, M Greenblatt, RM French, AL Villacres, MC Minkoff, H AF Althoff, Keri N. Eichelberger, Maryna Gange, Stephen J. Sharp, Gerald B. Gao, Jin Glesby, Marshall J. Young, Mary Greenblatt, Ruth M. French, Audrey L. Villacres, Maria C. Minkoff, Howard TI Seroincidence of 2009 H1N1 infection in HIV-infected and HIV-uninfected women prior to vaccine availability SO AIDS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFLUENZA-A; HIV-1-INFECTED PATIENTS; ANTIBODY-RESPONSES; INTERAGENCY HIV; MORTALITY; OUTBREAK; SEASON AB The 2009 H1N1 pandemic was a unique opportunity to investigate differences in influenza infection using serology by HIV status. Using serial serum specimens collected from 1 April to 30 September 2009 and the prior 2 years from Women's Interagency HIV study participants, there was no difference in serologic evidence of 2009 H1N1 infection among HIV-infected women with a CD4 cell count at least 350 cells/mu l compared with HIV-uninfected women. Owing to evidence showing a greater risk of influenza-related complications, HIV-infected individuals should continue to be a priority group for vaccination. C1 [Althoff, Keri N.; Gange, Stephen J.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Eichelberger, Maryna; Gao, Jin] US FDA, Bethesda, MD 20014 USA. [Sharp, Gerald B.] NIAID, NIH, Bethesda, MD 20892 USA. [Glesby, Marshall J.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Young, Mary] Georgetown Univ, Washington, DC USA. [Greenblatt, Ruth M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [French, Audrey L.] Rush Univ, CORE Ctr Stroger Hosp, Chicago, IL 60612 USA. [Villacres, Maria C.] Univ Calif Los Angeles, Los Angeles, CA USA. [Minkoff, Howard] Maimonides Hosp, Brooklyn, NY 11219 USA. RP Althoff, KN (reprint author), 615 N Wolfe St,Rm E7137, Baltimore, MD 21231 USA. EM kalthoff@jhsph.edu OI Gange, Stephen/0000-0001-7842-512X FU NCRR NIH HHS [UL1 RR024131, UL1 RR024131-04S3]; NIAID NIH HHS [U01-AI-42590, U01-AI-34994, U01 AI035004, U01 AI034993-15, U01 AI034989, U01 AI031834-16, K24 AI078884, U01-AI-34989, U01 AI042590-15, U01 AI034989-15, U01 AI034994, U01 AI042590, U01-AI-31834, U01-AI-34993, K24 AI078884-03, U01 AI031834, U01 AI034993, U01 AI034994-15, U01 AI035004-13, U01-AI-35004]; NICHD NIH HHS [U01-HD-32632, U01 HD032632-16, U01 HD032632] NR 18 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 1 PY 2011 VL 25 IS 9 BP 1229 EP 1232 DI 10.1097/QAD.0b013e3283471cf2 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 766BN UT WOS:000290753700012 PM 21505313 ER PT J AU Tembhare, P Yuan, CM Xi, LQ Morris, JC Liewehr, D Venzon, D Janik, JE Raffeld, M Stetler-Stevenson, M AF Tembhare, Prashant Yuan, Constance M. Xi, Liqiang Morris, John C. Liewehr, David Venzon, David Janik, John E. Raffeld, Mark Stetler-Stevenson, Maryalice TI Flow Cytometric Immunophenotypic Assessment of T-Cell Clonality by V-beta Repertoire Analysis Detection of T-Cell Clonality at Diagnosis and Monitoring of Minimal Residual Disease Following Therapy SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE T-cell clonality; Flow cytometry; V-beta repertoire ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; POLYMERASE-CHAIN-REACTION; LYMPHOPROLIFERATIVE DISORDERS; PERIPHERAL-BLOOD; EXPRESSION; GENE; LEUKEMIA/LYMPHOMA; QUANTITATION; EXPANSIONS AB Flow cytometric T-cell receptor (TCR)-V-beta repertoire analysis (TCR-V-beta-R) is a sensitive method for detection of T-cell clonality; however, no uniform approach exists to define clonality in neoplastic T cells. TCR-V-beta-R was evaluated in patients with a diagnosis of T-cell neoplasia in initial diagnostic specimens from 41 patients and for minimal residual disease (MRD) monitoring in 61 sequential samples from 14 patients with mature T-cell neoplasia. Gating strategies and criteria for detection of T-cell clonality were determined. In all 41 initial specimens, T-cell clonality was demonstrated via TCR-V-beta-R. The frequency of V-beta usage was consistent with random neoplastic transformation of TCR-V-beta-subsets. MRD was successfully detected in follow-up samples from all 14 patients evaluated, Furthermore, MRD after therapy was quantitated in 48 peripheral blood specimens. TCR-V-beta-R analysis is a sensitive method for detection of T-cell clonality and is useful for diagnosis and MRD detection in multiple specimen types. C1 [Stetler-Stevenson, Maryalice] NCI, Flow Cytometry Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Morris, John C.; Janik, John E.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Liewehr, David; Venzon, David] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Flow Cytometry Unit, Pathol Lab, NIH, Bldg 10,Room 2A-33,Mail Stop 1500, Bethesda, MD 20892 USA. FU National Institutes of Health, National Cancer Institute FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 26 TC 14 Z9 14 U1 0 U2 5 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 JUN PY 2011 VL 135 IS 6 BP 890 EP 900 DI 10.1309/AJCPV2D1DDSGJDBW PG 11 WC Pathology SC Pathology GA 767AA UT WOS:000290826500010 PM 21571962 ER PT J AU Weiss, BM Minter, A Abadie, J Howard, R Ascencao, J Schechter, GP Kuehl, M Landgren, O AF Weiss, Brendan M. Minter, Alex Abadie, Jude Howard, Robin Ascencao, Joao Schechter, Geraldine P. Kuehl, Michael Landgren, Ola TI Patterns of monoclonal immunoglobulins and serum free light chains are significantly different in black compared to white monoclonal gammopathy of undetermined significance (MGUS) patients SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID ASYMPTOMATIC MULTIPLE-MYELOMA; INDEPENDENT RISK-FACTOR; NON-HODGKINS-LYMPHOMA; UNITED-STATES; WALDENSTROM MACROGLOBULINEMIA; REFERENCE INTERVALS; ADULT-POPULATION; WORKING GROUP; LONG-TERM; FOLLOW-UP AB Monoclonal gammopathy of undetermined significance (MGUS), the precursor to multiple myeloma, is more common in blacks than whites. The serum free light chain (sFLC) assay is an important prognostic test in MGUS, but no study has evaluated sFLC levels and ratios in black MGUS patients. One-hundred and twenty-five black MGUS patients at two urban centers were compared to the white population of the Mayo Clinic. The median age for blacks was 73 years [41-94] and 75% were male. The M-protein isotype in blacks was 81% IgG, 13% IgA, 2% IgM, and 4% biclonal compared to 70%, 12%, 16%, and 2%, respectively, in whites, (P < 0.0005). The median M-protein concentration for blacks was 0.44 gm/dL (trace-2.33) compared to 1.2 gm/dl in whites. An abnormal sFLC ratio was present in 45% of black compared to 33% of white (P = 0.01) patients. Using the Mayo Clinic risk model, black patients had a significantly lower proportion of higher risk MGUS compared to whites: low 43%, low-intermediate 45%, high-intermediate 10%, and high 2% (P = 0.014). Black patients with MGUS have significantly different laboratory findings compared to whites. The biologic basis for these disparities and their effect on prognostic assessment is unknown. Prognostic models based on these biomarkers should be used cautiously in nonwhite populations. Am. J. Hematol. 86:475-478, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Weiss, Brendan M.] Walter Reed Army Med Ctr, Hematol Oncol Serv, Washington, DC 20307 USA. [Abadie, Jude] Brooke Army Med Ctr, Pathol Serv, San Antonio, TX USA. [Abadie, Jude] Brooke Army Med Ctr, Area Lab Serv, San Antonio, TX USA. [Ascencao, Joao; Schechter, Geraldine P.] Washington Vet Affairs Med Ctr, Hematol Sect, Washington, DC USA. [Ascencao, Joao; Schechter, Geraldine P.] George Washington Univ, Washington, DC USA. [Kuehl, Michael] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Landgren, Ola] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Weiss, BM (reprint author), Walter Reed Army Med Ctr, Hematol Oncol Serv, 6900 Georgia Ave NW, Washington, DC 20307 USA. EM brendan.weiss@us.army.mil FU Binding Site, Inc. FX Contract grant sponsors: The Binding Site, Inc. NR 44 TC 20 Z9 20 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JUN PY 2011 VL 86 IS 6 BP 475 EP 478 DI 10.1002/ajh.22025 PG 4 WC Hematology SC Hematology GA 766CI UT WOS:000290757400003 PM 21544856 ER PT J AU O'Seaghdha, CM Hwang, SJ Bhavsar, NA Kottgen, A Coresh, J Astor, BC Fox, CS AF O'Seaghdha, Conall M. Hwang, Shih-Jen Bhavsar, Nrupen A. Koettgen, Anna Coresh, Josef Astor, Brad C. Fox, Caroline S. TI Lower Urinary Connective Tissue Growth Factor Levels and Incident CKD Stage 3 in the General Population SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease; connective tissue growth factor; epidemiology ID CHRONIC KIDNEY-DISEASE; TGF-BETA; DIABETIC-NEPHROPATHY; TUBULOINTERSTITIAL FIBROSIS; ATHEROSCLEROSIS RISK; RENAL-INSUFFICIENCY; FACTOR EXCRETION; UNITED-STATES; EXPRESSION; PREVALENCE AB Background: Connective tissue growth factor (CTGF) is involved in the development and progression of kidney diseases, including diabetic nephropathy and kidney fibrosis, but also may have a role in mesangial repair after injury. It is unknown whether, in the general population, urinary CTGF levels are associated with a decrease in estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m(2) (ie, development of chronic kidney disease [CKD] stage 3). Study Design: Nested case-control. Setting & Participants: 100 cases of incident CKD stage 3 and 100 age-and sex-matched controls in the Framingham Heart Study; 141 cases and 135 age-, sex-, and race-matched controls in the Atherosclerosis Risk in Communities (ARIC) Study. Controls had eGFR >= 60 mL/min/1.73 m(2) at follow-up in both studies. Predictors: Urinary CTGF concentrations. Outcomes: Incident CKD stage 3, defined as eGFR <60 mL/min/1.73 m(2). Measurements: Stored urine samples from Framingham Heart Study and ARIC were measured for CTGF. Covariates were obtained from Framingham Heart Study and ARIC participant examinations. Results: In the Framingham Heart Study, the median baseline urinary CTGF concentration was lower in cases (1.35 ng/mL) than controls (2.35 ng/mL; paired t test, P < 0.0001). The multivariable-adjusted OR for incident CKD stage 3 was 0.33 (95% CI, 0.17-0.64; P < 0.001) per 1-standard deviation in log urinary CTGF level after adjustment for CKD risk factors, baseline eGFR, and baseline log urinary albumin-creatinine ratio, with similar results in participants without diabetes (n = 184). Results were not materially different when urinary CTGF level was indexed to urinary creatinine level (multivariable-adjusted OR, 0.34; 95% CI, 0.21-0.56; P < 0.001). A similar, but nonsignificant, trend of risk of incident CKD stage 3 with lower baseline urinary CTGF concentration was observed in an independent case-control study conducted in the ARIC Study, with the strongest results observed in participants free of diabetes. This inverse relationship was robust in meta-analysis of both the overall and diabetes-free groups. Limitations: Observational study; causality cannot be inferred. Conclusions: Lower urinary CTGF concentrations precede the onset of CKD stage 3 in the general population. Further work is required to fully characterize how CTGF level influences risk of CKD. Am J Kidney Dis. 57(6): 841-849. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham Heart Study, Framingham, MA 01702 USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham Heart Study, Bethesda, MD 20892 USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Bethesda, MD USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Brigham & Womens Hosp, Div Renal, Boston, MA 02114 USA. [Bhavsar, Nrupen A.; Koettgen, Anna; Coresh, Josef; Astor, Brad C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Bhavsar, Nrupen A.; Coresh, Josef; Astor, Brad C.] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Koettgen, Anna] Univ Hosp Freiburg, Div Renal, Freiburg, Germany. [Coresh, Josef; Astor, Brad C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [O'Seaghdha, Conall M.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Div Intramural Res, Framingham Heart Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov RI Kottgen, Anna/D-2920-2012 FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; American Diabetes Association; National Institute of Diabetes and Digestive and Kidney Diseases [1 R01 DK076770-01]; [U01HL075572-01] FX The Framingham Heart Study is supported by grant N01-HC-25195 from the National Heart, Lung, and Blood Institute (NHLBI); Framingham Heart Study UACR measurements were supported by an American Diabetes Association Research Grant. ARIC sample assays were supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1 R01 DK076770-01). ARIC is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022, with the ARIC carotid MRI examination funded by U01HL075572-01. NR 53 TC 13 Z9 14 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUN PY 2011 VL 57 IS 6 BP 841 EP 849 DI 10.1053/j.ajkd.2010.11.022 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 766MX UT WOS:000290788400008 PM 21292366 ER PT J AU Jonassaint, CR Szatkiewicz, JP Bulik, CM Thornton, LM Bloss, C Berrettini, WH Kaye, WH Bergen, AW Magistretti, P Strober, M Keel, PK Brandt, H Crawford, S Crow, S Fichter, MM Goldman, D Halmi, KA Johnson, C Kaplan, AS Klump, KL La Via, M Mitchell, JE Rotondo, A Treasure, J Woodside, DB AF Jonassaint, Charles R. Szatkiewicz, Jin Peng Bulik, Cynthia M. Thornton, Laura M. Bloss, Cinnamon Berrettini, Wade H. Kaye, Walter H. Bergen, Andrew W. Magistretti, Pierre Strober, Michael Keel, Pamela K. Brandt, Harry Crawford, Steve Crow, Scott Fichter, Manfred M. Goldman, David Halmi, Katherine A. Johnson, Craig Kaplan, Allan S. Klump, Kelly L. La Via, Maria Mitchell, James E. Rotondo, Alessandro Treasure, Janet Woodside, D. Blake TI Absence of Association Between Specific Common Variants of the Obesity-Related FTO Gene and Psychological and Behavioral Eating Disorder Phenotypes SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE FTO; SNPs; BMI ID GENOME-WIDE ASSOCIATION; ANOREXIA-NERVOSA; ENERGY-EXPENDITURE; SAMPLE DESCRIPTION; PHYSICAL-ACTIVITY; LINKAGE ANALYSIS; BULIMIA-NERVOSA; FAT MASS; TEMPERAMENT; POPULATION AB Extensive population-based genome-wide association studies have identified an association between the FTO gene and BMI; however, the mechanism of action is still unknown. To determine whether FTO may influence weight regulation through psychological and behavioral factors, seven single-nucleotide polymorphisms (SNPs) of the FTO gene were genotyped in 1,085 individuals with anorexia nervosa (AN) and 677 healthy weight controls from the international Price Foundation Genetic Studies of Eating Disorders. Each SNP was tested in association with eating disorder phenotypes and measures that have previously been associated with eating behavior pathology: trait anxiety, harm-avoidance, novelty seeking, impulsivity, obsessionality, compulsivity, and concern over mistakes. After appropriate correction for multiple comparisons, no significant associations between individual FTO gene SNPs and eating disorder phenotypes or related eating behavior pathology were identified in cases or controls. Thus, this study found no evidence that FTO gene variants associated with weight regulation in the general population are associated with eating disorder phenotypes in AN participants or matched controls. (C) 2011 Wiley-Liss, Inc. C1 [Szatkiewicz, Jin Peng; Bulik, Cynthia M.; Thornton, Laura M.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Jonassaint, Charles R.] Johns Hopkins Univ, Sch Med, Dept Gen Internal Med, Baltimore, MD USA. [Szatkiewicz, Jin Peng; La Via, Maria] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Bulik, Cynthia M.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Bloss, Cinnamon] Scripps Res Inst, La Jolla, CA 92037 USA. [Berrettini, Wade H.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Kaye, Walter H.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Bergen, Andrew W.] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Magistretti, Pierre] Ecole Polytech Fed Lausanne, Brain Mind Inst, Dept Psychiat, CH-1015 Lausanne, Switzerland. [Magistretti, Pierre] Univ Lausanne, Sch Med, Ctr Psychiat Neurosci, Lausanne, Switzerland. [Strober, Michael] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Keel, Pamela K.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. [Brandt, Harry; Crawford, Steve] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Crow, Scott] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Fichter, Manfred M.] Roseneck Hosp Behav Med, Prien Am Chiemsee, Germany. [Fichter, Manfred M.] Univ Munich, Dept Psychiat, D-8000 Munich, Germany. [Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. [Halmi, Katherine A.] Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, Westchester Div, White Plains, NY USA. [Johnson, Craig] Eating Recovery Ctr, Denver, CO USA. [Kaplan, Allan S.] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Kaplan, Allan S.; Woodside, D. Blake] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Kaplan, Allan S.; Woodside, D. Blake] Toronto Gen Hosp, Univ Hlth Network, Dept Psychiat, Toronto, ON, Canada. [Klump, Kelly L.] Michigan State Univ, Dept Psychol, E Lansing, MI 48824 USA. [Mitchell, James E.] Neuropsychiat Res Inst, Fargo, ND USA. [Mitchell, James E.] Univ N Dakota, Sch Med & Hlth Sci, Dept Clin Neurosci, Fargo, ND USA. [Rotondo, Alessandro] Univ Pisa, Pisa, Italy. [Treasure, Janet] Kings Coll London, Inst Psychiat, Eating Disorders Sect, London WC2R 2LS, England. RP Bulik, CM (reprint author), Univ N Carolina, Dept Psychiat, 101 Manning Dr,CB 7160, Chapel Hill, NC 27599 USA. EM cbulik@med.unc.edu RI Goldman, David/F-9772-2010; Jonassaint, Charles/I-2772-2014; OI Goldman, David/0000-0002-1724-5405; Jonassaint, Charles/0000-0002-5662-5806; Bergen, Andrew/0000-0002-1237-7644; Treasure, Janet/0000-0003-0871-4596 FU Intramural NIH HHS [Z01 AA000306-02]; NIMH NIH HHS [T32 MH076694, T32 MH076694-01A1] NR 53 TC 13 Z9 13 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JUN PY 2011 VL 156B IS 4 BP 454 EP 461 DI 10.1002/ajmg.b.31182 PG 8 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 766FA UT WOS:000290765200010 PM 21438147 ER PT J AU Samuels, J Wang, Y Riddle, MA Greenberg, BD Fyer, AJ McCracken, JT Rauch, SL Murphy, DL Grados, MA Knowles, JA Piacentini, J Cullen, B Bienvenu, OJ Rasmussen, SA Geller, D Pauls, DL Liang, KY Shugart, YY Nestadt, G AF Samuels, Jack Wang, Ying Riddle, Mark A. Greenberg, Benjamin D. Fyer, Abby J. McCracken, James T. Rauch, Scott L. Murphy, Dennis L. Grados, Marco A. Knowles, James A. Piacentini, John Cullen, Bernadette Bienvenu, O. Joseph, III Rasmussen, Steven A. Geller, Daniel Pauls, David L. Liang, Kung-Yee Shugart, Yin Y. Nestadt, Gerald TI Comprehensive Family-Based Association Study of the Glutamate Transporter Gene SLC1A1 in Obsessive-Compulsive Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE obsessive-compulsive disorder; glutamate transporter; candidate gene ID OCD COLLABORATIVE GENETICS; O-METHYLTRANSFERASE COMT; LINKAGE ANALYSIS; SEX; SCHIZOPHRENIA; SUPPORTS; AUTISM; SAMPLE AB SLC1A1 encodes a neuronal glutamate transporter and is a promising candidate gene for obsessive-compulsive disorder (OCD). Several independent research groups have reported significant associations between OCD and single nucleotide polymorphisms (SNPs) in this gene. Previously, we evaluated 13 SNPs in, or near, SLC1A1 and reported a strong association signal with rs301443, a SNP 7.5 kb downstream of the gene [Shugart et al. (2009); Am J Med Genet Part B 150B:886-892]. Theaims of the current study were first, to further investigate this finding by saturating the region around rs301443; and second, to explore the entire gene more thoroughly with a dense panel of SNP markers. We genotyped an additional 111 SNPs in or near SLC1A1, covering from 9 kb upstream to 84 kb downstream of the gene at average spacing of 1.7 kb per SNP, and conducted family-based association analyses in 1,576 participants in 377 families. We found that none of the surrounding markers were in linkage disequilibrium with rs301443, nor were any associated with OCD. We also found that SNP rs4740788, located about 8.8 kb upstream of the gene, was associated with OCD in all families (P = 0.003) and in families with male affecteds (P = 0.002). A three-SNP haplotype (rs4740788-rs10491734-rs10491733) was associated with OCD in the total sample (P = 0.00015) and in families with male affecteds (P = 0.0007). Although of nominal statistical significance considering the number of comparisons, these findings provide further support for the involvement of SLC1A1 in the pathogenesis of OCD. (C) 2011 Wiley-Liss, Inc. C1 [Samuels, Jack; Wang, Ying; Riddle, Mark A.; Grados, Marco A.; Cullen, Bernadette; Bienvenu, O. Joseph, III; Nestadt, Gerald] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21231 USA. [Greenberg, Benjamin D.; Rasmussen, Steven A.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Fyer, Abby J.] Columbia Univ, New York State Psychiat Inst, Dept Psychiat, Coll Phys & Surg, New York, NY USA. [McCracken, James T.; Piacentini, John] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Rauch, Scott L.; Geller, Daniel] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Knowles, James A.] Univ So Calif, Sch Med, Dept Psychiat, Los Angeles, CA USA. [Pauls, David L.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Liang, Kung-Yee] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Shugart, Yin Y.] NIMH, Genom Res Branch, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. RP Samuels, J (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 1629 Thames St,Suite 401, Baltimore, MD 21231 USA. EM jacks@jhmi.edu RI Liang, Kung-Yee/F-8299-2011; OI Samuels, Jack/0000-0002-6715-7905 FU National Institute of Mental Health [RO1MH50214, R01MH071507, NIH/NCRR/OPD-GCRC RR00052] FX Grant sponsor: National Institute of Mental Health; Grant numbers: RO1MH50214, R01MH071507, NIH/NCRR/OPD-GCRC RR00052. NR 40 TC 32 Z9 34 U1 1 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JUN PY 2011 VL 156B IS 4 BP 472 EP 477 DI 10.1002/ajmg.b.31184 PG 6 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 766FA UT WOS:000290765200012 PM 21445956 ER PT J AU Machado, CJ Nelson, EE AF Machado, Christopher J. Nelson, Eric E. TI Eye-Tracking With Nonhuman Primates is Now More Accessible Than Ever Before SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Editorial Material DE eye-tracking; noninvasive; method; visual perception; face scanning ID MONKEYS MACACA-MULATTA; RHESUS-MONKEYS; SEROTONIN TRANSPORTER; FACES; CHIMPANZEES; HUMANS; POLYMORPHISM; PERCEPTION; PUPILLARY; PICTURES AB Human and nonhuman primates rely almost exclusively on vision for social communication. Therefore, tracking eye movements and examining visual scan paths can provide a wealth of information about many aspects of primate social information processing. Although eye-tracking techniques have been utilized with humans for some time, similar studies in nonhuman primates have been less frequent over recent decades. This has largely been owing to the need for invasive manipulations, such as the surgical implantation of devices to limit head movement, which may not be possible in some laboratories or at some universities, or may not be congruent with some experimental aims (i.e., longitudinal studies). It is important for all nonhuman primate researchers interested in visual information processing or operant behavior to realize that such invasive procedures are no longer necessary. Here, we briefly describe new methods for fully noninvasive video eye-tracking with adult rhesus monkeys (Macaca mulatta). We also describe training protocols that require only similar to 30 days to accomplish and quality control measures that promote reliable data collection. It is our hope that this brief overview will reacquaint nonhuman primate researchers with the benefits of eye-tracking and promote expanded use of this powerful methodology. Am. J. Primatol. 73:562-569, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Machado, Christopher J.] Univ Calif Davis, Brain Mind & Behav Unit, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Machado, Christopher J.] Univ Calif Davis, Dept Psychiat & Behav Sci, Davis, CA 95616 USA. [Nelson, Eric E.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Machado, CJ (reprint author), Univ Calif Davis, Brain Mind & Behav Unit, Calif Natl Primate Res Ctr, 1 Shields Ave, Davis, CA 95616 USA. EM cjmachado@ucdavis.edu RI Nelson, Eric/B-8980-2008 OI Nelson, Eric/0000-0002-3376-2453 FU Intramural NIH HHS [Z99 MH999999]; NCRR NIH HHS [M01 RR000069]; NIMH NIH HHS [K99 MH083883, K99 MH083883-02, K99-MH083883, R37 MH057502, R37 MH057502-14, R37-MH57502] NR 34 TC 13 Z9 13 U1 2 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD JUN PY 2011 VL 73 IS 6 SI SI BP 562 EP 569 DI 10.1002/ajp.20928 PG 8 WC Zoology SC Zoology GA 766HX UT WOS:000290772700006 PM 21319204 ER PT J AU Toobert, DJ Strycker, LA Barrera, M Osuna, D King, DK Glasgow, RE AF Toobert, Deborah J. Strycker, Lisa A. Barrera, Manuel, Jr. Osuna, Diego King, Diane K. Glasgow, Russell E. TI Outcomes from a Multiple Risk Factor Diabetes Self-Management Trial for Latinas: !Viva Bien! SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Latina; Diabetes; Multiple behavior change; Self-management; Randomized controlled trial ID LIFE-STYLE INTERVENTION; CORONARY-HEART-DISEASE; FOOD FREQUENCY QUESTIONNAIRE; ILLNESS RESOURCES SURVEY; PHYSICAL-ACTIVITY; SOCIAL SUPPORT; ETHNIC-DIFFERENCES; MEXICAN-AMERICANS; UNITED-STATES; HEALTH TRIAL AB Background Culturally appropriate interventions are needed to assist Latinas in making multiple healthful lifestyle changes. Purpose The purpose of this study was to test a cultural adaptation of a successful multiple health behavior change program, !Viva Bien! Methods Random assignment of 280 Latinas with type 2 diabetes to usual care only or to usual care+!Viva Bien!, which included group meetings for building skills to promote the Mediterranean diet, physical activity, stress management, supportive resources, and smoking cessation. Results !Viva Bien! participants compared to usual care significantly improved psychosocial and behavioral outcomes (fat intake, stress management practice, physical activity, and social-environmental support) at 6 months, and some improvements were maintained at 12 months. Biological improvements included hemoglobin A1c and heart disease risk factors. Conclusions The !Viva Bien! multiple lifestyle behavior program was effective in improving psychosocial, behavioral, and biological/quality of life outcomes related to heart health for Latinas with type 2 diabetes (ClinicalTrials.gov no: NCT00233259). C1 [Toobert, Deborah J.; Strycker, Lisa A.; Barrera, Manuel, Jr.] Oregon Res Inst, Eugene, OR 97403 USA. [Barrera, Manuel, Jr.] Arizona State Univ, Phoenix, AZ USA. [Osuna, Diego; King, Diane K.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. RP Toobert, DJ (reprint author), Oregon Res Inst, 1715 Franklin Blvd, Eugene, OR 97403 USA. EM deborah@ori.org FU NHLBI NIH HHS [R01 HL076151, R01 HL077120, R01 HL076151-05] NR 56 TC 21 Z9 21 U1 3 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD JUN PY 2011 VL 41 IS 3 BP 310 EP 323 DI 10.1007/s12160-010-9256-7 PG 14 WC Psychology, Multidisciplinary SC Psychology GA 766QV UT WOS:000290802500004 PM 21213091 ER PT J AU Persky, S Eccleston, CP AF Persky, Susan Eccleston, Collette P. TI Impact of Genetic Causal Information on Medical Students' Clinical Encounters with an Obese Virtual Patient: Health Promotion and Social Stigma SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Obesity; Genetics; Stigma; Provider attitudes; Health behavior; Virtual reality ID ENVIRONMENT TECHNOLOGY; PHYSICIANS ATTITUDES; GENOMICS RESEARCH; BODY-WEIGHT; CARE; PEOPLE; COMMUNICATION; OVERWEIGHT; BARRIERS; BELIEFS AB Background Health care providers will increasingly encounter information about the genetics of obesity as genetics research progresses. Purpose This study explores whether information about the genetics of obesity reduces medical student stigmatization of obese patients, and how it affects rates of health behavior-related referral. Methods One hundred and ten third and fourth year medical students were randomly assigned to read about genetic or behavioral mechanisms of obesity, or a control topic. Students interacted with an obese virtual patient in a virtual clinic and completed a battery of measures. Results Rates of most health behavior screening recommendations (weight loss, exercise, and diet consultations) were lower among participants exposed to genetic causal information than control. The genetic causal information group exhibited less negative stereotyping of the patient than control, F(1,105)=5.00, p=0.028, but did not differ in anticipated patient adherence, F(1,105)=3.18, p=0.077. Conclusions Information highlighting genetic contributions to obesity may lead to both positive and negative outcomes. Communication about the genetics of obesity should discuss the multi-factorial and non-deterministic nature of genetic risk. C1 [Persky, Susan] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Eccleston, Collette P.] Syracuse Univ, Syracuse, NY 13244 USA. RP Persky, S (reprint author), NHGRI, Social & Behav Res Branch, NIH, 31 Ctr Dr,Room B1B36, Bethesda, MD 20892 USA. EM perskys@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 53 TC 22 Z9 22 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD JUN PY 2011 VL 41 IS 3 BP 363 EP 372 DI 10.1007/s12160-010-9242-0 PG 10 WC Psychology, Multidisciplinary SC Psychology GA 766QV UT WOS:000290802500009 PM 21136226 ER PT J AU Wong, SY Lee, JS Kwak, HK Via, LE Boshoff, HIM Barry, CE AF Wong, Sharon Y. Lee, Jong Seok Kwak, Hyun Kyung Via, Laura E. Boshoff, Helena I. M. Barry, Clifton E., III TI Mutations in gidB Confer Low-Level Streptomycin Resistance in Mycobacterium tuberculosis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID 16S RIBOSOMAL-RNA; DRUG-RESISTANCE; MOLECULAR-DETECTION; TREATMENT OUTCOMES; GLOBAL CONTROL; IDENTIFICATION; METHYLTRANSFERASE; AMINOGLYCOSIDES; PSEUDOKNOT; BACTEREMIA AB The global threat posed by drug-resistant strains of Mycobacterium tuberculosis demands a greater understanding of the genetic basis and molecular mechanisms that govern how such strains develop resistance against various antituberculous drugs. In this report, we examine a new genetic basis for resistance to one of the oldest and most widely used second-line drugs employed in tuberculosis therapy, streptomycin (SM). This marker for SM resistance was first discovered on the basis of genomic data obtained from drug-resistant M. tuberculosis strains collected in Japan, wherein an association was observed between SM resistance and a mutation in gidB, a putative 16S rRNA methyltransferase. By evaluating an isogenic Delta gidB mutant strain constructed from strain H37Rv, we demonstrate the causal role of gidB in conferring a low-level SM-resistant phenotype in M. tuberculosis with a 16-fold increase in the MIC over the parent strain. Among clinical isolates, the modest increase in SM resistance conferred by a gidB mutation leads to an MIC distribution of gidB mutation-containing strains that spans the recommended SM breakpoint concentration currently used in drug susceptibility testing protocols. As such, some gidB mutation-containing isolates are found to be SM sensitive, while others are SM resistant. On the basis of a pharmacodynamic analysis and Monte Carlo simulation, those isolates that are found to be SM sensitive should still respond favorably to SM treatment, while nearly half of those found to be SM resistant will likely respond poorly. This report provides the first microbiological evidence for the contribution of gidB in streptomycin resistance and examines the clinical implications of mutations in the gidB gene. C1 [Wong, Sharon Y.; Via, Laura E.; Boshoff, Helena I. M.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Lee, Jong Seok; Kwak, Hyun Kyung] Int TB Res Ctr, Chang Won, Gapo Dong, South Korea. RP Barry, CE (reprint author), CEB, Bldg 33,Rm 2W20D,33 North Dr, Bethesda, MD 20892 USA. EM cbarry@mail.nih.gov RI Barry, III, Clifton/H-3839-2012; OI Via, Laura/0000-0001-6074-9521 FU NIH, NIAID; Ministry for Health, Welfare and Family Affairs of the Republic of Korea; Korea Foundation for International Cooperation for Science and Technology through Ministry of Education and Science and Technology of the Republic of Korea FX Funding for this work was provided by the Intramural Research Program of the NIH, NIAID; the Ministry for Health, Welfare and Family Affairs of the Republic of Korea; and the Korea Foundation for International Cooperation for Science and Technology through a grant provided by the Ministry of Education and Science and Technology of the Republic of Korea. NR 39 TC 46 Z9 49 U1 1 U2 11 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 JUN PY 2011 VL 55 IS 6 BP 2515 EP 2522 DI 10.1128/AAC.01814-10 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 765NA UT WOS:000290713400003 PM 21444711 ER PT J AU Labunskyy, VM Lee, BC Handy, DE Loscalzo, J Hatfield, DL Gladyshev, VN AF Labunskyy, Vyacheslav M. Lee, Byung Cheon Handy, Diane E. Loscalzo, Joseph Hatfield, Dolph L. Gladyshev, Vadim N. TI Both Maximal Expression of Selenoproteins and Selenoprotein Deficiency Can Promote Development of Type 2 Diabetes-Like Phenotype in Mice SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID CELLULAR GLUTATHIONE-PEROXIDASE; SELENIUM SUPPLEMENTATION; ENDOPLASMIC-RETICULUM; CANCER PREVENTION; THIOREDOXIN REDUCTASE; INSULIN-RESISTANCE; PROSTATE-CANCER; TRANSGENIC MICE; PROTEIN; TRIAL AB Selenium (Se) is an essential trace element in mammals that has been shown to exert its function through selenoproteins. Whereas optimal levels of Se in the diet have important health benefits, a recent clinical trial has suggested that supplemental intake of Se above the adequate level potentially may raise the risk of type 2 diabetes mellitus. However, the molecular mechanisms for the effect of dietary Se on the development of this disease are not understood. In the present study, we examined the contribution of selenoproteins to increased risk of developing diabetes using animal models. C57BL/6J mice (n = 6-7 per group) were fed either Se-deficient Torula yeast-based diet or diets supplemented with 0.1 and 0.4 parts per million Se. Our data show that mice maintained on an Se-supplemented diet develop hyperinsulinemia and have decreased insulin sensitivity. These effects are accompanied by elevated expression of a selective group of selenoproteins. We also observed that reduced synthesis of these selenoproteins caused by overexpression of an i(6)A(-) mutant selenocysteine tRNA promotes glucose intolerance and leads to a diabetes-like phenotype. These findings indicate that both high expression of selenoproteins and selenoprotein deficiency may dysregulate glucose homeostasis and suggest a role for selenoproteins in development of diabetes. Antioxid. Redox Signal. 14, 2327-2336. C1 [Labunskyy, Vyacheslav M.; Lee, Byung Cheon; Handy, Diane E.; Loscalzo, Joseph; Gladyshev, Vadim N.] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Gladyshev, Vadim N.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE USA. [Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68583 USA. RP Gladyshev, VN (reprint author), Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, New Res Bldg,Room 435,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM vgladyshev@rics.bwh.harvard.edu RI Gladyshev, Vadim/A-9894-2013 FU National Institutes of Health [CA080946, AG021518, HL61795, HL81587, HL70819, HL48743]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We would like to thank Xin Gen Lei for providing mouse tissues from transgenic mice overexpressing GPx1 and Sergey Novoselov for help with glucose tolerance tests. This work was supported by National Institutes of Health grants CA080946 and AG021518 (to VNG), HL61795, HL81587, HL70819, and HL48743 (to JL), and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (to DLH). NR 40 TC 59 Z9 63 U1 2 U2 14 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUN PY 2011 VL 14 IS 12 BP 2327 EP 2336 DI 10.1089/ars.2010.3526 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 766LM UT WOS:000290783700001 PM 21194350 ER PT J AU Dorjgochoo, T Gao, YT Chow, WH Shu, XO Yang, G Cai, QY Rothman, N Cai, H Li, HL Deng, XQ Shrubsole, MJ Murff, H Milne, G Zheng, W Dai, Q AF Dorjgochoo, Tsogzolmaa Gao, Yu-Tang Chow, Wong-Ho Shu, Xiao-ou Yang, Gong Cai, Quiyin Rothman, Nathaniel Cai, Hui Li, Honglan Deng, Xinqing Shrubsole, Martha J. Murff, Harvey Milne, Ginger Zheng, Wei Dai, Qi TI Obesity, Age, and Oxidative Stress in Middle-Aged and Older Women SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID MAJOR URINARY METABOLITE; LIPID-PEROXIDATION; IN-VIVO; BIOLOGICAL-FLUIDS; OXIDANT STRESS; F-2-ISOPROSTANES; RISK; ISOPROSTANES; HEALTH; QUANTIFICATION AB Recent evidence suggests that urinary F(2)-isoprostanes (F(2)-IsoPs) are more accurate markers of oxidative stress than other available biomarkers. Most previous studies used unmetabolized F(2)-IsoPs as a biomarker. Few previous studies measured 15-F(2t)-IsoP-M, a metabolite of one of the most common F(2)-IsoPs, 15-F(2t)-IsoP. Unlike 15-F(2t)-IsoP, 15-F(2t)-IsoP-M is not subject to autoxidation and renal production. To our knowledge, no study has compared the associations of age and body mass index (BMI) with F(2)-IsoPs to those with 15-F(2t)-IsoP-M. Urinary levels of F(2)-IsoPs and 15-F(2t)-IsoP-M were measured using gas chromatography-mass spectrometry for 845 healthy women aged 40-70 years. Both F(2)-IsoPs and 15-F(2t)-IsoP-M were elevated among smokers. The level of 15-F(2t)-IsoP-M increased with age, particularly after menopause, and with BMI. In contrast, F(2)-IsoPs decreased with age, regardless of menopausal status, and was not related to BMI. The association of 15-F(2t)-IsoP-M with age or menopausal status did not differ by BMI category, and the association with BMI was also independent of age or menopausal status. 15-F(2t)-IsoP-M appears to be a valuable biomarker of oxidative stress in age-and obesity-related diseases. Antioxid. Redox Signal. 14, 2453-2460. C1 [Dorjgochoo, Tsogzolmaa; Shu, Xiao-ou; Yang, Gong; Cai, Quiyin; Cai, Hui; Deng, Xinqing; Shrubsole, Martha J.; Murff, Harvey; Zheng, Wei; Dai, Qi] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Dept Med, Nashville, TN 37203 USA. [Gao, Yu-Tang; Li, Honglan] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Chow, Wong-Ho; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Milne, Ginger] Vanderbilt Univ, Sch Med, Div Clin Pharmacol, Dept Med & Pharmacol, Nashville, TN 37203 USA. RP Dai, Q (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Dept Med, 2525 W End Ave,6th Floor,Suite 600, Nashville, TN 37203 USA. EM qi.dai@vanderbilt.edu RI Milne, Ginger/D-7648-2014; Shrubsole, Martha/K-5052-2015 OI Milne, Ginger/0000-0003-3890-151X; Shrubsole, Martha/0000-0002-5591-7575 FU National Institutes of Health [R37CA70867, N02 CP1101066]; [R01CA106591] FX Dr. Jason Morrow, our beloved colleague, long-term collaborator, and key co-investigator of the project, passed away. Without him, our research work would have been impossible. This article is dedicated to his memory. The authors thank the Shanghai residents who participated in the study and the research staff of the SWHS for their dedication and contributions to the study. This work was supported by research grant R01CA106591 as well as parent studies R37CA70867 and N02 CP1101066 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 35 TC 17 Z9 17 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUN PY 2011 VL 14 IS 12 BP 2453 EP 2460 DI 10.1089/ars.2010.3337 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 766LM UT WOS:000290783700011 PM 21043829 ER PT J AU Koya, E Hope, BT AF Koya, Eisuke Hope, Bruce T. TI Cocaine and Synaptic Alterations in the Nucleus Accumbens SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID RECEPTOR; NEURONS; PLASTICITY; EXPRESSION; AMPHETAMINE; EXPOSURE; D1 C1 [Koya, Eisuke; Hope, Bruce T.] NIDA, Behav Neurosci Branch, IRP, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Hope, BT (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,Dept Hlth & Human Serv, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM bhope@intra.nida.nih.gov RI Hope, Bruce/A-9223-2010 OI Hope, Bruce/0000-0001-5804-7061 FU Intramural NIH HHS [ZIA DA000467-08] NR 15 TC 3 Z9 4 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 2011 VL 69 IS 11 BP 1013 EP 1014 DI 10.1016/j.biopsych.2011.04.001 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 760CQ UT WOS:000290300600002 PM 21550434 ER PT J AU Holmes, A AF Holmes, Andrew TI Merger Fever: Can Two Separate Mechanisms Work Together to Explain Why We Drink? SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID ETHANOL-RELATED BEHAVIORS; GLUTAMATERGIC NEUROTRANSMISSION; MICE LACKING; ALCOHOLISM; NMDA; INTOXICATION C1 NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. RP Holmes, A (reprint author), NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM andrew.holmes@mail.nih.gov FU Intramural NIH HHS [ZIA AA000411-07]; NIAAA NIH HHS [Z01 AA000411] NR 13 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 2011 VL 69 IS 11 BP 1015 EP 1016 DI 10.1016/j.biopsych.2011.04.010 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 760CQ UT WOS:000290300600003 PM 21550435 ER PT J AU Zeng, WX Baumann, C Schmidtmann, A Honaramooz, A Tang, L Bondareva, A Dores, C Fan, T Xi, SC Geiman, T Rathi, R de Rooij, D De La Fuente, R Muegge, K Dobrinski, I AF Zeng, Wenxian Baumann, Claudia Schmidtmann, Anja Honaramooz, Ali Tang, Lin Bondareva, Alla Dores, Camila Fan, Tao Xi, Sichuan Geiman, Theresa Rathi, Rahul de Rooij, Dirk De La Fuente, Rabindranath Muegge, Kathrin Dobrinski, Ina TI Lymphoid-Specific Helicase (HELLS) Is Essential for Meiotic Progression in Mouse Spermatocytes SO BIOLOGY OF REPRODUCTION LA English DT Article DE chromosomes; developmental biology; HELLS; LSH; meiosis; spermatogenesis; testis; transplantation ID GERM-CELLS; MAMMALIAN MEIOSIS; TESTIS XENOGRAFTS; TESTICULAR TISSUE; SNF2 FAMILY; MICE; LSH; SPERM; GENE; SPERMATOGENESIS AB Lymphoid-specific helicase (HELLS; also known as LSH) is a member of the SNF2 family of chromatin remodeling proteins. Because Hells-null mice die at birth, a phenotype in male meiosis cannot be studied in these animals. Allografting of testis tissue from Hells(-/-) to wild-type mice was employed to study postnatal germ cell differentiation. Testes harvested at Day 18.5 of gestation from Hells(-/-), Hells(+/-), and Hells(+/+) mice were grafted ectopically to immunodeficient mice. Bromodeoxyuridine incorporation at 1 wk postgrafting revealed fewer dividing germ cells in grafts from Hells(-/-) than from Hells(+/+) mice. Whereas spermatogenesis proceeded through meiosis with round spermatids in grafts from Hells heterozygote and wildtype donor testes, spermatogenesis arrested at stage IV, and midpachytene spermatocytes were the most advanced germ cell type in grafts from Hells(-/-) mice at 4, 6, and 8 wk after grafting. Analysis of meiotic configurations at 22 days posttransplantation revealed an increase in Hells(-/-) spermatocytes with abnormal chromosome synapsis. These results indicate that in the absence of HELLS, proliferation of spermatogonia is reduced and germ cell differentiation arrested at the midpachytene stage, implicating an essential role for HELLS during male meiosis. This study highlights the utility of testis tissue grafting to study spermatogenesis in animal models that cannot reach sexual maturity. C1 [Zeng, Wenxian; Baumann, Claudia; Honaramooz, Ali; Rathi, Rahul; De La Fuente, Rabindranath; Dobrinski, Ina] Univ Penn, Sch Vet Med, Ctr Anim Transgenesis & Germ Cell Res, Kennett Sq, PA 19348 USA. [Schmidtmann, Anja; Fan, Tao; Xi, Sichuan; Geiman, Theresa; Muegge, Kathrin] NCI, Lab Canc Prevent, SAIC FCRDC, Frederick, MD 21701 USA. [Honaramooz, Ali] Univ Saskatchewan, Dept Vet Biomed Sci, Saskatoon, SK, Canada. [Tang, Lin; Bondareva, Alla; Dores, Camila; Dobrinski, Ina] Univ Calgary, Dept Comparat Biol & Expt Med, Calgary, AB T2N 4N1, Canada. [De La Fuente, Rabindranath] Univ Georgia, Coll Vet Med, Dept Physiol & Pharmacol, Athens, GA 30602 USA. [de Rooij, Dirk] Univ Amsterdam, Acad Med Ctr, Ctr Reprod Med, NL-1105 AZ Amsterdam, Netherlands. RP Dobrinski, I (reprint author), Univ Calgary, Dept Comparat Biol & Expt Med, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada. EM idobrins@ucalgary.ca OI de Rooij, Dirk/0000-0003-3932-4419 FU National Institutes of Health [NCRR 2R01RR17359-08, NICHD 2RO1HD042740-04]; National Cancer Institute [N01-C0-12400] FX Supported by National Institutes of Health (NCRR 2R01RR17359-08 to I.D. and NICHD 2RO1HD042740-04 to R. D. L. F.) and National Cancer Institute (contract N01-C0-12400 to K.M.). NR 29 TC 11 Z9 11 U1 0 U2 1 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 JUN PY 2011 VL 84 IS 6 BP 1235 EP 1241 DI 10.1095/biolreprod.110.085720 PG 7 WC Reproductive Biology SC Reproductive Biology GA 766PL UT WOS:000290797900020 PM 21349825 ER PT J AU Yoshimura, Y Yamazaki, Y Saito, Y Natori, Y Imamichi, T Takahata, H AF Yoshimura, Yuichi Yamazaki, Yoshiko Saito, Yukako Natori, Yoshihiro Imamichi, Tomozumi Takahata, Hiroki TI Synthesis of 5-thiodidehydropyranylcytosine derivatives as potential anti-HIV agents SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Nucleoside; 4 '-Thionucleoside; Anti-HIV; Antiviral; Pummerer reaction ID REVERSE-TRANSCRIPTASE INHIBITORS; ANTIVIRAL EVALUATION; NUCLEOSIDE; RESISTANCE; PROTEASE; DESIGN AB As a part of our ongoing efforts to identify new anti-HIV agents, a 5'-thiopyrano-nucleoside derivative 4, designed based on 4'-thioD4C 1 and cyclohexenylnucleoside 3, was synthesized. The dihydrothiopyran skeleton of 4 was constructed by the ring closing metathesis of 21 which was synthesized from but-2-yne-1,4-diol. After converting the protecting group from MOM to TBS followed by oxidation, a Pummerer-type thioglycosylation reaction of 24 with persilylated uracil gave the desired 5-thiodihydrothiopyranyluracils 25 and 26 as a mixture of anomers. The conversion of 25 to a cytosine derivative and subsequent deprotection gave a 5-thiodidehydropyranosylcytosine derivative 4 in good yield. The anti-HIV activity of 4 was also evaluated. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Yoshimura, Yuichi; Yamazaki, Yoshiko; Saito, Yukako; Natori, Yoshihiro; Takahata, Hiroki] Tohoku Pharmaceut Univ, Fac Pharmaceut Sci, Aoba Ku, Sendai, Miyagi 9818558, Japan. [Yamazaki, Yoshiko] SEED CO Ltd, Dept Res & Dev, Kounosu, Saitama 3690131, Japan. [Imamichi, Tomozumi] NIAID, Lab Human Retrovirol, Appl & Dev Res Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. RP Yoshimura, Y (reprint author), Tohoku Pharmaceut Univ, Fac Pharmaceut Sci, Aoba Ku, 4-4-1 Komatsushima, Sendai, Miyagi 9818558, Japan. EM yoshimura@tohoku-pharm.ac.jp FU JSPS [21590119]; Ministry of Education, Culture, Sports, Science and Technology of Japan FX This work was supported in part by a Grant-in-Aid for Scientific Research (No. 21590119), JSPS (Y.Y.) and by High Technology Research Program from Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 23 TC 9 Z9 10 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 1 PY 2011 VL 21 IS 11 BP 3313 EP 3316 DI 10.1016/j.bmcl.2011.04.006 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 765LR UT WOS:000290708300024 PM 21524575 ER PT J AU Montoro-Garcia, S Lip, PL Chan, CC Lip, GYH AF Montoro-Garcia, Silvia Lip, Peck-Lin Chan, Chi-Chao Lip, Gregory Y. H. TI Soluble vascular endothelial growth factor receptor (VEGFR)-2 in macular oedema-a mechanism for regulating angiogenesis? SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Editorial Material ID ANGIOPOIETIN-2; RETINOPATHY; MATURATION; FORMS C1 [Montoro-Garcia, Silvia; Lip, Gregory Y. H.] Univ Birmingham, Ctr Cardiovasc Sci, City Hosp, Haemostasis Thrombosis & Vasc Biol Unit, Birmingham B18 7QH, W Midlands, England. [Montoro-Garcia, Silvia] Hosp Univ Virgen de la Arrixaca, Dept Cardiol, Murcia, Spain. [Lip, Peck-Lin] Birmingham & Midland Eye Ctr, Birmingham, W Midlands, England. [Chan, Chi-Chao] NEI, NIH, Bethesda, MD 20892 USA. RP Lip, GYH (reprint author), Univ Birmingham, Ctr Cardiovasc Sci, City Hosp, Haemostasis Thrombosis & Vasc Biol Unit, Dudley Rd, Birmingham B18 7QH, W Midlands, England. EM g.y.h.lip@bham.ac.uk RI Montoro-Garcia, Silvia/K-8101-2014 OI Montoro-Garcia, Silvia/0000-0002-1948-1022 NR 17 TC 2 Z9 2 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD JUN PY 2011 VL 95 IS 6 BP 757 EP 758 DI 10.1136/bjo.2010.198002 PG 2 WC Ophthalmology SC Ophthalmology GA 766OJ UT WOS:000290793600001 PM 21325396 ER PT J AU Mondul, AM Rohrmann, S Menke, A Feinleib, M Nelson, WG Platz, EA Albanes, D AF Mondul, Alison M. Rohrmann, Sabine Menke, Andy Feinleib, Manning Nelson, William G. Platz, Elizabeth A. Albanes, Demetrius TI Association of serum alpha-tocopherol with sex steroid hormones and interactions with smoking: implications for prostate cancer risk SO CANCER CAUSES & CONTROL LA English DT Article DE Gonadal steroid hormones; Alpha-Tocopherol; Smoking; Prostatic neoplasms; Cross-sectional studies ID DIETARY VITAMIN-E; CIGARETTE-SMOKING; BETA-CAROTENE; LIFE-STYLE; FREE TESTOSTERONE; CONTROLLED-TRIAL; NUTRIENT INTAKE; OLDER MEN; US MEN; RETINOL AB Vitamin E may protect against prostate cancer, possibly only in smokers and, we hypothesize, through altered sex steroid hormones. A controlled trial in smokers showed that sex hormone levels were inversely associated with baseline serum alpha-tocopherol and decreased in response to vitamin E supplementation. The vitamin E-hormone relation is understudied in non-smokers. Serum sex steroid hormones and alpha-tocopherol were measured for 1,457 men in NHANES III. Multivariable-adjusted geometric mean hormone concentrations by alpha-tocopherol quintile were estimated. We observed lower mean testosterone, estradiol, and SHBG concentrations with increasing serum alpha-tocopherol (Q1 = 5.5 and Q5 = 4.6 ng/ml, p-trend = 0.0007; Q1 = 37.8 and Q5 = 33.1 pg/ml, p-trend = 0.02; Q1 = 38.8 and Q5 = 30.6 pg/ml, p-trend = 0.05, respectively). Interactions between serum alpha-tocopherol and exposure to cigarette smoke for total testosterone, total estradiol, and SHBG were found with the inverse relation observed only among smokers. Results from this nationally representative, cross-sectional study indicate an inverse association between serum alpha-tocopherol and circulating testosterone, estradiol, and SHBG, but only in men who smoked. Our findings support vitamin E selectively influencing sex hormones in smokers and afford possible mechanisms through which vitamin E may impact prostate cancer risk. C1 [Mondul, Alison M.; Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rohrmann, Sabine] Univ Zurich, Inst Social & Prevent Med, CH-8006 Zurich, Switzerland. [Menke, Andy; Feinleib, Manning; Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Menke, Andy] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Nelson, William G.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Nelson, William G.] Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA. [Nelson, William G.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Nelson, William G.; Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Nelson, William G.; Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, Brady Urol Res Inst, Baltimore, MD USA. RP Mondul, AM (reprint author), 6120 Execut Blvd,Ste 320, Rockville, MD 20852 USA. EM mondulam@mail.nih.gov RI Perez , Claudio Alejandro/F-8310-2010; Rohrmann, Sabine/D-2113-2012; Albanes, Demetrius/B-9749-2015 OI Perez , Claudio Alejandro/0000-0001-9688-184X; FU Maryland Cigarette Restitution Fund at Johns Hopkins FX This is the 26th paper from the Hormone Demonstration Program funded by the Maryland Cigarette Restitution Fund at Johns Hopkins. NR 49 TC 6 Z9 6 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2011 VL 22 IS 6 BP 827 EP 836 DI 10.1007/s10552-011-9753-4 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 764ZA UT WOS:000290672000002 PM 21424597 ER PT J AU Mirabello, L Pfeiffer, R Murphy, G Daw, NC Patino-Garcia, A Troisi, RJ Hoover, RN Douglass, C Schuz, J Craft, AW Savage, SA AF Mirabello, Lisa Pfeiffer, Ruth Murphy, Gwen Daw, Najat C. Patino-Garcia, Ana Troisi, Rebecca J. Hoover, Robert N. Douglass, Chester Schuz, Joachim Craft, Alan W. Savage, Sharon A. TI Height at diagnosis and birth-weight as risk factors for osteosarcoma SO CANCER CAUSES & CONTROL LA English DT Article DE Osteosarcoma; Height; Birth-weight; Meta-analysis; Epidemiology ID GROWTH-FACTOR-I; CHILDHOOD-CANCER; OSTEOGENIC-SARCOMA; PROSTATE-CANCER; EWINGS-SARCOMA; BREAST-CANCER; BONE CANCER; CHILDREN; METAANALYSIS; TUMORS AB Osteosarcoma typically occurs during puberty. Studies of the association between height and/or birth-weight and osteosarcoma are conflicting. Therefore, we conducted a large pooled analysis of height and birth-weight in osteosarcoma. Patient data from seven studies of height and three of birth-weight were obtained, resulting in 1,067 cases with height and 434 cases with birth-weight data. We compared cases to the 2000 US National Center for Health Statistics Growth Charts by simulating 1,000 age- and gender-matched controls per case. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between height or birth-weight and risk of osteosarcoma for each study were estimated using logistic regression. All of the case data were combined for an aggregate analysis. Compared to average birth-weight subjects (2,665-4,045 g), individuals with high birth-weight (a parts per thousand yen4,046 g) had an increased osteosarcoma risk (OR 1.35, 95% CI 1.01-1.79). Taller than average (51st-89th percentile) and very tall individuals (a parts per thousand yen90th percentile) had an increased risk of osteosarcoma (OR 1.35, 95% CI 1.18-1.54 and OR 2.60, 95% CI 2.19-3.07, respectively; P (trend) < 0.0001). This is the largest analysis of height at diagnosis and birth-weight in relation to osteosarcoma. It suggests that rapid bone growth during puberty and in utero contributes to OS etiology. C1 [Mirabello, Lisa] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Mirabello, Lisa; Pfeiffer, Ruth; Murphy, Gwen; Troisi, Rebecca J.; Hoover, Robert N.; Savage, Sharon A.] NCI, US Dept HHS, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Daw, Najat C.] Univ Tennessee, Coll Med, Dept Pediat, Memphis, TN USA. [Daw, Najat C.] Univ Tennessee, Coll Med, St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN USA. [Patino-Garcia, Ana] Univ Navarra Clin, Pediat Oncol Unit, Pediat Lab, Dept Pediat, Pamplona, Spain. [Troisi, Rebecca J.] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Douglass, Chester] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Schuz, Joachim] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. Johannes Gutenberg Univ Mainz, Inst Med Biostat Epidemiol & Informat, Mainz, Germany. [Craft, Alan W.] Newcastle Univ, Dept Child Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. RP Mirabello, L (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 7101, Rockville, MD 20852 USA. EM mirabellol@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Patino-Garcia, Ana/I-4299-2012; Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics and the Center for Cancer Research. NR 68 TC 30 Z9 33 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2011 VL 22 IS 6 BP 899 EP 908 DI 10.1007/s10552-011-9763-2 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 764ZA UT WOS:000290672000009 PM 21465145 ER PT J AU Barbash, IM Saikus, CE Ratnayaka, K Faranesh, AZ Kocaturk, O Wu, V Bell, JA Schenke, WH Raman, VK Lederman, RJ AF Barbash, Israel M. Saikus, Christina E. Ratnayaka, Kanishka Faranesh, Anthony Z. Kocaturk, Ozgur Wu, Vincent Bell, Jamie A. Schenke, William H. Raman, Venkatesh K. Lederman, Robert J. TI Limitations of Closing Percutaneous Transthoracic Ventricular Access Ports Using a Commercial Collagen Vascular Closure Device SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE transapical; heart rupture; tamponade; paravalvular leak; valve repair ID AORTIC-VALVE IMPLANTATION; BEATING-HEART; EXPERIENCE AB Introduction: Closed-chest access and closure of direct cardiac punctures may enable a range of therapeutic procedures. We evaluate the safety and feasibility of closing percutaneous direct ventricular access sites using a commercial collagen-based femoral artery closure device. Methods: Yorkshire swine underwent percutaneous transthoracic left ventricular access (n = 13). The access port was closed using a commercial collagen- based vascular closure device (Angio-Seal, St. Jude Medical) with or without prior separation of the pericardial layers by instillation of fluid into the pericardial space ("permissive pericardial tamponade''). After initial nonsurvival feasibility experiments (n = 6); animals underwent 1-week (n = 3) or 6-week follow-up (n = 4). Results: In naive animals, the collagen plug tended to deploy outside the parietal pericardium, where it failed to accomplish hemostasis. "Permissive pericardial tamponade'' was created under MRI, and accomplished early hemostasis by allowing the collagen sponge to seat on the epicardial surface inside the pericardium. After successful closure, six of seven animals accumulated a large pericardial effusion 5 +/- 1 days after closure. Despite percutaneous drainage during 6-week follow-up, the large pericardial effusion recurred in half, and was lethal in one. Conclusions: A commercial collagen-based vascular closure device may achieve temporary but not durable hemostasis when closing a direct left ventricular puncture port, but only after intentional pericardial separation. These insights may contribute to development of a superior device solution. Elective clinical application of this device to close apical access ports should be avoided. (C) 2011 Wiley-Liss, Inc. C1 [Barbash, Israel M.; Saikus, Christina E.; Ratnayaka, Kanishka; Faranesh, Anthony Z.; Kocaturk, Ozgur; Wu, Vincent; Bell, Jamie A.; Schenke, William H.; Raman, Venkatesh K.; Lederman, Robert J.] NHLBI, Translat Med Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Lederman, RJ (reprint author), NHLBI, Translat Med Branch, Div Intramural Res, NIH, Bldg 10,Room 2C713 MSC1538, Bethesda, MD 20892 USA. EM lederman@nih.gov RI Kocaturk, Ozgur/A-1419-2016; OI lederman, robert/0000-0003-1202-6673 FU Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health [1ZIAHL005062-07] FX Grant sponsor: Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health; grant number: 1ZIAHL005062-07 NR 15 TC 4 Z9 4 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD JUN 1 PY 2011 VL 77 IS 7 BP 1079 EP 1085 DI 10.1002/ccd.22941 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 767MT UT WOS:000290861400032 PM 21234923 ER PT J AU Suryadevara, M Cummings, E Bonville, CA Bartholoma, N Riddell, S Kiska, D Rosenberg, HF Domachowske, JB AF Suryadevara, Manika Cummings, Erin Bonville, Cynthia A. Bartholoma, Nadine Riddell, Scott Kiska, Deanna Rosenberg, Helene F. Domachowske, Joseph B. TI Viral Etiology of Acute Febrile Respiratory Illnesses in Hospitalized Children Younger Than 24 Months SO CLINICAL PEDIATRICS LA English DT Article DE respiratory infections; multiplex PCR; respiratory viral pathogens ID SYNCYTIAL VIRUS; HUMAN METAPNEUMOVIRUS; TRACT INFECTIONS; SEVERE BRONCHIOLITIS; INFANTS; DISEASE; SEVERITY; SINGLE; IMPACT AB Background: Respiratory infections are a leading cause of pediatric hospitalizations. This study investigated whether virus-virus or virus-Bordetella co-infections are more frequent or more severe than previously recognized. Methods: This is a 3-year prospective study of children younger than 24 months hospitalized with a febrile respiratory illness. Viral pathogens were detected using multiplex polymerase chain reaction (PCR), enzyme-linked immunoassays, and/or viral cultures from nasopharyngeal samples. Bordetella infections were detected by PCR. Results: A total of 201 patients were enrolled. Respiratory viruses were detected in 187 (93%) patients, with 52 (28%) multipathogen infections. The most common viruses detected were respiratory syncytial virus and rhinovirus/enterovirus. There were no differences in illness severity when comparing patients infected with one pathogen and those with multipathogen infection. Conclusion: Virus co-infection in young children hospitalized with an acute febrile respiratory infection is common but does not appear to be associated with illness severity. C1 [Domachowske, Joseph B.] SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY 13210 USA. [Rosenberg, Helene F.] NIAID, NIH, Bethesda, MD 20892 USA. RP Domachowske, JB (reprint author), SUNY Upstate Med Univ, Dept Pediat, 750 E Adams St, Syracuse, NY 13210 USA. EM domachoj@upstate.edu FU Central New York Children's Miracle Network [5553]; NIAID Division of Intramural Research [Z01-AI000943] FX The authors disclosed receipt of the following financial support for the research and/or authorship of this article: Funding of this project was provided by Central New York Children's Miracle Network (IRB# 5553 to JBD) and NIAID Division of Intramural Research (Grant No. Z01-AI000943 to HFR). NR 26 TC 15 Z9 15 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 J9 CLIN PEDIATR JI Clin. Pediatr. PD JUN PY 2011 VL 50 IS 6 BP 513 EP 517 DI 10.1177/0009922810394834 PG 5 WC Pediatrics SC Pediatrics GA 763US UT WOS:000290585800006 PM 21262758 ER PT J AU Solomon, BD Raam, MS Pineda-Alvarez, DE AF Solomon, Benjamin D. Raam, Manu S. Pineda-Alvarez, Daniel E. TI Analysis of genitourinary anomalies in patients with VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities) association SO CONGENITAL ANOMALIES LA English DT Article DE genitourinary anomalies; VACTERL; VACTERL association; VATER; VATER association ID ESOPHAGEAL ATRESIA; VATER-ASSOCIATION; SONIC HEDGEHOG; SPECTRUM; DYSPLASIA; MUTATION AB The goal of this study was to describe a novel pattern of genitourinary (GU) anomalies in VACTERL association, which involves congenital anomalies affecting the vertebrae, anus, heart, trachea and esophagus, kidneys, and limbs. We collected clinical data on 105 patients diagnosed with VACTERL association and analyzed a subset of 89 patients who met more stringent inclusion criteria. Twenty-one percent of patients have GU anomalies, which are more severe (but not more frequent) in females. Anomalies were noted in patients without malformations affecting the renal, lower vertebral, or lower gastrointestinal systems. There should be a high index of suspicion for the presence of GU anomalies even in patients who do not have spatially similar malformations. C1 [Solomon, Benjamin D.; Raam, Manu S.; Pineda-Alvarez, Daniel E.] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Raam, Manu S.] Howard Hughes Med Inst, Natl Inst Hlth Res Scholars Program, Chevy Chase, MD USA. RP Solomon, BD (reprint author), Bldg 35,Room 1B-207,35 Convent Dr MSC 3717, Bethesda, MD 20892 USA. EM solomonb@mail.nih.gov FU Division of Intramural Research; National Human Genome Research Institute; National Institutes of Health; Human Services, United States of America FX 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. The authors would like to thank Dr Maximilian Muenke for his support and mentorship, and would like to extend their deepest gratitude to all participating patients and families. NR 24 TC 13 Z9 14 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0914-3505 J9 CONGENIT ANOM JI Congenit. Anom. PD JUN PY 2011 VL 51 IS 2 BP 87 EP 91 DI 10.1111/j.1741-4520.2010.00303.x PG 5 WC Pediatrics SC Pediatrics GA 766WB UT WOS:000290816200006 PM 21235632 ER PT J AU Altaweel, L Chen, ZC Moayeri, M Cui, XZ Li, Y Su, JW Fitz, Y Johnson, S Leppla, SH Purcell, R Eichacker, PQ AF Altaweel, Laith Chen, Zhaochun Moayeri, Mahtab Cui, Xizhong Li, Yan Su, Junwu Fitz, Yvonne Johnson, Syd Leppla, Stephen H. Purcell, Robert Eichacker, Peter Q. TI Delayed treatment with W1-mAb, a chimpanzee-derived monoclonal antibody against protective antigen, reduces mortality from challenges with anthrax edema or lethal toxin in rats and with anthrax spores in mice SO CRITICAL CARE MEDICINE LA English DT Article DE Bacillus anthracis; lethal and edema toxins; protective-antigen-directed mAb; treatment; rodent ID BACILLUS-ANTHRACIS; INHALATIONAL ANTHRAX; CYCLIC-AMP; IN-VIVO; DYSFUNCTION; SHOCK; BIOTERRORISM; INACTIVATION; MACROPHAGES; APOPTOSIS AB Objective: W1-mAb is a chimpanzee-derived monoclonal antibody to protective antigen that improved survival when administered before anthrax lethal toxin challenge in rats. To better define W1-mAb's efficacy for anthrax, we administered it after initiation of 24-hr infusions of edema toxin and lethal toxin either alone or together in rats or following anthrax spore challenge in mice. Interventions: W1-mAb or placebo treatment. Methods and Main Results: In toxin-challenged rats treated with placebo, survival rates were lower with edema toxin (500 mu g/kg) compared to lethal toxin either alone (175 mu g/kg) or with edema toxin (175 mu g/kg each) (8%, 33%, and 32%, respectively), but the median time to death was longer (36, 11, and 9 hrs, respectively) (p <=.01 for all comparisons). W1-mAb administered up to 12 hrs after edema toxin and 6 hrs after lethal toxin increased survival and reduced hypotension (p <= .01). However, only administration of W1-mAb at 0 hrs improved these variables with lethal toxin and edema toxin together (p <=.0002). In C57BL/6J mice challenged with anthrax spores subcutaneously, compared to placebo treatment (0 of 15 animals survived), W1-mAb administered beginning 24 hrs after challenge increased survival (13 of 15 survived) (p <=.0001). Conclusion: While rapidity of lethality may influence the effectiveness of delayed W1-mAb treatment, these rat and mouse studies provide a basis for further exploring this agent's usefulness for anthrax. (Crit Care Med 2011; 39: 1439-1447) C1 [Altaweel, Laith; Cui, Xizhong; Li, Yan; Su, Junwu; Fitz, Yvonne; Eichacker, Peter Q.] NIAID, Dept Crit Care Med, NIH, Bethesda, MD 20892 USA. [Chen, Zhaochun; Purcell, Robert] NIAID, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Chen, Zhaochun; Purcell, Robert] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Moayeri, Mahtab; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. [Johnson, Syd] Macrogenics Inc, Rockville, MD USA. RP Altaweel, L (reprint author), NIAID, Dept Crit Care Med, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM peichacker@mail.cc.nih.gov FU Critical Care Department, Clinical Center, National Institutes of Health (Bethesda, MD); National Institutes of Health (Bethesda, MD) FX Supported, in part, by the Critical Care Department, Clinical Center, National Institutes of Health (Bethesda, MD).; Dr. Altaweel, Dr. Johnson, and Dr. Su received funding from the National Institutes of Health (Bethesda, MD). Dr. Moayeri and Dr. Leppla have a pending patent from the U.S. Government. The remaining authors have not disclosed any potential conflicts of interest. NR 31 TC 7 Z9 7 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JUN PY 2011 VL 39 IS 6 BP 1439 EP 1447 DI 10.1097/CCM.0b013e3182120691 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA 765NM UT WOS:000290715000030 PM 21336113 ER PT J AU Zhang, F Dong, L Zhang, CP Li, B Wen, J Gao, W Sun, S Lv, F Tian, H Tuomilehto, J Qi, L Zhang, CL Yu, Z Yang, X Hu, G AF Zhang, F. Dong, L. Zhang, C. P. Li, B. Wen, J. Gao, W. Sun, S. Lv, F. Tian, H. Tuomilehto, J. Qi, L. Zhang, C. L. Yu, Z. Yang, X. Hu, G. TI Increasing prevalence of gestational diabetes mellitus in Chinese women from 1999 to 2008 SO DIABETIC MEDICINE LA English DT Article DE China; gestational diabetes mellitus; incidence ID IMPAIRED GLUCOSE-TOLERANCE; INTERNATIONAL WORKSHOP-CONFERENCE; LIFE-STYLE; PREGNANCY OUTCOMES; RISK-FACTORS; PREVENTION; RECOMMENDATIONS; OVERWEIGHT; METFORMIN; OBESITY AB P>Aims To investigate the trend in the prevalence of gestational diabetes mellitus during 1999-2008 in women living in urban Tianjin, China. Methods A universal screening for gestational diabetes mellitus has become an integral part of the antenatal care in Tianjin, China from 1998. A total of 105 473 pregnant women living in the six urban districts of Tianjin, China, participated in the gestational diabetes mellitus screening programme between December 1998 and December 2008. The screening test consisted of a 50-g 1-h glucose test. Women who had a glucose reading >= 7.8 mmol/l at the initial screening were invited to undergo the standard 2-h oral glucose tolerance test with a 75-g glucose load. Gestational diabetes mellitus was confirmed using the World Health Organization's diagnostic criteria. Results The adjusted prevalence of gestational diabetes mellitus increased by 2.8 times during 1999-2008, from 2.4 to 6.8% (P < 0.0001 for linear trend). In 2008, the age-specific prevalence of gestational diabetes mellitus was the highest among women aged 30-34 years (11.3%) and lowest among women aged 25 and under (1.2%). In women aged 35 years and more, the prevalence was 5.3%. Conclusions The prevalence of gestational diabetes mellitus has markedly been increasing in a universally screened urban Chinese female population and has become an important public health problem in China. C1 [Hu, G.] Pennington Biomed Res Ctr, Chron Dis Epidemiol Lab, Baton Rouge, LA 70808 USA. [Zhang, F.; Dong, L.; Zhang, C. P.; Li, B.; Wen, J.; Gao, W.; Sun, S.; Lv, F.; Tian, H.] Tianjin Womens & Childrens Hlth Ctr, Tianjin, Peoples R China. [Tuomilehto, J.] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Tuomilehto, J.] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Qi, L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Zhang, C. L.] NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Yu, Z.] Chinese Acad Sci, Key Lab Nutr & Metab, Inst Nutr Sci, Shanghai Inst Biol Sci,Grad Sch, Shanghai, Peoples R China. [Yang, X.] Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China. RP Hu, G (reprint author), Pennington Biomed Res Ctr, Chron Dis Epidemiol Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM yang.xilin@cuhk.edu.hk; gang.hu@pbrc.edu RI Hossain, Sarah /C-7332-2009 OI Hossain, Sarah /0000-0003-1355-0979 FU Tianjin Women's and Children's Health Center; European Foundation for the Study of Diabetes (EFSD)/Chinese Diabetes Society (CDS) FX This study was supported by grants from Tianjin Women's and Children's Health Center, and the European Foundation for the Study of Diabetes (EFSD)/ChineseDiabetes Society (CDS)/Lilly Programme for Collaborative Research between China and Europe. NR 30 TC 63 Z9 73 U1 2 U2 16 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0742-3071 J9 DIABETIC MED JI Diabetic Med. PD JUN PY 2011 VL 28 IS 6 BP 652 EP 657 DI 10.1111/j.1464-5491.2010.03205.x PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 764KS UT WOS:000290629000004 PM 21569085 ER PT J AU Lui, JC Baron, J AF Lui, Julian C. Baron, Jeffrey TI Mechanisms Limiting Body Growth in Mammals SO ENDOCRINE REVIEWS LA English DT Review ID CATCH-UP GROWTH; SKELETAL-MUSCLE MASS; OLIGODENDROCYTE PRECURSOR CELLS; MAJOR DEVELOPMENTAL TRANSITION; ESTROGEN-RECEPTOR-ALPHA; EARLY XENOPUS-EMBRYOS; LIVER-REGENERATION; PLATE SENESCENCE; POSTNATAL-GROWTH; MYOSTATIN GENE AB Recent studies have begun to provide insight into a long-standing mystery in biology-why body growth in animals is rapid in early life but then progressively slows, thus imposing a limit on adult body size. This growth deceleration in mammals is caused by potent suppression of cell proliferation in multiple tissues and is driven primarily by local, rather than systemic, mechanisms. Recent evidence suggests that this progressive decline in proliferation results from a genetic program that occurs in multiple organs and involves the down-regulation of a large set of growth-promoting genes. This program does not appear to be driven simply by time, but rather depends on growth itself, suggesting that the limit on adult body size is imposed by a negative feedback loop. Different organs appear to use different types of information to precisely target their adult size. For example, skeletal and cardiac muscle growth are negatively regulated by myostatin, the concentration of which depends on muscle mass itself. Liver growth appears to be modulated by bile acid flux, a parameter that reflects organ function. In pancreas, organ size appears to be limited by the initial number of progenitor cells, suggesting a mechanism based on cell-cycle counting. Further elucidation of the fundamental mechanisms suppressing juvenile growth is likely to yield important insights into the pathophysiology of childhood growth disorders and of the unrestrained growth of cancer. In addition, improved understanding of these growth-suppressing mechanisms may someday allow their therapeutic suspension in adult tissues to facilitate tissue regeneration. (Endocrine Reviews 32: 422-440, 2011) C1 [Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, CRC, Bethesda, MD 20892 USA. RP Baron, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, CRC, Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM jeffrey.baron@nih.gov RI Lui, Chun Kin Julian/E-2253-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 213 TC 41 Z9 46 U1 3 U2 28 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0163-769X J9 ENDOCR REV JI Endocr. Rev. PD JUN PY 2011 VL 32 IS 3 BP 422 EP 440 DI 10.1210/er.2011-0001 PG 19 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 767IL UT WOS:000290849300005 PM 21441345 ER PT J AU Li, S Bjelobaba, I Yan, ZH Kucka, M Tomic, M Stojilkovic, SS AF Li, Shuo Bjelobaba, Ivana Yan, Zonghe Kucka, Marek Tomic, Melanija Stojilkovic, Stanko S. TI Expression and Roles of Pannexins in ATP Release in the Pituitary Gland SO ENDOCRINOLOGY LA English DT Article ID CELL-CELL COMMUNICATION; GAP-JUNCTION PROTEINS; ANTERIOR-PITUITARY; P2X(7) RECEPTOR; FOLLICULOSTELLATE CELLS; GENE-EXPRESSION; CONNEXIN FAMILY; CHANNELS; HEMICHANNELS; RAT AB Pannexins are a newly discovered three-member family of proteins expressed in the brain and peripheral tissues that belong to the superfamily of gap junction proteins. However, in mammals pannexins do not form gap junctions, and their expression and function in the pituitary gland have not been studied. Here we show that the rat pituitary gland expresses mRNA and protein transcripts of pannexins 1 and 2 but not pannexin 3. Pannexin 1 was more abundantly expressed in the anterior lobe, whereas pannexin 2 was more abundantly expressed in the intermediate and posterior pituitary. Pannexin 1 was identified in corticotrophs and a fraction of somatotrophs, the S100-positive pituicytes of the posterior pituitary and AtT-20 (mouse pituitary adrenocorticotropin-secreting cells) and rat immortalized pituitary cells secreting prolactin, whereas pannexin 2 was detected in the S100-positive folliculostellate cells of the anterior pituitary, melanotrophs of the intermediate lobe, and vasopressin-containing axons and nerve endings in the posterior lobe. Overexpression of pannexins 1 and 2 in AtT-20 pituitary cells enhanced the release of ATP in the extracellular medium, which was blocked by the gap junction inhibitor carbenoxolone. Basal ATP release in At-T20 cells was also suppressed by down-regulating the expression of endogenous pannexin 1 but not pannexin 2 with their short interfering RNAs. These results indicate that pannexins may provide a pathway for delivery of ATP, which is a native agonist for numerous P2X cationic channels and G protein-coupled P2Y receptors endogenously expressed in the pituitary gland. (Endocrinology 152: 2342-2352, 2011) C1 [Li, Shuo; Yan, Zonghe; Kucka, Marek; Tomic, Melanija; Stojilkovic, Stanko S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Bjelobaba, Ivana] Univ Belgrade, Dept Neurobiol, Inst Biol Res Sinisa Stankovic, Belgrade 11000, Serbia. RP Stojilkovic, SS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Serbian Ministry of Science and Technology [41014] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and the Serbian Ministry of Science and Technology, project no. 41014. NR 51 TC 33 Z9 34 U1 0 U2 3 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 JUN PY 2011 VL 152 IS 6 BP 2342 EP 2352 DI 10.1210/en.2010-1216 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 766MY UT WOS:000290788500021 PM 21467198 ER PT J AU Otsuka, N Tong, ZB Vanevski, K Tu, W Cheng, MH Nelson, LM AF Otsuka, Noriyuki Tong, Zhi-Bin Vanevski, Konstantina Tu, Wei Cheng, Mickie H. Nelson, Lawrence M. TI Autoimmune Oophoritis with Multiple Molecular Targets Mitigated by Transgenic Expression of Mater SO ENDOCRINOLOGY LA English DT Article ID PREMATURE OVARIAN FAILURE; EARLY EMBRYONIC-DEVELOPMENT; THYMECTOMIZED MICE; SELF-TOLERANCE; MOUSE MATER; T-CELLS; DISEASE; ANTIGEN; INSUFFICIENCY; AUTOANTIGEN AB Primary ovarian insufficiency (POI) resulting from ovarian autoimmunity is a poorly understood clinical condition lacking in effective treatments. Understanding the targets of the autoimmune response and induction of ovarian-specific tolerance would allow development of focused therapies to preserve fertility in an at-risk population. MATER (maternal antigen that embryos require) is a known ovarian autoantigen targeted in autoimmune syndromes of POI. We attempt to induce ovarian-specific tolerance via transgenic expression of the MATER antigen on potentially tolerogenic antigen-presenting cells (APC), which typically present antigen via the major histocompatibility complex (MHC) class II molecule. We hypothesize that expression of MATER in a MHC class II-dependent manner on APC can mediate induction of ovarian tolerance. We utilized a well-characterized murine model of ovarian autoimmunity, whereby oophoritis develops after d 3 neonatal thymectomy (NTx). Wild-type and transgenic mice, carrying an MHC Class II-driven Mater gene (IE-Mater), were subjected to NTx and assessed for evidence of autoimmune oophoritis. After disease induction by NTx, female mice carrying the IE-Mater transgene had significant reductions in histological oophoritis (56%) and circulating ovarian autoantibodies (28%) compared with wild-type females (94% and 82%, respectively). Incidence of other autoimmunity was unaffected as assessed by antinuclear autoantibodies. Transgenic expression of MATER in APC can induce antigen-specific tolerance with a significant reduction in ovarian autoimmunity. Lack of complete disease protection suggests that other antigens may also play a role in autoimmune oophoritis. As a known autoantigen in the human APS1 (autoimmune polyglandular syndrome type 1), which is associated with POI, MATER may represent a relevant target for future diagnostic and therapeutic clinical interventions. (Endocrinology 152: 2465-2473, 2011) C1 [Cheng, Mickie H.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Otsuka, Noriyuki; Tong, Zhi-Bin; Vanevski, Konstantina; Tu, Wei; Nelson, Lawrence M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Integrat Reprod Med Grp, Intramural Res Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Cheng, MH (reprint author), Univ Calif San Francisco, Ctr Diabet, 513 Parnassus Ave,HSW 1102 Box 0540, San Francisco, CA 94143 USA. EM mickie.cheng@ucsf.edu FU National Institute of Child Health and Human Development, National Institutes of Health [K08HD058599] FX This work was supported in part by the Intramural Research Program, National Institute of Child Health and Human Development, National Institutes of Health. L.M.N. is a commissioned officer in the United States Public Health Service. M.H.C. is supported by funding from the National Institute of Child Health and Human Development, National Institutes of Health (Grant K08HD058599). NR 29 TC 11 Z9 11 U1 1 U2 3 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 JUN PY 2011 VL 152 IS 6 BP 2465 EP 2473 DI 10.1210/en.2011-0022 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 766MY UT WOS:000290788500033 PM 21447630 ER PT J AU Simon-Sanchez, J van Hilten, JJ van de Warrenburg, B Post, B Berendse, HW Arepalli, S Hernandez, DG de Bie, RMA Velseboer, D Scheffer, H Bloem, B van Dijk, KD Rivadeneira, F Hofman, A Uitterlinden, AG Rizzu, P Bochdanovits, Z Singleton, AB Heutink, P AF Simon-Sanchez, Javier van Hilten, Jacobus J. van de Warrenburg, Bart Post, Bart Berendse, Henk W. Arepalli, Sampath Hernandez, Dena G. de Bie, Rob M. A. Velseboer, Daan Scheffer, Hans Bloem, Bas van Dijk, Karin D. Rivadeneira, Fernando Hofman, Albert Uitterlinden, Andre G. Rizzu, Patrizia Bochdanovits, Zoltan Singleton, Andrew B. Heutink, Peter TI Genome-wide association study confirms extant PD risk loci among the Dutch SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE SNCA; BST1; GAK/DGKQ; HLA; MAPT; PD ID SPORADIC PARKINSONS-DISEASE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; POSITRON-EMISSION-TOMOGRAPHY; ALPHA-SYNUCLEIN PROMOTER; NIGRA PARS COMPACTA; TAU-GENE HAPLOTYPE; SUBSTANTIA-NIGRA; DOPAMINERGIC FUNCTION; REACTIVE MICROGLIA; MAPT REGION AB In view of the population-specific heterogeneity in reported genetic risk factors for Parkinson's disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514 799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P=1.63x10(-5), OR=1.325 and BST1, rs12502586: P=1.63x10(-3), OR=1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3' and 5' ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P=1.22x10(-4), OR=1.51; HLA, rs4248166: P=4.39x10(-5), OR=1.36; and MAPT, rs3785880: P=1.9x10(-3), OR=1.19). European Journal of Human Genetics (2011) 19, 655-661; doi:10.1038/ejhg.2010.254; published online 19 January 2011 C1 [Simon-Sanchez, Javier; Rizzu, Patrizia; Bochdanovits, Zoltan; Heutink, Peter] Vrije Univ Amsterdam, Med Ctr, Sect Med Genom, Dept Clin Genet, NL-1081 BT Amsterdam, North Holland, Netherlands. [van Hilten, Jacobus J.] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. [van de Warrenburg, Bart; Post, Bart; Bloem, Bas] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6525 ED Nijmegen, Netherlands. [Berendse, Henk W.; van Dijk, Karin D.] Vrije Univ Amsterdam, Med Ctr, Dept Neurol, NL-1081 BT Amsterdam, North Holland, Netherlands. [Arepalli, Sampath; Hernandez, Dena G.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [de Bie, Rob M. A.; Velseboer, Daan] Univ Amsterdam, Acad Med Ctr, Dept Neurol, NL-1105 AZ Amsterdam, Netherlands. [Scheffer, Hans] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Rivadeneira, Fernando; Hofman, Albert; Uitterlinden, Andre G.] Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. RP Simon-Sanchez, J (reprint author), Vrije Univ Amsterdam, Med Ctr, Sect Med Genom, Dept Clin Genet, NL-1081 BT Amsterdam, North Holland, Netherlands. EM j.simonsanchez@vumc.nl RI Singleton, Andrew/C-3010-2009; Scheffer, Hans/E-4644-2012; Bloem, Bastiaan/E-3812-2010; Bloem, B.R./H-8013-2014; Rivadeneira, Fernando/O-5385-2015; van de Warrenburg, Bart/D-1935-2010 OI Scheffer, Hans/0000-0002-2986-0915; Rivadeneira, Fernando/0000-0001-9435-9441; FU National Institute on Aging (National Institutes of Health, Department of Health and Human services) [Z01 AG000949 04] FX We thank the subjects involved in this study for making this work possible. We also want to thank the Hersenstichting Nederland (http://www.hersenstichting.nl), the Neuroscience Campus Amsterdam and the section of Medical genomics (MGA) and the Intramural Research Program of the National Institute on Aging (National Institutes of Health, Department of Health and Human services; project number Z01 AG000949 04) for supporting in part the work presented here. Last, we would like to thank the Prinses Beatrix Fonds (http://www.prinsesbeatrixfonds.nl) for sponsoring this work. NR 66 TC 92 Z9 95 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD JUN PY 2011 VL 19 IS 6 BP 655 EP 661 DI 10.1038/ejhg.2010.254 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 766FF UT WOS:000290765700006 PM 21248740 ER PT J AU Higley, AE Kiefer, SW Li, X Gaal, J Xi, ZX Gardner, EL AF Higley, Amanda E. Kiefer, Stephen W. Li, Xia Gaal, Jozsef Xi, Zheng-Xiong Gardner, Eliot L. TI Dopamine D-3 receptor antagonist SB-277011A inhibits methamphetamine self-administration and methamphetamine-induced reinstatement of drug-seeking in rats SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Methamphetamine; Dopamine D-3 receptor; SB-277011A; Self-administration; Reward; Reinstatement ID BRAIN-STIMULATION REWARD; COCAINE-SEEKING; PROGRESSIVE-RATIO; PHARMACOLOGICAL ACTIONS; REINFORCING EFFICACY; ANIMAL-MODELS; ADDICTION; BEHAVIOR; NGB-2904; AGONIST AB We have previously reported that selective blockade of brain dopamine D-3 receptors by SB-277011A significantly attenuates cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior. In the present study, we investigated whether SB-277011A similarly inhibits methamphetamine self-administration and methamphetamine-induced reinstatement to drug-seeking behavior. Male Long Evans rats were allowed to intravenously self-administer methamphetamine (0.05 mg/kg/infusion) under fixed-ratio 2 (FR2) or progressive-ratio (PR) reinforcement conditions, and some rats were tested for methamphetamine-induced reinstatement of drug-seeking behavior after extinction of self-administration. The effects of SB-277011A on each of these methamphetamine-supported behaviors were then tested. Acute intraperitoneal (i.p.) administration of SB-277011A failed to alter methamphetamine self-administration under FR2 reinforcement, but significantly lowered the break-point for methamphetamine self-administration under PR reinforcement. SB-277011A also significantly inhibited methamphetamine-triggered reinstatement of extinguished drug-seeking behavior. Overall, these data show that blockade of dopamine D-3 receptors by SB-277011A attenuates the rewarding and incentive motivational effects of methamphetamine in rats, supporting the development of selective dopamine D-3 antagonists for the treatment of methamphetamine addiction. Published by Elsevier B.V. C1 [Higley, Amanda E.; Li, Xia; Xi, Zheng-Xiong; Gardner, Eliot L.] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Higley, Amanda E.; Kiefer, Stephen W.] Kansas State Univ, Dept Psychol, Manhattan, KS 66506 USA. [Gaal, Jozsef] MegaPharma Pharmaceut Kft, Budapest, Hungary. RP Higley, AE (reprint author), 10550 N Torrey Pines Rd TPC-5, La Jolla, CA 92037 USA. EM ahigley@scripps.edu FU National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 57 TC 35 Z9 35 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JUN 1 PY 2011 VL 659 IS 2-3 BP 187 EP 192 DI 10.1016/j.ejphar.2011.02.046 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 766YO UT WOS:000290822700013 PM 21466803 ER PT J AU DeCherney, AH AF DeCherney, Alan H. TI There is no pimping at Harvard SO FERTILITY AND STERILITY LA English DT Editorial Material AB As I slowly close the door on this part of my career-but keeping the peephole open-I feel that the timing is perfect, that it's time for a new generation to have their influence. (Fertil Steril (R) 2011;95:2180-1. (C)2011 by American Society for Reproductive Medicine.) C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP DeCherney, AH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bldg 10,CRC,1 East,Rm 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM decherna@mail.nih.gov 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 JUN PY 2011 VL 95 IS 7 BP 2180 EP 2181 DI 10.1016/j.fertnstert.2011.04.087 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 766NT UT WOS:000290791000032 PM 21601664 ER PT J AU Louis, GMB Lum, KJ Sundaram, R Chen, Z Kim, S Lynch, CD Schisterman, EF Pyper, C AF Louis, Germaine M. Buck Lum, Kirsten J. Sundaram, Rajeshwari Chen, Zhen Kim, Sungduk Lynch, Courtney D. Schisterman, Enrique F. Pyper, Cecilia TI Stress reduces conception probabilities across the fertile window: evidence in support of relaxation SO FERTILITY AND STERILITY LA English DT Article DE Alpha amylase; conception; cortisol; fecundity; fertile window; stress ID SALIVARY ALPHA-AMYLASE; PSYCHOSOCIAL STRESS; MENSTRUAL-CYCLE; CORTISOL; PREGNANCY; ADOPTION; COUPLES; WOMEN AB Objective: To assess salivary stress biomarkers (cortisol and alpha-amylase) and female fecundity. Design: Prospective cohort design. Setting: United Kingdom. Patient(s): 274 women aged 18 to 40 years who were attempting pregnancy. Intervention(s): Observation for six cycles or until pregnancy: women collected basal saliva samples on day 6 of each cycle, and used fertility monitors to identify ovulation and pregnancy test kits for pregnancy detection. Main Outcome Measure(s): Salivary cortisol (mu g/dL) and alpha-amylase (U/mL) concentration measurements; fecundity measured by time-to-pregnancy and the probability of pregnancy during the fertile window as estimated from discrete-time survival and Bayesian modeling techniques, respectively. Result(s): Alpha-amylase but not cortisol concentrations were negatively associated with fecundity in the first cycle (fecundity odds ratio = 0.85; 95% confidence interval 0.67, 1.09) after adjusting for the couples' ages, intercourse frequency, and alcohol consumption. Statistically significant reductions in the probability of conception across the fertile window during the first cycle attempting pregnancy were observed for women whose salivary concentrations of alpha-amylase were in the upper quartiles in comparison with women in the lower quartiles (highest posterior density: -0.284; 95% interval -0.540, -0.029). Conclusion(s): Stress significantly reduced the probability of conception each day during the fertile window, possibly exerting its effect through the sympathetic medullar pathway. (Fertil Steril (R) 2011;95:2184-9. (C)2011 by American Society for Reproductive Medicine.) C1 [Louis, Germaine M. Buck; Lum, Kirsten J.; Sundaram, Rajeshwari; Chen, Zhen; Kim, Sungduk; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Lynch, Courtney D.] Ohio State Univ, Coll Publ Hlth & Med, Columbus, OH 43210 USA. [Pyper, Cecilia] Univ Oxford, Natl Perinatal Epidemiol Unit, Oxford, England. RP Louis, GMB (reprint author), NICHD, Epidemiol Branch, 6100 Execut Blvd,Room 7B05C, Rockville, MD 20852 USA. EM louisg@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002; Schisterman, Enrique/0000-0003-3757-641X; Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; U.K. National Health Service; DLM Charitable Trust; Unipath Corporation FX Supported in part by intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (partial support of data collection and for complete analysis of the salivary biomarkers); the U.K. National Health Service Executive Primary Care Career Scientist and Service Research and Development Awards (to principal investigator, C. P.); the DLM Charitable Trust (research team salaries); and the Unipath Corporation (fertility monitors, pregnancy tests, and related technical assistance for devices). NR 35 TC 36 Z9 38 U1 2 U2 20 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 JUN PY 2011 VL 95 IS 7 BP 2184 EP 2189 DI 10.1016/j.fertnstert.2010.06.078 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 766NT UT WOS:000290791000034 PM 20688324 ER PT J AU Hadnott, TN Gould, HN Gharib, AM Bondy, CA AF Hadnott, Tracy N. Gould, Harley N. Gharib, Ahmed M. Bondy, Carolyn A. TI Outcomes of spontaneous and assisted pregnancies in Turner syndrome: the US National Institutes of Health experience SO FERTILITY AND STERILITY LA English DT Article DE Fetal outcome; maternal risk; pregnancy; Turner syndrome ID OOCYTE DONATION; AORTIC DISSECTION; HIGH-RISK; 45,X KARYOTYPE; THE-LITERATURE; FERTILE WOMAN; PATIENT; WOMEN; PREVALENCE; OVARIES AB Objective: To assess fetal and maternal outcomes of pregnancies in women with Turner syndrome (TS). Design: Retrospective case series. Setting: Clinical research center. Patient(s): 276 adults with cytogenetically proven TS participating in an intramural natural history protocol. Intervention(s): None. Main Outcome Measure(s): Menstrual and obstetric histories, 50-cell karyotypes, and cardiovascular evaluation including aortic diameter measurements. Result(s): Our cohort included five women with spontaneous pregnancies and five with pregnancies using assisted reproduction (ART). All five women with spontaneous pregnancies had spontaneous puberty, despite 45, X in >= 90% of their 50-cell karyotype. Participants had a total of 13 pregnancies and 14 live births. One child had cerebral palsy; the others were chromosomally and developmentally normal. Delivery was by cesarean section in four out of seven spontaneous and six out of six ART-related pregnancies. One mother experienced preeclampsia in an ART-related twin pregnancy that required a preterm delivery; she has marked but stable aortic dilation years later. Conclusion(s): Approximately 2% of our study cohort experienced spontaneous pregnancies despite high-grade X monosomy, and a similar number achieved pregnancy via oocyte donation and ART. The potential for life-threatening cardiovascular complications warrants comprehensive screening before conception or single-embryo transfer, and caution regarding unintentional pregnancies for TS women. (Fertil Steril (R) 2011;95:2251-6. (C)2011 by American Society for Reproductive Medicine.) C1 [Hadnott, Tracy N.; Gould, Harley N.; Bondy, Carolyn A.] NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Hadnott, Tracy N.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Gharib, Ahmed M.] NIDDK, NIH, Bethesda, MD USA. RP Bondy, CA (reprint author), 10 CRC Hatfield Clin Res Ctr, 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM bondyc@mail.nih.gov RI Gharib, Ahmed/O-2629-2016 OI Gharib, Ahmed/0000-0002-2476-481X FU National Institutes of Health, Division of Intramural Research, Bethesda, Maryland [HD000628-18]; Howard Hughes Medical Institute (HHMI-NIH), Chevy Chase, Maryland FX Supported by National Institutes of Health, Division of Intramural Research, Bethesda, Maryland, grant no. HD000628-18; Research Scholar Program, Howard Hughes Medical Institute (HHMI-NIH), Chevy Chase, Maryland. NR 49 TC 44 Z9 47 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 JUN PY 2011 VL 95 IS 7 BP 2251 EP 2256 DI 10.1016/j.fertnstert.2011.03.085 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 766NT UT WOS:000290791000046 PM 21496813 ER PT J AU Goldman, KN Moon, KS Yauger, BJ Payson, MD Segars, JH Stegmann, BJ AF Goldman, Kara N. Moon, Kimberly S. Yauger, Belinda J. Payson, Mark D. Segars, James H. Stegmann, Barbara J. TI Proficiency in oocyte retrieval: how many procedures are necessary for training? SO FERTILITY AND STERILITY LA English DT Article DE Follicular aspiration; fellowship; competency; learning curve ID IN-VITRO FERTILIZATION; EMBRYO-TRANSFER; RELIABILITY; RESIDENTS; SKILLS; CURVE AB Objective: To determine a minimum number of procedures required for proficiency in oocyte retrieval and to characterize skill acquisition. Design: Retrospective analysis. Setting: Reproductive endocrinology and infertility fellowship training program. Subject(s): Fellows in training from 2005 to 2007 and 2008 to 2010. Intervention(s): None. Main Outcome Measure(s): Proficiency scores were calculated by dividing the number of oocytes retrieved by oocytes expected. The 2005 to 2007 trainees were grouped and proficiency scores calculated as an average during specific points in their training. The 2008 to 2010 trainees were compared individually to determine differences in individual skill acquisition. Result(s): A greater number of oocytes were retrieved than expected, 8.6 versus 7.6. A relatively lower proficiency score was noted during the first 10 trainee aspirations (proficiency score 1.1) compared with subsequent aspirations (proficiency score = 1.25 for retrievals 11-20, proficiency score = 1.21 for retrievals 21-30 and > 31). When individual fellows' scores were calculated, the majority achieved proficiency by 20 aspirations, and all but one trainee achieved the mean staff proficiency score by 50 retrievals. Conclusion(s): Regardless of a trainee's initial proficiency in oocyte retrieval, there were no statistically significant differences in the learning curve between trainees. The majority of individual fellows in training demonstrate proficiency in follicular aspirations within 20 procedures; however, a minority may require 50 procedures to achieve the proficiency of an attending physician. (Fertil Steril (R) 2011; 95: 2279-82. (C) 2011 by American Society for Reproductive Medicine.) C1 [Stegmann, Barbara J.] Univ Iowa Hosp & Clin, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Iowa City, IA 52246 USA. [Goldman, Kara N.; Moon, Kimberly S.; Yauger, Belinda J.; Payson, Mark D.; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Goldman, Kara N.] Northwestern Univ, Prentice Womens Hosp, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Payson, Mark D.] Walter Reed Army Med Ctr, Assisted Reprod Technol Program, Div Reprod Endocrinol & Infertil, Washington, DC 20307 USA. RP Stegmann, BJ (reprint author), Univ Iowa Hosp & Clin, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, 200 Hawkins Dr,31324 PFP, Iowa City, IA 52246 USA. EM Barbara-Stegmann@uiowa.edu OI Goldman, Kara/0000-0002-5455-627X FU National Institutes of Health; National Institute of Child Health and Human Development FX Supported by the Intramural Research Program of the National Institutes of Health, Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development. NR 16 TC 6 Z9 6 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 JUN PY 2011 VL 95 IS 7 BP 2279 EP 2282 DI 10.1016/j.fertnstert.2011.02.055 PG 4 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 766NT UT WOS:000290791000051 PM 21457969 ER PT J AU McCarthy-Keith, DM Malik, M Britten, J Segars, J Catherino, WH AF McCarthy-Keith, Desiree M. Malik, Minnie Britten, Joy Segars, James Catherino, William H. TI Gonadotropin-releasing hormone agonist increases expression of osmotic response genes in leiomyoma cells SO FERTILITY AND STERILITY LA English DT Article DE Leiomyoma; leuprolide acetate; myometrium; NFAT5; osmotic stress ID LEUPROLIDE ACETATE DEPOT; SMOOTH-MUSCLE-CELLS; UTERINE LEIOMYOMATA; TRANSCRIPTION FACTOR; DIFFERENTIAL EXPRESSION; HUMAN MYOMETRIUM; ANALOG THERAPY; UNITED-STATES; GNRH ANALOGS; DOUBLE-BLIND AB Objective: To characterize hyperosmolarity-responsive genes in leiomyoma cells and determine whether gonadotropin-releasing hormone (GnRH) agonist treatment altered their expression. Design: Laboratory study. Setting: University hospital. Patient(s): None. Intervention(s): Cell culture under hypertonic conditions and with GnRH agonist treatment, RNA isolation, and real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Main Outcome Measure(s): Expression of nuclear factor of activated T cells 5 (NFAT5), aldose reductase (AR), and sodium myo-inositol transporter 1 (SMIT) messenger RNA (mRNA) in immortalized leiomyoma and patient-matched myometrial cells. Result(s): Leiomyoma cells had increased basal expression of NFAT5 mRNA (1.7 +/- 0.08-fold) compared with myometrial cells. The NFAT5 increased further in leiomyoma cells cultured under hyperosmolar conditions (3.0 +/- 0.46-fold at 50 mM NaCl and 3.3 +/- 0.48-fold at 100 mM NaCl). The NFAT5-regulated mRNA transcripts for AR and SMIT were increased in untreated leiomyoma cells compared with myometrial cells and further increased in leiomyoma cells exposed to osmotic stress. The NFAT5 transcripts were decreased with low-dose GnRH agonist treatment but increased with supraphysiologic doses. Conclusion(s): Expression of hyperosmolarity genes was increased in leiomyoma cells relative to myometrial cells. Pharmacologic concentrations of GnRH agonist decreased NFAT5 expression, suggesting that water flows out of leiomyoma cells at pharmacologic doses. (Fertil Steril (R) 2011; 95: 2383-7. (C) 2011 by American Society for Reproductive Medicine.) C1 [McCarthy-Keith, Desiree M.; Malik, Minnie; Britten, Joy; Segars, James; Catherino, William H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [McCarthy-Keith, Desiree M.; Segars, James; Catherino, William H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Catherino, WH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bldg A,Room 3078,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM wcatherino@usuhs.mil OI Malik, Minnie/0000-0003-1129-6575 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Ferring Pharmaceuticals FX Supported in part by the Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and a research grant by Ferring Pharmaceuticals. NR 43 TC 14 Z9 14 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 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2011 VL 95 IS 7 BP 2383 EP 2387 DI 10.1016/j.fertnstert.2011.03.084 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 766NT UT WOS:000290791000070 PM 21496801 ER PT J AU Ejiogu, N Norbeck, JH Mason, MA Cromwell, BC Zonderman, AB Evans, MK AF Ejiogu, Ngozi Norbeck, Jennifer H. Mason, Marc A. Cromwell, Bridget C. Zonderman, Alan B. Evans, Michele K. TI Recruitment and Retention Strategies for Minority or Poor Clinical Research Participants: Lessons From the Healthy Aging in Neighborhoods of Diversity Across the Life Span Study SO GERONTOLOGIST LA English DT Article DE Cultural proficiency; Health disparities; Community-based research platform ID COMMUNITY-BASED RESEARCH; UNDERREPRESENTED POPULATIONS; AFRICAN-AMERICANS; EMERGENCY-DEPARTMENT; SOCIOECONOMIC-STATUS; BARRIERS; TRIALS; DISPARITIES; ADULTS; URBAN AB Purpose of the study: Investigating health disparities requires studies designed to recruit and retain racially and socioeconomically diverse cohorts. It is critical to address the barriers that disproportionately affect participation in clinical research by minorities and the socioeconomically disadvantaged. This study sought to identify and rectify these barriers to recruit and retain a biracial (African American and non-Hispanic White) and socioeconomically diverse cohort for a longitudinal study. Design and Method: The Healthy Aging in Neighborhoods of Diversity across the Life Span study is a 20-year longitudinal examination of how race and socioeconomic status influence the development of age-related health disparities. One goal was to create a multifactorial recruitment and retention strategy. The recruitment paradigm targeted known barriers and identified those unique to the study's urban environment. The retention paradigm mirrored the recruitment plan but was based on specifically developed approaches. Results: This cohort recruitment required attention to developing community partnerships, designing the research study to meet the study hypotheses and to provide benefit to participants, providing a safe community-based site for the research and creating didactics to develop staff cultural proficiency. These efforts facilitated study implementation and enhanced recruitment resulting in accrual of a biracial and socioeconomically diverse cohort of 3,722 participants. Implications: Recruiting and retaining minority or poor research participants is challenging but possible. The essential facets include clear communication of the research hypothesis, focus on providing a direct benefit for participants, and selection of a hypothesis that is directly relevant to the community studied. C1 [Ejiogu, Ngozi; Norbeck, Jennifer H.; Mason, Marc A.; Cromwell, Bridget C.; Zonderman, Alan B.; Evans, Michele K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH,NIH Biomed Res Ctr, Baltimore, MD 21224 USA. [Mason, Marc A.; Cromwell, Bridget C.] MedStar Hlth Res Inst, Hyattsville, MD USA. RP Evans, MK (reprint author), NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH,NIH Biomed Res Ctr, 251 Bayview Blvd,Suite 100,Room 4C-222, Baltimore, MD 21224 USA. OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS NR 43 TC 56 Z9 56 U1 1 U2 24 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD JUN PY 2011 VL 51 SU 1 BP S33 EP S45 DI 10.1093/geront/gnr027 PG 13 WC Gerontology SC Geriatrics & Gerontology GA 764EL UT WOS:000290611300005 PM 21565817 ER PT J AU Sood, JR Stahl, SM AF Sood, Johanna R. Stahl, Sidney M. TI Community Engagement and the Resource Centers for Minority Aging Research SO GERONTOLOGIST LA English DT Editorial Material ID CLINICAL-TRIALS; RECRUITMENT AB The National Institute on Aging created the Resource Centers for Minority Aging Research (RCMARs) to address infrastructure development intended to reduce health disparities among older adults. The overall goals of the RCMARs are to (a) increase the size of the cadre of researchers conducting research on issues related to minority aging; (b) increase the diversity of researchers conducting research on minority aging; (c) create and test reliable measures for use in older diverse populations; and (d) conduct research on recruitment and retention of community-dwelling older adults for research addressing behavioral, social, and medical issues. Along with this latter goal, the RCMARs developed and maintain academic-community partnerships. To accomplish the recruitment and retention goal, the RCMARs established Community Liaison Working Groups using a collaborative approach to scientific inquiry; this special issue will identify research priorities for moving the science of recruitment and retention forward. In addition, sustainable and efficient methods for fostering long-term partnerships will be identified between community and academia. Evidence-based approaches to the recruitment and retention of diverse elders are explored. We expect this supplement to serve as a catalyst for researchers interested in engaging diverse community-dwelling elders in health-related research. In addition, this supplement should serve as a source of the most contemporary evidence-based approaches to the recruitment and retention of diverse older populations for participation in social, behavioral, and clinical research. C1 [Sood, Johanna R.; Stahl, Sidney M.] NIA, Div Behav & Social Res, NIH, Bethesda, MD 20892 USA. RP Stahl, SM (reprint author), NIA, Div Behav & Social Res, NIH, 7201 Wisconsin Ave,Suite 533, Bethesda, MD 20892 USA. EM sidney_stahl@nih.gov NR 7 TC 8 Z9 8 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD JUN PY 2011 VL 51 SU 1 BP S5 EP S7 DI 10.1093/geront/gnr036 PG 3 WC Gerontology SC Geriatrics & Gerontology GA 764EL UT WOS:000290611300002 PM 21565819 ER PT J AU Geier, H Celli, J AF Geier, Henriette Celli, Jean TI Phagocytic Receptors Dictate Phagosomal Escape and Intracellular Proliferation of Francisella tularensis SO INFECTION AND IMMUNITY LA English DT Article ID MACROPHAGE MANNOSE RECEPTOR; MURINE MACROPHAGES; RESPIRATORY BURST; MYCOBACTERIUM-TUBERCULOSIS; MOUSE MACROPHAGES; HUMAN NEUTROPHILS; SERUM; LVS; ACIDIFICATION; SURVIVAL AB Francisella tularensis, the causative agent of tularemia, survives and proliferates within macrophages of the infected host as part of its pathogenic strategy, through an intracellular life cycle that includes phagosomal escape and extensive proliferation within the macrophage cytosol. Various in vitro models of Francisella-macrophage interactions have been developed, using either opsonic or nonopsonic phagocytosis, and have generated discrepant results on the timing and extent of Francisella phagosomal escape. Here we have investigated whether either complement or antibody opsonization of the virulent prototypical type A strain Francisella tularensis subsp. tularensis Schu S4 affects its intracellular cycle within primary murine bone marrow-derived macrophages. Opsonization of Schu S4 with either human serum or purified IgG enhanced phagocytosis but restricted phagosomal escape and intracellular proliferation. Opsonization of Schu S4 with either fresh serum or purified antibodies redirected bacteria from the mannose receptor (MR) to the complement receptor CR3, the scavenger receptor A (SRA), and the Fc gamma receptor (Fc gamma R), respectively. CR3-mediated uptake delayed maturation of the early Francisella-containing phagosome (FCP) and restricted phagosomal escape, while Fc gamma R-dependent phagocytosis was associated with superoxide production in the early FCP and restricted phagosomal escape and intracellular growth in an NADPH oxidase-dependent manner. Taken together, these results demonstrate that opsonophagocytic receptors alter the intracellular fate of Francisella by delivering bacteria through phagocytic pathways that restrict phagosomal escape and intracellular proliferation. C1 [Geier, Henriette; Celli, Jean] NIAID, Tularemia Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Celli, J (reprint author), NIAID, Tularemia Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM jcelli@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 45 TC 37 Z9 37 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2011 VL 79 IS 6 BP 2204 EP 2214 DI 10.1128/IAI.01382-10 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 765LJ UT WOS:000290707200007 PM 21422184 ER PT J AU Kamino, H Yamazaki, Y Saito, K Takizawa, D Kakizaki, S Moore, R Negishi, M AF Kamino, Hiroki Yamazaki, Yuichi Saito, Kosuke Takizawa, Daich Kakizaki, Satoru Moore, Rick Negishi, Masahiko TI Nuclear receptor CAR-regulated expression of the FAM84A gene during the development of mouse liver tumors SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE CAR; nuclear receptor; FAM84A; phenobarbital; liver cancer; non-genotoxic carcinogenesis ID HEPATOCELLULAR-CARCINOMA; MICE; HEPATOCARCINOGENESIS; RAT; CYTOCHROME-P450; PROMOTION; ENZYMES; STRAIN; PXR AB The nuclear xenobiotic receptor CAR is a phenobarbital (PB)-activated transcription factor. Using a mouse model of two-step liver tumorigenesis, in which tumor growth was initiated by diethyl nitrosamine (DEN) and promoted by chronic treatment with PB, we previously demonstrated that tumors developed only in the presence of CAR. Here, we have identified the FAM84A (family with sequence similarity 84, member A) gene as a CAR-regulated gene that is over-expressed during development of phenobarbital-promoted mouse liver tumors. FAM84A mRNA was induced in the liver of DEN/PB-treated mice prior to the development of liver tumors and this induction continued in the non-tumor as well as tumor tissues of a tumor-bearing liver. Western blotting demonstated that FAM84A protein expression increased in mouse liver after PB treatment; however, the FAM84A protein in liver and liver tumors was not phosphorylated at the serine 38 residue, which has been reported to correlate with morphological changes in cells. Immunohistochemistry analysis revealed the cytoplasmic localization of FAM84A protein and its expression during tumor development in normal tissues (especially in hepatocytes around the central vein), eosinophilic foci, adenomas and carcinomas. HepG2 cell-based reporter assays indicated that CAR activated the FAM84A promoter. Exogenous over-expression of FAM84A in HepG2 cells resulted in increased cell migration. The physiological function of FAM84A remains unknown, but our results suggest that FAM84A is up-regulated by CAR during the development of liver tumors, and may play an important role in the progression of liver cancer by increasing cell migration. C1 [Kamino, Hiroki; Yamazaki, Yuichi; Saito, Kosuke; Moore, Rick; Negishi, Masahiko] NIEHS, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Takizawa, Daich; Kakizaki, Satoru] Gunma Univ, Grad Sch Med, Dept Med & Mol Sci, Gunma 3718511, Japan. RP Negishi, M (reprint author), NIEHS, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU National Institutes of Health; National Institute of Environmental Health Sciences [Z01ES1005-01] FX This research was supported by the Intramural Research Program of the National Institutes of Health, and National Institute of Environmental Health Sciences, Z01ES1005-01. We would like to acknowledge the efforts of all the staff of the NIEHS DNA Sequencing Core and Immunohistochemistry Core. We especially thank for Dr Todd Painter for valuable immunohistological discussion. NR 25 TC 3 Z9 4 U1 0 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JUN PY 2011 VL 38 IS 6 BP 1511 EP 1520 DI 10.3892/ijo.2011.980 PG 10 WC Oncology SC Oncology GA 764AV UT WOS:000290601700004 PM 21424122 ER PT J AU Housri, N Ning, H Ondos, J Choyke, P Camphausen, K Citrin, D Arora, B Shankavaram, U Kaushal, A AF Housri, Nadine Ning, Holly Ondos, John Choyke, Peter Camphausen, Kevin Citrin, Deborah Arora, Barbara Shankavaram, Uma Kaushal, Aradhana TI PARAMETERS FAVORABLE TO INTRAPROSTATIC RADIATION DOSE ESCALATION IN MEN WITH LOCALIZED PROSTATE CANCER SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE IMRT; Prostate cancer; Dose escalation; Radiotherapy; Treatment planning ID INTENSITY-MODULATED RADIOTHERAPY; 3-DIMENSIONAL CONFORMAL RADIOTHERAPY; SIMULTANEOUS INTEGRATED BOOST; DISTANT METASTASES; TUMOR-CONTROL; 90 GY; MRI; IMRT; TOXICITY; LESIONS AB Purpose: To identify, within the framework of a current Phase I trial, whether factors related to intraprostatic cancer lesions (IPLs) or individual patients predict the feasibility of high-dose intraprostatic irradiation. Methods and Materials: Endorectal coil MRI scans of the prostate from 42 men were evaluated for dominant IPLs. The IPLs, prostate, and critical normal tissues were contoured. Intensity-modulated radiotherapy plans were generated with the goal of delivering 75.6 Gy in 1.8-Gy fractions to the prostate, with IPLs receiving a simultaneous integrated boost of 3.6 Gy per fraction to a total dose of 151.2 Gy, 200% of the prescribed dose and the highest dose cohort in our trial. Rectal and bladder dose constraints were consistent with those outlined in current Radiation Therapy Oncology Group protocols. Results: Dominant IPLs were identified in 24 patients (57.1%). Simultaneous integrated boosts (SIB) to 200% of the prescribed dose were achieved in 12 of the 24 patients without violating dose constraints. Both the distance between the IPL and rectum and the hip-to-hip patient width on planning CT scans were associated with the feasibility to plan an SIB (p = 0.002 and p = 0.0137, respectively). Conclusions: On the basis of this small cohort, the distance between an intraprostatic lesion and the rectum most strongly predicted the ability to plan high-dose radiation to a dominant intraprostatic lesion. High-dose SIB planning seems possible for select intraprostatic lesions. (C) 2011 Elsevier Inc. C1 [Housri, Nadine; Ning, Holly; Ondos, John; Camphausen, Kevin; Citrin, Deborah; Arora, Barbara; Shankavaram, Uma; Kaushal, Aradhana] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Choyke, Peter] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kaushal, A (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bldg 10 CRC,B2-3561, Bethesda, MD 20892 USA. EM kaushala@mail.nih.gov FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; NIH; Pfizer Inc FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research.; N.H. was supported through the Clinical Research Training Program, a public private partnership supported jointly by the NIH and Pfizer Inc (via a grant to the Foundation for NIH from Pfizer Inc). NR 37 TC 19 Z9 19 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 JUN 1 PY 2011 VL 80 IS 2 BP 614 EP 620 DI 10.1016/j.ijrobp.2010.06.050 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 767EC UT WOS:000290837100040 PM 20932672 ER PT J AU Harman, JL Griswold, ME Jeffries, NO Sumner, AE Sarpong, DF Akylbekova, EL Walker, ER Wyatt, SB Taylor, HA AF Harman, Jane L. Griswold, Michael E. Jeffries, Neal O. Sumner, Anne E. Sarpong, Daniel F. Akylbekova, Ermeg L. Walker, Evelyn R. Wyatt, Sharon B. Taylor, Herman A., Jr. TI Age is positively associated with high-density lipoprotein cholesterol among African Americans in cross-sectional analysis: The Jackson Heart Study SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Article DE African Americans; Aging; Cohort studies; Epidemiology; High-density lipoprotein cholesterol; Triglycerides ID BLACK-WHITE DIFFERENCES; DISEASE RISK-FACTORS; CARDIOVASCULAR-DISEASE; HDL CHOLESTEROL; EVANS COUNTY; LIFE-STYLE; LIPIDS; DECREASE; EFFLUX; SERUM AB BACKGROUND: African Americans have historically had high high-density lipoprotein cholesterol (HDL-C) compared with other races and ethnicities. OBJECTIVE: We sought to characterize whether there is a cross-sectional association between age and HDL-C in a contemporary community-based study of African Americans. METHODS: Cross-sectional data were modeled by logistic regression for predictors of HDL-C among African Americans, ages 35-74, participating in the baseline examination of a community-based study of cardiovascular disease in Jackson, Mississippi, during 2000-2004. After excluding persons taking lipid-lowering medications, hormone replacement therapy, oral contraceptives, or thyroid replacement, the analytical data set comprised 2420 persons (1370 women, 1050 men). RESULTS: HDL-C had a significant positive association with age after controlling for serum triglycerides, sex, waist circumference, percent dietary calories from carbohydrates, alcohol use, and leisure physical activity. Sex was a significant effect modifier of this relationship, whereby the increase in HDL-C with age was steeper for women than for men. CONCLUSIONS: Cross-sectional analysis found a positive association of HDL-C with age while controlling for triglycerides. Careful evaluation of longitudinal data will be needed to confirm whether this is a true effect of aging, or a cohort or survivor effect. Published by Elseiver Inc on behalf of National Lipid Association. C1 [Harman, Jane L.] NHLBI, Program Prevent & Populat Sci, Div Cardiovasc Sci, NIH, Bethesda, MD 20982 USA. [Griswold, Michael E.; Wyatt, Sharon B.; Taylor, Herman A., Jr.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Jeffries, Neal O.] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bethesda, MD 20982 USA. [Sumner, Anne E.] NIDDK, NIH, Bethesda, MD USA. [Sarpong, Daniel F.; Akylbekova, Ermeg L.; Taylor, Herman A., Jr.] Jackson State Univ, Jackson, MS USA. [Taylor, Herman A., Jr.] Tougaloo Coll, Tougaloo, MS USA. RP Harman, JL (reprint author), NHLBI, Program Prevent & Populat Sci, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Suite 10018, Bethesda, MD 20982 USA. EM harmanj@mail.nih.gov FU National Institutes of Health, National Heart, Lung and Blood Institute [N01-HC-95170, N01-HC-95171, N01-HC-95172]; National Institutes of Health, National Institute for Minority Health and Health Disparities; National Institute of Diabetes and Digestive and Kidney Diseases FX The Jackson Heart Study is conducted by the Jackson State University, the University of Mississippi Medical Center, and Tougaloo College and is supported by National Institutes of Health contracts N01-HC-95170, N01-HC-95171, and N01-HC-95172 from the National Heart, Lung and Blood Institute and the National Institute for Minority Health and Health Disparities. Anne E. Sumner is supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 30 TC 3 Z9 3 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD JUN PY 2011 VL 5 IS 3 BP 173 EP 178 DI 10.1016/j.jacl.2011.02.002 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 765YP UT WOS:000290745600008 PM 21600522 ER PT J AU Reed, RM Iacono, A DeFilippis, A Eberlein, M Girgis, RE Jones, S AF Reed, Robert M. Iacono, Aldo DeFilippis, Andrew Eberlein, Michael. Girgis, Reda E. Jones, Steven TI Advanced chronic obstructive pulmonary disease is associated with high levels of high-density lipoprotein cholesterol SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article DE HDL; COPD; phospholipid transfer protein; lung transplantation ID ATHEROSCLEROSIS; APOLIPOPROTEINS; TORCETRAPIB; PLASMA; ADULTS; LIPIDS; RISK; HDL AB BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory systemic disease associated with numerous extrapulmonary manifestations. Amongst these is an increased risk for cardiovascular disease. The mechanisms for this association remain unclear. We sought to examine lipid trends in a well-characterized cohort of patients with severe COPD. METHODS: We conducted a retrospective prospective analysis of 126 consecutive individuals evaluated for lung transplantation with a diagnosis of COPD in whom lipid values were available. Observed lipid values were compared with a reference population without severe COPD. RESULTS: Compared with the reference population, mean low-density lipoprotein cholesterol (LDL-C) levels were slightly reduced at 108 +/- 44 vs 117 +/- 29.5 mg/dl (p = 0.02) in men but were no different in women. Mean high-density lipoprotein cholesterol (HDL-C) levels were significantly elevated at 62 +/- 24 vs 45 +/- 12 mg/dl (p < 0.0001) in men and at 83 +/- 27 vs 59 +/- 16 mg/dl in women (p < 0.0001). Prednisone use correlated with higher HDL-C levels but did not fully explain the extent of elevation. Angiographically proven coronary artery disease was found in 61% of individuals and was unrelated to HDL-C levels. CONCLUSIONS: Severe COPD is associated with increased levels of HDL-C, which is partially attributable to oral steroid use. HDL-C in this population is not associated with reduced risk of angiographically proven coronary artery disease. J Heart Lung Transplant 2011;30:674-8 (C) 2011 International Society for Heart and Lung Transplantation. All rights reserved. C1 [Reed, Robert M.; Iacono, Aldo] Univ Maryland, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21201 USA. [DeFilippis, Andrew; Jones, Steven] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Eberlein, Michael.; Girgis, Reda E.] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD USA. [Eberlein, Michael.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Reed, RM (reprint author), Univ Maryland Phys, Div Pulm & Crit Care Med, 110 S Paca St,2nd Flr, Baltimore, MD 21201 USA. EM rreed@medicine.umaryland.edu NR 30 TC 11 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD JUN PY 2011 VL 30 IS 6 BP 674 EP 678 DI 10.1016/j.healun.2010.12.010 PG 5 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 767DD UT WOS:000290834600010 PM 21306919 ER PT J AU Martinu, T Kinnier, CV Gowdy, KM Kelly, FL Snyder, LD Jiang, DH Foster, WM Garantziotis, S Belperio, JA Noble, PW Palmer, SM AF Martinu, Tereza Kinnier, Christine V. Gowdy, Kymberly M. Kelly, Francine L. Snyder, Laurie D. Jiang, Dianhua Foster, W. Michael Garantziotis, Stavros Belperio, John A. Noble, Paul W. Palmer, Scott M. TI Innate immune activation potentiates alloimmune lung disease independent of chemokine (C-X-C motif) receptor 3 SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article DE pulmonary graft-versus-host disease; lung rejection; CXCR3; lipopolysaccharide; innate immunity ID STEM-CELL TRANSPLANTATION; ACUTE ALLOGRAFT-REJECTION; INHALED LIPOPOLYSACCHARIDE; BRONCHIOLITIS OBLITERANS; CARDIAC ALLOGRAFT; T-CELLS; CXCR3; SURVIVAL; PATHOGENESIS; LYMPHOCYTES AB BACKGROUND: Pulmonary graft-versus-host disease (GVHD) after hematopoietic cell transplant (HCT) and allograft rejection after lung transplant are parallel immunologic processes that lead to significant morbidity and mortality. Our murine model of pulmonary GVHD after inhaled lipopolysaccharide (LPS) suggests that innate immune activation potentiates pulmonary transplant-related alloimmunity. We hypothesized that the chemokine (C-X-C motif) receptor 3 (CXCR3) receptor is necessary for the development of LPS-induced pulmonary GVHD. METHODS: Recipient mice underwent allogeneic or syngeneic HCT, followed by inhaled LPS. CXCR3 inhibition was performed by using CXCR3-knockout donors or by systemic anti-CXCR3 antibody blockade. Pulmonary histopathology, cellular sub-populations, cytokine proteins, and transcripts were analyzed. RESULTS: Compared with the lungs of LPS-unexposed and syngeneic controls, lungs of LPS-exposed allogeneic HCT mice demonstrated prominent lymphocytic pen-vascular and peri-bronchiolar infiltrates. This pathology was associated with increased CD4(+) and CD8(+) T cells as well as an increase in CXCR3 expression on T cells, a 2-fold upregulation of CXCR3 transcript, and a 4-fold increase in its ligand CXCL10/Interferon gamma-induced protein 10 kDa (IP-10). CXCR3 inhibition using gene-knockout strategy or antibody blockade did not change the severity of pulmonary pathology, with a mean pathology score of 6.5 for sufficient vs 6.5 for knockout (p = 1.00) and a mean score of 6.8 for antibody blockade vs 7.4 for control (p = 0.46). CXCR3 inhibition did not prevent CD3 infiltration or prevent production of interleukin-12p40 or significantly change other Th1, Th2., or Th17 cytokines in the lung. CONCLUSIONS: In the setting of allogeneic HCT, innate immune activation by LPS potentiates pulmonary GVHD through CXCR3-independent mechanisms. Clinical strategies focused on inhibition of CXCR3 may prove insufficient to ameliorate transplant-related lung disease. J Heart Lung Transplant 2011;30:717-25 (C) 2011 International Society for Heart and Lung Transplantation. All rights reserved. C1 [Martinu, Tereza; Kinnier, Christine V.; Gowdy, Kymberly M.; Kelly, Francine L.; Snyder, Laurie D.; Jiang, Dianhua; Foster, W. Michael; Noble, Paul W.; Palmer, Scott M.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Garantziotis, Stavros] NIEHS, Res Triangle Pk, NC 27709 USA. [Belperio, John A.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. RP Martinu, T (reprint author), Duke Univ, Med Ctr, Dept Med, 106 Res Dr,Bldg MSRB2,Ste 2073-2,DUMC Box 103000, Durham, NC 27710 USA. EM tereza.martinu@duke.edu RI Jiang, Dianhua/B-1421-2009; Garantziotis, Stavros/A-6903-2009 OI Jiang, Dianhua/0000-0002-4508-3829; Garantziotis, Stavros/0000-0003-4007-375X FU International Society for Heart and Lung Transplantation [6860201585]; National Institutes of Health [1P50-HL084917-01, 1F32HL090265-01, RR024 127-03, 1 K24 HL91140-01A2] FX This work was supported by a research award from the International Society for Heart and Lung Transplantation 6860201585 to Dr Martinu, and by National Institutes of Health Grants 1P50-HL084917-01, project 3, to Dr Palmer and a training grant to Dr Martinu; 1F32HL090265-01 to Dr Martinu, RR024 127-03 to Dr Martinu, and 1 K24 HL91140-01A2 to Dr Palmer. NR 33 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD JUN PY 2011 VL 30 IS 6 BP 717 EP 725 DI 10.1016/j.healun.2011.01.711 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 767DD UT WOS:000290834600016 PM 21444213 ER PT J AU Feng, Y Broder, CC Kennedy, PE Berger, EA AF Feng, Yu Broder, Christopher C. Kennedy, Paul E. Berger, Edward A. TI HIV-1 Entry Cofactor: Functional cDNA Cloing of a Seven-Transmembrane, G protein-Coupled Receptor SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFECTION; CELLS; FUSION; BRAIN AB A cofactor for HIV-1 (human immunodeficiency virus-type 1) fusion and entry was identified with the use of a novel functional complementary DNA (cDNA) cloning strategy. This protein, designated "fusin," is a putative G protein-coupled receptor with seven transmembrane segments. Recombinant fusin enabled CD4-expressing nonhuman cell types to support HIV-1 Env-mediated cell fusion and HIV-1 infection. Antibodies to fusin blocked cell fusion and infection with normal CD4-positive human target cells. Fusin messenger RNA levels correlated with HIV-1 permissiveness in diverse human cell types. Fusin acted preferentially for T cell line-tropic isolates, in comparison to its activity with macrophage-tropic HIV-1 isolates. C1 [Feng, Yu; Broder, Christopher C.; Kennedy, Paul E.; Berger, Edward A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Berger, EA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. FU National Research Council; NIH FX Y.F. is a recipient of a National Research Council Research Associated fellowship, and C.C.B. is a recipient of an NIH Intramural Research Training Award. Support was provided by the NIH Intramural AIDS Targeted Antiviral Program. We are grateful to P. Clapham and R. Weiss, Chesler Beathy Laboratories. Institute for Cancer Research, London, for donation of the CD4+ transformant of Mv 1 oratory of Molecular Structure, NIAID, for synthetic peptide synthesis, purification and coupling and to J. Sister, Laboratory for Viral Diseases, NIAID for oligonucleotide synthesis and assistance with DNA sequencing. We thank P. Murphy, NIAID, and B. Moss, NIAID, for helpful discussions and comments on the manuscript. NR 43 TC 1 Z9 1 U1 1 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2011 VL 186 IS 11 BP 872 EP 877 DI 10.1126/science.272.5263.872 PG 6 WC Immunology SC Immunology GA 766BX UT WOS:000290755700004 ER PT J AU Bonnefoy, F Couturier, M Clauzon, A Remy-Martin, JP Gaugler, B Tiberghien, P Chen, WJ Saas, P Perruche, S AF Bonnefoy, Francis Couturier, Melanie Clauzon, Amandine Remy-Martin, Jean-Paul Gaugler, Beatrice Tiberghien, Pierre Chen, Wanjun Saas, Philippe Perruche, Sylvain TI TGF-beta-Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; REGULATORY T-CELLS; COLLAGEN-INDUCED ARTHRITIS; PROSTAGLANDIN E-2; CUTTING EDGE; I INTERFERON; LYMPH-NODES; MOUSE; DIFFERENTIATION; TOLERANCE AB TGF-beta is required for both Foxp3(+) regulatory T cell (Treg) and Th17 commitment. Plasmacytoid DCs (pDC) have been shown to participate to both Treg and Th17 commitment as well. However, few studies have evaluated the direct effect of TGF-beta on pDC, and to our knowledge, no study has assessed the capacity of TGF-beta-exposed pDC to polarize naive CD4(+) T cells. In this paper, we show that TGF-beta-treated pDC favor Th17 but not Treg commitment. This process involves a TGF-beta/Smad signal, because TGF-beta treatment induced Smad2 phosphorylation in pDC and blockade of TGF-beta signaling with the SD208 TGF-beta RI kinase inhibitor abrogated Th17 commitment induced by TGF-beta b-treated pDC. Moreover, TGF-beta mRNA synthesis and active TGF-beta release were induced in TGF-beta-treated pDC and anti-TGF-beta Ab blocked Th17 commitment. Unexpectedly, TGF-beta treatment also induced increased IL-6 production by pDC, which serves as the other arm for Th17 commitment driven by TGF-beta-exposed pDC, because elimination of IL-6-mediated signal with either IL-6- or IL-6R alpha-specific Abs prevented Th17 commitment. The in vivo pathogenic role of TGF-beta-treated pDC was further confirmed in the Th17-dependent collagen-induced arthritis model in which TGF-beta-treated pDC injection significantly increased arthritis severity and pathogenic Th17 cell accumulation in the draining lymph nodes. Thus, our data reveal a previously unrecognized effect of TGF-beta-rich environment on pDC ability to trigger Th17 commitment. Such findings have implications in the pathogenesis of autoimmune diseases or immune responses against mucosal extracellular pathogens. The Journal of Immunology, 2011, 186: 6157-6164. C1 [Bonnefoy, Francis; Couturier, Melanie; Clauzon, Amandine; Remy-Martin, Jean-Paul; Gaugler, Beatrice; Tiberghien, Pierre; Saas, Philippe; Perruche, Sylvain] INSERM, Unite Mixte Rech 645, F-25020 Besancon, France. [Bonnefoy, Francis; Couturier, Melanie; Clauzon, Amandine; Remy-Martin, Jean-Paul; Gaugler, Beatrice; Tiberghien, Pierre; Saas, Philippe; Perruche, Sylvain] Univ Franche Comte, Inst Federatif Rech 133, F-25020 Besancon, France. [Bonnefoy, Francis; Couturier, Melanie; Clauzon, Amandine; Remy-Martin, Jean-Paul; Gaugler, Beatrice; Tiberghien, Pierre; Saas, Philippe; Perruche, Sylvain] Etab Francais Sang Bourgogne Franche Comte, F-25020 Besancon, France. [Chen, Wanjun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Perruche, S (reprint author), INSERM, Unite Mixte Rech 645, 1 Blvd Alexandre Fleming, F-25000 Besancon, France. EM sylvain.perruche@efs.sante.fr RI SAAS, Philippe/M-3550-2015; OI SAAS, Philippe/0000-0002-8857-9939 FU Association pour la Recherche sur le Cancer [3851, 5084]; Ligue contre le cancer; Fondation Transplantation [ET-090658]; Conseil Regional de Franche-Comte; Arthritis Foundation Courtin; INSERM; National Institutes of Health, National Institute of Dental and Craniofacial Research FX This work was supported by the Association pour la Recherche sur le Cancer (Grant 3851 [to P.S.] and Grant 5084 [to S.P.]), the Ligue contre le cancer (to P.S. and S.P.), the Fondation Transplantation (Grant ET-090658 to F.B.), the Conseil Regional de Franche-Comte (AutoMACS Pro; to P.S.), and the Arthritis Foundation Courtin (to S.P.). F.B. and A.C. received financial support from the Conseil Regional de Franche-Comte and INSERM. This work was also supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. NR 42 TC 25 Z9 26 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2011 VL 186 IS 11 BP 6157 EP 6164 DI 10.4049/jimmunol.1002497 PG 8 WC Immunology SC Immunology GA 766BX UT WOS:000290755700013 PM 21518970 ER PT J AU Chen, Q Kim, YC Laurence, A Punkosdy, GA Shevach, EM AF Chen, Qian Kim, Yong Chan Laurence, Arian Punkosdy, George A. Shevach, Ethan M. TI IL-2 Controls the Stability of Foxp3 Expression in TGF-beta-Induced Foxp3(+) T Cells In Vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DNA METHYLATION; REGULATORY PHENOTYPE; GENE-EXPRESSION; INDUCTION; EXPANSION; LINEAGE; DEMETHYLATION; STIMULATION; TOLERANCE; COMPLEXES AB Stimulation of naive mouse CD4(+)Foxp3(-) T cells in the presence of TGF-beta results in the induction of Foxp3 expression and T suppressor function. However, Foxp3 expression in these induced regulatory T cells (iTreg) is unstable, raising the possibility that iTreg would not be useful for treatment of autoimmune diseases. To analyze the factors that control the stability of Foxp3 expression in iTreg, we generated OVA-specific iTreg from OT-II Foxp3-GFP knockin mice. Following transfer to normal C57BL/6 mice, OT-II GFP(+) cells maintained high levels of Foxp3 expression for 8 d. However, they rapidly lost Foxp3 expression upon stimulation with OVA in IFA in vivo. This unstable phenotype was associated with a strong methylation of the Treg-specific demethylated region within the Foxp3 locus. Administration of IL-2/anti-IL-2 complexes expanded the numbers of transferred Foxp3(+) iTreg in the absence of Ag challenge. Notably, when the iTreg were stimulated with Ag, treatment with IL-2/anti-IL-2 complexes stabilized Foxp3 expression and resulted in enhanced demethylation of the Treg-specific demethylated region. Conversely, neutralization of IL-2 or disruption of its signaling by deletion of Stat5 diminished the level of Foxp3 expression resulting in decreased suppressor function of the iTreg in vivo. Our data suggest that stimulation with TGF-beta in vitro is not sufficient for imprinting T cells with stable expression of Foxp3. Administration of IL-2 in vivo results in stabilization of Foxp3 expression and may prove to be a valuable adjunct for the use of iTreg for the treatment of autoimmune diseases. The Journal of Immunology, 2011, 186: 6329-6337. C1 [Chen, Qian; Kim, Yong Chan; Punkosdy, George A.; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Laurence, Arian] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov RI Laurence, Arian/A-8770-2009 OI Laurence, Arian/0000-0003-0942-8292 FU National Institute of Allergy and Infectious Diseases FX This work was supported by funds from the Intramural Program of the National Institute of Allergy and Infectious Diseases. NR 33 TC 107 Z9 112 U1 1 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2011 VL 186 IS 11 BP 6329 EP 6337 DI 10.4049/jimmunol.1100061 PG 9 WC Immunology SC Immunology GA 766BX UT WOS:000290755700032 PM 21525380 ER PT J AU Qi, J Buzas, K Fan, HT Cohen, JI Wang, KN Mont, E Klinman, D Oppenheim, JJ Howard, OMZ AF Qi, Jia Buzas, Krisztina Fan, Huiting Cohen, Jeffrey I. Wang, Kening Mont, Erik Klinman, Dennis Oppenheim, Joost J. Howard, O. M. Zack TI Painful Pathways Induced by TLR Stimulation of Dorsal Root Ganglion Neurons SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; DOUBLE-STRANDED-RNA; CANCER PAIN; SENSORY NEURONS; NERVOUS-SYSTEM; CHEMOKINE RECEPTORS; GENE-EXPRESSION; CELL-ADHESION; SCHWANN-CELLS; HYPERALGESIA AB We hypothesize that innate immune signals from infectious organisms and/or injured tissues may activate peripheral neuronal pain signals. In this study, we demonstrated that TLRs 3, 7, and 9 are expressed by human dorsal root ganglion neurons (DRGNs) and in cultures of primary mouse DRGNs. Stimulation of murine DRGNs with TLR ligands induced expression and production of proinflammatory chemokines and cytokines CCL5 (RANTES), CXCL10 (IP-10), IL-1 alpha, IL-1 beta, and PGE(2), which have previously been shown to augment pain. Further, TLR ligands upregulated the expression of a nociceptive receptor, transient receptor potential vanilloid type 1 (TRPV1), and enhanced calcium flux by TRPV1-expressing DRGNs. Using a tumor-induced temperature sensitivity model, we showed that in vivo administration of a TLR9 antagonist, known as a suppressive oligodeoxynucleotide, blocked tumor-induced temperature sensitivity. Taken together, these data indicate that stimulation of peripheral neurons by TLR ligands can induce nerve pain. The Journal of Immunology, 2011, 186: 6417-6426. C1 [Qi, Jia; Buzas, Krisztina; Fan, Huiting; Oppenheim, Joost J.; Howard, O. M. Zack] NCI, Mol Immunoregulat Lab, Canc & Inflammatory Program, Ctr Canc Res, Frederick, MD 21702 USA. [Cohen, Jeffrey I.; Wang, Kening] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Mont, Erik] Nova Scotia Med Examiner Serv, Halifax, NS B3J1H6, Canada. [Klinman, Dennis] NCI, Expt Immunol Lab, Canc & Inflammatory Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Howard, OMZ (reprint author), NCI, Mol Immunoregulat Lab, Canc & Inflammatory Program, Ctr Canc Res, POB B,1050 Boyles St, Frederick, MD 21702 USA. EM howardz@mail.nih.gov RI Howard, O M Zack/B-6117-2012; QI, JIA/A-6337-2014 OI Howard, O M Zack/0000-0002-0505-7052; FU National Cancer Institute; National Institute of Allergy and Infectious Diseases FX This work was supported by the intramural research programs of the National Cancer Institute and the National Institute of Allergy and Infectious Diseases. NR 52 TC 63 Z9 64 U1 2 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2011 VL 186 IS 11 BP 6417 EP 6426 DI 10.4049/jimmunol.1001241 PG 10 WC Immunology SC Immunology GA 766BX UT WOS:000290755700041 PM 21515789 ER PT J AU Qian, XS Ning, H Zhang, JD Hoft, DF Stumpo, DJ Blackshear, PJ Liu, JG AF Qian, Xuesong Ning, Huan Zhang, Jidong Hoft, Daniel F. Stumpo, Deborah J. Blackshear, Perry J. Liu, Jianguo TI Posttranscriptional Regulation of IL-23 Expression by IFN-gamma through Tristetraprolin SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; NECROSIS-FACTOR-ALPHA; MESSENGER-RNA STABILITY; T-HELPER-CELLS; GENE-EXPRESSION; RHEUMATOID-ARTHRITIS; DENDRITIC CELLS; KAPPA-B; C-REL; P19 AB IL-23 plays an essential role in maintenance of IL-17-producing Th17 cells that are involved in the pathogenesis of several autoimmune diseases. Regulation of Th17 cells is tightly controlled by multiple factors such as IL-27 and IFN-gamma. However, the detailed mechanisms responsible for IFN-gamma-mediated Th17 cell inhibition are still largely unknown. In this study, we demonstrate that IFN-gamma differentially regulates IL-12 and IL-23 production in both dendritic cells and macrophages. IFN-gamma suppresses IL-23 expression by selectively targeting p19 mRNA stability through its 3'-untranslated region (3'UTR). Furthermore, IFN-gamma enhances LPS-induced tristetraprolin (TTP) mRNA expression and protein production. Overexpression of TTP suppresses IL-23 p19 mRNA expression and p19 3'UTR-dependent luciferase activity. Additionally, deletion of TTP completely abolishes IFN-gamma-mediated p19 mRNA degradation. We further demonstrate that IFN-gamma suppresses LPS-induced p38 phosphorylation, and blockade of p38 MAPK signaling pathway with SB203580 inhibits IFN-gamma- and LPS-induced p19 mRNA expression, whereas over-expression of p38 increases p19 mRNA expression via reducing TTP binding to the p19 3'UTR. Finally, inhibition of p38 phosphorylation by IFN-gamma leads to TTP dephosphorylation that could result in stronger binding of the TTP to the adenosine/uridine-rich elements in the p19 3'UTR and p19 mRNA degradation. In summary, our results reveal a direct link among TTP, IFN-gamma, and IL-23, indicating that IFN-gamma-mediated Th17 cell suppression might act through TTP by increasing p19 mRNA degradation and therefore IL-23 inhibition. The Journal of Immunology, 2011, 186: 6454-6464. C1 [Qian, Xuesong; Ning, Huan; Zhang, Jidong; Hoft, Daniel F.; Liu, Jianguo] St Louis Univ, Sch Med, Dept Internal Med, Div Infect Dis Allergy & Immunol, St Louis, MO 63104 USA. [Stumpo, Deborah J.; Blackshear, Perry J.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Liu, JG (reprint author), St Louis Univ, Sch Med, Dept Internal Med, Div Infect Dis Allergy & Immunol, 1100 S Grand Blvd, St Louis, MO 63104 USA. EM jliu9@slu.edu FU National Institutes of Health [AR055353] FX This work was supported, in whole or in part, by Grant AR055353 from the National Institutes of Health (to J.L.). NR 46 TC 27 Z9 27 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2011 VL 186 IS 11 BP 6454 EP 6464 DI 10.4049/jimmunol.1002672 PG 11 WC Immunology SC Immunology GA 766BX UT WOS:000290755700045 PM 21515794 ER PT J AU Chandra, R Federici, S Nemeth, ZH Horvath, B Pacher, P Hasko, G Deitch, EA Spolarics, Z AF Chandra, Rachna Federici, Stephanie Nemeth, Zoltan H. Horvath, Bela Pacher, Pal Hasko, Gyoergy Deitch, Edwin A. Spolarics, Zoltan TI Female X-Chromosome Mosaicism for NOX2 Deficiency Presents Unique Inflammatory Phenotype and Improves Outcome in Polymicrobial Sepsis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELLULAR MOSAICISM; IMMUNE-RESPONSES; SEX-DIFFERENCES; NADPH OXIDASE; INACTIVATION; GENDER; TRAUMA; MORTALITY; DISEASE; INJURY AB Cellular X-chromosome mosaicism, which is unique to females, may be advantageous during pathophysiological challenges compared with the single X-chromosome machinery of males, and it may contribute to gender dimorphism in the inflammatory response. We tested the hypothesis of whether cellular mosaicism for the X-linked gp91phox (NOX2) deficiency, the catalytic component of the superoxide anion-generating NADPH oxidase complex, is advantageous during polymicrobial sepsis. Deficient, wild-type (WT), and heterozygous/mosaic mice were compared following polymicrobial sepsis initiated by cecal ligation and puncture. Compared with WT littermates, sepsis-induced mortality was improved in deficient mice, as well as in mosaic animals carrying both deficient and WT phagocyte subpopulations. In contrast, blood bacterial counts were greatest in deficient mice. Consistent with poor survival, WT mice also showed the most severe organ damage following sepsis. In mosaic animals, the deficient neutrophil subpopulations displayed increased organ recruitment and elevated CD11b membrane expression compared with WT neutrophil subpopulations within the same animal. The dynamics of sepsis-induced blood and organ cytokine content and WBC composition changes, including lymphocyte subsets in blood and bone marrow, showed differences among WT, deficient, and mosaic subjects, indicating that mosaic mice are not simply the average of the deficient and WT responses. Upon oxidative burst, interchange of oxidants between WT and deficient neutrophil subpopulations occurred in mosaic mice. This study suggests that mice mosaic for gp91phox expression have multiple advantages compared with WT and deficient mice during the septic course. The Journal of Immunology, 2011, 186: 6465-6473. C1 [Chandra, Rachna; Federici, Stephanie; Hasko, Gyoergy; Deitch, Edwin A.; Spolarics, Zoltan] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Nemeth, Zoltan H.] Morristown Mem Hosp, Dept Surg, Morristown, NJ 07962 USA. [Horvath, Bela; Pacher, Pal] NIAAA, Bethesda, MD 20892 USA. RP Spolarics, Z (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, 185 S Orange Ave,MSB G 578, Newark, NJ 07103 USA. EM spolaric@umdnj.edu RI Horvath, Bela/A-7368-2009; Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU National Institutes of Health-National Institute of General Medical Sciences [GM-106864]; National Institutes of Health/National Institute of Alcohol Abuse and Alcoholism FX This work was supported by National Institutes of Health-National Institute of General Medical Sciences Grant GM-106864 (to Z.S.) and the Intramural Research Program of the National Institutes of Health/National Institute of Alcohol Abuse and Alcoholism (to P.P.). NR 39 TC 8 Z9 8 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2011 VL 186 IS 11 BP 6465 EP 6473 DI 10.4049/jimmunol.1100205 PG 9 WC Immunology SC Immunology GA 766BX UT WOS:000290755700046 PM 21502376 ER PT J AU Pazdrak, K Young, TW Straub, C Stafford, S Kurosky, A AF Pazdrak, Konrad Young, Travis W. Straub, Christof Stafford, Susan Kurosky, Alexander TI Priming of Eosinophils by GM-CSF Is Mediated by Protein Kinase C beta II-Phosphorylated L-Plastin SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; PLATELET-ACTIVATING-FACTOR; ACTIN-DEPOLYMERIZING FACTOR; HUMAN BLOOD EOSINOPHILS; PKC-BETA; COMPLEMENT RECEPTOR-TYPE-3; HUMAN NEUTROPHILS; PERIPHERAL-BLOOD; BUNDLING PROTEIN; FORMYL-PEPTIDE AB The priming of eosinophils by cytokines leading to augmented response to chemoattractants and degranulating stimuli is a characteristic feature of eosinophils in the course of allergic inflammation and asthma. Actin reorganization and integrin activation are implicated in eosinophil priming by GM-CSF, but their molecular mechanism of action is unknown. In this regard, we investigated the role of L-plastin, an eosinophil phosphoprotein that we identified from eosinophil proteome analysis. Phosphoproteomic analysis demonstrated the upregulation of phosphorylated L-plastin after eosinophil stimulation with GM-CSF. Additionally, coimmunoprecipitation studies demonstrated a complex formation of phosphorylated L-plastin with protein kinase C beta II (PKC beta II), GM-CSF receptor alpha-chain, and two actin-associated proteins, paxilin and cofilin. Inhibition of PKC beta II with 4,5-bis (4-fluoroanilino) phtalimide or PKC beta II-specific small interfering RNA blocked GM-CSF-induced phosphorylation of L-plastin. Furthermore, flow cytometric analysis also showed an upregulation of alpha(M)beta(2) integrin, which was sensitive to PKC beta II inhibition. In chemotaxis assay, GM-CSF treatment allowed eosinophils to respond to lower concentrations of eotaxin, which was abrogated by the above-mentioned PKC beta II inhibitors. Similarly, inhibition of PKC beta II blocked GM-CSF induced priming for degranulation as assessed by release of eosinophil cationic protein and eosinophil peroxidase in response to eotaxin. Importantly, eosinophil stimulation with a synthetic L-plastin peptide (residues 2-19) phosphorylated on Ser(5) upregulated alpha(M)beta(2) integrin expression and increased eosinophil migration in response to eotaxin independent of GM-CSF stimulation. Our results establish a causative role for PKC beta II and L-plastin in linking GM-CSF-induced eosinophil priming for chemotaxis and degranulation to signaling events associated with integrin activation via induction of PKC beta II-mediated L-plastin phosphorylation. The Journal of Immunology, 2011, 186: 6485-6496. C1 [Kurosky, Alexander] Univ Texas Galveston, Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. Univ Texas Galveston, Med Branch, NHLBI, Proteom Ctr, Galveston, TX 77555 USA. RP Kurosky, A (reprint author), Univ Texas Galveston, Med Branch, Dept Biochem & Mol Biol, 301 Univ Blvd, Galveston, TX 77555 USA. EM akurosky@utmb.edu FU National Institutes of Health/National Heart, Lung, and Blood Institute Proteomics Initiative [N01-HV-00245]; National Institutes of Health/National Center for Research Resources [KL2RR029875]; National Institute for Environmental Health Science Center [P30-ES006676]; James W. McLaughlin Predoctoral Fellowship FX This work was supported in part by the National Institutes of Health/National Heart, Lung, and Blood Institute Proteomics Initiative N01-HV-00245 (to A.K.), National Institutes of Health/National Center for Research Resources Grant KL2RR029875 (to K.P.), National Institute for Environmental Health Science Center Grant P30-ES006676 (to C. Elferink and A.K.), and a James W. McLaughlin Predoctoral Fellowship (to C.S.). NR 67 TC 18 Z9 19 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2011 VL 186 IS 11 BP 6485 EP 6496 DI 10.4049/jimmunol.1001868 PG 12 WC Immunology SC Immunology GA 766BX UT WOS:000290755700048 PM 21525390 ER PT J AU Boulware, DR Hullsiek, KH Puronen, CE Rupert, A Baker, JV French, MA Bohjanen, PR Novak, RM Neaton, JD Sereti, I AF Boulware, David R. Hullsiek, Katherine Huppler Puronen, Camille E. Rupert, Adam Baker, Jason V. French, Martyn A. Bohjanen, Paul R. Novak, Richard M. Neaton, James D. Sereti, Irini CA INSIGHT Study Grp TI Higher Levels of CRP, D-dimer, IL-6, and Hyaluronic Acid Before Initiation of Antiretroviral Therapy (ART) Are Associated With Increased Risk of AIDS or Death SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID RECONSTITUTION INFLAMMATORY SYNDROME; IMMUNE RESTORATION DISEASE; HIV-INFECTION; INTERFERON-ALPHA; CASE DEFINITIONS; MORTALITY; TUBERCULOSIS; INDIVIDUALS; PROGRESSION; MORBIDITY AB Background. Substantial morbidity occurs during the first year of antiretroviral therapy (ART) in persons with advanced human immunodeficiency virus (HIV) disease despite HIV suppression. Biomarkers may identify high-risk groups. Methods. Pre-ART and 1-month samples from an initial ART trial were evaluated for biomarkers associated with AIDS events or death within 1-12 months. Case patients (n = 63) and control patients (n = 126) were 1: 2 matched on baseline CD4 cell count, hepatitis status, and randomization date. All had >= 1 log(10) HIV RNA level decrease at 1 month. Results. Case patients had more frequent prior AIDS events, compared with control patients (P = .004), but similar HIV RNA levels at baseline. Pre-ART and 1-month C-reactive protein (CRP), D-dimer, and interleukin 6 (IL-6) levels and pre-ART hyaluronic acid (HA) levels were associated with new AIDS events or death (P <= .01). Patients who experienced immune reconstitution inflammatory syndrome (IRIS) events had higher pre-ART tumor necrosis factor alpha (TNF-alpha) and HIV RNA levels and significant 1-month increases in CRP, D-dimer, IL-6, interleukin 8, CXCL10, TNF-alpha, and interferon-gamma levels, compared with patients who experienced non-IRIS events (P <= .03). Individuals with baseline CRP and HA levels above the cohort median (>2.1 mg/L and >50.0 ng/mL, respectively) had increased risk of AIDS or death (OR, 4.6 [95% CI, 2.0-10.3]; P < .001) and IRIS (OR, 8.7 [95% CI, 2.2-34.8] P = .002). Conclusions. Biomarkers of Inflammation (CRP, IL-6), coagulation (D-dimer), and tissue fibrosis (HA) measured pre-ART and at 1 month are associated with higher risk of AIDS events, IRIS, or death, warranting additional study as risk stratification strategies. C1 [Puronen, Camille E.; Sereti, Irini] Intramural Natl Inst Allergy & Infect Dis, NIH, Bethesda, MD USA. [Boulware, David R.; Hullsiek, Katherine Huppler; Baker, Jason V.; Bohjanen, Paul R.; Neaton, James D.] Univ Minnesota, Minneapolis, MN USA. [Rupert, Adam] NCI, AIDS Monitoring Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Baker, Jason V.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Novak, Richard M.] Univ Illinois, Chicago, IL USA. [French, Martyn A.] Univ Western Australia, Sch Pathol & Lab Med, Perth, WA 6009, Australia. RP Sereti, I (reprint author), NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bldg 10,Rm 11B-07A,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov RI Boulware, David/B-5516-2011; Boulware, David/I-4533-2013; Bohjanen, Paul/B-2329-2015; OI Bohjanen, Paul/0000-0002-2772-3597; Boulware, David/0000-0002-4715-0060 FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health [U01AI042170, U01AI046362, U01AI068641, CPCRA 058]; INSIGHT; NIAID [K23AI073192-02]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; [K12RR023247-05] FX This work was supported in part through the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health through grants U01AI042170, U01AI046362, and U01AI068641 for the FIRST Study (CPCRA 058) and INSIGHT, as well as through the Intramural Research Program of NIAID. In addition, this project has been supported in part by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. D. R. B. is supported by NIAID grant K23AI073192-02, and J. V. B. by grant K12RR023247-05. NR 37 TC 120 Z9 120 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2011 VL 203 IS 11 BP 1637 EP 1646 DI 10.1093/infdis/jir134 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 767LT UT WOS:000290858800019 PM 21592994 ER PT J AU Wardenburg, JB Schneewind, O DeLeo, FR AF Wardenburg, Juliane Bubeck Schneewind, Olaf DeLeo, Frank R. TI Expectations Regarding Vaccines and Immune Therapies Directed Against Staphylococcus aureus alpha-Hemolysin Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter C1 [Wardenburg, Juliane Bubeck] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Wardenburg, Juliane Bubeck; Schneewind, Olaf] Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA. [DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Wardenburg, JB (reprint author), Univ Chicago, Dept Pediat, 920 E 58th St,CLSC 607A, Chicago, IL 60637 USA. EM jbubeckw@peds.bsd.uchicago.edu NR 12 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2011 VL 203 IS 11 BP 1693 EP 1694 DI 10.1093/infdis/jir142 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 767LT UT WOS:000290858800026 ER PT J AU Muehlenbachs, A Fried, M McGready, R Nosten, F Duffy, PE AF Muehlenbachs, Atis Fried, Michal McGready, Rose Nosten, Francois Duffy, Patrick E. TI Grading Schemes for Placental Malaria Response SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID PLASMODIUM-FALCIPARUM; INFECTION; TRANSMISSION C1 [Muehlenbachs, Atis] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Fried, Michal; Duffy, Patrick E.] NIAID, Washington, DC USA. [McGready, Rose; Nosten, Francois] Shoklo Malaria Res Inst, Mae Sot, Thailand. RP Duffy, PE (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, Twinbrook 1,Room 1111,5640 Fishers Ln, Rockville, MD 20852 USA. EM duffype@niaid.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2011 VL 203 IS 11 DI 10.1093/infdis/jir154 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 767LT UT WOS:000290858800028 ER PT J AU Chakir, K Zhu, WZ Tsang, S Woo, AYH Yang, DM Wang, XH Zeng, XK Rhee, MH Mende, U Koitabashi, N Takimoto, E Blumer, KJ Lakatta, EG Kass, DA Xiao, RP AF Chakir, Khalid Zhu, Weizhong Tsang, Sharon Woo, Anthony Yiu-Ho Yang, Dongmei Wang, Xianhua Zeng, Xiaokun Rhee, Man-Hee Mende, Ulrike Koitabashi, Norimichi Takimoto, Eiki Blumer, Kendall J. Lakatta, Edward G. Kass, David A. Xiao, Rui-Ping TI RGS2 is a primary terminator of beta(2)-adrenergic receptor-mediated G(i) signaling SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE beta(2)-Adrenergic receptor; RGS2; G(i) proteins; Cardiomyocyte contractility ID GTPASE-ACTIVATING PROTEINS; MOUSE CARDIAC MYOCYTES; DILATED CARDIOMYOPATHY; ALPHA-SUBUNITS; HEART-FAILURE; CA2+ CHANNELS; HYPERTROPHY; SELECTIVITY; MECHANISMS; REGULATORS AB Two major beta-adrenergic receptor (beta AR) subtypes, beta(1)AR and beta(2)AR, are expressed in mammalian heart with beta(1)AR coupling to G(s) and beta(2)AR dually coupling to G(s) and G(i) proteins. In many types of chronic heart failure, myocardial contractile response to both beta(1)AR and beta(2)AR stimulation is severely impaired. The dysfunction of beta AR signaling in failing hearts is largely attributable to an increase in G(i) signaling, because disruption of the G(i) signaling restores myocardial contractile response to beta(1)AR as well as beta(2)AR stimulation. However, the mechanism terminating the beta(2)AR-G(i) signaling remains elusive, while it has been shown activation of the G(i) signaling is dependent on agonist stimulation and subsequent PKA-mediated phosphorylation of the receptor. Here we demonstrate that regulator of G protein signaling 2 (RGS2) is a primary terminator of the beta(2)AR-G(i) signaling. Specifically, prolonged absence of agonist stimulation for 24 h impairs the beta(2)AR-G(i) signaling, resulting in enhanced beta(2)AR-but not beta(1)AR-mediated contractile response in cultured adult mouse cardiomyocytes. Increased beta(2)AR contractile response is accompanied by a selective upregulation of RGS2 in the absence of alterations in other major cardiac RCS proteins (RGS3-5) or G(s), G(i) or beta AR subtypes. Administration of a beta AR agonist, isoproterenol (ISO, 1.0 nM), prevents RGS2 upregulation and restores the beta AR-G(i) signaling in cultured cells. Furthermore, RGS2 ablation, similar to beta AR agonist stimulation, sustains the beta(2)AR-G(i) signaling in cultured cells, whereas adenoviral overexpression of RGS2 suppresses agonist-activated beta(2)AR-G(i) signaling in cardiomyocytes and HEK293 cells. These findings not only define RGS2 as a novel negative regulator of the beta(2)AR-G(i) signaling but also provide a potential novel target for the treatment of chronic heart failure. Published by Elsevier Ltd. C1 [Chakir, Khalid; Zhu, Weizhong; Tsang, Sharon; Woo, Anthony Yiu-Ho; Yang, Dongmei; Wang, Xianhua; Zeng, Xiaokun; Lakatta, Edward G.; Xiao, Rui-Ping] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Rhee, Man-Hee; Blumer, Kendall J.] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. [Mende, Ulrike] Brown Univ, Rhode Isl Hosp, Cardiovasc Res Ctr, Providence, RI 02903 USA. [Mende, Ulrike] Brown Univ, Warren Alpert Med Sch, Providence, RI 02903 USA. [Chakir, Khalid; Koitabashi, Norimichi; Takimoto, Eiki; Kass, David A.] Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Woo, Anthony Yiu-Ho; Wang, Xianhua; Xiao, Rui-Ping] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. RP Zhu, WZ (reprint author), Thomas Jefferson Univ, Dept Med, Ctr Translat Med, 1025 Walnut St, Philadelphia, PA 19107 USA. EM Weizhong.Zhu@jefferson.edu; Xiaor@pku.edu.cn RI Blumer, Kendall/C-5268-2012; Woo, Anthony/D-4305-2014; Tsang, Sharon/O-4790-2016 OI Woo, Anthony/0000-0003-0662-698X; FU NIH, National Institute on Aging; NIH FX This work was supported by the Intramural Research Program of the NIH, National Institute on Aging (R.P. Xiao, W. Zhu, S. Tsang, A.Y.H. Woo, D. Yang, X. Wang, X. Zeng, E.G. Lakatta) and, in part, by NIH extramural grants to D.A. Kass, U. Mende, and K.J. Blumer. NR 42 TC 22 Z9 22 U1 0 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2011 VL 50 IS 6 BP 1000 EP 1007 DI 10.1016/j.yjmcc.2011.01.015 PG 8 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 766ZW UT WOS:000290826100010 PM 21291891 ER PT J AU Smith, C Santi, M Rushing, EJ Cornelison, R MacDonald, TJ Vukmanovic, S AF Smith, Courtney Santi, Mariarita Rushing, Elisabeth J. Cornelison, Robert MacDonald, Tobey J. Vukmanovic, Stanislav TI Characterization of signaling function and expression of HLA class I molecules in medulloblastoma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE HLA; Medulloblastoma; Cerebellum; Signaling ID MHC CLASS-I; CENTRAL-NERVOUS-SYSTEM; HISTOCOMPATIBILITY COMPLEX ANTIGENS; LONG-TERM POTENTIATION; ACTIVATED T-CELLS; SYNAPTIC PLASTICITY; GENE-EXPRESSION; DOWN-REGULATION; HEAVY-CHAIN; HUMAN CEREBELLUM AB Although known for the important function in the immune system, MHC class I molecules are increasingly ascribed an alternative role in modifying signal transduction. In medulloblastoma, HLA class I molecules are associated with poor prognosis, and can induce ERK1/2 activation upon engagement with ligands that bind to incompletely assembled complexes (so called open conformers). We here demonstrate that ERK1/2 activation in medulloblastoma can occur in the absence of endogenously synthesized beta 2m, formally excluding involvement of closed HLA class conformation. In addition, several experimental observations suggest that heterogeneity of HLA class I expression may be a reflection of the status of original cells before transformation, rather than a consequence of immune-based selection of HLA-loss mutants. These results contribute to our understanding of an immune system-independent role of HLA class I in the pathology of medulloblastoma, and cancer in general. C1 [Smith, Courtney; MacDonald, Tobey J.; Vukmanovic, Stanislav] Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Childrens Res Inst, Washington, DC 20010 USA. [Santi, Mariarita] Childrens Natl Med Ctr, Dept Pathol, Washington, DC 20010 USA. [Smith, Courtney; MacDonald, Tobey J.; Vukmanovic, Stanislav] George Washington Univ, Sch Med, Dept Pediat, Washington, DC 20052 USA. [Rushing, Elisabeth J.] Armed Forces Inst Pathol, Dept Neuropathol, Washington, DC 20306 USA. [Cornelison, Robert] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Vukmanovic, S (reprint author), Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Childrens Res Inst, 111 Michigan Ave NW, Washington, DC 20010 USA. EM svukmano@cnmc.org RI MacDonald, Tobey/D-4554-2013 FU national Institutes of Health [R01 CA111835] FX This work was partially supported by national Institutes of Health grant (R01 CA111835) awarded to TJM. NR 65 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JUN PY 2011 VL 103 IS 2 BP 197 EP 206 DI 10.1007/s11060-010-0378-3 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 766IB UT WOS:000290773100003 PM 20811766 ER PT J AU Altorki, NK Christos, P Port, JL Lee, PC Mirza, F Spinelli, C Keresztes, R Beneck, D Paul, S Stiles, BM Zhang, YW Schrump, DS AF Altorki, Nasser K. Christos, Paul Port, Jeff L. Lee, Paul C. Mirza, Farooq Spinelli, Cathy Keresztes, Roger Beneck, Debra Paul, Subroto Stiles, Brendon M. Zhang, Yuwei Schrump, David S. TI Preoperative Taxane-Based Chemotherapy and Celecoxib for Carcinoma of the Esophagus and Gastroesophageal Junction Results of a Phase 2 Trial SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE COX-2; Celecoxib; Esophageal cancer ID SQUAMOUS-CELL CARCINOMA; METASTATIC COLORECTAL-CANCER; LUNG-CANCER; CYCLOOXYGENASE-2 EXPRESSION; COX-2 INHIBITION; PHASE-II; COLON CARCINOGENESIS; 1ST-LINE TREATMENT; RADIATION-THERAPY; CONTROLLED-TRIAL AB Purpose: The primary objective of this study was to determine the rate of pathological response after preoperative celecoxib and concurrent taxane-based chemotherapy in patients with cancer of the esophagus and gastroesophageal junction. Methods: Thirty-nine patients were enrolled in this single-arm, phase II clinical trial. Patients were administered daily celecoxib in combination with two to three cycles of carboplatin and paclitaxel with preoperative intent. Levels of cyclooxygenase (COX)-2 expression in resected tumors were analyzed by immunohistochemistry and correlated with clinical outcome measures. Postoperatively, patients were administered daily celecoxib for 1 year or until documented tumor recurrence. Results: All patients received two to three cycles of chemotherapy plus celecoxib 800 mg/d. Toxicities were as expected. A major clinical response (complete response + partial response) was noted in 22 patients (56%); six patients (15%) had a complete clinical response. Thirty-seven patients underwent esophagectomy. Five patients had a major pathological response (12.8%). Four-year overall and disease-free survivals were 40.9% and 30.3%, respectively. Patients with tumors expressing COX-2 demonstrated a higher likelihood of a major clinical response response (62% versus 50%) and an improved overall survival, compared with patients with COX-2-negative tumors. Conclusions: Preoperative celecoxib with concurrent chemotherapy demonstrated sufficient effect on pathologic response to warrant further study. Patients with tumors expressing COX-2 demonstrated trends toward improved response to preoperative therapy and improved overall survival compared with nonexpressors. C1 [Altorki, Nasser K.; Port, Jeff L.; Lee, Paul C.; Mirza, Farooq; Spinelli, Cathy; Paul, Subroto; Stiles, Brendon M.] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Cardiothorac Surg, Thorac Surg Div, New York, NY USA. [Christos, Paul] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Publ Hlth, Div Biostat & Epidemiol, New York, NY USA. [Keresztes, Roger] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA. [Beneck, Debra] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Pathol, New York, NY USA. [Zhang, Yuwei; Schrump, David S.] NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Altorki, NK (reprint author), Cornell Univ, New York Presbyterian Hosp, Div Gen Thorac Surg, Weill Med Coll, 525 E 68th St,Box 110, New York, NY 10021 USA. EM nkaltork@med.cornell.edu FU Clinical Translational Science Center (CTSC) [UL1-RR024996] FX Supported by a grant from Pfizer. Dr. Paul Christos was partially supported by the following grant: Clinical Translational Science Center (CTSC) (UL1-RR024996). NR 53 TC 14 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JUN PY 2011 VL 6 IS 6 BP 1121 EP 1127 DI 10.1097/JTO.0b013e31821529a9 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 766FM UT WOS:000290766400022 PM 21532508 ER PT J AU Ciccone, EJ Greenwald, JH Lee, PI Biancotto, A Read, SW Yao, MA Hodge, JN Thompson, WL Kovacs, SB Chairez, CL Migueles, SA Kovacs, JA Margolis, LB Sereti, I AF Ciccone, Emily J. Greenwald, Jamieson H. Lee, Philip I. Biancotto, Angelique Read, Sarah W. Yao, Michael A. Hodge, Jessica N. Thompson, William L. Kovacs, Stephen B. Chairez, Cheryl L. Migueles, Stephen A. Kovacs, Joseph A. Margolis, Leonid B. Sereti, Irini TI CD4(+) T Cells, Including Th17 and Cycling Subsets, Are Intact in the Gut Mucosa of HIV-1-Infected Long-Term Nonprogressors SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; ACTIVE ANTIRETROVIRAL THERAPY; INTESTINAL LAMINA PROPRIA; ACUTE SIV INFECTION; MICROBIAL TRANSLOCATION; GASTROINTESTINAL-TRACT; GENE-EXPRESSION; IMMUNE CONTROL; LYMPHOID-TISSUE AB During acute human immunodeficiency virus (HIV) infection, there is a massive depletion of CD4(+) T cells in the gut mucosa that can be reversed to various degrees with antiretroviral therapy. Th17 cells have been implicated in mucosal immunity to extracellular bacteria, and preservation of this subset may support gut mucosal immune recovery. However, this possibility has not yet been evaluated in HIV-1-infected long-term nonprogressors (LTNPs), who maintain high CD4(+) T cell counts and suppress viral replication in the absence of antiretroviral therapy. In this study, we evaluated the immunophenotype and function of CD4(+) T cells in peripheral blood and gut mucosa of HIV-uninfected controls, LTNPs, and HIV-1-infected individuals treated with prolonged antiretroviral therapy (ART) (VL [viral load] < 50). We found that LTNPs have intact CD4(+) T cell populations, including Th17 and cycling subsets, in the gut mucosa and a preserved T cell population expressing gut homing molecules in the peripheral blood. In addition, we observed no evidence of higher monocyte activation in LTNPs than in HIV-infected (HIV-) controls. These data suggest that, similar to nonpathogenic simian immunodeficiency virus (SIV) infection, LTNPs preserve the balance of CD4(+) T cell populations in blood and gut mucosa, which may contribute to the lack of disease progression observed in these patients. C1 [Ciccone, Emily J.; Greenwald, Jamieson H.; Lee, Philip I.; Hodge, Jessica N.; Thompson, William L.; Kovacs, Stephen B.; Chairez, Cheryl L.; Migueles, Stephen A.; Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Yao, Michael A.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Read, Sarah W.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Biancotto, Angelique; Margolis, Leonid B.] NICHD, Sect Intercellular Interact, NIH, Bethesda, MD 20892 USA. [Kovacs, Joseph A.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Sereti, I (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 11B07A, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov FU NIAID FX This work was supported in part by the Intramural Research Program of NIAID. NR 45 TC 46 Z9 47 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2011 VL 85 IS 12 BP 5880 EP 5888 DI 10.1128/JVI.02643-10 PG 9 WC Virology SC Virology GA 766CD UT WOS:000290756600016 PM 21471231 ER PT J AU Yang, Z Bruno, DP Martens, CA Porcella, SF Moss, B AF Yang, Zhilong Bruno, Daniel P. Martens, Craig A. Porcella, Stephen F. Moss, Bernard TI Genome-Wide Analysis of the 5 ' and 3 ' Ends of Vaccinia Virus Early mRNAs Delineates Regulatory Sequences of Annotated and Anomalous Transcripts SO JOURNAL OF VIROLOGY LA English DT Article ID HIGH-RESOLUTION ANALYSIS; VIRAL GENE-EXPRESSION; INTERMEDIATE-STAGE; POLY(A) SEQUENCES; TERMINATION; VIRIONS; PURIFICATION; POLYMERASE; IDENTIFICATION; PROMOTERS AB Poxviruses are large DNA viruses that encode a multisubunit RNA polymerase, stage-specific transcription factors, and enzymes that cap and polyadenylate mRNAs within the cytoplasm of infected animal cells. Genome-wide microarray and RNA-seq technologies have been used to profile the transcriptome of vaccinia virus (VACV), the prototype member of the family. Here, we adapted tag-based methods in conjunction with SOLiD and Illumina deep sequencing platforms to determine the precise 5' and 3' ends of VACV early mRNAs and map the putative transcription start sites (TSSs) and polyadenylation sites (PASs). Individual and clustered TSSs were found preceding 104 annotated open reading frames (ORFs), excluding pseudogenes. In the majority of cases, a 15-nucleotide consensus core motif was present upstream of the ORF. This motif, however, was also present at numerous other locations, indicating that it was insufficient for transcription initiation. Further analysis revealed a 10-nucleotide AT-rich spacer following functional core motifs that may facilitate DNA unwinding. Additional putative TSSs occurred in anomalous locations that may expand the functional repertoire of the VACV genome. However, many of the anomalous TSSs lacked an upstream core motif, raising the possibility that they arose by a processing mechanism as has been proposed for eukaryotic systems. Discrete and clustered PASs occurred about 40 nucleotides after an UUUUUNU termination signal. However, a large number of PASs were not preceded by this motif, suggesting alternative polyadenylation mechanisms. Pyrimidine-rich coding strand sequences were found immediately upstream of both types of PASs, signifying an additional feature of VACV 3'-end formation and polyadenylation. C1 [Yang, Zhilong; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Bruno, Daniel P.; Martens, Craig A.; Porcella, Stephen F.] NIAID, Res Technol Sect, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bmoss@nih.gov RI Yang, Zhilong/E-8967-2010 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 63 TC 27 Z9 28 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2011 VL 85 IS 12 BP 5897 EP 5909 DI 10.1128/JVI.00428-11 PG 13 WC Virology SC Virology GA 766CD UT WOS:000290756600018 PM 21490097 ER PT J AU Kamya, P Boulet, S Tsoukas, CM Routy, JP Thomas, R Cote, P Boulassel, MR Baril, JG Kovacs, C Migueles, SA Connors, M Suscovich, TJ Brander, C Tremblay, CL Bernard, N AF Kamya, Philomena Boulet, Salix Tsoukas, Christos M. Routy, Jean-Pierre Thomas, Rejean Cote, Pierre Boulassel, Mohamed-Rachid Baril, Jean-Guy Kovacs, Colin Migueles, Stephen A. Connors, Mark Suscovich, Todd J. Brander, Christian Tremblay, Cecile L. Bernard, Nicole CA Canadian Cohort HIV Infected Slow TI Receptor-Ligand Requirements for Increased NK Cell Polyfunctional Potential in Slow Progressors Infected with HIV-1 Coexpressing KIR3DL1*h/*y and HLA-B*57 SO JOURNAL OF VIROLOGY LA English DT Article ID NATURAL-KILLER-CELLS; CD8(+) T-CELLS; HLA-B MOLECULES; COMPLEX CLASS-I; ANTIRETROVIRAL THERAPY; INHIBITORY RECEPTORS; VIRUS-REPLICATION; INTERFERON-GAMMA; MISSING SELF; KIR3DL1 AB Carriage of the natural killer (NK) receptor genotype KIR3DL1*h/*y with its HLA-B*57 ligand (*h/*y+B*57) is associated with slow time to AIDS and low viral load (VL). To provide a functional basis for these epidemiological observations, we assessed whether HIV-1-infected slow progressors (SP) carrying the *h/*y+B*57 compound genotype would have increased NK cell polyfunctional potential in comparison to SP with other killer immunoglobulin-like receptor (KIR)/HLA compound genotypes and whether this enhanced poly-functionality was dependent upon the coexpression of both KIR3DL1*h/*y and HLA-B*57. The functional potential of NK cells was investigated by stimulating peripheral blood mononuclear cells with HLA-devoid targets or single HLA transfectants. Multiparametric flow cytometry was used to detect NK cells with seven functional profiles representing all permutations of CD107a expression and gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) secretion. NK cells from individuals carrying KIR3DL1 receptor-HLA-Bw4 ligand pairs had greater trifunctional responses than those from KIR3DL1 homozygotes (hmz), who were Bw6 homozygotes. NK cells from subjects carrying the *h/*y+B*57 genotypes exhibited the highest trifunctional potential, and this was dependent on cocarriage of the NK receptor and its ligand. Trifunctional cells secreted more of each function tested on a per-cell basis than each corresponding monofunctional NK subset. Although VL influenced NK functionality, individuals with defined KIR/HLA genotypes exhibited differences in NK cell polyfunctionality that could not be accounted for by VL alone. The protective effect of HLA-B*57 on slow progression to AIDS and low VL may be mediated through its interaction with KIR3DL1 alleles to educate NK cells for potent activity upon stimulation. C1 [Kamya, Philomena; Boulet, Salix; Tsoukas, Christos M.; Routy, Jean-Pierre; Bernard, Nicole] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ H3G 1A4, Canada. [Kamya, Philomena; Tsoukas, Christos M.; Bernard, Nicole] McGill Univ, Div Expt Med, Montreal, PQ H3G 1A4, Canada. [Tsoukas, Christos M.; Bernard, Nicole] McGill Univ, Ctr Hlth, Div Clin Immunol & Allergy, Montreal, PQ H3G 1A4, Canada. [Routy, Jean-Pierre; Boulassel, Mohamed-Rachid] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Immunodeficiency Serv, Montreal, PQ H3G 1A4, Canada. [Routy, Jean-Pierre; Boulassel, Mohamed-Rachid] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Div Hematol, Montreal, PQ H3G 1A4, Canada. [Thomas, Rejean] Clin Actuel, Montreal, PQ, Canada. [Cote, Pierre; Baril, Jean-Guy] Clin Quartier Latin, Montreal, PQ, Canada. [Kovacs, Colin] Maple Leaf Med Clin, Toronto, ON, Canada. [Migueles, Stephen A.; Connors, Mark] NIAID, NIH, Bethesda, MD 20892 USA. [Suscovich, Todd J.] Benaroya Res Inst, Seattle, WA USA. [Brander, Christian] Hosp Badalona Germans Trias & Pujol, Irsicaixa AIDS Res Inst, Barcelona, Spain. [Brander, Christian] ICREA, Barcelona, Spain. [Tremblay, Cecile L.] Ctr Hosp Univ Montreal, Ctr Rech, Montreal, PQ, Canada. RP Bernard, N (reprint author), McGill Univ, Montreal Gen Hosp, Ctr Hlth, Res Inst, 1650 Cedar Ave,Room C10-160, Montreal, PQ H3G 1A4, Canada. EM nicole.bernard@mcgill.ca OI Brander, Christian/0000-0002-0548-5778 FU Canadian Institutes for Health Research [HOP-86862]; Canadian Association for AIDS Research [022-110]; Fonds de Recherche en Sante du Quebec (FRSQ) AIDS and Infectious Disease Network; FRSQ FX This work was supported by grant HOP-86862 from the Canadian Institutes for Health Research, Canadian Association for AIDS Research grant 022-110, and a grant from the Fonds de Recherche en Sante du Quebec (FRSQ) AIDS and Infectious Disease Network. S.B. was supported by a Ph.D. scholarship from the FRSQ, and J.-P.R. is a scientific scholar receiving support from FRSQ. NR 55 TC 40 Z9 40 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2011 VL 85 IS 12 BP 5949 EP 5960 DI 10.1128/JVI.02652-10 PG 12 WC Virology SC Virology GA 766CD UT WOS:000290756600023 PM 21471235 ER PT J AU Fadda, L O'Connor, GM Kumar, S Piechocka-Trocha, A Gardiner, CM Carrington, M McVicar, DW Altfeld, M AF Fadda, Lena O'Connor, Geraldine M. Kumar, Swati Piechocka-Trocha, Alicja Gardiner, Clair M. Carrington, Mary McVicar, Daniel W. Altfeld, Marcus TI Common HIV-1 Peptide Variants Mediate Differential Binding of KIR3DL1 to HLA-Bw4 Molecules SO JOURNAL OF VIROLOGY LA English DT Article ID HLA-B; NK CELLS; INFECTION; MUTATION; RECEPTOR; AIDS; SUBTYPES; ESCAPE; GAG AB Epidemiological studies have shown the protective effect of KIR3DL1/HLA-Bw4 genotypes in human immunodeficiency virus type 1 (HIV-1) infection; however, the functional correlates for the protective effect remain unknown. We investigated whether human leukocyte antigen (HLA)-Bw4-presented HIV-1 peptides could affect the interaction between the inhibitory natural killer (NK) cell receptor KIR3DL1 and its ligand HLA-Bw4. Distinct HIV-1 epitopes differentially modulated the binding of KIR3DL1 to HLA-Bw4. Furthermore, cytotoxic T lymphocyte (CTL) escape mutations within the immunodominant HLA-B57 (Bw4)-restricted Gag epitope TSTLQEQIGW abrogated KIR3DL1 binding to HLA-B57, suggesting that sensing of CTL escape variants by NK cells can contribute to the protective effect of the KIR3DL1/HLA-Bw4 compound genotype. C1 [Fadda, Lena; Kumar, Swati; Piechocka-Trocha, Alicja; Carrington, Mary; Altfeld, Marcus] Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Charlestown, MA 02129 USA. [O'Connor, Geraldine M.; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Gardiner, Clair M.] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin, Ireland. [Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Altfeld, M (reprint author), Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Bldg 149,13th St, Charlestown, MA 02129 USA. EM maltfeld@partners.org RI McVicar, Daniel/G-1970-2015 FU NIH [RO1AI067031]; Doris Duke Charitable Foundation; Bill and Melinda Gates Foundation; Susan and Philip T. Ragon Foundation; Ragon Institute of MGH, MIT, and Harvard; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX These studies were supported by the NIH (RO1AI067031), the Doris Duke Charitable Foundation, the Bill and Melinda Gates Foundation, and the Susan and Philip T. Ragon Foundation. L. F. is supported by a Ragon Fellowship of the Ragon Institute of MGH, MIT, and Harvard. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 17 TC 37 Z9 40 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2011 VL 85 IS 12 BP 5970 EP 5974 DI 10.1128/JVI.00412-11 PG 5 WC Virology SC Virology GA 766CD UT WOS:000290756600025 PM 21471246 ER PT J AU Xing, SF Bullen, CK Shroff, NS Shan, L Yang, HC Manucci, JL Bhat, S Zhang, H Margolick, JB Quinn, TC Margolis, DM Siliciano, JD Siliciano, RF AF Xing, Sifei Bullen, Cynthia K. Shroff, Neeta S. Shan, Liang Yang, Hung-Chih Manucci, Jordyn L. Bhat, Shridhar Zhang, Hao Margolick, Joseph B. Quinn, Thomas C. Margolis, David M. Siliciano, Janet D. Siliciano, Robert F. TI Disulfiram Reactivates Latent HIV-1 in a Bcl-2-Transduced Primary CD4(+) T Cell Model without Inducing Global T Cell Activation SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; RESERVOIR; INFECTION; DRUG AB Highly active antiretroviral therapy (HAART) can reduce plasma HIV-1 levels to below the detection limit. However, due to the latent reservoir in resting CD4(+) cells, HAART is not curative. Elimination of this reservoir is critical to curing HIV-1 infection. Agents that reactivate latent HIV-1 through nonspecific T cell activation are toxic. Here we demonstrate in a primary CD4(+) T cell model that the FDA-approved drug disulfiram reactivates latent HIV-1 without global T cell activation. The extent to which disulfiram reactivates latent HIV-1 in patient cells is unclear, but the drug alone or in combination may be useful in future eradication strategies. C1 [Xing, Sifei; Bullen, Cynthia K.; Shan, Liang; Yang, Hung-Chih; Manucci, Jordyn L.; Quinn, Thomas C.; Siliciano, Janet D.; Siliciano, Robert F.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Xing, Sifei; Shan, Liang; Bhat, Shridhar] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Shroff, Neeta S.; Siliciano, Robert F.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. [Zhang, Hao; Margolick, Joseph B.] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Margolis, David M.] Univ N Carolina, Chapel Hill, NC USA. RP Siliciano, RF (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, 720 Rutland Ave, Baltimore, MD 21205 USA. EM rsiliciano@jhmi.edu RI Bhat, Shridhar/C-5412-2012; OI YANG, HUNG-CHIH/0000-0003-3864-9895; Margolis, David/0000-0001-5714-0002 FU NIH [AI43222, DA030156]; Division of Intramural Research, NIAID, NIH; American Foundation for AIDS Research FX This work was supported by NIH grants AI43222 and DA030156, by the Division of Intramural Research, NIAID, NIH, and by an ARCHE grant from the American Foundation for AIDS Research. NR 16 TC 94 Z9 95 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2011 VL 85 IS 12 BP 6060 EP 6064 DI 10.1128/JVI.02033-10 PG 5 WC Virology SC Virology GA 766CD UT WOS:000290756600035 PM 21471244 ER PT J AU Summers, TA Jaffe, ES AF Summers, Thomas A. Jaffe, Elaine S. TI Hairy cell leukemia diagnostic criteria and differential diagnosis SO LEUKEMIA & LYMPHOMA LA English DT Article DE Hairy cell leukemia; bone marrow; spleen; B-cells; immunophenotyping; lymphocytes; lymphocytosis ID FEATURES; LYMPHOMA AB Hairy cell leukemia (HCL) is a disease with distinctive clinical findings, as well as a unique morphology and immunophenotype. These features typically allow for a reliable and reproducible diagnosis in nearly all situations. However, certain morphological features of HCL, such as villous cytoplasmic projections or characteristic tissue specific infiltrative patterns, including red pulp expansion with pseudosinuses, may be seen in other B-cell lymphoproliferative disorders. A methodical and thorough approach evaluating the clinical, cytological, histological, architectural, and immunophenotypic features is described and will aid in rendering the appropriate diagnosis. This is paramount as current data indicate that hairy cell leukemia - variant and other splenic B-cell lymphomas must be distinguished from HCL, as the response to therapy differs in these disorders. C1 [Summers, Thomas A.; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 2B 42,10 Ctr Dr MSC-1500, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov OI Jaffe, Elaine/0000-0003-4632-0301 NR 8 TC 14 Z9 14 U1 0 U2 0 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 JUN PY 2011 VL 52 SU 2 BP 6 EP 10 DI 10.3109/10428194.2011.565435 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 767PU UT WOS:000290869300002 PM 21417827 ER PT J AU Stetler-Stevenson, M Tembhare, PR AF Stetler-Stevenson, Maryalice Tembhare, Prashant R. TI Diagnosis of hairy cell leukemia by flow cytometry SO LEUKEMIA & LYMPHOMA LA English DT Article DE flow cytometry; hairy cell leukemia; CD103; CD11c; CD123 ID VILLOUS LYMPHOCYTES; CHAIN GENE; DISORDERS; HEAVY AB Flow cytometric immunophenotpying (FCI) is a vital tool in the diagnosis of hairy cell leukemia (HCL). HCL has a distinctive immunophenotype based upon staining with antibodies to CD5 (negative), CD10 (negative), CD23 (negative), CD20 (abnormally bright), CD22 (abnormally bright), CD11c (abnormally bright), CD25 (abnormally bright), CD103 (positive), and CD123 (positive). Due to this unique immunophenotype, FCI can differentiate malignant hairy cells from normal B-cells and other lymphoproliferative disorders, especially the morphologically similar hairy cell leukemia variant and splenic lymphoma with villous lymphocytes. FCI is extremely sensitive in the detection of minimal disease and is useful in monitoring response to therapy. C1 [Stetler-Stevenson, Maryalice; Tembhare, Prashant R.] NCI, Flow Cytometry Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Flow Cytometry Unit, Pathol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM stetler@mail.nih.gov NR 8 TC 8 Z9 8 U1 1 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 JUN PY 2011 VL 52 SU 2 BP 11 EP 13 DI 10.3109/10428194.2011.570820 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA 767PU UT WOS:000290869300003 PM 21504292 ER PT J AU Janik, JE AF Janik, John E. TI Tumor markers in hairy cell leukemia SO LEUKEMIA & LYMPHOMA LA English DT Article DE CD25; CD22; CD307; serum soluble proteins ID RECEPTOR; SERA AB Despite the availability of highly effective therapies for hairy cell leukemia, including cladrabine, deoxycoformycin, and interferon a, a significant fraction of patients relapse. The use of flow cytometry, bone marrow examination for minimal residual disease, and peripheral blood counts provides details about the level of disease activity, but the optimal method for following patient response and risk for relapse has not been established. Flow cytometry provides accurate assessments of circulating malignant cell counts even at very low levels, but does not provide details on the extent of bone marrow involvement. Bone marrow involvement can be assessed by biopsy, but is a painful procedure, and the extent of involvement by hairy cell leukemia is not always uniform. Thus, a single biopsy may not identify active disease when it is present. Magnetic resonance imaging is being evaluated as a means for assessing total body burden of disease in the marrow and shows great promise. Tumor markers that can be measured in the serum provide a method for assessing total body disease burden. Cell surface proteins can be shed by tumor cells through proteolytic cleavage to release portions of their extracellular domains. These proteolytic degradation products can be measured in the serum and provide a tool to monitor disease burden and response to therapy. Three cell surface molecules expressed by the malignant hairy cells, CD25, CD22, and CD307, have been used to monitor disease activity and follow patients at risk for relapse. Serum tumor markers provide a reliable, inexpensive, and non-invasive means of following patients with hairy cell leukemia for response to treatment and relapse. C1 [Janik, John E.] NCI, Metab Branch, Bethesda, MD 20892 USA. RP Janik, JE (reprint author), Bristol Myers Squibb Co, Route 206 & Prov Line Rd, Lawrenceville, NJ 08543 USA. EM john.janik@bms.com NR 10 TC 5 Z9 5 U1 1 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 JUN PY 2011 VL 52 SU 2 BP 69 EP 71 DI 10.3109/10428194.2011.568651 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA 767PU UT WOS:000290869300017 PM 21463109 ER PT J AU Fitzgerald, DJ Moskatel, E Ben-Josef, G Traini, R Tendler, T Sharma, A Antignani, A Mussai, F Wayne, A Kreitman, RJ Pastan, I AF Fitzgerald, David J. Moskatel, Elizabeth Ben-Josef, Gal Traini, Roberta Tendler, Tara Sharma, Ashima Antignani, Antonella Mussai, Francis Wayne, Alan Kreitman, Robert J. Pastan, Ira TI Enhancing immunotoxin cell-killing activity via combination therapy with ABT-737 SO LEUKEMIA & LYMPHOMA LA English DT Article DE apoptosis; ABT-737; BH3-only; Pseudomonas exotoxin ID PSEUDOMONAS EXOTOXIN; MEDIATED APOPTOSIS; PROTEINS; CANCER; TUMORS; MCL-1 AB Immunotoxins are antibody-toxin fusion proteins directed to kill cancer cells displaying specific target antigens on their surface. Remarkably, immunotoxins directed to CD22 on hairy cell leukemia have produced complete remissions in approximately 60% of patients enrolled in phase I/II trials. For reasons that are not yet clear, 40% of patients responded less well. In addition, patients with other CD22-positive malignancies have not yet achieved complete remissions. In trying to understand 'resistance' to immunotoxin therapy, a number of challenging issues have been raised. These include insufficient dosing, the production of neutralizing anti-immunotoxin antibodies, poor access to malignant cells, and resistance to toxin killing. In designing immunotoxins, we employ truncated Pseudomonas exotoxin, which enzymatically inactivates protein synthesis and produces cell death in sensitive cells. To begin to address toxin resistance we have explored combination therapy with the BH3-only mimetic, ABT-737. Our results indicate that immunotoxin-ABT combinations often exhibit greater killing activity than either compound alone and in some instances overcome resistance. Expression of high levels of prosurvival Bcl-2 proteins may contribute to toxin resistance. C1 [Fitzgerald, David J.; Moskatel, Elizabeth; Ben-Josef, Gal; Traini, Roberta; Tendler, Tara; Sharma, Ashima; Antignani, Antonella; Mussai, Francis; Kreitman, Robert J.; Pastan, Ira] NCI, Mol Biol Lab, CCR, NIH,HHS, Bethesda, MD 20892 USA. [Mussai, Francis; Wayne, Alan] NCI, Pediat Oncol Branch, CCR, NIH,HHS, Bethesda, MD 20892 USA. RP Fitzgerald, DJ (reprint author), NCI, Mol Biol Lab, CCR, NIH,HHS, Bldg 37, Bethesda, MD 20892 USA. EM djpf@helix.nih.gov NR 7 TC 11 Z9 11 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 JUN PY 2011 VL 52 SU 2 BP 79 EP 81 DI 10.3109/10428194.2011.569961 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA 767PU UT WOS:000290869300020 PM 21599608 ER PT J AU Kreitman, RJ Arons, E Stetler-Stevenson, M Fitzgerald, DJP Wilson, WH Pastan, I AF Kreitman, Robert J. Arons, Evgeny Stetler-Stevenson, Maryalice Fitzgerald, David J. P. Wilson, Wyndham H. Pastan, Ira TI Recombinant immunotoxins and other therapies for relapsed/refractory hairy cell leukemia SO LEUKEMIA & LYMPHOMA LA English DT Article DE Monoclonal; bendamustine; cladribine; pentostatin; rituximab; LMB-2; BL22; Moxetumomab pasudotox ID MINIMAL RESIDUAL DISEASE; FOLLOW-UP; B-CELL; CLADRIBINE; ERADICATION; PENTOSTATIN; RITUXIMAB; BL22 AB Standard treatment for hairy cell leukemia (HCL) is markedly effective, but the constant decrease in disease-free survival, together with the presence of minimal residual disease (MRD), suggests that few if any are cured. HCL cells in MRD are always strongly CD20+and CD22+, and also CD25+ unless the patient has the poor-prognosis variant HCLv. To target relapsed/refractory HCL, immunotherapy has been developed using anti-CD25 and anti-CD22 recombinant immunotoxins, or the anti-CD20 monoclonal antibody (mAb) rituximab alone or combined with purine analogs. The recombinant immunotoxins contain an Fv fragment of a mAb fused to a truncated form of Pseudomonas exotoxin called PE38. BL22 targeting CD22, in phase I and II testing of relapsed/refractory HCL, achieved 47-61% complete remissions (CRs), several of them ongoing after 9-10 years. A completely reversible form of hemolytic uremic syndrome (HUS) was observed in 12% of patients, several of whom could later achieve a partial remission (PR) or CR with LMB-2 targeting CD25. A higher-affinity version of BL22, termed HA22, CAT-8015, or moxetumomab pasudotox, developed to more effectively treat other hematologic malignancies, also achieves CRs in HCL, and with only non-dose-limiting HUS. In separate randomized trials, rituximab is undergoing phase II testing with cladribine for early HCL and with bendamustine or pentostatin for multiply relapsed HCL. C1 [Kreitman, Robert J.; Arons, Evgeny; Fitzgerald, David J. P.; Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), 9000 Rockville PK 37-5124B, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU National Cancer Institute; MedImmune, LLC FX This work was supported in part by the National Cancer Institute, Intramural Program. Work regarding moxetumomab pasudotox (HA22 or CAT-8015) and BL22 (CAT-3888) was supported in part by MedImmune, LLC. NR 13 TC 12 Z9 15 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 JUN PY 2011 VL 52 SU 2 BP 82 EP 86 DI 10.3109/10428194.2011.565843 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 767PU UT WOS:000290869300021 PM 21599609 ER PT J AU Pastan, I Onda, M Weldon, J Fitzgerald, D Kreitman, RJ AF Pastan, Ira Onda, Masanori Weldon, John Fitzgerald, David Kreitman, Robert J. TI Immunotoxins with decreased immunogenicity and improved activity SO LEUKEMIA & LYMPHOMA LA English DT Article DE Recombinant immunotoxins; hairy cell leukemia ID B-CELL EPITOPES; PHASE-I TRIAL; RECOMBINANT; TOXICITY; INFUSION; CANCER; BL22; SS1P; CD22 AB Recombinant immunotoxins, containing an Fv fragment and a bacterial toxin, frequently elicit neutralizing antibodies, nearly always against the toxin. Moxetumomab pasudotox (previously called CAT-8015 or HA22) contains an anti-CD22 Fv fused to PE38, a truncated form of Pseudomonas exotoxin, containing amino acids 253-364 and 381-613. One avenue to reducing immunogenicity is to identify B-and T-cell epitopes and remove them while retaining toxin activity. To determine B-cell epitopes on PE38, 60 monoclonal antibodies against PE38 were tested in a pairwise manner, and seven major epitope groups with 13 subgroups were identified. The locations of many of these epitopes were identified by mutating large surface-exposed residues to alanine. A mutant of moxetumomab pasudotox containing eight epitope-eliminating mutations (HA22-8X) was prepared, and greatly reduced immunogenicity in mice. In parallel, two large sections of PE38 containing lysosomal protease cleavage sites were removed, leaving only amino acids 274-284 and 394-613 of the toxin. The resulting molecule, HA22-LR, retained cytotoxicity toward CD22+ cell lines, killed primary chronic lymphocytic leukemia cells more potently than moxetumomab pasudotox, was much less toxic to mice, and had significantly improved antitumor activity toward murine xenografts. The immunogenicity and activity of recombinant immunotoxins may be optimized by combinations of these approaches. C1 [Pastan, Ira; Onda, Masanori; Weldon, John; Fitzgerald, David; Kreitman, Robert J.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NCI, Mol Biol Lab, NIH, 37-5124B,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov OI Weldon, John/0000-0002-6516-9064 FU National Cancer Institute; MedImmune, LLC FX This work was supported in part by the National Cancer Institute, Intramural Program, and MedImmune, LLC. NR 9 TC 8 Z9 8 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 JUN PY 2011 VL 52 SU 2 BP 87 EP 90 DI 10.3109/10428194.2011.573039 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 767PU UT WOS:000290869300022 PM 21504287 ER PT J AU Arons, E Kreitman, RJ AF Arons, Evgeny Kreitman, Robert J. TI Molecular variant of hairy cell leukemia with poor prognosis SO LEUKEMIA & LYMPHOMA LA English DT Article DE Immunoglobulin rearrangement; HCL; HCLv; VH4-34; IGHV4-34 ID MINIMAL RESIDUAL DISEASE; V-H GENE; SOMATIC HYPERMUTATION; IMMUNOGLOBULIN HEAVY; REPERTOIRE; SELECTION; FEATURES; USAGE; BL22; FORM AB Hairy cell leukemia variant (HCLv), described 30 years ago, was reported to present with high disease burden and less often leukopenia, and later was reported to be resistant to purine analogs. Patients with HCLv were overrepresented among patients with HCL seeking relapsed/refractory trials. To compare clinical and molecular features of classic HCL (HCLc) and HCLv, 85 rearrangements expressing immunoglobulin variable heavy chain were sequenced, taken from 20 patients with HCLv and 62 with HCLc. The gene VH4-34, commonly used in autoimmune disorders, was found in eight patients (40%) with HCLv versus six (10%) with HCLc (p = 0.004). Ninety-three percent of the VH4-34 rearrangements were unmutated, defined as >98% homologous to the germline sequence. Clinical features of VH4-34+ patients that were similar to those with HCLv included higher white blood cell counts at diagnosis (p = 0.002) and lower response (p = 0.00001) and progression-free survival (p = 0.007) after first-line cladribine, and shorter overall survival from diagnosis (p < 0.0001). It was found that VH4-34 was independent from HCLv and a stronger predictor than HCLv in associating with poor prognosis. We conclude that VH4-34+ hairy cell leukemia, which only partly overlaps with HCLv, is associated with poor prognosis after single-agent cladribine. However, cases are observed which respond well to antibody therapy either alone or in combination with purine analog. C1 [Arons, Evgeny; Kreitman, Robert J.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NCI, Mol Biol Lab, NIH, 37-5124B,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU National Cancer Institute FX This work was supported in part by the National Cancer Institute, Intramural Program. A portion of this research was originally published in Blood by Arons et al. (see ref 9). NR 15 TC 10 Z9 10 U1 0 U2 0 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 JUN PY 2011 VL 52 SU 2 BP 99 EP 102 DI 10.3109/10428194.2011.565841 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 767PU UT WOS:000290869300025 PM 21599610 ER PT J AU Sato, A Tichy, H Grant, PR Grant, BR Sato, T O'hUigin, C AF Sato, Akie Tichy, Herbert Grant, Peter R. Grant, B. Rosemary Sato, Tetsuji O'hUigin, Colm TI Spectrum of MHC Class II Variability in Darwin's Finches and Their Close Relatives SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE Darwin's finches; MHC class II; species polymorphism; phylogeny; variability; continental finches ID MAJOR HISTOCOMPATIBILITY COMPLEX; EVOLUTIONARY GENETICS; GENOMICS; HYBRIDIZATION; POLYMORPHISM; PERSPECTIVE; PHYLOGENY; DIVERSITY; CHICKEN; ORIGIN AB The study describes > 400 major histocompatibility complex (MHC) class II B exon 2 and 114 intron 2 sequences of 36 passerine bird species, 13 of which belong to the group of Darwin's finches (DFs) and the remaining 23 to close or more distant relatives of DFs in Central and South America. The data set is analyzed by a combination of judiciously selected statistical methods. The analysis reveals that reliable information concerning MHC organization, including the assignment of sequences to loci, and evolution, as well as the process of species divergence, can be obtained in the absence of genomic sequence data, if the analysis is taken several steps beyond the standard phylogenetic tree construction approach. The main findings of the present study are these: The MHC class II B region of the passerine birds is as elaborate in its organization, divergence, and genetic diversity as the MHC of the eutherian mammals, specifically the primates. Hence, the reported simplicity of the fowl MHC is an oddity. With the help of appropriate markers, the divergence of the MHC genes can be traced deep in the phylogeny of the bird taxa. Transspecies polymorphism is rampant at many of the bird MHC loci. In this respect, the DFs behave as if they were a single, genetically undifferentiated population. There is thus far no indication of alleles that could be considered species, genus, or even DF group specific. The implication of these findings is that DFs are in the midst of adaptive radiations, in which morphological differentiation into species is running ahead of genetic differentiation in genetic systems such as the MHC or the mitochondrial DNA. The radiations are so young that there has not been enough time to sort out polymorphisms at most of the loci among the morphologically differentiating species. These findings parallel those on Lake Victoria haplochromine fishes. Several of the DF MHC allelic lineages can be traced back to the MHC genes of the species Tiaris obscura, which we identified previously as the closest extant relative of DFs in continental America. C1 [Sato, Akie; Sato, Tetsuji] Tsurumi Univ, Sch Dent Med, Dept Anat, Yokohama, Kanagawa, Japan. [Tichy, Herbert] Max Planck Inst Biol, Immungenet Abt, D-7400 Tubingen, Germany. [Grant, Peter R.; Grant, B. Rosemary] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [O'hUigin, Colm] SAIC Frederick Inc, Basic Sci Program, Expt Immunol Lab, NCI Frederick, Frederick, MD USA. RP Sato, A (reprint author), Tsurumi Univ, Sch Dent Med, Dept Anat, Yokohama, Kanagawa, Japan. EM sato-ake@tsurumi-u.ac.jp FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The experimental part of this research was carried out at the now defunct Max-Planck Institut fur Biologie, Abteilung Immungenetik, Tubingen, Germany. Drs. Nikolas Nikolaidis and Dimitra Chalkia were involved in the early stage of the analysis on this study. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does it mention trade names, commercial products, or organizations imply endorsement by the US Government. NR 37 TC 17 Z9 17 U1 1 U2 30 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 JUN PY 2011 VL 28 IS 6 BP 1943 EP 1956 DI 10.1093/molbev/msr015 PG 14 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 766VM UT WOS:000290814600016 PM 21273633 ER PT J AU Fozzatti, L Lu, CX Kim, DW Cheng, SY AF Fozzatti, Laura Lu, Changxue Kim, Dong-Wook Cheng, Sheue-yann TI Differential Recruitment of Nuclear Coregulators Directs the Isoform-Dependent Action of Mutant Thyroid Hormone Receptors SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID BETA-RECEPTOR; GLUCOSE-UTILIZATION; TARGETED MUTATION; MICE; ALPHA; RESISTANCE; GENE; ACTIVATION; GROWTH; ADIPOGENESIS AB Studies using mice deficient in thyroid hormone receptors (TR) indicate that the two TR isoforms, TR alpha 1 and TR beta 1, in addition to mediating overlapping biological activities of the thyroid hormone, T3, also mediate distinct functions. Mice harboring an identical dominant negative mutation (denoted PV) at the C terminus of TR alpha 1 (Thra1(PV) mice) or beta 1 (Thrb(PV) mice) also exhibit distinct phenotypes. These knockin mutant mice provide an opportunity to understand the molecular basis of isoform-dependent functions in vivo. Here we tested the hypothesis that the distinct functions of TR mutant isoforms are directed by a subset of nuclear regulatory proteins. Tandem-affinity chromatography of HeLa nuclear extracts showed that distinct 33 nuclear proteins including nuclear receptor corepressor (NCoR1) and six other proteins preferentially associated with TR alpha 1PV or TR beta 1PV, respectively. These results indicate that recruitment of nuclear regulatory proteins by TR mutants is subtype dependent. The involvement of NCoR1 in mediating the distinct liver phenotype of Thra1PV and ThrbPV mice was further explored. NCoR1 preferentially interacted with TR alpha 1PV rather than with TR beta 1PV. NCoR1 was recruited more avidly to the thyroid hormone response element-bound TR alpha 1PV than to TR beta 1PV in the promoter of the CCAAT/enhancer-binding protein alpha gene to repress its expression in the liver of Thra1(PV) mice, but not in Thrb(PV) mice. This preferential recruitment of NCoR1 by mutant isoforms could contribute, at least in part, to the distinct liver lipid phenotype of these mutant mice. The present study highlights a novel mechanism by which TR isoforms direct their selective functions via preferential recruitment of a subset of nuclear coregulatory proteins. (Molecular Endocrinology 25: 908-921, 2011) C1 [Fozzatti, Laura; Lu, Changxue; Kim, Dong-Wook; Cheng, Sheue-yann] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@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 National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 40 TC 9 Z9 9 U1 1 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN PY 2011 VL 25 IS 6 BP 908 EP 921 DI 10.1210/me.2010-0474 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 766NX UT WOS:000290791600002 PM 21474540 ER PT J AU Conway-Campbell, BL George, CL Pooley, JR Knight, DM Norman, MR Hager, GL Lightman, SL AF Conway-Campbell, Becky L. George, Charlotte L. Pooley, John R. Knight, David M. Norman, Michael R. Hager, Gordon L. Lightman, Stafford L. TI The HSP90 Molecular Chaperone Cycle Regulates Cyclical Transcriptional Dynamics of the Glucocorticoid Receptor and Its Coregulatory Molecules CBP/p300 During Ultradian Ligand Treatment SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID DUAL-SPECIFICITY PHOSPHATASES; SUBNUCLEAR TRAFFICKING; LIVING CELLS; NUCLEOCYTOPLASMIC TRAFFICKING; SPATIOTEMPORAL REGULATION; CORTISOL PULSATILITY; STRESS; PROMOTER; HEAT-SHOCK-PROTEIN-90; ACETYLATION AB Glucocorticoid (GC) hormones are secreted from the adrenal gland in a characteristic pulsatile pattern. This ultradian secretory activity exhibits remarkable plasticity, with distinct changes in response to both physiological and stressful stimuli in humans and experimental animals. It is therefore important to understand how the pattern of GC exposure regulates intracellular signaling through the GC receptor (GR). We have previously shown that each pulse of ligand initiates rapid, transient GR activation in several physiologically relevant and functionally diverse target cell types. Using chromatin immunoprecipitation assays, we detect cyclical shifts in the net equilibrium position of GR association with regulatory elements of GC-target genes and have investigated in detail the mechanism of pulsatile transcriptional regulation of the GC-induced Period 1 gene. Transient recruitment of the histone acetyl transferase complex cAMP response element-binding protein (CREB) binding protein (CBP)/p300 is found to precisely track the ultradian hormone rhythm, resulting in transient localized net changes in lysine acetylation at GC-regulatory regions after each pulse. Pulsatile changes in histone H4 acetylation and concomitant recruitment of RNA polymerase 2 precede ultradian bursts of Period 1 gene transcription. Finally, we report the crucial underlying role of the intranuclear heat shock protein 90 molecular chaperone complex in pulsatile GR regulation. Pharmacological interference of heat shock protein 90 (HSP90) with geldanamycin during the intranuclear chaperone cycle completely ablated GR's cyclical activity, cyclical cAMP response element-binding protein (CREB) binding protein (CBP)/p300 recruitment, and the associated cyclical acetylation at the promoter region. These data imply a key role for an intact nuclear chaperone cycle in cyclical transcriptional responses, regulated in time by the pattern of pulsatile hormone. (Molecular Endocrinology 25: 944-954, 2011) C1 [Conway-Campbell, Becky L.; George, Charlotte L.; Pooley, John R.; Knight, David M.; Norman, Michael R.; Lightman, Stafford L.] Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol BS1 3NY, Avon, England. [Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Conway-Campbell, BL (reprint author), Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Dorothy Hodgkin Bldg,Whitson St, Bristol BS1 3NY, Avon, England. EM b.conway-campbell@bristol.ac.uk FU Wellcome Trust [089647/Z/09/Z, 078407, 075548/Z/04/Z]; Needham Cooper Charitable Trust FX This work was supported by the Wellcome Trust Program Grant Reference 089647/Z/09/Z (to S. L. L. and B. L. C.-C.) and the Needham Cooper Charitable Trust (C. L. G. and D. M. K.). The IN Cell 1000 Analyzer was purchased with funds from the Wellcome Trust Equipment Grant 078407 (to S. L. L. and C. A. M.) and the Applied Biosystems 7500 System for running quantitative PCR experiments with the Wellcome Trust Equipment Grant 075548/Z/04/Z (to S.L.L.). NR 42 TC 32 Z9 32 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN PY 2011 VL 25 IS 6 BP 944 EP 954 DI 10.1210/me.2010-0073 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 766NX UT WOS:000290791600005 PM 21511880 ER PT J AU Liu, X Cannon, DM Akula, N Moya, PR Knudsen, GM Arentzen, TE Steele, J Laje, G Drevets, WC McMahon, FJ AF Liu, X. Cannon, D. M. Akula, N. Moya, P. R. Knudsen, G. M. Arentzen, T. E. Steele, J. Laje, G. Drevets, W. C. McMahon, F. J. TI A non-synonymous polymorphism in galactose mutarotase (GALM) is associated with serotonin transporter binding potential in the human thalamus: results of a genome-wide association study SO MOLECULAR PSYCHIATRY LA English DT Letter ID POSITRON-EMISSION-TOMOGRAPHY; BIPOLAR DISORDER; PET C1 [Liu, X.; Akula, N.; Steele, J.; Laje, G.; McMahon, F. J.] NIMH, Genet Mood & Anxiety Disorders Sect, NIH, Bethesda, MD 20892 USA. [Cannon, D. M.; Drevets, W. C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Cannon, D. M.] Natl Univ Ireland Galway, Clin Neuroimaging Lab, Dept Psychiat, Galway, Ireland. [Moya, P. R.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Knudsen, G. M.; Arentzen, T. E.] Univ Copenhagen, Rigshosp, Ctr Integrated Mol Brain Imaging, DK-2100 Copenhagen, Denmark. [Drevets, W. C.] Univ Oklahoma, Coll Med, Dept Psychiat, Laureate Inst Brain Res, Tulsa, OK USA. RP Liu, X (reprint author), NIMH, Genet Mood & Anxiety Disorders Sect, NIH, Bethesda, MD 20892 USA. EM xl2269@columbia.edu RI liu, xinmin/D-7017-2011; Cannon, Dara/C-1323-2009; Laje, Gonzalo/L-2654-2014; Knudsen, Gitte/C-1368-2013; OI Cannon, Dara/0000-0001-7378-3411; Laje, Gonzalo/0000-0003-2763-3329; Knudsen, Gitte/0000-0003-1508-6866; McMahon, Francis/0000-0002-9469-305X FU Intramural NIH HHS [ZIA MH002810-08] NR 10 TC 7 Z9 7 U1 0 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 JUN PY 2011 VL 16 IS 6 BP 584 EP 585 DI 10.1038/mp.2011.1 PG 2 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 767JF UT WOS:000290851800002 PM 21339755 ER PT J AU Breuer, R Hamshere, ML Strohmaier, J Mattheisen, M Degenhardt, F Meier, S Paul, T O'Donovan, MC Muhleisen, TW Schulze, TG Nothen, MM Cichon, S Craddock, N Rietschel, M AF Breuer, R. Hamshere, M. L. Strohmaier, J. Mattheisen, M. Degenhardt, F. Meier, S. Paul, T. O'Donovan, M. C. Muehleisen, T. W. Schulze, T. G. Noethen, M. M. Cichon, S. Craddock, N. Rietschel, M. TI Independent evidence for the selective influence of GABA(A) receptors on one component of the bipolar disorder phenotype SO MOLECULAR PSYCHIATRY LA English DT Letter ID RELIABILITY; CRITERIA C1 [Breuer, R.; Strohmaier, J.; Meier, S.; Paul, T.; Schulze, T. G.; Rietschel, M.] Univ Heidelberg, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-6800 Mannheim, Germany. [Hamshere, M. L.; O'Donovan, M. C.; Craddock, N.] Cardiff Univ, Dept Psychol Med, Sch Med, Cardiff, S Glam, Wales. [Mattheisen, M.; Degenhardt, F.; Muehleisen, T. W.; Noethen, M. M.; Cichon, S.] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Mattheisen, M.; Degenhardt, F.; Muehleisen, T. W.; Noethen, M. M.; Cichon, S.] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany. [Mattheisen, M.] Univ Bonn, IMBIE, D-5300 Bonn, Germany. [Schulze, T. G.] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Cichon, S.] Res Ctr Juelich, Inst Neurosci & Med INM 1, Julich, Germany. [Rietschel, M.] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. RP Breuer, R (reprint author), Univ Heidelberg, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-6800 Mannheim, Germany. EM rene.breuer@zi-mannheim.de RI Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Mattheisen, Manuel/B-4949-2012; OI Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Mattheisen, Manuel/0000-0002-8442-493X; O'Donovan, Michael/0000-0001-7073-2379; Nothen, Markus/0000-0002-8770-2464 FU Medical Research Council [G0800509] NR 10 TC 15 Z9 16 U1 0 U2 5 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 JUN PY 2011 VL 16 IS 6 BP 587 EP 589 DI 10.1038/mp.2010.67 PG 4 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 767JF UT WOS:000290851800004 PM 20548298 ER PT J AU Milaneschi, Y Bandinelli, S Penninx, BW Vogelzangs, N Corsi, AM Lauretani, F Kisialiou, A Vazzana, R Terracciano, A Guralnik, JM Ferrucci, L AF Milaneschi, Y. Bandinelli, S. Penninx, B. W. Vogelzangs, N. Corsi, A. M. Lauretani, F. Kisialiou, A. Vazzana, R. Terracciano, A. Guralnik, J. M. Ferrucci, L. TI Depressive symptoms and inflammation increase in a prospective study of older adults: a protective effect of a healthy (Mediterranean-style) diet SO MOLECULAR PSYCHIATRY LA English DT Letter C1 [Milaneschi, Y.; Ferrucci, L.] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Bandinelli, S.] ASF, Geriatr Unit, Florence, Italy. [Penninx, B. W.; Vogelzangs, N.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Penninx, B. W.; Vogelzangs, N.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst, Amsterdam, Netherlands. [Corsi, A. M.; Lauretani, F.; Kisialiou, A.] Tuscany Hlth Reg Agcy, Florence, Italy. [Vazzana, R.] Univ G DAnnunzio Chieti, Dept Med & Sci Aging, Lab Clin Epidemiol, Chieti, Italy. [Terracciano, A.] NIA, Lab Personal & Cognit, Baltimore, MD 21224 USA. [Guralnik, J. M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Milaneschi, Y (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. EM ferruccilu@grc.nia.nih.gov RI terracciano, antonio/B-1884-2008; Kisialiou, Aliaksei/J-8771-2016; Lauretani, Fulvio/K-5115-2016 OI Kisialiou, Aliaksei/0000-0001-7287-9454; Lauretani, Fulvio/0000-0002-5287-9972 FU Intramural NIH HHS [Z99 AG999999, ZIA AG000197-03, ZIA AG000197-04, Z01 AG000015-49] NR 10 TC 14 Z9 14 U1 0 U2 11 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 JUN PY 2011 VL 16 IS 6 BP 589 EP 590 DI 10.1038/mp.2010.113 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 767JF UT WOS:000290851800005 PM 21042319 ER PT J AU Bigos, KL Bies, RR Pollock, BG Lowy, JJ Zhang, F Weinberger, DR AF Bigos, K. L. Bies, R. R. Pollock, B. G. Lowy, J. J. Zhang, F. Weinberger, D. R. TI Genetic variation in CYP3A43 explains racial difference in olanzapine clearance SO MOLECULAR PSYCHIATRY LA English DT Article DE CYP450; CYP3A43; genetics; olanzapine; pharmacogenetics; pharmacokinetics ID HUMAN CYTOCHROME-P450; SEQUENCE DIVERSITY; DRUG-METABOLISM; SCHIZOPHRENIA; ANTIPSYCHOTICS; ASSOCIATION; EXPRESSION; CLONING; CATIE AB The antipsychotic drug, olanzapine, one of the most widely used drugs in clinical medicine, has a high rate of discontinuation due to inefficacy and/or adverse effects. We identified a single nucleotide polymorphism in the drug metabolizing enzyme, cytochrome P450 3A43 (CYP3A43; rs472660), that highly significantly predicted olanzapine clearance in the Clinical Antipsychotic Trials of Intervention Effectiveness trial (P = 5.9e(-7)). Moreover, at standard antipsychotic doses, 50% of individuals with the high clearance genotype (AA) have trough blood levels below the therapeutic range. Interestingly, a much higher proportion of African Americans carry the A allele compared with Caucasians (allele frequency 67 vs 14%). After accounting for CYP3A43 genotype, race is no longer a significant predictor of olanzapine clearance. Olanzapine clearance was associated with measures of clinical response. Patients with greater clearance had higher symptom ratings and were more likely to discontinue treatment due to an inadequate response. Our data identify a genetic mechanism for variation in olanzapine response and demonstrate that blood level monitoring of olanzapine treatment is advisable. Molecular Psychiatry (2011) 16, 620-625; doi:10.1038/mp.2011.38; published online 26 April 2011 C1 [Weinberger, D. R.] NIMH, GCAP, DIRP, Genes Cognit & Psychosis Program,NIH, Bethesda, MD 20892 USA. [Bies, R. R.] Indiana Univ Sch Med, Dept Med, Div Clin Pharmacol, Indianapolis, IN USA. [Pollock, B. G.] Univ Toronto, Rotman Res Inst, Toronto, ON, Canada. [Pollock, B. G.] Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Weinberger, D. R.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, GCAP, DIRP, Genes Cognit & Psychosis Program,NIH, 10 Ctr Dr,MSC 1379, Bethesda, MD 20892 USA. EM weinberd@mail.nih.gov FU Division of Intramural Research, National Institute of Mental Health, National Institutes of Health; National Institute of Mental Health [N01 MH900001, MH074027]; Eli Lilly and Company FX This research was supported (in part) by the Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health. The principal investigators of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trial were Jeffrey A Lieberman, MD, T Scott Stroup, MD, MPH and Joseph P McEvoy, MD. The CATIE trial was funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company. We thank Alette Wessels for sharing the ziprasidone population pharmacokinetic model. NR 23 TC 22 Z9 25 U1 1 U2 4 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 JUN PY 2011 VL 16 IS 6 BP 620 EP 625 DI 10.1038/mp.2011.38 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 767JF UT WOS:000290851800010 PM 21519338 ER PT J AU Liao, W Lin, JX Wang, L Li, P Leonard, WJ AF Liao, Wei Lin, Jian-Xin Wang, Lu Li, Peng Leonard, Warren J. TI Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages SO NATURE IMMUNOLOGY LA English DT Article ID ALPHA-CHAIN EXPRESSION; TH2 DIFFERENTIATION; INTERFERON-GAMMA; BET; INTERLEUKIN-2; PROLIFERATION; LYMPHOCYTES; INDUCTION; SIGNALS; STAT5B AB Helper T cells control host defense against pathogens. The receptors for interleukin 12 (IL-12), IL-4 and IL-6 are required for differentiation into the T(H)1, T(H)2 and T(H)17 subsets of helper T cells, respectively. IL-2 signaling via the transcription factor STAT5 controls T(H)2 differentiation by regulating both the T(H)2 cytokine gene cluster and expression of Il4ra, the gene encoding the IL-4 receptor a-chain. Here we show that IL-2 regulated T(H)1 differentiation, inducing STAT5-dependent expression of the IL-12 receptor beta 2-chain (IL-12R beta 2) and the transcription factor T-bet, with impaired human T(H)1 differentiation when IL-2 was blocked. T(H)1 differentiation was also impaired in mouse Il2(-/-) T cells but was restored by IL-12Rb2 expression. Consistent with the inhibition of T(H)17 differentiation by IL-2, treatment with IL-2 resulted in lower expression of the genes encoding the IL-6 receptor a-chain (Il6ra) and the IL-6 signal transducer gp130 (encoded by Il6st), and retroviral transduction of Il6st augmented T(H)17 differentiation even when IL-2 was present. Thus, IL-2 influences helper T cell differentiation by modulating the expression of cytokine receptors to help specify and maintain differentiated states. C1 [Liao, Wei; Lin, Jian-Xin; Wang, Lu; Li, Peng; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov FU Division of Intramural Research of the National Heart, Lung, and Blood Institute (US National Institutes of Health) FX We thank G. Robinson and L. Hennighausen (National Institute of Diabetes and Digestive and Kidney Diseases of the US National Institutes of Health) for mice with loxP-flanked Stat5a-Stat5b; K. Zhao and D. Schones for discussions; R. H. Schwartz, R. Spolski and Y. Rochman for comments; K. Cui for help in generating ChIP-Seq data; T. A. Waldmann (National Cancer Institute) for anti-human IL-2R alpha (anti-Tac) and IL-2R beta (Mik beta 1); K. Murphy (Washington University St. Louis) for the pRV-Il12rb2 retroviral construct; and J. Zhu (National Institute of Allergy and Infectious Diseases of the US National Institutes of Health) for the pRV-Tbx21 construct. Supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (US National Institutes of Health). NR 35 TC 159 Z9 165 U1 1 U2 15 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 JUN PY 2011 VL 12 IS 6 BP 551 EP U247 DI 10.1038/ni.2030 PG 10 WC Immunology SC Immunology GA 765LI UT WOS:000290707100016 PM 21516110 ER PT J AU Donaldson, JG Jackson, CL AF Donaldson, Julie G. Jackson, Catherine L. TI ARF family G proteins and their regulators: roles in membrane transport, development and disease SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID NUCLEOTIDE EXCHANGE FACTORS; GTPASE-ACTIVATING PROTEIN; ADP-RIBOSYLATION FACTORS; BREAST-CANCER INVASION; GOLGI INTERMEDIATE COMPARTMENT; CLASS-II ARFS; PLASMA-MEMBRANE; CAENORHABDITIS-ELEGANS; VESICLE TRAFFICKING; INDEPENDENT ENDOCYTOSIS AB Members of the ADP-ribosylation factor (ARF) family of guanine-nucleotidebindin- g (G) proteins, including the ARF-like (ARL) proteins and SAR1, regulate membrane traffic and organelle structure by recruiting cargo-sorting coat proteins, modulating membrane lipid composition, and interacting with regulators of other G proteins. New roles of ARF and ARL proteins are emerging, including novel functions at the Golgi complex and in cilia formation. Their function is under tight spatial control, which is mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that catalyse GTP exchange and hydrolysis, respectively. Important advances are being gained in our understanding of the functional networks that are formed not only by the GEFs and GAPs themselves but also by the inactive forms of the ARF proteins. C1 [Donaldson, Julie G.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Jackson, Catherine L.] Univ Paris 07, CNRS, UMR 7592, Inst Jacques Monod, F-75205 Paris, France. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov; jackson@ijm.univ-paris-diderot.fr RI Jackson, Catherine/A-3421-2013 OI Jackson, Catherine/0000-0002-0843-145X FU Division of Intramural Research in the National Heart, Lung, and Blood Institute, US National Institutes of Health; Agence Nationale de la Recherche; Centre National de la Recherche Scientifique, France FX We apologize to authors whose work we could not cite owing to space limitations. We thank C. Eyster, L. Maldonado-Baez, J. Menetrey and C. Le Clainche for critical reading of the manuscript. Work in our laboratories is supported by the Division of Intramural Research in the National Heart, Lung, and Blood Institute, US National Institutes of Health (J.G.D.) and grants from the Agence Nationale de la Recherche and the Centre National de la Recherche Scientifique, France (C.L.J.). NR 140 TC 246 Z9 248 U1 5 U2 60 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD JUN PY 2011 VL 12 IS 6 BP 362 EP 375 DI 10.1038/nrm3117 PG 14 WC Cell Biology SC Cell Biology GA 767IB UT WOS:000290848200011 PM 21587297 ER PT J AU Liu, JV Bock, NA Silva, AC AF Liu, Junjie V. Bock, Nicholas A. Silva, Afonso C. TI Rapid high-resolution three-dimensional mapping of T-1 and age-dependent variations in the non-human primate brain using magnetization-prepared rapid gradient-echo (MPRAGE) sequence SO NEUROIMAGE LA English DT Article DE Aging; Development; Longitudinal relaxation; Magnetic resonance imaging; Relaxometry ID VARIABLE FLIP ANGLES; IN-VIVO; MULTIPLE-SCLEROSIS; STEADY-STATE; LONGITUDINAL RELAXATION; ACCURATE MEASUREMENT; VOLUMETRIC T-1; T1 MEASUREMENT; GLOBAL CHANGES; OPTIMIZATION AB The use of quantitative T-1 mapping in neuroscience and neurology has raised strong interest in the development of T-1-mapping techniques that can measure T-1 in the whole brain, with high accuracy and precision and within short imaging and computation times. Here, we present a new inversion-recovery (IR) based T-1-mapping method using a standard 3D magnetization-prepared rapid gradient-echo (MPRAGE) sequence. By varying only the inversion time (TI), but keeping other parameters constant. MPRAGE image signals become linear to exp( -TI/T-1), allowing for accurate T-1 estimation without flip angle correction. We also show that acquiring data at just 3 TIs, with the three different TI values optimized, gives maximum T-1 precision per unit time, allowing for new efficient approaches to measure and compute T-1. We demonstrate the use of our method at 7 T to obtain 3D T-1 maps of the whole brain in common marmosets at 0.60 mm resolution and within 11 min. T-1 maps from the same individuals were highly reproducible across different days. Across subjects, the peak of cerebral gray matter T-1 distribution was 1735 +/- 52 ms, and the lower edge of cerebral white matter T-1 distribution was 1270 +/- 43 ms. We found a significant decrease of T-1 in both gray and white matter of the marmoset brain with age over a span of 14 years, in agreement with previous human studies. This application illustrates that MPRAGE-based 3D T-1 mapping is rapid, accurate and precise, and can facilitate high-resolution anatomical studies in neuroscience and neurological diseases. Published by Elsevier Inc. C1 [Liu, Junjie V.; Bock, Nicholas A.; Silva, Afonso C.] Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Bock, Nicholas A.] McMaster Univ, Hamilton, ON L8S 4L8, Canada. RP Liu, JV (reprint author), Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,Bldg 10,Room B1D109, Bethesda, MD 20892 USA. EM liu@junjie.com RI Silva, Afonso/A-7129-2009 FU NINDS, National Institutes of Health FX The authors would like to thank Lisa Zhang for her technical assistance. This research was supported by the Intramural Research Program of the NINDS, National Institutes of Health. NR 39 TC 11 Z9 12 U1 1 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUN 1 PY 2011 VL 56 IS 3 BP 1154 EP 1163 DI 10.1016/j.neuroimage.2011.02.075 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 764RF UT WOS:000290649300030 PM 21376814 ER PT J AU Soltysik, DA Thomasson, D Rajan, S Gonzalez-Castillo, J DiCamillo, P Biassou, N AF Soltysik, David A. Thomasson, David Rajan, Sunder Gonzalez-Castillo, Javier DiCamillo, Paul Biassou, Nadia TI Head-repositioning does not reduce the reproducibility of fMRI activation in a block-design motor task SO NEUROIMAGE LA English DT Article DE fMRI; Reproducibility; Test-retest; Finger-tapping ID FUNCTIONAL MRI; REGISTRATION; VARIABILITY; RELIABILITY; RESOLUTION AB It is hypothesized that, based upon partial volume effects and spatial non-uniformities of the scanning environment, repositioning a subject's head inside the head coil between separate functional MRI scans will reduce the reproducibility of fMRI activation compared to a series of functional runs where the subject's head remains in the same position. Nine subjects underwent fMRI scanning where they performed a sequential, oppositional finger-tapping task. The first five runs were conducted with the subject's head remaining stable inside the head coil. Following this, four more runs were collected after the subject removed and replaced his/her head inside the head coil before each run. The coefficient of variation was calculated for four metrics: the distance from the anterior commisure to the center of mass of sensorimotor activation, maximum t-statistic, activation volume, and average percent signal change. These values were compared for five head-stabilization runs and five head-repositioning runs. Voxelwise intraclass correlation coefficients were also calculated to assess the spatial distribution of sources of variance. Interestingly, head repositioning was not seen to significantly affect the reproducibility of fMRI activation (p<0.05). In addition, the threshold level affected the reproducibility of activation volume and percent signal change. Published by Elsevier Inc. C1 [Soltysik, David A.; Rajan, Sunder] US FDA, Div Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Thomasson, David; DiCamillo, Paul; Biassou, Nadia] NIH, Dept Radiol, Bethesda, MD 20892 USA. [Gonzalez-Castillo, Javier] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Soltysik, DA (reprint author), US FDA, Div Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM david.soltysik@fda.hhs.gov RI Gonzalez-Castillo, Javier/B-6903-2012; OI SOLTYSIK, DAVID/0000-0002-6597-5226; Gonzalez-Castillo, Javier/0000-0002-6520-5125 FU Radiology and Imaging Sciences Department of the Warren G. Magnuson Clinical Center at the National Institutes of Health FX This project is supported by the Radiology and Imaging Sciences Department of the Warren G. Magnuson Clinical Center at the National Institutes of Health. NR 33 TC 7 Z9 7 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUN 1 PY 2011 VL 56 IS 3 BP 1329 EP 1337 DI 10.1016/j.neuroimage.2011.03.023 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 764RF UT WOS:000290649300046 PM 21406235 ER PT J AU Marinova, Z Leng, Y Leeds, P Chuang, DM AF Marinova, Zoya Leng, Yan Leeds, Peter Chuang, De-Maw TI Histone deacetylase inhibition alters histone methylation associated with heat shock protein 70 promoter modifications in astrocytes and neurons SO NEUROPHARMACOLOGY LA English DT Article DE Valproic acid; Histone methylation; Heat shock protein 70; MS-275; NF-Y; p300 ID HEAT-SHOCK-PROTEIN; REGULATES MEMORY FORMATION; VALPROIC ACID; EPIGENETIC REGULATION; DOPAMINERGIC-NEURONS; POTENTIAL ROLES; H3 ACETYLATION; BRAIN; SCHIZOPHRENIA; TRANSCRIPTION AB The mood-stabilizing and anticonvulsant drug valproic acid (VPA) inhibits histone deacetylases (HDACs). The aim of the present study was to determine the effect of HDAC inhibition on overall and target gene promoter-associated histone methylation in rat cortical neurons and astrocytes. We found that VPA and other HDAC inhibitors, including sodium butyrate (SB), trichostatin A (TSA), and the Class I HDAC inhibitors MS-275 and apicidin all increased levels of histone 3 lysine 4 dimethylation and trimethylation (H3K4Me2 and H3K4Me3); these processes are linked to transcriptional activation in rat cortical neurons and astrocytes. VPA, SB, TSA, MS-275, and apicidin also upregulated levels of the neuroprotective heat shock protein 70 (HSP70) in rat astrocytes. Moreover, Class I HDAC inhibition by VPA and MS-275 increased H3K4Me2 levels at the HSP70 promoter in astrocytes and neurons. We also found that VPA treatment facilitated the recruitment of acetyltransferase p300 to the HSP70 promoter and that p300 interacted with the transcription factor NF-Y in astrocytes. Taken together, the results suggest that Class I HDAC inhibition is key to upregulating overall and gene-specific H3K4 methylation in primary neuronal and astrocyte cultures. In addition, VPA-induced activation of the HSP70 promoter in astrocytes appears to involve an increase in H3K4Me2 levels and recruitment of p300. This article is part of a Special Issue entitled 'Trends in Neuropharmacology: In Memory of Erminio Costa'. Published by Elsevier Ltd. C1 [Marinova, Zoya; Leng, Yan; Leeds, Peter; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, Bldg 10,Rm 3D-38,10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov FU National Institute of Mental Health (NIMH); HSU Family Foundation FX This work was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH), and a gift fund from the HSU Family Foundation. We thank loline Henter, Emily Fessler and Kelly Shan of NIMH for editorial assistance and discussions. NR 44 TC 35 Z9 36 U1 0 U2 6 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 JUN PY 2011 VL 60 IS 7-8 SI SI BP 1109 EP 1115 DI 10.1016/j.neuropharm.2010.09.022 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 764RB UT WOS:000290648900011 PM 20888352 ER PT J AU Harris-Love, ML Morton, SM Perez, MA Cohen, LG AF Harris-Love, Michelle L. Morton, Susanne M. Perez, Monica A. Cohen, Leonardo G. TI Mechanisms of Short-Term Training-Induced Reaching Improvement in Severely Hemiparetic Stroke Patients: A TMS Study SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE stroke; arm movements; transcallosal inhibition; stroke rehabilitation; transcranial magnetic stimulation ID TRANSCRANIAL MAGNETIC STIMULATION; PRIMARY MOTOR CORTEX; INDUCED MOVEMENT THERAPY; UPPER EXTREMITY FUNCTION; SILENT PERIOD; INTERHEMISPHERIC INHIBITION; TRUNK RESTRAINT; UPPER-LIMB; TRANSCALLOSAL INHIBITION; CORTICAL EXCITABILITY AB Background. The neurophysiological mechanisms underlying improved upper-extremity motor skills have been partially investigated in patients with good motor recovery but are poorly understood in more impaired individuals, the majority of stroke survivors. Objective. The authors studied changes in primary motor cortex (M1) excitability (motor evoked potentials [MEPs], contralateral and ipsilateral silent periods [CSPs and ISPs] using transcranial magnetic stimulation [TMS]) associated with training-induced reaching improvement in stroke patients with severe arm paresis (n = 11; Upper-Extremity Fugl-Meyer score (F-M) = 27 +/- 6). Methods. All patients underwent a single session of reaching training focused on moving the affected hand from a resting site to a target placed at 80% of maximum forward reaching amplitude in response to a visual "GO" cue. Triceps contribute primarily as agonist and biceps primarily as antagonist to the trained forward reaching movement. Response times were recorded for each reaching movement. Results. Preceding training (baseline), greater interhemispheric inhibition (measured by ISP) in the affected triceps muscle, reflecting inhibition from the nonlesioned to the lesioned M1, was observed in patients with lower F-M scores (more severe motor impairment). Training-induced improvements in reaching were greater in patients with slower response times at baseline. Increased MEP amplitudes and decreased ISPs and CSPs were observed in the affected triceps but not in the biceps muscle after training. Conclusion. These results indicate that along with training-induced motor improvements, training-specific modulation of intrahemispheric and interhemispheric mechanisms occurs after reaching practice in chronic stroke patients with substantial arm impairment. C1 [Harris-Love, Michelle L.] Georgetown Univ, Natl Rehabil Hosp, Washington, DC USA. [Morton, Susanne M.] Univ Iowa, Iowa City, IA USA. [Perez, Monica A.] Univ Pittsburgh, Pittsburgh, PA USA. [Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), 10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov RI Harris-Love, Michelle/J-1388-2014 OI Harris-Love, Michelle/0000-0001-5571-3858 FU National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS); National Institute of Child Health and Development [K01 HD050369] FX The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: this work was supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS), Intramural Program (MH-L, MAP, LGC), and the National Institute of Child Health and Development K01 HD050369 (SMM). NR 75 TC 32 Z9 32 U1 0 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD JUN PY 2011 VL 25 IS 5 BP 398 EP 411 DI 10.1177/1545968310395600 PG 14 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 765NR UT WOS:000290715500001 PM 21343522 ER PT J AU Hoffman, MK Bailit, JL Branch, DW Burkman, RT Van Veldhusien, P Lu, L Kominiarek, MA Hibbard, JU Landy, HJ Haberman, S Wilkins, I Quintero, VHG Gregory, KD Hatjis, CG Ramirez, MM Reddy, UM Troendle, J Zhang, J AF Hoffman, Matthew K. Bailit, Jennifer L. Branch, D. Ware Burkman, Ronald T. Van Veldhusien, Paul Lu, Li Kominiarek, Michelle A. Hibbard, Judith U. Landy, Helain J. Haberman, Shoshana Wilkins, Isabelle Quintero, Victor H. Gonzalez Gregory, Kimberly D. Hatjis, Christos G. Ramirez, Mildred M. Reddy, Uma M. Troendle, James Zhang, Jun CA Consortium Safe Labor TI A Comparison of Obstetric Maneuvers for the Acute Management of Shoulder Dystocia SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID DELIVERY AB OBJECTIVE: To assess the efficacy of obstetric maneuvers for resolving shoulder dystocia and the effect that these maneuvers have on neonatal injury when shoulder dystocia occurs. METHODS: Using an electronic database encompassing 206,969 deliveries, we identified all women with a vertex fetus beyond 34 0/7 weeks of gestation who incurred a shoulder dystocia during the process of delivery. Women whose fetuses had a congenital anomaly and women with an antepartum stillbirth were excluded. Medical records of all cases were reviewed by trained abstractors. Cases involving neonatal injury (defined as brachial plexus injury, clavicular or humerus fracture, or hypoxic-ischemic encephalopathy or intrapartum neonatal death attributed to the shoulder dystocia) were compared with those without injury. RESULTS: Among 132,098 women who delivered a term cephalic liveborn fetus vaginally, 2,018 incurred a shoulder dystocia (1.5%), and 101 (5.2%) of these incurred a neonatal injury. Delivery of the posterior shoulder was associated with the highest rate of delivery when compared with other maneuvers (84.4% compared with 24.3-72.0% for other maneuvers; P<.005 to P<.001) and similar rates of neonatal injury (8.4% compared with 6.1-14.0%; P=.23 to P=.7). The total number of maneuvers performed significantly correlated with the rate of neonatal injury (P<.001). CONCLUSION: Delivery of the posterior shoulder should be considered following the McRoberts maneuver and suprapubic pressure in the management of shoulder dystocia. The need for additional maneuvers was associated with higher rates of neonatal injury. (Obstet Gynecol 2011;117:1272-8) DOI: 10.1097/AOG.0b013e31821a12c9 C1 Christiana Care Hlth Syst, Newark, DE USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. Univ Utah, Salt Lake City, UT USA. Intermt Healthcare, Salt Lake City, UT USA. Tufts Univ, Baystate Med Ctr, Springfield, MA USA. EMMES Corp, Rockville, MD USA. Indiana Univ Clarian Hlth, Indianapolis, IN USA. Univ Illinois, Chicago, IL USA. Georgetown Univ Hosp, MedStar Hlth, Washington, DC 20007 USA. Maimonides Hosp, Brooklyn, NY 11219 USA. Univ Miami, Miami, FL USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Akron City Hosp, Summa Hlth Syst, Akron, OH USA. Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. RP Hoffman, MK (reprint author), Christiana Care Hlth Syst, Dept Obstet & Gynecol, 4755 Ogletown Stanton Rd, Newark, DE 19718 USA. EM Mhoffman@Christianacare.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through a contract (Contract No. HHSN267200603425C). NR 14 TC 22 Z9 25 U1 1 U2 6 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 JUN PY 2011 VL 117 IS 6 BP 1272 EP 1278 DI 10.1097/AOG.0b013e31821a12c9 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 768AT UT WOS:000290904200005 PM 21555962 ER PT J AU Reddy, UM Bettegowda, VR Dias, T Yamada-Kushnir, T Ko, CW Willinger, M AF Reddy, Uma M. Bettegowda, Vani R. Dias, Todd Yamada-Kushnir, Tomoko Ko, Chia-Wen Willinger, Marian TI Term Pregnancy A Period of Heterogeneous Risk for Infant Mortality SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID BIRTH CERTIFICATES; GESTATIONAL-AGE AB OBJECTIVE: To estimate the trend of maternal racial and ethnic differences in mortality for early-term (37 0/7 to 38 6/7 weeks of gestation) compared with full-term births (39 0/7 to 41 6/7 weeks of gestation). METHODS: We analyzed 46,329,018 singleton live births using the National Center for Health Statistics U.S. period-linked birth and infant death data from 1995 to 2006. Infant mortality rates, neonatal mortality rates, and post-neonatal mortality rates were calculated according to gestational age, race and ethnicity, and cause of death. RESULTS: Overall, infant mortality rates have decreased for early-term and full-term births between 1995 and 2006. At 37 weeks of gestation, Hispanics had the greatest decline in infant mortality rates (35.4%; 4.8 per 1,000 to 3.1 per 1,000) followed by 22.4% for whites (4.9 per 1,000 to 3.8 per 1,000); blacks had the smallest decline (6.8%; 5.9 per 1,000 to 5.5 per 1,000) as a result of a stagnant neonatal mortality rate. At 37 weeks compared with 40 weeks of gestation, neonatal mortality rates increase. For Hispanics, the relative risk is 2.6 (95% confidence interval [CI] 2.0-3.3); for whites, the relative risk is 2.6 (95% CI 2.2-3.1); and for blacks, the relative risk is 2.9 (95% CI 2.2-3.8). Neonatal mortality rates are still increased at 38 weeks of gestation. At both early-and full-term gestations, neonatal mortality rates for blacks are 40% higher than for whites and post-neonatal mortality rates 80% higher, whereas Hispanics have a reduced post-neonatal mortality rate when compared with whites. CONCLUSION: Early-term births are associated with higher neonatal, postneonatal, and infant mortality rates compared with full-term births with concerning racial and ethnic disparity in rates and trends. (Obstet Gynecol 2011;117:1279-87) DOI: 10.1097/AOG.0b013e3182179e28 C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. US FDA, Silver Spring, MD USA. March Dimes, White Plains, NY USA. RP Reddy, UM (reprint author), 6100 Execut Blvd,Room 4B03F, Bethesda, MD 20892 USA. EM reddyu@mail.nih.gov NR 14 TC 81 Z9 82 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2011 VL 117 IS 6 BP 1279 EP 1287 DI 10.1097/AOG.0b013e3182179e28 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 768AT UT WOS:000290904200006 PM 21606738 ER PT J AU Tita, ATN Landon, M Lai, YL Spong, CY AF Tita, Alan T. N. Landon, Mark Lai, Yinglei Spong, Catherine Y. TI Timing of Elective Repeat Cesarean Delivery at Term and Maternal Perioperative Outcomes Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Tita, Alan T. N.] Univ Alabama, Birmingham, AL 35294 USA. [Landon, Mark] Ohio State Univ, Columbus, OH 43210 USA. [Lai, Yinglei] George Washington Univ, Ctr Biostat, Washington, DC USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Tita, ATN (reprint author), Univ Alabama, Birmingham, AL 35294 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2011 VL 117 IS 6 BP 1437 EP 1438 DI 10.1097/AOG.0b013e31821df4e4 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 768AT UT WOS:000290904200032 ER PT J AU Colloca, L AF Colloca, Luana TI Learned placebo analgesia in sequential trials: What are the Pros and Cons? SO PAIN LA English DT Editorial Material ID PAIN C1 NIH, Natl Ctr Complementary & Alternat Med, Dept Bioeth, Bethesda, MD 20892 USA. RP Colloca, L (reprint author), NIH, Natl Ctr Complementary & Alternat Med, Dept Bioeth, 10 Ctr Dr,10-1C118, Bethesda, MD 20892 USA. EM luana.colloca@nih.gov OI Colloca, Luana/0000-0002-6503-4709 NR 8 TC 3 Z9 3 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUN PY 2011 VL 152 IS 6 BP 1215 EP 1216 DI 10.1016/j.pain.2011.02.043 PG 2 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 765MD UT WOS:000290710100002 PM 21377800 ER PT J AU Ehrenkranz, RA Das, A Wrage, LA Poindexter, BB Higgins, RD Stoll, BJ Oh, W AF Ehrenkranz, Richard A. Das, Abhik Wrage, Lisa A. Poindexter, Brenda B. Higgins, Rosemary D. Stoll, Barbara J. Oh, William CA Eunice Kennedy Shriver Natl Inst C TI Early Nutrition Mediates the Influence of Severity of Illness on Extremely LBW Infants SO PEDIATRIC RESEARCH LA English DT Article ID LOW-BIRTH-WEIGHT; RANDOMIZED CONTROLLED-TRIAL; NEONATAL INTENSIVE-CARE; IMPROVING HEAD GROWTH; PRETERM INFANTS; BRONCHOPULMONARY DYSPLASIA; DEVELOPMENTAL OUTCOMES; RISK; PROTEIN; INDEX AB To evaluate whether differences in early nutritional support provided to extremely premature infants mediate the effect of critical illness on later outcomes, we examined whether nutritional support provided to "more critically ill" infants differs from that provided to "less critically ill" infants during the initial weeks of life, and if, after controlling for critical illness, that difference is associated with growth and rates of adverse outcomes. One thousand three hundred sixty-six participants in the NICHD Neonatal Research Network parenteral glutamine supplementation randomized controlled trial who were alive on day of life 7 were stratified by whether they received mechanical ventilation for the first 7 d of life. Compared with more critically ill infants, less critically ill infants received significantly more total nutritional support during each of the first 3 wk of life, had significantly faster growth velocities, less moderate/severe bronchopulmonary dysplasia, less late-onset sepsis, less death, shorter hospital stays, and better neurodevelopmental outcomes at 18-22 mo corrected age. Rates of necrotizing enterocolitis were similar. Adjusted analyses using general linear and logistic regression modeling and a formal mediation framework demonstrated that the influence of critical illness on the risk of adverse outcomes was mediated by total daily energy intake during the first week of life. (Pediatr Res 69: 522-529, 2011) C1 [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD 20852 USA. [Wrage, Lisa A.] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC 27709 USA. [Poindexter, Brenda B.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Stoll, Barbara J.] Emory Univ, Sch Med & Childrens Healthcare Atlanta, Dept Pediat, Atlanta, GA 30322 USA. [Oh, William] Brown Univ, Dept Pediat, Women & Infants Hosp, Providence, RI 02905 USA. RP Ehrenkranz, RA (reprint author), Yale Univ, Sch Med, Dept Pediat, 333 Cedar St,POB 208064, New Haven, CT 06520 USA. EM richard.ehrenkranz@yale.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported by the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development by grant support provided to the cooperating centers of the Neonatal Research Network (NAN). NR 30 TC 72 Z9 80 U1 1 U2 7 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 W CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD JUN PY 2011 VL 69 IS 6 BP 522 EP 529 DI 10.1203/PDR.0b013e318217f4f1 PG 8 WC Pediatrics SC Pediatrics GA 767CA UT WOS:000290831700010 PM 21378596 ER PT J AU Fears, TR Sagebiel, RW Halpern, A Elder, DE Holly, EA Guerry, D Tucker, MA AF Fears, Thomas R. Sagebiel, Richard W. Halpern, Allan Elder, David E. Holly, Elizabeth A. Guerry, DuPont Tucker, Margaret A. TI Sunbeds and sunlamps: who used them and their risk for melanoma SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE Sunbeds; sunlamps; risk factor; melanoma; ultraviolet radiation; dysplastic nevi ID CUTANEOUS MALIGNANT-MELANOMA; ULTRAVIOLET-RADIATION; SUN EXPOSURE; WOMEN; SKIN; POPULATION; TRENDS AB P>Sunbed/sunlamp use was recently classified as carcinogenic. This report considers characteristics of those who use sunbeds/sunlamps and the effect of sunbed/sunlamp use on their risk for melanoma within a large case-control study carried out in 1991-1992. Females were more likely than males to have used sunbeds/sunlamps. Use by females increased strongly and significantly with younger ages and with the perceived ability to tan. For females, the individual risk for melanoma increased with typical session time and frequency of sessions. Use before age 20, current use and years of use were not significant. The use patterns of occasional and frequent users were very different. We estimate that typical 5-min sessions would increase the risk for melanoma by 19% for frequent users (10+ sessions) and by 3% for occasional users (1-9 sessions). Body sites that are not generally exposed to sunlight were more common sites of primary melanomas for frequent sunbed/sunlamp users. For males, measures of sunbed/sunlamp use were not significantly associated with melanoma risk. C1 [Fears, Thomas R.; Tucker, Margaret A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Sagebiel, Richard W.] Sutter Pacific Med Fdn, Melanoma Program, San Francisco, CA USA. [Halpern, Allan] Mem Sloan Kettering Canc Ctr, Dermatol Serv, New York, NY 10021 USA. [Elder, David E.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Holly, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Holly, Elizabeth A.] Univ Calif San Francisco, Melanoma Clin, San Francisco, CA 94143 USA. [Guerry, DuPont] Univ Penn, Sch Med, Melanoma Program, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Tucker, MA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM tuckerp@mail.nih.gov RI Tucker, Margaret/B-4297-2015 FU Intramural NIH HHS [Z99 CA999999, ZIA CP005803-16] NR 23 TC 13 Z9 13 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD JUN PY 2011 VL 24 IS 3 BP 574 EP 581 DI 10.1111/j.1755-148X.2011.00842.x PG 8 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 764KG UT WOS:000290627800020 PM 21362155 ER PT J AU Miller, FG Kallmes, DF Buchbinder, R AF Miller, Franklin G. Kallmes, David F. Buchbinder, Rachelle TI Vertebroplasty and the Placebo Response SO RADIOLOGY LA English DT Editorial Material ID OSTEOPOROTIC VERTEBRAL FRACTURES; PERCUTANEOUS VERTEBROPLASTY; COMPRESSION FRACTURES; RANDOMIZED-TRIAL; KYPHOPLASTY; VERTOS C1 [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Kallmes, David F.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Buchbinder, Rachelle] Monash Univ, Dept Clin Epidemiol, Clayton, Vic 3800, Australia. RP Miller, FG (reprint author), NIH, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov RI Buchbinder, Rachelle/G-2952-2011 FU Intramural NIH HHS NR 28 TC 17 Z9 17 U1 0 U2 0 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 JUN PY 2011 VL 259 IS 3 BP 621 EP 625 DI 10.1148/radiol.11102412 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 767ZB UT WOS:000290898100002 PM 21602500 ER PT J AU De Lay, N Gottesman, S AF De Lay, Nicholas Gottesman, Susan TI Role of polynucleotide phosphorylase in sRNA function in Escherichia coli SO RNA LA English DT Article DE Hfq; RNase E; polynucleotide phosphorylase ID PLASMID COPY NUMBER; TRANSPORTER MESSENGER-RNA; OUTER-MEMBRANE PROTEINS; GLUCOSE-TRANSPORTER; NONCODING RNAS; HOST FACTOR; POSTTRANSCRIPTIONAL REGULATION; RIBONUCLEASE-E; KEY PLAYER; Q-BETA AB In Escherichia coli, many small noncoding regulatory RNAs (sRNAs) post-transcriptionally regulate gene expression by base-pairing to mRNAs in a process that is mediated by the RNA chaperone Hfq. Binding of the sRNA to the mRNA can lead to increased or decreased mRNA stability and/or translation. It is not known if proteins other than Hfq are necessary for this process. In order to identify additional genes required for the post-transcriptional regulation of gene expression by Hfq-dependent sRNAs, we developed a novel combined genetic selection and screen for mutants defective in sRNA regulation. In our combined genetic selection and screen, we isolated hfq mutants and mutants in pnp, encoding polynucleotide phosphorylase (PNPase). We show that loss-of-function mutations in pnp result in a decreased stability of several sRNAs including RyhB, SgrS, and CyaR and also decrease both the negative and positive regulation by sRNAs. The defect in stability of CyaR and in negative and positive regulation are suppressed by deletion mutations in RNase E. Altogether, our results suggest that the lack of sRNA-mediated regulation in the absence of an active form of PNPase is due to the rapid turnover of sRNA resulting from an increase in RNase E activity and/or an increase in access of other ribonucleases to sRNAs. C1 [De Lay, Nicholas; Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bethesda, MD 20892 USA. EM susang@helix.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Gisela Storz and members of our laboratory including N. Majdalani, P. Milanesio, D. Schu, K. Moon, A. Battesti, and T. Song for their comments on this manuscript and their advice. We thank H. Aiba and M. Guillier for providing us with strains. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 61 TC 49 Z9 49 U1 0 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 1355-8382 EI 1469-9001 J9 RNA JI RNA PD JUN PY 2011 VL 17 IS 6 BP 1172 EP 1189 DI 10.1261/rna.2531211 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 764WW UT WOS:000290666300017 PM 21527671 ER PT J AU Soriano, FG Lorigados, CB Pacher, P Szabo, C AF Soriano, Francisco Garcia Lorigados, Clara Batista Pacher, Pal Szabo, Csaba TI EFFECTS OF A POTENT PEROXYNITRITE DECOMPOSITION CATALYST IN MURINE MODELS OF ENDOTOXEMIA AND SEPSIS SO SHOCK LA English DT Article ID LECITHINIZED SUPEROXIDE-DISMUTASE; ISCHEMIA-REPERFUSION INJURY; SEPTIC SHOCK; NITRIC-OXIDE; VASCULAR DYSFUNCTION; LIPID-PEROXIDATION; NITROSATIVE STRESS; CIRCULATORY SHOCK; DOSE-RESPONSE; RABBIT HEART AB Excessive free-radical production due to various bacterial components released during bacterial infection has been linked to cell death and tissue injury. Peroxynitrite is a highly reactive oxidant produced by the combination of nitric oxide (NO) and superoxide anion, which has been implicated in cell death and tissue injury in various forms of critical illness. Pharmacological decomposition of peroxynitrite may represent a potential therapeutic approach in diseases associated with the overproduction of NO and superoxide. In the present study, we tested the effect of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. Mice were injected i.p. with LPS 40 mg/kg with or without FP15 [Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether) pyridyl porphyrin] (0.1, 0.3, 1, 3, or 10 mg/kg per hour). Mice were killed 12 h later, followed by the harvesting of samples from the lung, liver, and gut for malondialdehyde and myeloperoxidase measurements. In other subsets of animals, blood samples were obtained by cardiac puncture at 1.5, 4, and 8 h after LPS administration for cytokine (TNF-alpha, IL-1 beta, and IL-10), nitrite/nitrate, alanine aminotransferase, and blood urea nitrogen measurements. Endotoxemic animals showed an increase in survival from 25% to 80% at the FP15 doses of 0.3 and 1 mg/kg per hour. The same dose of FP15 had no effect on plasma levels of nitrite/nitrate. There was a reduction in liver and lung malondialdehyde in the endotoxemic animals pretreated with FP15, as well as in hepatic myeloperoxidase and biochemical markers of liver and kidney damage (alanine aminotransferase and blood urea nitrogen). In a bacterial model of sepsis induced by cecal ligation and puncture, FP15 treatment (0.3 mg/kg per day) significantly protected against mortality. The current data support the view that peroxynitrite is a critical factor mediating liver, gut, and lung injury in endotoxemia and septic shock: its pharmacological neutralization may be of therapeutic benefit. C1 [Szabo, Csaba] Univ Texas Med Branch, Dept Anesthesiol, Galveston, TX 77555 USA. [Soriano, Francisco Garcia; Lorigados, Clara Batista] Univ Sao Paulo, Fac Med, Lab Disciplina Emergencias Clin, Sao Paulo, Brazil. [Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. RP Szabo, C (reprint author), Univ Texas Med Branch, Dept Anesthesiol, 601 Harborside Dr,Bldg 21,Room 3-202D, Galveston, TX 77555 USA. EM szabocsaba@aol.com RI Soriano, Francisco/C-3382-2012; Pacher, Pal/B-6378-2008; Ji, Haofeng/G-6206-2012 OI Soriano, Francisco/0000-0003-4898-0135; Pacher, Pal/0000-0001-7036-8108; FU National Institutes of Health [R01GM060915]; Shriners Burns Hospitals [8661] FX The work of C. S. is supported by a grant from the National Institutes of Health (R01GM060915) and by a grant from Shriners Burns Hospitals (8661). NR 44 TC 26 Z9 28 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD JUN PY 2011 VL 35 IS 6 BP 560 EP 566 DI 10.1097/SHK.0b013e31820fe5d5 PG 7 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 764VO UT WOS:000290662700004 PM 21263378 ER PT J AU Monteiro-Cunha, JP Araujo, AF Santos, E Galvao-Castro, B Alcantara, LC AF Monteiro-Cunha, Joana Paixao Araujo, Adriano Fernando Santos, Edson Galvao-Castro, Bernardo Junior Alcantara, Luiz Carlos TI Lack of High-Level Resistance Mutations in HIV Type 1 BF Recombinant Strains Circulating in Northeast Brazil SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL DRUG-RESISTANCE; HETERODUPLEX MOBILITY ASSAY; SOUTHERN BRAZIL; BLOOD-DONORS; BAHIA STATE; IDENTIFICATION; DIVERSITY; SUBTYPES; EPIDEMIC AB The genetic variability and the prevalence of drug resistance-associated mutations (DRAM) of HIV-1 isolates from 50 women and 8 children from Feira de Santana, Bahia, Brazil were investigated. DNA samples were obtained and pol sequences were generated by PCR and direct sequencing. Phylogenetic analysis showed that 39 (67.2%) samples were subtype B, four (6.9%) F, one (1.7%) C, and 14 (24.1%) BF recombinants. Four different BF recombination patterns were detected. Twelve (20.7%) samples shared the same breakpoint within the reverse transcriptase (RT) sequence. Fifty-five (94.8%) isolates showed several resistance-associated mutations in the RT and the protease (PR) genes. Ten (17.2%) isolates presented mutations associated with a high level of resistance: nine (15.5%) to nucleoside RT inhibitors (NRTI), four (6.9%) to nonnucleoside RT inhibitors (NNRTI), and three (5.2%) to PR inhibitors (PIs). Subtype B-infected patients had, on average, 0.5 high-level DRAM per sequence while no mutations were observed in BF recombinants, although the two groups were under ARV for a similar period of time. Our data indicate the predominance of the subtype B, followed by BF recombinants in this population, and the dissemination of a recombinant strain in Bahia, which could be related to adaptive advantages of these variants over the predominant subtype B. C1 [Monteiro-Cunha, Joana Paixao; Araujo, Adriano Fernando; Galvao-Castro, Bernardo; Junior Alcantara, Luiz Carlos] Fiocruz MS, CPqGM, LASP, BR-40296710 Salvador, BA, Brazil. [Santos, Edson; Galvao-Castro, Bernardo; Junior Alcantara, Luiz Carlos] FBDC, EBMSP, Salvador, BA, Brazil. [Junior Alcantara, Luiz Carlos] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. RP Monteiro-Cunha, JP (reprint author), Fiocruz MS, CPqGM, LASP, Rua Waldemar Falcao 121, BR-40296710 Salvador, BA, Brazil. EM jmonteiro@bahia.fiocruz.br OI Araujo, Fernando/0000-0001-6471-5564 FU Brazilian Ministry of Health; CNPq; FBDC; FIOCRUZ; Fundacao de Amparo a Pesquisa do Estado da Bahia (FAPESB) FX This work was supported by grants from the Brazilian Ministry of Health STD/AIDS Program, CNPq, FBDC, and FIOCRUZ. J.P.M. acknowledges the Fundacao de Amparo a Pesquisa do Estado da Bahia (FAPESB) for a postdoctoral fellowship and support. We thank Mrs. Elisabeth Deliege Vasconcelos for editing and revising this manuscript. J.P.M. and A.F.A. contributed equally to this work. NR 45 TC 5 Z9 5 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN PY 2011 VL 27 IS 6 BP 623 EP 631 DI 10.1089/aid.2010.0126 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 769LJ UT WOS:000291014700006 PM 21087197 ER PT J AU Sells, JR Schwandt, ML Kwako, LE Hommer, DW Heilig, M George, DT Ramchandani, VA AF Sells, J. R. Schwandt, M. L. Kwako, L. E. Hommer, D. W. Heilig, M. George, D. T. Ramchandani, V. A. TI CHARACTERISTICS OF TREATMENT-SEEKING ALCOHOLICS WITH COMORBID POSTTRAUMATIC STRESS DISORDER SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Sells, J. R.; Schwandt, M. L.; Kwako, L. E.; Hommer, D. W.; Heilig, M.; George, D. T.; Ramchandani, V. A.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 17A EP 17A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300027 ER PT J AU Kwako, LE Schwandt, ML Ramchandani, VA George, DT Hommer, DW Heilig, M AF Kwako, L. E. Schwandt, M. L. Ramchandani, V. A. George, D. T. Hommer, D. W. Heilig, M. TI IDENTIFICATION OF EMPIRICAL SUBTYPES AMONG TREATMENT-SEEKING ALCOHOLICS USING LATENT CLASS ANALYSIS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Kwako, L. E.; Schwandt, M. L.; Ramchandani, V. A.; George, D. T.; Hommer, D. W.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 18A EP 18A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300032 ER PT J AU Steckler, LE Momenan, R van Rafelghem, S Hommer, DW AF Steckler, L. E. Momenan, R. van Rafelghem, S. Hommer, D. W. TI EFFECTS OF ALCOHOL DEPENDENCE ON CORTICAL THICKNESS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Steckler, L. E.; Momenan, R.; van Rafelghem, S.; Hommer, D. W.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 28A EP 28A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300070 ER PT J AU Grodin, EN Lin, H Momenan, R Hommer, DW AF Grodin, E. N. Lin, H. Momenan, R. Hommer, D. W. TI A VOXEL-BASED MORPHOMETIC STUDY OF GENDER DIFFERENCES IN BRAIN DENSITY OF ALCOHOLICS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Grodin, E. N.; Lin, H.; Momenan, R.; Hommer, D. W.] NIAAA, Lab Clin & Translat Studies, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 29A EP 29A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300074 ER PT J AU Capik, NA Lovinger, DM Mateo, Y AF Capik, N. A. Lovinger, D. M. Mateo, Y. TI CHRONIC ADOLESCENT METYHLPHENIDATE EXPOSURE ALTERS ETHANOL EFFECTS ON ADULT STRIATAL SYNAPTIC PLASTICITY AND DOPAMINE IN MICE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Capik, N. A.; Lovinger, D. M.; Mateo, Y.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 57A EP 57A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300189 ER PT J AU Xiong, W Lovinger, DM Zhang, L AF Xiong, W. Lovinger, D. M. Zhang, L. TI PRETREATMENT WITH Delta(9)-TETRAHYDROCANNABINOID INCREASES THE SENSITIVITY OF alpha 1 GLYRS TO ETHANOL-INDUCED POTENTIATION SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Xiong, W.; Lovinger, D. M.; Zhang, L.] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 62A EP 62A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300207 ER PT J AU Bell, L Zook, M Thorsell, A Eskay, R Sun, H Marugan, J Patnaik, S Ferrer, M Zheng, W Ciccocioppo, R Heilig, M AF Bell, L. Zook, M. Thorsell, A. Eskay, R. Sun, H. Marugan, J. Patnaik, S. Ferrer, M. Zheng, W. Ciccocioppo, R. Heilig, M. TI THE EFFECTS OF NOVEL NPS ANTAGONIST NCG-0018568403 ON PALATABLE FOOD INTAKE AND ETHANOL SELF-ADMINISTRATION IN RATS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Bell, L.; Zook, M.; Thorsell, A.; Eskay, R.; Sun, H.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Marugan, J.; Patnaik, S.; Ferrer, M.; Zheng, W.] NIH, Chem Genom Ctr, Rockville, MD 20850 USA. [Ciccocioppo, R.] Univ Camerino, I-62032 Camerino, Italy. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 67A EP 67A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300229 ER PT J AU Schank, JR Barbier, E Rowe, KE Cheng, K Rice, KC Thorsell, A Heilig, M AF Schank, J. R. Barbier, E. Rowe, K. E. Cheng, K. Rice, K. C. Thorsell, A. Heilig, M. TI THE NEUROKININ-1 RECEPTOR ANTAGONIST L822429 REDUCES EXCESSIVE ALCOHOL CONSUMPTION IN THE P RAT SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 NIAAA, Lab Clin & Translat Studies, Bethesda, MD USA. Natl Inst Drug Abuse, Chem Biol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 67A EP 67A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300228 ER PT J AU Stangl, BL Zametkin, M Vatsalya, V Cooke, ME Hommer, DW Ramchandani, VA AF Stangl, B. L. Zametkin, M. Vatsalya, V. Cooke, M. E. Hommer, D. W. Ramchandani, V. A. TI INFLUENCE OF PERSONALITY MEASURES AND PRIMING EFFECTS ON IV ALCOHOL SELF-ADMINISTRATION IN SOCIAL DRINKERS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Stangl, B. L.; Zametkin, M.; Vatsalya, V.; Cooke, M. E.; Hommer, D. W.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, LCTS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 110A EP 110A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804300398 ER PT J AU Cooke, ME Thiyagarajan, A Gilman, J Hommer, D Heilig, M Ramchandani, VA AF Cooke, M. E. Thiyagarajan, A. Gilman, J. Hommer, D. Heilig, M. Ramchandani, V. A. TI SUBJECTIVE RESPONSE TO INTRAVENOUS ALCOHOL IS PREDICTED BY INITIAL SENSITIVITY AND RECENT DRINKING HISTORY IN NONDEPENDENT DRINKERS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Cooke, M. E.; Thiyagarajan, A.; Gilman, J.; Hommer, D.; Heilig, M.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, LCTS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 217A EP 217A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301319 ER PT J AU Umhau, JC Schwandt, ML George, DT Heilig, M AF Umhau, J. C. Schwandt, M. L. George, D. T. Heilig, M. TI CEREBROSPINAL FLUID CYTOKINES AND INDICATORS OF ALCOHOLISM SEVERITY SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Umhau, J. C.; Schwandt, M. L.; George, D. T.; Heilig, M.] NIAAA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 239A EP 239A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301408 ER PT J AU Barbier, E Bell, L Schank, J Salvatore, P Thorsell, A Schuebel, K Heilig, M AF Barbier, E. Bell, L. Schank, J. Salvatore, P. Thorsell, A. Schuebel, K. Heilig, M. TI ALCOHOL INDUCED EPIGENETIC MODIFICATIONS IN A POST-DEPENDENT RAT MODEL SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Barbier, E.; Bell, L.; Schank, J.; Salvatore, P.; Thorsell, A.; Schuebel, K.; Heilig, M.] NIAAA, LCTS, NIH, Bethesda, MD 20877 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 253A EP 253A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301464 ER PT J AU Tapocik, J Sommer, W Schwandt, M Thorsell, A Heilig, M AF Tapocik, J. Sommer, W. Schwandt, M. Thorsell, A. Heilig, M. TI GENE EXPRESSION PROFILING IN THE ALCOHOL-DEPENDENT RAT SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Tapocik, J.; Sommer, W.; Schwandt, M.; Thorsell, A.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Sommer, W.] Cent Inst Mental Hlth, D-6800 Mannheim, Germany. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 262A EP 262A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301499 ER PT J AU Gremel, CM Carlson, VC Lovinger, DM AF Gremel, C. M. Carlson, V. C. Lovinger, D. M. TI PRENATAL ETHANOL EXPOSURE DISRUPTS SUBSEQUENT HABIT FORMATION IN ADULT MICE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Gremel, C. M.; Carlson, V. C.; Lovinger, D. M.] NIAAA, Sect Vivo Neural Funct, Lab Integrat Neurosci, NIH, Bethesda, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 263A EP 263A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301505 ER PT J AU Gilman, JM Ramchandani, VA Crouss, TM Hommer, DW AF Gilman, J. M. Ramchandani, V. A. Crouss, T. M. Hommer, D. W. TI DRINKING HISTORY AND SRE SCORES PREDICT NEURAL ACTIVATION TO INTRAVENOUS ALCOHOL SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 34th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 25-29, 2011 CL Atlanta, GA SP Res Soc Alcoholism C1 [Gilman, J. M.; Ramchandani, V. A.; Crouss, T. M.; Hommer, D. W.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2011 VL 35 IS 6 SU S BP 290A EP 290A PG 1 WC Substance Abuse SC Substance Abuse GA 766RN UT WOS:000290804301610 ER EF